JP2010520223A - Compositions and methods for stroke related disorders - Google Patents

Abstract

The present invention relates to the therapeutic and / or prophylactic use of pyridazine compounds and their compounds for treating disorders characterized by conduction disorders, electric shock convulsions and / or seizures, in particular epilepsy, more particularly pediatric epilepsy. The present invention relates to a pharmaceutical composition containing one or more of the following as an active ingredient. In one aspect of the invention, the pyridazine compound has the formula Ia or Ib:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in the specification.

Description

  This invention was made with government support under grant numbers AG028561 and NS044998 awarded by the National Institutes of Health. The US government has certain rights in the invention.

  The present invention relates to compositions and methods for the treatment of patients with seizure-related disorders, particularly epilepsy patients.

  Epilepsy is a common but devastating disorder that affects millions of people around the world. Epilepsy is a chronic neurological condition characterized by recurrent, excessive or abnormal disorders that are transient with respect to neural activity. These disorders can manifest as movement, convulsions, sensory or psychological signs, especially in the form of seizures and loss of consciousness.

  Epilepsy syndrome has been classified into over 40 different types based on characteristic signs, seizure types, causes, age of onset and EEG pattern. These are absence seizures, psychomotor epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, occipital lobe epilepsy, parietal lobe epilepsy, Lennox-Gastau syndrome, Rasmussen encephalitis, childhood absence epilepsy, Ramsey Hunt syndrome type II, benign epilepsy Syndrome, infant benign encephalopathy, neonatal benign convulsions, early myoclonic encephalopathy, progressive epilepsy and infantile epilepsy, but are not limited to these.

  Seizure patients are often limited to the types of activities they can participate in. Seizures can prevent people from driving, working, or participating in many other things that society has to offer. Some patients often have severe seizures so that they are effectively disabled. Furthermore, they are often progressive and may be accompanied by degenerative disorders and pathologies. Over time, seizures are often more frequent and heavier, and in particularly severe cases can lead to deterioration of other brain functions as well as physical impairments.

  Many therapies that suppress convulsions have been developed for the control of epilepsy and other disorders, including seizures, but seizures remain unsuppressed in, for example, approximately one third of patients with epilepsy and treatment This failure is common (Non-Patent Document 1). Even more important, over time, patients often become drug resistant. Moreover, many anti-seizure drugs cause undesirable side effects, neurotoxicity, and drug interactions.

Loscher, W.M. and Scmidt, D.M. 2002, Epilepsy Res. 50: 3-16

  Thus, there is an ongoing need for pharmaceutical compositions to treat or prevent conditions including, for example, seizures such as epilepsy and its associated symptoms, with minimal side effects.

  The present invention relates to the therapeutic and / or prophylactic use of pyridazine compounds for the treatment of seizure-related disorders including epilepsy and to pharmaceutical compositions comprising one or more of these compounds as active ingredients.

  The present invention provides a composition comprising a therapeutically effective amount of a pyridazine compound for the treatment of stroke related disorders in a subject. In particular, the present invention provides a composition comprising a therapeutically effective amount of a pyridazine compound for the treatment of epilepsy in a subject. The compositions of the invention generally comprise a pyridazine compound in a pharmaceutically acceptable carrier, excipient or vehicle.

  In one aspect, the pharmaceutical composition of the invention comprises a therapeutically effective amount of a pyridazine compound to provide a beneficial effect, particularly a beneficial effect that is sustained after treatment.

  In other embodiments, the pharmaceutical composition comprises a pyridazine compound having a favorable pharmacological profile, particularly for pediatric patients and / or patients undergoing long-term treatment that need to be enhanced in safety and tolerance. Adapt.

  The present invention further provides a method for producing the composition of the present invention. In one aspect, the invention provides a method of making a pharmaceutical composition comprising a pyridazine compound suitable for use in the disorders disclosed herein. One method can include formulating one or more pyridazine compounds and optionally a pharmaceutically acceptable carrier, excipient or vehicle. A pharmaceutically acceptable carrier, excipient, or vehicle may be selected that is effective to physically stabilize the pyridazine compound (s). After the composition is manufactured, it can be placed in a suitable container and labeled for the treatment of indications. For administration of the compositions of the invention, such labels can include dosage, frequency of administration and method of administration.

  In some embodiments, the invention provides commercially available pills, tablets, caplets, soft gelatin capsules and hard gelatin capsules comprising a pyridazine compound suitable for use in the disorders disclosed herein. Lozenges, sachets, veggie caps, drops, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media) suppositories, sterile injectable solutions, and / or sterile A method for producing a packaged powder of the present invention is provided.

  The present invention also provides for one or more pyridazines of the present invention to prevent and / or ameliorate the severity of the disorder, symptoms of the disorder, and / or reduce the recurrence cycle of the disorder disclosed herein. Intended for use of the compound or method.

  Accordingly, the present invention contemplates the prevention and treatment of the disorders disclosed herein in a subject using the pyridazine compounds or compositions of the present invention. In particular, the invention provides a method of treating a disorder disclosed herein in a subject comprising administering to the subject a therapeutically effective amount of one or more pyridazine compounds or compositions of the invention. The methods of the invention can be used prophylactically or therapeutically in subjects that are susceptible to or predisposed to a predisposition to the disorders disclosed herein.

  In one aspect, the invention is a method for the prevention and / or treatment intervention of a disorder disclosed herein in a subject, comprising administering to the subject at least one pyridazine compound or composition of the invention. A method comprising:

  The present invention is a method of treating a disorder disclosed herein, comprising administering at least one pyridazine compound or composition of the present invention to a subject in need of such treatment, Provides a method of producing a more beneficial effect, in particular a sustained beneficial effect after treatment. In one aspect, the compound or composition is administered orally or systemically.

  In one aspect, the invention is a method for ameliorating the progression of such a disorder or obtaining a less severe condition in a subject suffering from a disorder disclosed herein. A method comprising administering a therapeutically effective amount of one or more pyridazine compounds or compositions of the invention.

  The present invention relates to a method of delaying the progression of a disorder disclosed herein, comprising administering a therapeutically effective amount of one or more pyridazine compounds or compositions of the present invention.

  The present invention is also a method for increasing the survival rate of a subject suffering from a disorder disclosed herein, comprising administering a therapeutically effective amount of one or more pyridazine compounds or compositions of the present invention. It also relates to a method comprising:

  In one embodiment, the invention provides a method of prolonging the life of a subject suffering from a disorder disclosed herein, comprising a therapeutically effective amount of one or more pyridazine compounds or compositions of the invention. To a method comprising administering.

  In certain embodiments of the invention, the compositions and methods may prevent, alleviate, and / or prevent seizure-related disorders (eg, seizures, conduction disorders, and electric shock convulsions) and their symptoms, regardless of the cause of the subject's condition. Useful for treatment.

  The present invention provides a method for the prevention, alleviation and / or treatment of epilepsy in pediatric patients comprising inhibiting glial activation. In one particular aspect, the present invention is for the prevention, alleviation and / or treatment of epilepsy in pediatric patients comprising reducing pro-inflammatory cytokines (eg, IL-β and S100B) after an infantile attack. Provide a way.

  The treatment methods of the present invention can be sustained for days, weeks, months, years, thereby having a significant beneficial effect on the severity of the disorder or its complications.

  The present invention also contemplates the use of one or more pyridazine compounds as a medicament or for the manufacture of a medicament for preventing and / or treating the disorders disclosed herein.

  The present invention further provides the use of the pharmaceutical composition of the present invention as a medicament or in the manufacture of a medicament for preventing and / or treating the disorders disclosed herein. In aspects of the invention, the medicament provides a beneficial effect, preferably a beneficial effect that is sustained after treatment. The medicament is in a form suitable for the subject to take, such as pills, tablets, caplets, soft gelatin capsules and hard gelatin capsules, lozenges, sachets, veggie caps, drops, elixirs, It can be in the form of suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media) suppositories, sterile injectable solutions, and / or sterile packaged powders.

  The compositions or methods of the invention can be administered to healthy subjects or subjects suffering from the disorders disclosed herein. Thus, in one embodiment, the pyridazine compounds or compositions of the invention should be administered before or after onset in the subject.

  The present invention also provides a kit comprising the pyridazine compound or pharmaceutical composition of the present invention in the form of a kit. In one aspect, the invention includes a kit comprising one or more pyridazine compounds or pharmaceutical compositions of the invention, a container and instructions for use in treating and / or preventing a disorder disclosed herein. I will provide a.

  These and other aspects, features, and advantages of the present invention should be apparent to those skilled in the art from the following detailed description.

(A) Latency to seizure onset; (B) Survival; and (C, D) Quantification of neuronal damage following kainate (KA) -induced seizures in immature and adult rats. (A) Seizure latency (min ± SEM) at days after birth (P) 15 (KA-PBS) is reduced compared to adult (P45) seizures (PBS-KA). Infancy seizures are indicated by a reduced latency of seizures in the “Two-hit” (P15 and P45) seizure group (KA-KA) compared to the adult seizure (PBS-KA) group Increases susceptibility to seizures in adulthood. (B) Kaplan-Meier survival curves for recovery over 40 days after administration of KA or vehicle (PBS) at P15 are significantly different (log rank test, p <0.05). Survival is significantly reduced in the KA-KA group after a second hit of KA. (C) Representative microscope showing Fluoro-Jade B (FJB) fluorescence of dead or dead neurons (green), counterstained with DAPI, in hippocampal CA1 region of “two-hit (KA-KA)” animals Photo. (D) Quantification of FJB-fluorescence after a 40-day recovery period in the hippocampus of control (PBS-PBS) and KA-PBS groups does not show any evidence of injury. “Two-hit” (KA-KA) animals exhibit greater injury compared to mature animals initially exposed to KA (PBS-KA). (E) The region of interest for the number of cells in the cross section of the hippocampus. Digital images of CA1, CA2, CA3, dentate gyrus (DG), and polymorphic dentate gyrus (PoDG) were obtained at low power (10X). Each image was analyzed for positive staining and the results taken into account to display the total hippocampal staining. ^*** p <0.001; ^** PBS PBS by p <0.01 versus analysis of variance (ANOVA). Scale bar, (C) 100 μm; (E) 200 μm. KA-induced seizures increase hippocampal pro-inflammatory cytokine protein levels after 24 hours of recovery. (A) A significant increase in IL-1β was present in neonates (P15 KA) and adults (P45 KA). No differences between groups were seen for IL-6 or TNF-α (B, C). (D) S100B levels were significantly elevated compared to controls after seizures in both neonates and adults. P values were measured with ANOVA. (A) KA-induced seizures in neonates result in damage in hippocampal related tasks. Continuous measurements of spontaneous alternation behavior of rats in the Y-maze after infantile seizures (KA-PBS) show a decrease compared to a 40-day recovery control (PBS-PBS). (BF) KA-induced seizures at P15 cause a persistent increase in hippocampal expression of GFAP at P55. Representative photomicrographs are controls (B, PBS-PBS), infantile seizures (C, KA-PBS), adult seizures (D, PBS-KA), and “two hits” (E, KA-KA). ) Illustrates GFAP immunostaining in the hippocampal CA1 region of animals. The morphology of GFAP positive astrocytes in the CA1 region of the KA-PBS, PBS-KA and KA-KA groups resembles activated glia compared to the control (PBS-PBS). (F) Quantification of GFAP immunoreactive cells in the combined area of the four groups of hippocampus. All three KA treatment groups showed a significant increase in GFAP expression compared to the control. KA-induced seizures at (G-K) P15 lead to a long-term increase in hippocampal expression of S100B over 40 days of recovery. (GJ) Representative photomicrographs illustrating S100B immunostaining in the hippocampal CA1 region of PBS-PBS (G), KA-PBS (H), PBS-KA (I), and KA-KA (J) animals. . (K) Quantification of S100B immunoreactive cells in the combined area of the four groups of hippocampus. All three KA treatment groups showed a significant increase in S100B expression compared to the control. The counterstain is hematoxylin. Insets (B-E; G-J) represent higher magnification micrographs of CA1. ^*** p <0.001 vs. PBS-PBS; ^** p <0.01 vs. PBS-PBS (by ANOVA). Scale bar, (B) 200 μm; inset (B) 100 μm. KA-induced microglia activation in mature animals is facilitated by infantile seizures. (AD) Representative photomicrographs illustrating Ibal immunostaining in the hippocampal CA1 region of PBS-PBS (A), KA-PBS (B), PBS-KA (C) and KA-KA (D) animals. Insets (AD) are higher magnification micrographs of CA1. (E) Quantification of Ibal immunoreactive cells in the combined area of group 4 hippocampus does not show a long-term increase in microglia activation after infantile seizures (KA-PBS). The “two-hit” (KA-KA) group showed significantly greater microglial activation compared to the adult seizure group (PBS-KA). The values for both groups were increased compared to the control (PBS-PBS). ^*** p <0.001 vs PBSPBS; ^** p <0.01 vs PBS-PBS (by ANOVA). Scale bar (A) 200 μm; insets (AD) 100 μm. Hippocampal factor H (FH) and clusterin levels after KA exposure. (A) Relative quantification of Western blot micrographs and FH blot density does not show significant changes in FH protein levels 24 hours after neonatal and adult KA-induced seizures. (B) Representative photomicrograph of FH immunostaining in hippocampal CA1 region of “two-hit” (KA-KA) animals at P55. (Inset B) Micrograph showing FH immunoreactive astrocytes. (C) Quantification of FH immunoreactive cells at P55 in the combined hippocampal region of the long-term recovery group does not show significant differences between groups. (D) Relative quantification of Western blot micrographs and clusterin blot density shows a significant increase in hippocampal clusterin protein levels at 24 hours after seizures at P15 and P45. (EG) Long-term recovery group, control group (inset E, PBS-PBS), infantile seizure group (E, KA-PBS), adult seizure group (F, PBS-KA; inset, CA1) Higher magnification view of clusterin immunoreactive cells in), and representative photomicrographs showing clusterin immunostaining in the hippocampal CA1 region of “two hit” (G, KA-KA) animals. (H) Quantification of clusterin immunoreactive cells at P55 in the combined hippocampal area of the long-term recovery group is compared to adult stroke (PBS-KA) animals in the “two-hit” (KA-KA) group. Shows a significant increase. (I, J) Representative photomicrographs showing that NeuN positive cells do not co-stain with clusterin. (I) NeuN (grey) and clusterin (red) are not co-labeled. (J) Immunofluorescence detection shows a similar pattern of NeuN (green) and clusterin (red). (K) Immunofluorescent double labeling of GFAP (green) and clusterin (red) indicates that clusterin positive cells are not astrocytes. Clusterin positive cells are Iba1 immunoreactive (L), suggesting that these cells are microglia. (H) ^*** p <0.001 vs. PBS-PBS (according to ANOVA). (B) Scale bar (B, F, G) 200 μm; (E, J) 100 μm; (I, L) 50 μm. KA-induced seizures in P45 animals result in an increase in the glial-specific glutamate transporters, GLAST and GLT-1. (AC) Representative photomicrographs showing GLAST immunostaining in the hippocampal CA1 region of PBS-PBS (inset A), KA-PBS (A), PBSKA (B) and KA-KA (C) animals. Inset (C) shows a higher magnification view of GLAST immunoreactive cells at CA1. (D) Quantification of GLAST immunoreactive cells with P55 in the hippocampal combined area in the long-term recovery group showed increased expression in PBS-KA and KA-KA compared to control (PBS-PBS). Show. PBS-KA and KA-KA are not significantly different from each other. The GLT-1 results are similar to GLAST (data not shown). ^** p <0.01 vs PBS-PBS; ^* p <0.05 vs PBS-PBS (by ANOVA). Scale bar 200 μm; (Inset C) 100 μm. (A) Minozaku (Mzc) administration and Y-maze test timetable. Following either intraperitoneal (ip) administration of either PBS or kainic acid (KA) at P15, the animals were either Mzc (5 mg / kg, ip) or saline diluent (Sal) after 3 hours and 9 hours of recovery. ). A group of animals from each group (PBS-Sal, KA-Sal and KA-Mzc) was sacrificed at 12 hours for assessment of hippocampal pro-inflammatory cytokine changes. The remaining animals were allowed to recover for 30 days (P45). In these groups, the Y-maze test for hippocampal-dependent behavior began at weaning time (P21, 6 days recovery) and continued until sacrifice. (B) Continuous measurement of spontaneous alternation behavior in the Y-maze after infantile seizures shows protection by Mzc over 30 days of recovery. ^*** p <0.001 vs. KA-Sal (according to ANOVA). Effect of Minozaku (Mzc) on the rapid increase of pro-inflammatory cytokines after KA-induced seizures (AD) at P15 and glial activation after 30 days recovery (EL). (A) Administration of Mzc after an infantile attack suppressed the acute increase in IL-1β seen in untreated animals (KA-Sal). Similar results were seen for IL-6 (B), TNF-α (C), and S100B (D). Tissue for brain homogenate was collected 12 hours after KA injection. (EL) Minozaku (Mzc) suppresses long-term glial activation response to KA-induced infantile seizures after 30 days of recovery from KA exposure at P15. (EG) Representative microscope of GFAP immunostaining in the CA1 region of control (E, PBS-Sal), infantile stroke (F, KA-Sal) and Mzc-treated (G, KA-Mzc) animals. Photo. (H) Quantification of GFAP positive cells in the hippocampus shows that Mzc treated animals (KA-Mzc) have significantly less glial activation compared to untreated animals (KA-Sal). (IL) Representative photomicrographs of S100B immunostaining in the CA1 region of PBS-Sal (I), KA-Sal (J) and KA-Mzc (K) animals. (L) Quantification of S100B immunopositive cells indicates that Mzc suppressed the increased S100B expression seen with KA-Sal. Data (D) were expressed as control (%) ± SEM. Data (H, L) are immunopositive cells (%) ± SEM. ^* P <0.05 vs KA-Sal, ^** p <0.01 vs KA-Sal; ^*** p <0.001 vs KA-Sal (according to ANOVA). Scale bar (E) 200 μm; (Inset F, G, J, K) 100 μm. Proposed scheme for the role of astrocyte activation and microglia activation in accelerated seizure susceptibility. Summary of kainic acid administration at 15 days after birth (P) (A) and at P45 (B) including “two hits” (P15 and 45) (B). At P15, a transient increase in pro-inflammatory cytokines is followed by microglial activation and sustained (40 days) astrocyte activation. A similar pattern of cytokine and microglia activation occurs at P45 when the astrocyte glutamate transporter is increased. Importantly, the “two-hit” group exposed to kainic acid at P15 and P45 shows accelerated microglia activation (B, green dotted line). 2- (4- (4-Methyl-6-phenylpyridazin-3-yl) piperazin-1-yl) pyrimidine dihydrochloride (MW01-9-034WH, also referred to herein as “Minozak”)) Represents a synthetic production scheme. Reagents and conditions: (a) N ₂ H ₄ , EtOH, reflux, (b) CuCl ₂ , CH ₃ CN, reflux, (c) POCl ₃ , CH ₃ CN, reflux, (d) 1- (2-pyrimidyl) Piperazine, water, reflux, (e) HCl, isopropanol.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

  Numerical ranges referred to herein by endpoints include all numbers and fractions subsumed within that range (eg 1 to 5 is 1, 1.5, 2, 2.75, 3, 3 .90, 4 and 5). It should also be understood that all numbers and fractions thereof are modified by the term “about”. The term “about” means plus or minus 0.1-50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15% of the number mentioned. means. Further, “a”, “an”, and “the” should be understood to include a plurality of objects unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds.

  As used herein, the terms “administering” and “administration” mean that a therapeutically effective amount of a compound or composition contemplated herein is delivered to a subject for prophylactic and / or therapeutic purposes. Means the process. The composition is administered according to good medical practice, taking into account the subject's clinical condition, site and method of administration, dose, patient age, sex, weight, and other factors known to the physician.

  The term “treating” means reversing, reducing or inhibiting the progression of a disorder to which such term applies or one or more symptoms of such disorder. Depending on the condition of the subject, the term also means preventing the disorder and includes preventing the onset of the disorder or preventing symptoms associated with the disorder. Treatment may be performed either acutely or chronically. The term also means reducing the severity of the disorder or symptoms associated with such disorder prior to the pain associated with the disorder. Prevention or reduction of the severity of a disorder prior to such distress means administration of a compound or composition of the invention to a subject not afflicted with the disorder at the time of administration. “Preventing” also means preventing the recurrence of a disorder or one or more symptoms associated with such disorder. “Treatment” and “therapeutically” refer to a therapeutic act as defined above as “treating”. Prophylactic and therapeutic intervention is to counter such disorders, administration of active compounds to prevent or delay the onset of symptoms or complications, or to reduce symptoms or complications, or such disorders Including excluding.

  In embodiments of the invention in which the disorder is epileptogenesis, particularly epilepsy, the treatment comprises (i) partial or complete regression of epileptogenesis, (ii) prevention of epileptogenesis, or reduction or delay in the incidence of epilepsy, (iii) And / or (iv) preventing, delaying, stopping and / or reversing the process of epileptogenesis.

  The terms “subject”, “individual”, or “patient” are used interchangeably herein and mean an animal, preferably a warm-blooded animal, such as a mammal. Mammals include, but are not limited to, any member of a mammal. Mammals as subjects or patients in the present disclosure can be from families of primates, carnivores, long-nosed eyes, terrestrial hoofs, artiopods, rodents, and rabbit eyes. In certain embodiments, the mammal is a human. In other embodiments, the animal can be treated; the animal is a vertebrate, including both birds and mammals. In one aspect of the invention, the term also refers to livestock raised as edible or pets, including horses, cows, sheep, poultry, fish, pigs, dogs, and cats, and zoo animals, goats, monkeys ( For example, gorillas or chimpanzees), and rodents such as rats and mice.

  In an aspect of the invention, the term refers to a living body that is treated by the method of the invention. In the context of certain aspects of the invention, the term “subject” has received or has received treatment (eg, pyridazine compound (s) or composition) for a disorder disclosed in the present invention. Generally means an individual.

  General subjects for treatment include those who are suspected of having, or are susceptible to, having, or have had a disorder disclosed herein. A subject may or may not have a genetic predisposition to a disorder disclosed herein, such as epilepsy. In certain aspects of the invention, the subject is a pediatric patient. In certain aspects, the subject may be a healthy subject.

  As used herein, the term “healthy subject” refers to a subject, particularly a mammal, that has not been diagnosed with a disorder, weakness or disease disclosed herein.

  As used herein, the terms “co-administration”, “combination therapy”, and “combination administration” mean administration to a subject of one or more pyridazine compounds and an additional therapeutic agent or therapy. In embodiments, administration of two or more drugs / therapy occurs simultaneously. In other embodiments, the first agent / therapy is administered prior to the second agent / therapy. In this embodiment, each component can be administered separately, but provides the desired effect, particularly a beneficial additive or synergistic effect, in sufficiently close time. Formulations, routes of administration and appropriate doses for co-administration can be readily determined by one skilled in the art. In some embodiments, when drugs / therapies are co-administered, each drug / therapy is administered at a dosage that is less than appropriate for their single administration. Thus, co-administration is particularly desirable in embodiments where drug / therapy co-administration reduces the required dosage of known potentially harmful (eg, toxic) drugs.

  By “beneficial effect” is meant the effect of a pyridazine compound or composition of the invention, including advantageous pharmacological and / or therapeutic effects, as well as improved biological activity. In aspects of the invention, beneficial effects include, without limitation, enhanced stability, longer half-life, and / or accelerated intake. In other embodiments, the beneficial effect comprises one or more of: (a) a reduction or improvement in neuronal dysfunction or damage after an infantile attack; (b) a reduction in pro-inflammatory cytokines or Suppression; (c) decreased astrocyte activation; (d) decreased GFAP immunoreactive cells; (e) decreased microglia activation and (f) decreased glial activation and hippocampal-dependent behavioral impairment. The beneficial effect can be a statistically significant effect by statistical analysis of the effect of the pyridazine compound or composition of the invention versus the effect without the compound or composition not within the scope of the invention. A “statistically significant” or “significantly different” effect or level may represent a level that is higher or lower than the standard. In aspects of the invention, the difference is 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, compared to the effect obtained without the pyridazine compound or composition of the invention. It may be 15, 20, 25 or 50 times higher or lower.

  In embodiments, the beneficial effect is a “sustained beneficial effect” in which the beneficial effect persists over a long period of time after the end of treatment. Treatment can last for days, weeks, months or years and as a result has a major beneficial effect on the severity of the disorder and its complications. In embodiments of the invention, the beneficial effect is at least about 1-3 days, 2-4 weeks, 2-5 weeks, 3-5 weeks, 2-6 weeks, 2-8 weeks, 2-10 weeks after treatment. Long term of weeks, 2-12 weeks, 2-14 weeks, 2-16 weeks, 2-20 weeks, 2-24 weeks, 2 weeks-12 months, 2 weeks-18 months, 2 weeks-24 months, or several years Can last for a long time. The period during which the beneficial effect is sustained may correlate with the duration and timing of the treatment. Subjects are continuous or about or at least about 1-3 days, 1 week, 2-4 weeks, 2-6 weeks, 2-8 weeks, 2-10 weeks, 2-12 weeks, 2-14 weeks, 2 It may be treated regularly or continuously for -16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or several years.

  The term “pharmaceutically acceptable carrier, excipient, or vehicle” means a vehicle that does not interfere with the effectiveness or activity of the active ingredient and is not toxic to the host to which it is administered. As a carrier, excipient, or vehicle, necessary to prepare diluents, binders, adhesives, lubricants, disintegrants, bulking agents, wetting or emulsifying agents, pH buffering agents, and certain compositions And various materials such as absorbents that can be considered. Examples of carriers and the like include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for active substances is well known in the art.

  “Therapeutically effective amount” refers to an amount or dose of an active pyridazine compound or composition of the invention that elicits one or more desired effects, in particular one or more beneficial effects, more particularly a therapeutic effect. means. A therapeutically effective amount of a substance can vary depending on factors such as the disorder state, age, sex, and subject weight, and the ability of the substance to elicit the desired response in the subject. Dosage regimes may be adjusted to provide the optimum therapeutic response (eg, a sustained beneficial effect). For example, several divided doses may be administered daily, or the dose may be reduced in proportion to the urgency of the treatment condition. Generally, in treating a CNS disorder, an effective amount of a compound or composition is an amount sufficient to cross the subject's blood-brain barrier and interact with the relevant receptor in the subject's brain. It is.

  “Pyridazine compound” refers to a compound of formula I, II, III, IV, or V, or a compound described in Tables 1, 2, 3, 4 or 5, especially Tables 2, 3, 4, or 5. . In embodiments of the invention, a pyridazine compound refers to a pendant pyridazinyl group having aryl or substituted aryl, heteroaryl or substituted heteroaryl. In some aspects, the term includes structures disclosed in US Patent Application Nos. 20030176437 and 20060073472.

  In embodiments, pyridazine compounds that exhibit a beneficial effect, particularly a statistically significant beneficial effect, are selected for use in the present invention.

  In an embodiment of the invention, the following compounds of formula Ia or Ib are used.

Wherein R ¹ , R ² , and R ³ are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, Cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thio Alkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxyl Be Bokisamido; R ⁷ is a substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, Arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo , Silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide Or R ⁷ may be absent, and there is a double bond between the C 1 position of N and 6-positions; R ^{4, R 5,} and R ⁶ is independently hydrogen, alkyl R ¹ and R ² , R ¹ and R ⁷ , or R ² and R ³ may form a heteroaryl or heterocycle); or an isomer or pharmaceutical thereof Acceptable salt.

In one aspect, compounds of formula Ia or Ia are used when: (a) R ¹ is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, cyano, amino, cycloalkyl, Sulfonyl, sulfinyl, sulfenyl, thioaryl, thioalkyl, carbonyl, silyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, —SR ²⁰ (where R ²⁰ is an optionally substituted alkyl, carbonyl, carboxyl, carbamoyl, aryl, (B) R ² is optionally substituted, halo, hydroxyl, alkyl, alkenyl, alkoxy, carbonyl, carboxyl, phenyl, benzyl, amino, aryl, cyano,- COH, pipette Jiniru, alcohol, piperidinyl, morpholinyl or naphthyl,; (c) R ³ is optionally substituted, hydrogen, halo, hydroxyl, alkyl, alkenyl, alkoxy, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiol, sul Phenyl, sulfonyl, sulfinyl, or nitro; (d) R ⁴ is hydrogen, halo, or nitro; (e) R ⁵ is optionally substituted hydrogen, halo, alkoxy, or amide; f) R ⁷ is substituted or unsubstituted hydrogen halo, hydroxy, alkyl, alkenyl, alkoxy, carboxy, morpholino, imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, or R ⁷ is absent and N in position 1 Between the 6th and C Have a double bond; and / or (g) R ¹ and R ² , R ¹ and R ⁷ , or R ² and R ³ may form a substituted or unsubstituted heteroaryl or heterocycle .

In another aspect of the invention, R ¹ is C ¹ or Br, —NH ₂ , alkyl, —CN, ═S, silyl, sulfonyl, thioalkyl, thioaryl, piperazinyl, piperidinyl, morpholinyl, pyrrolyl, or pyrrolidinyl, Is halo, ═O, alkoxy, alkenyl, alkyl, substituted alkyl, —CN, —SR ²¹ where R ²¹ is optionally substituted methyl, ethyl, phenyl, heterocycle, or heteroaryl. Or a compound of formula Ia or Ib, optionally substituted with —CO substituted with phenyl or substituted phenyl, is used.

In another embodiment of the invention, R ² is carbonyl, piperazinyl, morpholinyl, sulfonyl, sulfinyl, sulfenyl, or phenyl, —CN, —COH, —CH ₂ OH, —OCH ₂ CH ₃ , or alkyl (alkyl, alkoxy , Amino, halo, phenyl, substituted phenyl, benzyl, hydroxyl, amino, piperidinyl, or morpholinyl, which are optionally substituted) are used.

In another aspect of the invention, R ³ is piperazinyl; substituted piperdinyl; optionally substituted alkyl; phenyl; substituted phenyl; alkyl or alkylamine (eg, NHCOOC (CH ₃ ) ₃ ), Compounds of formula Ia or Ib are used which are carboxyl, or amino optionally substituted with substituted carboxyl; hydroxyl; or nitro.

In another aspect of the invention, compounds of formula Ia or Ib are used wherein R ⁴ is nitro or hydrogen.

In another aspect of the invention, a compound of formula Ia or Ib is used wherein R ⁵ is hydrogen, halo, —OCH ₂ CH ₂ CH ₂ NHCOOC (CH ₃ ) ₃ , or —OCH ₃ .

In another embodiment of the present invention, R ⁷ is alkyl, morpholinyl, benzyl, imidazolyl, —CH ₂ COOCH ₂ CH ₃ , CH ₂ C═COOCH ₂ CH ₃ , CH ₂ CH ₂ CH ₂ SO ₂ OH, CH ₂ CH _2. Compounds of formula Ia or Ib that are CH ₂ SO ₃ —, CH ₂ CH ₂ CH ₂ CH ₂ PO (OH) ₂ , or CH ₂ CH ₂ CH ₂ PO (OH) ₂ are used.

In another aspect of the invention, compounds of formula Ia or Ib are used in which R ⁷ is absent and a double bond is present between N at position 1 and C at position 6.

In a further aspect, R ¹ , R ² , R ³ , and R ⁷ are independently substituted aliphatic, lower alkyl substituted amino, lower alkyl substituted halogen, cycloaliphatic, or substituted cycloaliphatic. A compound is used.

In still further aspects of the invention, piperazinyl where R ¹ may be substituted (eg, with a pyrimidinyl moiety); halo; optionally substituted amino; cyano; —SR ²² where R ²² is alkyl or aryl ( Phenyl), which may be substituted (eg, with halo); substituted alkyl (eg, alkyl substituted with halogen such as CH (Br) ₂ ); morpholinyl; optionally substituted pyrrolyl Hydroxyl; -OR ²⁸ where R ²⁸ is alkyl; -C = CHR ³⁰ where R ³⁰ is alkyl; or a compound of formula Ia or Ib that is pyrrolidinyl is used .

In yet a further aspect of the invention, R ² is hydrogen; morpholinyl; piperazinyl optionally substituted (eg, with a pyrimidinyl moiety); phenyl; alkyl; alkoxy (eg, CH (OCH ₃ ) ₂ ); substituted alkyl; substituted aryl Compounds of formula Ia or Ib are used which are (eg phenyl); cyano; or hydroxyl.

In another aspect of the invention, a compound of formula Ib is used wherein R ¹ is pyridinyl and R ² is N-substituted piperidinyl.

In another embodiment, compounds of formula Ib are used wherein R ¹ is amino substituted with alkyl or cycloalkyl and R ² is pyridinyl.

In yet a further aspect of the invention, R ³ is hydrogen; hydroxyl; optionally substituted alkyl (eg, with halo); optionally substituted amino; —COR ³¹ where R ³¹ is hydrogen, hydroxyl, alkoxy A compound of formula Ia or Ib is used that is (eg, —OCH ₃ ); or an aryl (eg, a phenyl group) that may be substituted (eg, with an alkyl).

In yet a further aspect of the invention, a compound of formula Ia or Ib is used, wherein R ⁴ is hydrogen or halo; R ⁵ is hydrogen or halo; R ⁶ is hydrogen or halo.

In yet a further aspect of the invention, R ⁷ is hydrogen; optionally substituted alkyl (eg, with a phenyl group); —CH ₂ CH ₂ COOR ³² where R ³² is alkyl, —CH ₂ C = COOR ³³ (where R ³³ is alkyl), CH ₂ CH ₂ CH ₂ S (O) ₂ OH, morpholinyl, benzyl, imidazolyl, or [CH ₂ ] _n PO (OH) ₂ (where , N is 1 to 6, in particular 3 or 4).

In yet a further aspect of the invention, compounds of formula Ia or Ib are used in which R ¹ and R ² form a piperidinyl ring optionally substituted by carboxyl.

In yet a further aspect of the invention, a compound of formula Ia is used in which R ¹ and R ⁷ form a pyrimidinyl ring optionally substituted by alkyl, aryl, halo, or hydroxyl.

In certain embodiments, R ¹ is —NR ³⁴ R ^35, wherein R ³⁴ is hydrogen or alkyl, and R ³⁵ is hydrogen, alkyl, carbonyl, aryl, amino, cycloalkane, heterocycle, or substituted. A compound of formula Ia or Ib is used which is a good heteroaryl. In embodiments, R ³⁵ is hydrogen, C ₁ -C ₆ alkyl (eg, methyl or ethyl) (optionally substituted hydroxyl, alkyl, amino, carbonyl, carboxyl, morpholinyl, isoquinolinyl). , Or amino (optionally substituted with one or more optionally substituted alkyl, benzyl, carboxyl, alcohol, heteroaryl or heterocycle), propanol, phenyl optionally substituted with halo , Benzyl optionally substituted with alkoxy, cyclohexyl, piperidinyl optionally substituted with phenyl optionally substituted, pyrrolidinyl, pyrrolidinylalkyl optionally substituted with alkyl, -COOR ⁸ (where R ⁸ is , Optionally substituted alkyl Or [CH ₂ ] _m -piperidinyl, where m is 1-4, especially 1-3, and piperidinyl is optionally substituted with optionally substituted alkyl, phenyl, or benzyl. And may be selected from them.

In ^{embodiments, R 35 is} a ^-R 44 ^{R 45, wherein, R 44} _{is, -NH [CH 2] w NH} (w is 1 to 4, in particular 2 or 3) R ⁴⁵ is optionally substituted, particularly piperazinyl substituted with pyrimidinyl substituted with alkyl.

In ^{embodiments, R 35 is} a ^-R 46 ^{R 47, wherein, R 46} _{is, - [CH 2] w N} (CH 3) (w is 1 to 4, particularly 2 or 3 R ⁴⁷ is optionally substituted, particularly piperazinyl substituted with pyrimidinyl substituted with alkyl.

In one aspect of the invention, R ¹ is halo, in particular chlorine or bromine, and R ² may be substituted, in particular alkyl, substituted aryl (alkyl, alkoxy), which may be substituted with alkoxy (eg methoxy, dimethoxy). , (Eg, benzyl, methoxyphenyl), halo (eg, bromine or chlorine), or substituted or unsubstituted saturated 3-6 membered monocyclic ring containing 1 to 4 nitrogen atoms Formula heterocyclic groups (eg piperidinyl and piperazinyl) or saturated 3-6 membered monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg morpholinyl; sydnonyl), Particularly substituted morpholinyl, piperazinyl, or piperazinyl substituted with heteroaryl, said heteroaryl having 1 to 4 nitrogen atoms. Unsaturated 5- to 6-membered monocyclic heterocyclic groups containing atoms, specifically pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, especially Compounds of formula Ia or Ib are used that are pyrimidinyl and optionally where R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen.

In another aspect of the invention, R ¹ is halo, in particular chlorine or bromine, and R ³ is a substituted or unsubstituted saturated 3-6 membered monocyclic heterocycle containing 1 to 4 nitrogen atoms. Groups (eg piperidinyl and piperazinyl) or saturated 3-6 membered monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg morpholinyl; sydnonyl), in particular substituted morpholinyl , Piperazinyl, or alkyl-substituted piperazinyl, or heteroaryl (unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms), especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2 - pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, especially pyrimidinyl, or R There substituted amino, an alkyl or substituted alkyl (especially, alkyl substituted by alkoxycarbonyl) and amino substituted with ^{optionally, R 2, R 4, R} 5, R 6, and ^{R 7} is hydrogen Certain compounds of formula Ia are used.

In a further aspect, R ¹ is halo, in particular bromine or chlorine, R ² and R ³ form an unsaturated ring, in particular phenyl, and R ⁵ is heteroaryl, in particular 1 to 4 nitrogen atoms. A substituted or unsubstituted unsaturated 5-6 membered heteromonocyclyl group containing, in particular pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, especially imidazolyl, optionally in which R ⁴ , R ⁶ , and R ⁷ are hydrogen is there.

In a further aspect, R ¹ is halo, in particular bromine or chlorine, R ⁴ is nitro, and optionally R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ are hydrogen.

In a further aspect, the present invention relates to a thiol (thioalkyl) wherein R ¹ is substituted with alkyl; substituted alkyl, in particular a substituted or unsubstituted saturated 3-6 membered monocyclic heterocycle containing 1 to 4 nitrogen atoms. A ring group (eg, pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl) or a saturated 3-6 membered monocyclic heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (eg, morpholinyl; sydnonyl) ), In particular, alkyl substituted with substituted morpholinyl or piperidinyl; aryl; substituted aryl; carboxyl optionally substituted with substituted or unsubstituted aryl; optionally R ² is alkyl, especially lower alkyl; Optionally R ³ is alkyl, especially lower alkyl or nitro; optionally R ⁵ is A compound of formula Ia is used wherein R is alkoxy; optionally R ⁷ is alkyl; optionally R ⁴ , R ⁵ , and R ⁶ are hydrogen.

In a further aspect of the invention, R ¹ is ═S, optionally R ² is alkyl, especially lower alkyl, R ⁵ is alkoxy, R ³ , R ⁴ , R ⁶ , and Compounds of formula Ia are used in which R ⁷ is hydrogen.

In a further aspect of the invention, R ¹ is sulfonyl which may be substituted with substituted or unsubstituted aryl, in particular substituted phenyl, optionally R ² is alkyl and R ³ , R ⁴ , R Compounds of formula Ia are used in which ⁵ , R ⁶ and R ⁷ are hydrogen.

In a further aspect of the invention, R ¹ is substituted or unsubstituted alkyl or alkynyl, in particular alkyl substituted with aryl, substituted aryl, halo, cyano, or alkynyl substituted with alkyl. Optionally, a compound of formula Ia is used wherein R ² is alkyl, R ⁷ is alkyl and R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen.

In a further aspect of the invention, the compound of formula Ia, wherein R ¹ is cyano, R ² is aryl or alkyl, and optionally R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen Is used.

In a further aspect of the invention, one or both of R ¹ and R ² is a saturated 3-6 membered monocyclic heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (eg, Morpholinyl; sidnonyl), in particular substituted morpholinyl, optionally using a compound of formula Ia wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen.

In a further aspect of the invention, R ¹ is a saturated 3-6 membered monocyclic heterocyclic group containing 1-4 nitrogen atoms, which may be substituted with a substituted or unsubstituted carboxyl (eg pyrrolidinyl). Yes, a compound of formula Ia is used where R ² is alkyl or halo and optionally R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen.

In a further aspect of the invention, ¹ to 4 R ¹ is hydroxyl; R ² is alkyl or substituted alkyl, or R ³ is optionally substituted with heteroaryl (eg, pyrimidinyl) A saturated 3-6 membered monocyclic heterocyclic group containing a nitrogen atom (for example, piperidinyl and piperazinyl), the other of R ² or R ³ is hydrogen, and optionally R ⁴ , R ⁵ , R ⁶ And a compound of formula Ia where R ⁷ is hydrogen is used.

In a further aspect of the invention, R ¹ is a saturated 3-6 membered monocyclic heterocyclic group containing ¹ to 4 nitrogen atoms (eg piperidinyl, and piperazinyl), wherein the monocyclic heterocyclic group is May be substituted by carboxyl, or alkyl or alkoxy, or carboxyl substituted by prinyl or substituted prynyl; R ² is alkyl or substituted alkyl, especially alkylaryl, optionally R ³ , R ⁴ , Compounds of formula Ia are used in which R ⁵ , R ⁶ , and R ⁷ are hydrogen.

In a further aspect of the invention, R ¹ is ═O and R ² is alkyl, alkylaryl, cyano, alkoxy, or substituted alkoxy, optionally R ³ , R ⁴ , R ⁵ , R ⁶ , And a compound of formula Ia in which R ⁷ is hydrogen is used.

In a further aspect of the invention, R ¹ is alkoxy, R ² is alkyl, substituted alkyl, or alkoxy, and optionally R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen. Certain compounds of formula Ia are used.

In a further aspect of the invention, R ¹ and R ² are, for example, a heterocycle optionally substituted with alkyl, halo, carboxyl or alkoxycarbonyl, in particular saturated 3-6 membered containing 1 to 4 nitrogen atoms. Cyclic heterocyclic groups, especially 6-membered rings containing 1 or 2 nitrogen atoms (eg piperidinyl and piperazinyl), optionally R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ A compound of formula Ia is used in which is hydrogen.

In a further aspect of the invention, R ¹ and R ⁷ are heteroaryl, in particular an unsaturated 5-6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, R ² is hydrogen or alkyl, and R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are A compound of formula Ia is used which is hydrogen.

In a further aspect of the invention, R ¹ is an optionally substituted silyl, especially silyl optionally substituted with alkyl, R ² is alkyl, R ³ , R ⁴ , R ⁵ , R ⁶ , and Compounds of formula Ia are used in which R ⁷ is hydrogen.

In some embodiments, one or more of the following compounds do not fall within the scope of pyridazine compounds of formula Ia or Ib used in the present invention:
a) When R ¹ is ═O, R ³ is —COOCH ₃ , CH═CHCOOCH ₃ , —CH═CHC (═O) -phenyl, —CH═CH (C (═O) CH ₃ ). _2, -S- _{phenyl, -CH = CH (COCH 3)} (COOCH 3), CH = CH (COOCH 2 CH 3) 2, - phenyl -COOCH _3, -CH = CHCO- _phenyl, -CH 2 CH (Cl ) (CH ₂ OH), -methylphenyl, R ⁷ is hydrogen or —CH ₂ OCH ₃ , and R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen;
b) when R ¹ is ═O, R ² is cyano, R ³ is —C (═O) OCH ₃ , and R ³ , R ⁴ , R ⁵ , and R ⁶ are hydrogen. Compound;
c) a compound wherein when R ¹ is ═O, R ² is -methylthiophene or benzyl and R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen;
d) when R ¹ is ═O, R ² is methyl, R ⁵ is hydrogen, hydroxyl, chlorine, or bromine, R ⁷ is hydrogen or ethylmorpholinyl, R ³ , The compound wherein R ⁴ and R ⁶ are hydrogen;
e) when R ² is methyl, R ⁵ is chlorine, bromine, or hydrogen, R ⁷ is hydrogen or —CH ₂ CH ₂ -morpholinyl, R ¹ , R ³ , R ⁴ and The compound wherein R ⁶ is hydrogen;
f) a compound wherein when R ¹ is piperazinyl, piperazinyl substituted with pyridinyl, phenyl or methyl, R ² is hydrogen or methyl and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
g) when R ¹ is chlorine or bromine, R ² is C ₁ -C ₃ alkyl, phenyl, amino, benzyl, morpholinyl, chlorine, —C (═O) NH ₂ , —NH ₂ , C ₁ -C _{3 alkylphenyl, -CH (CH 3) 2,} -CH 2 CH (CH 3) 2, - benzyl chloro ^compound R ^3, R 4, ^{R 5} preliminary ^{R 6} is hydrogen;
h) when R ¹ is chlorine or bromine, R ³ is hydroxyl, chlorine, bromine, C ₁ -C ₃ alkyl, phenyl, or —N (CH ₃ ) ₂ , R ² , R ⁴ , The compound wherein R ⁵ and R ⁶ are hydrogen;
i) A compound wherein, when R ¹ is chlorine, R ² is methyl, R ⁵ is hydroxyl, and R ³ , R ⁴ and R ⁶ are hydrogen;
j) a compound wherein when R ¹ is chlorine, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
k) a compound wherein when R ¹ is hydroxyl, R ² is C ₁ -C ₄ alkyl and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
l) When R ¹ is —C ₁ -C ₄ alkoxy, or C ₁ -C ₄ alkoxy substituted with —N (CH ₃ ) ₂ , piperidinyl substituted with morpholinyl, or benzyl, R ² is , Hydrogen or methyl, compounds wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen and R ⁷ is absent, hydrogen or methyl;
m) when R ¹ is —SH, —SCH ₃ , or —SCH ₂ C (═O) CH ₃ , R ² is hydrogen or methyl, and R ³ , R ⁴ , R ⁵ and R ⁶ are A compound that is hydrogen;
n) A compound wherein when R ¹ is ═S, R ² is hydrogen or methyl, R ⁷ is methyl or benzyl, and R ³ , R ⁴ and R ⁶ are hydrogen;
o) A compound wherein when R ¹ is ═S, R ² is methyl, R ⁵ is chlorine, or R ⁷ is methyl and R ³ , R ⁴ and R ⁶ are hydrogen;
p) A compound wherein when R ¹ is hydroxyl, R ² is hydrogen, methyl or butyl and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
q) a compound wherein when R ¹ is methoxy, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
r) When R ¹ is C ₁ -C ₄ alkoxy substituted with C ₁ -C ₂ alkoxy or morpholinyl, -N (CH ₃ ) ₂ , or piperidinyl substituted with benzyl, R ² is methyl A compound in which R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
s) compounds wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
t) R ¹ is cyano substituted with cyano or —C (OCH ₂ CH ₃ ) ₂ , —CH (OH) (CH ₃ ), —Si (CH ₂ CH ₃ ) ₂ , cyclohexol, —CH ₂ O A compound which is trimethyldiphenylsilyl or cyclohexyl substituted with hydroxyl and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
u) R ¹ is cyano, —Si (CH ₂ CH ₃ ) ₂ , morpholinyl, trimethyldiphenylsilyl, or —CH (OCH ₂ CH ₃ ) ₂ substituted with —CH (OH) (CH ₃ ) ₂ , R ² is methyl, and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
v) A compound wherein R ⁷ is oxy, R ² is hydrogen or methyl, and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
w) a compound wherein R ¹ is methyl and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
x) a compound wherein R ² is methyl and R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
y) a compound wherein R ¹ is methoxycarbonyl, R ³ is hydrogen and R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen;
z) R ¹ is —NH ₂ and R ² is methyl, chlorophenyl, methoxyphenyl, ethylphenyl, ethylmethoxyphenyl, propylphenyl, or —CH (CH ₃ ) ₂ , R ⁴ , R ⁵ and A compound wherein R ⁶ is hydrogen and R ⁷ is absent or —CH ₂ CH ₂ CH ₂ COOH;
aa) R ¹ is —OR ^29, where R ²⁹ is ethylmorpholinyl or —CH ₂ CH ₂ N (CH ₃ ) ₂ , and R ² , R ³ , R ⁴ , R ⁵ And a compound wherein R ⁶ is hydrogen;
bb) a compound wherein R ¹ is —NH ₂ , R ³ is —NH ₂ , and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
cc) a compound wherein R ¹ is —NH ₂ , R ⁵ and R ⁶ are methoxy, and R ³ and R ⁴ are hydrogen;
dd) a compound wherein R ¹ is —NH ₂ , R ³ is methyl, and R ⁴ , R ⁵ and R ⁶ are hydrogen;
ee) A compound wherein R ¹ is —NH ₂ , R ⁵ is chlorine, and R ³ , R ⁴ and R ⁶ are hydrogen;
ff) compounds wherein R ¹ is —NH-chlorophenyl, R ² and R ³ form a phenyl group, and R ⁴ , R ⁵ and R ⁶ are hydrogen;
gg) a compound wherein R ¹ is —NH ₂ , R ⁴ and R ⁵ are methoxy, and R ² , R ³ and R ⁶ are hydrogen;
hh) a compound wherein R ¹ is —NH ₂ , R ² is ethylmethoxyphenyl, R ⁷ is carboxyethyl or carboxypropyl, and R ³ , R ⁴ and R ⁶ are hydrogen;
ii) R ¹ is —NHR ⁴⁸ (where R ⁴⁸ is ethylmorpholinyl, ethylmorpholinyl substituted with ═O, —CH ₂ CH ₂ OCH ₃ , —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _3, a _{-CH 2 CH 2 CH 2 CH 2} OH, a -CH 2 _CH 2 OH or _{-CH 2 CH 2 OCH 3,)} , R 2 is hydrogen, methyl, ethyl, _-CHO, -CH 2 _{OH, -COOH, chlorine, -CH 2 CH 2 NH 2,} -NO 2, -C≡N, -C (= O) OCH 2 CH 3 or -C (= O) NH _2, A compound wherein R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
jj) ^{R 1} is -NHR ^{49 (wherein, R 49} is ethanol, methylpiperidinyl benzyl, ethyl piperidinylmethyl, ethyl piperidinylmethyl benzyl or butyl piperidinylmethyl benzyl,), ^{R 2} is , Hydrogen, methyl, or —C (CH ₃ ) ₂ , wherein R ³ , R ⁴ , R ^5, and R ⁶ are hydrogen;
kk) A compound wherein R ¹ is —NHR ⁵⁵ (where R ⁵⁵ is hydrogen) and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
11) R ¹ is —NHR ⁵⁶ (where R ⁵⁶ is —CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ or ethylmorpholinyl), R ³ is ethyl, R ⁴ , The compound wherein R ⁵ and R ⁶ are hydrogen;
mm) A compound wherein R ¹ is —NHNH ₂ , R ³ is hydrogen, alkyl, or phenyl, and R ³ , R ⁴ , R ^5, and R ⁶ are hydrogen;
nn) R ¹ is —NHR ⁵⁷ (where R ⁵⁷ is NH ₂ , —CH ₂ CH ₂ OH, CH ₂ CH (OH) (CH ₃ ), ethylmorpholinyl, ethylmol substituted with ═O) Folinyl, ethylphenyl, —CH ₂ CH ₂ NHCH ₃ , —CH ₂ CH ₂ N (—CH ₂ CH ₂ CH ₃ ) ₂ , ethyl piperidinyl, or ethyl piperidinyl benzyl), R ² A compound wherein R ³ is methyl and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
oo) R ¹ is morpholinyl and R ² is —C (F) ₃ , —C (═O), —CH ₂ OH, —C (═O) H, —COOH, chlorine, —NO ₂ , or A compound that is cyano and wherein R ³ , R ⁴ , R ^5, and R ⁶ are hydrogen;
pp) R ¹ is —NHR ⁵⁸ (where R ⁵⁸ is heptyl, phenyl, benzyl, or ethylphenyl), R ² is hydrogen, methyl, or chlorophenyl, R ⁴ , R ⁵ and The compound wherein R ⁶ is hydrogen;
qq) the compound wherein R ¹ is —NR ⁹ (where R ⁹ is phenyl) and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
rr) A compound wherein R ¹ is morpholinyl and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
ss) a compound wherein R ¹ is methylpiperazinyl and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
tt) the compound wherein R ¹ is —NHCH ₂ CH ₂ OH or NHCH ₂ CH ₂ OCH ₃ , R ² is phenyl, and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
uu) R ¹ is —NHR ⁵⁹ (where R ⁵⁹ is ethylamino, butylamino, ethylaminomethyl) and R ² is hydrogen, methyl, or —C (═O) HN ₂ , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen;
vv) R ¹ is —NHR ⁶⁰ (where R ⁶⁰ is ethylpiperidinyl, methylpiperidinylbenzyl, piperidinylbenzyl, ethylpiperidinylbenzyl, methylpyrrolidinylmethyl, ethylpiperazinylbenzyl, -CH ₂ C (= O) - piperazinyl benzyl, -C (= O) - _{methylnaphthyl, -CH 2 CH 2 CH 2 CH} 2 CH 2 N (CH 3) (C 7 H 7), - CH 2 C (═O) -piperidinylbenzyl, —C (═O) -methylpiperidinylbenzyl, or —CH (CH ₃ ) ₂ ), and R ³ , R ⁴ , R ⁵ and R ⁶ are A compound that is hydrogen;
ww) R ¹ is —CHCH ₂ CH ₂ -isoquinolinyl, —NHCH ₂ CH ₂ N (CH ₂ CH ₂ CH ₃ ) ₂ , piperidinyl fused to phenyl, propyl, —NHCH ₂ CH ₂ , or a phenyl moiety A compound that is —NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ substituted with piperidinyl fused to two adjacent carbon atoms of
xx) compounds wherein R ¹ is —NH substituted with two pyrrolidinyl groups; R ³ is methyl, and R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen;
yy) the compound wherein R ¹ is —COOCH ₃ , R ³ is methyl, and R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen;
zz) A compound wherein R ¹ is hydrogen, R ² is methyl, and R ⁷ is oxygen;
aaa) A compound wherein R ⁷ is methyl or oxygen and R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen;
bbb) compounds wherein R ¹ is —NHCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ , R ³ is ethyl, and R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen; and ccc) R ¹ is —NHCH ₂ CH (OH) (CH ₃ ) or —NHCH ₂ CH ₂ NHCH ₂ CH ₂ OH, R ² is methyl, and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen. Compound.

In embodiments of the present invention, R ¹ is piperazinyl or substituted piperazinyl, especially the following formula A:

A compound of formula Ia or Ib which is piperazinyl substituted with pyrimidinyl is used.

  Accordingly, pyridazine compounds for use in the present invention have the formula II:

Wherein R ¹⁰ and R ¹¹ are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy , Aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro Ureido, phosphonate, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, or carboxa Containing or an isomer or pharmaceutically acceptable salts; the compounds of the de is a).

In one aspect of the invention, R ¹⁰ is hydrogen; hydroxyl; alkyl; aryl (eg, optionally substituted phenyl (eg, halide)); substituted (eg, substituted with pyrimidinyl) piperazinyl; ³⁶ R ³⁷ (where R ³⁶ is hydrogen or alkyl, R ³⁷ is optionally substituted phenyl or optionally substituted alkyl (eg amino, especially —CH ₂ CH ₂ NH ₂ ; CH ₂ CH ₂ NHCOOC (CH ₃ ) ₃ ); optionally substituted morpholinyl; or —SR ²³ (wherein R ²³ is optionally substituted phenyl); R ¹¹ is hydrogen or substituted A compound of formula II is used which is a good aryl (eg phenyl).

In certain embodiments of the invention, R ¹⁰ is hydrogen, halo, optionally substituted hydroxyl, alkyl, pyridinyl, phenyl, benzyl, piperazinyl, amino, morpholinyl, or —SR ²⁴ where R ²⁴ is alkyl or A compound of formula II which is aryl) is used. In one embodiment, R ¹⁰ is —NH [CH ₂ ] _m NR ⁶¹ R ^62, wherein m is 1-6, especially 2-4, R ⁶¹ is hydrogen, R ⁶² is carboxyl, especially — COOC (CH ₃ ) ₃ ).

In one aspect of the invention, a compound of formula II is used wherein R ¹¹ is hydrogen, halo, optionally substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl, or phenyl.

In another aspect of the invention, compounds of formula II are used in which both R ¹⁰ and R ¹¹ are not hydrogen.

In certain embodiments of the invention one or more of R ¹⁰ and R ¹¹ is alkyl, especially C ₁ -C ₆ alkyl, and the other of R ¹⁰ and R ¹¹ is hydrogen.

In certain embodiments of the invention, one or more of R ¹⁰ and R ¹¹ is aryl, particularly phenyl or benzyl, and the other of R ¹⁰ and R ¹¹ is hydrogen.

  In certain embodiments of the invention, the compound of formula II is the compound of Table 3, and more specifically, MW01-2-065LKM, MW01-2-069SRM, MW01-2-151SRM, MW01-5 188WH, MW01-6-127WH, MW01-6-189WH, or MW01-7-107WH, and pharmaceutically acceptable salts and derivatives thereof.

  In embodiments, the present invention provides compounds of formula III:

Wherein R ¹⁵ and R ¹⁶ are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cyclo Alkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, Nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, = O, = S, phosphonate, carboxyl, carbonyl, carbamoyl, or carbo The compounds of the is) Samido; or to use the isomer or pharmaceutically acceptable salt thereof.

  In another aspect, the present invention provides a compound of formula IV:

Wherein R ⁷⁰ and R ⁷¹ are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cyclo Alkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, Nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, or carbamoyl) Compounds; or to use the isomer or pharmaceutically acceptable salt thereof.

In other embodiments, R ⁷⁰ is a substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, Heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, = O, = S, carboxyl, carbonyl, carbamoyl, or carboxamide, especially heterocyclic, heteroaryl, amino, and substituted amino, R ⁷¹ is aryl or substituted aryl That compounds of the formula IV; or an isomer or pharmaceutically acceptable salt thereof is used.

In another embodiment, R ⁷⁰ is a heterocycle, particularly a saturated 3-6 membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, more specifically pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl, especially piperazinyl Or piperidinyl (optionally substituted with alkyl, especially methyl, dimethyl, cycloalkyl, especially cyclohexyl, aryl, especially phenyl), substituted or unsubstituted unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, especially Indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl, quinolididinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, carbazolyl, purinyl, benzimidazolyl, quinolyl A compound of formula IV is used, which is benzoimidazolyl, substituted with isoquinolyl, quinolinyl, isoquinolinyl or indazolyl, in particular oxy.

In other embodiments, compounds of formula IV are used wherein R ⁷⁰ is amino or substituted amino and optionally R ⁷¹ is aryl, especially phenyl. In one aspect, R ⁷⁰ is —N—R ^63, where R ⁶³ is hydrogen or alkyl, especially C ₁ -C ₆ alkyl, more specifically methyl or dimethyl, or —N—R ⁴⁰ R ⁴¹ (where R ⁴⁰ is hydrogen or alkyl, especially C ₁ -C ₆ alkyl, more specifically methyl, and R ⁴¹ is alkyl, heterocycle, substituted heterocycle substituted with amino or substituted amino. Ring, or cycloalkyl). In one embodiment, R ⁷⁰ is —NR ⁴² R ⁴³ , wherein R ⁴² is hydrogen or alkyl, especially C ₁ -C ₆ alkyl, more specifically methyl, and R ⁴³ is C ₁ -C ₆ alkyl, methyl or dimethyl been particularly substituted cycloalkyl (in particular cyclopropyl), heterocyclic, in particular piperidinyl, pyrrolidinyl, or morpholinyl, they can be substituted, particularly aryl, especially substituted benzyl May have been.

  Compounds of formula IV have the structure specified in Table 5 as compounds 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, or 139 Includes pharmaceutically acceptable salts, isomers, or derivatives.

  In a further aspect, the present invention provides compounds of formula V:

Wherein R ⁵⁰ , R ⁵¹ , and R ⁵² are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cyclo Alkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy , Thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, or carboxami Using the or an isomer or pharmaceutically acceptable salts; compounds of the a).

In an embodiment of the invention, R ⁵⁰ is substituted or unsubstituted hydrogen, alkyl, aryl, or heterocycle; R ⁵¹ is substituted or unsubstituted hydrogen or alkyl, and R ⁵² is substituted or unsubstituted. Compounds of formula V are used that are hydrogen, alkyl, cycloalkyl, heteroaryl or halo. In one aspect, R ⁵⁰ is hydrogen, C ₁ -C ₆ alkyl (which may be substituted with alkyl, especially methyl or trimethyl), phenyl, or a 3-6 membered monocycle containing 1-4 nitrogen atoms. A heterocyclic group of formula, more specifically piperidinyl or morpholinyl, R ⁵¹ is hydrogen or alkyl, in particular methyl, and R ⁵² is hydrogen, alkyl, in particular methyl, dimethyl, ethyl or propyl, cyclohexyl, chlorine Or unsaturated 5-6 membered monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms, in particular pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl Or a compound of the formula V which is pyridazinyl, in particular pyridinyl, is used. In one embodiment, R ⁵⁰ is aryl, R ⁵¹ is hydrogen, and R ⁵² is C ₁ -C ₆ alkyl.

  The compound of formula V is compound MW01-7-057WH, or structures 32, 34, 36, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 63, 69 in Table 5. , 70, 71, 75, 76, 77, 78, 79, 80, 81, or 82, or a pharmaceutically acceptable salt, isomer or derivative thereof.

  In embodiments of the present invention, the pyridazine compound is an isolated, pure, particularly substantially pure compound of formula I, II, III, IV, or V, or an isomer or pharmaceutically acceptable salt thereof. Salt. As used herein, the term “pure” is generally better than 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% purity. “Substantially pure” means that a compound made in view of the composition or dose described herein or available for use is readily purified by conventional purification methods. Alternatively, it means a compound synthesized to have only impurities that cannot be reasonably removed.

  The pyridazine compounds used in the present invention include derivatives, especially derivatives of compounds of formula I, II, III, IV, or V. The term “derivative” as used herein refers to a chemically modified compound in which chemical modification occurs at a functional group of the compound or on an aromatic ring. Non-limiting examples of derivatives of compounds of formula I, II, III, IV, or V (eg, pyridazine derivatives of the present invention) include N-acetyl, N-methyl at any available nitrogen in the compound And N-hydroxy group. Derivative groups that can be used to modify compounds of formula I, II, III, IV, or V are described in U.S. Patent Application No. 20030176437, which is hereby incorporated by reference in its entirety for all purposes. Can be found).

  In some embodiments, the organic compounds listed in Tables 1, 2, 3, 4, or 5 and / or their heterocyclic derivatives are used specifically in Tables 2, 3, 4, or 5.

  In certain aspects, the present invention uses compounds of formula I, II, III, IV, or V as defined herein, but excludes the compounds described in Table 1.

  In other specific embodiments, the present invention uses compounds of formula II, but excludes the compounds described in Table 1.

  In a further specific embodiment, the present invention uses compounds of formula III, but excludes the compounds described in Table 1.

  In a further particular embodiment, the present invention uses compounds of formula IV, but excludes the compounds described in Table 1.

  In yet a further specific embodiment, the present invention uses compounds of formula V, but excludes the compounds described in Table 1.

  According to aspects of the present invention, pyridazine compounds and / or related heterocyclic derivatives thereof (see, eg, the tables herein, particularly Tables 2, 3, 4, and / or 5, or heterocyclic derivatives thereof) Used to treat or prevent the disorders disclosed herein. In some embodiments, the compound used is one described in Tables 2, 3, 4, and / or 5, or derivatives thereof. In some embodiments, the present invention is described herein as MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MW01-2-189WH, and MW01-2-151SRM. One or more compounds shown in the above, or isomers or pharmaceutically acceptable salts thereof are used.

  In some embodiments, the present invention is described herein as MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MW01-2-189WH, and MW01-2-151SRM. One or more compounds shown in the above, or isomers or pharmaceutically acceptable salts thereof are used.

  In some embodiments, the present invention provides MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MW01-2-151SRM, MW01-2-189WH, and MW01- One or more compounds designated as 1-01-L-D07 and / or related derivatives of these compounds, in particular heterocyclic derivatives, are used. In another specific embodiment of the invention, MW01-2-151SRM, its isomers, pharmaceutically acceptable salts, or derivatives are used in the present invention. In certain embodiments of the invention, MW01-5-188WH, its isomers, pharmaceutically acceptable salts, or derivatives are used in the present invention.

  Further, the pyridazine compound includes “pharmaceutically acceptable salt (s)”. Pharmaceutically acceptable salts do not have excessive toxicity, irritation, allergic reactions, etc., are suitable for use in contact with the subject or patient tissue, and are in proportion to a reasonable benefit / risk ratio. It means that there is. Pharmaceutically acceptable salts are, for example, S. cerevisiae. M.M. Berge et al. Pharmaceutical Sciences, 1977, 66: 1. Examples of the salt include MW01-1-01-L-D10, MW01-1-01-E02, MW01-1-01-LE08, MW01-1-03-LA-05, MW01-1-16-L- D09, and compounds shown herein as MW01-1-17-L-G04.

  In embodiments of the present invention, acid addition salts of compounds of formula II, in particular halide salts, more specifically chlorides, more particularly hydrochlorides are used. In certain embodiments, a pharmaceutically acceptable halide of the pyridazine compound 4-methyl-6-phenyl-3- (4-pyrimidin-2-ylpiperazin-1-yl) pyridazine (5) shown in FIG. Salt is used.

  In one embodiment, the pharmaceutically acceptable salt used in the present invention is 4-methyl-6-phenyl-3- (4-pyrimidin-2-ylpiperazin-1-yl) pyridazine as shown in FIG. It is a chloride salt of (5). In certain embodiments, the pharmaceutically acceptable salt is 4-methyl-6-phenyl-3- (4-pyrimidin-2-ylpiperazin-1-yl) pyridazine (5) hydrochloride shown in FIG. Salt, more particularly, the following (ie MW01-9-034WH) (16) (ie 2- (4- (4-methyl-6-phenylpyridazin-3-yl) piperazin-1-yl) pyrimidine di Dihydrochloride hydrate salt shown in (hydrochloride) (6).

In an embodiment of the invention, the dihydrochloride hydrate salt of the compound of formula V characterized by high solubility, in particular 2- (4- (4-methyl-6-phenylpyridazin-3-yl) piperazine as shown in FIG. -1-yl) pyrimidine dihydrochloride (6) is utilized in the present invention. The dihydrochloride hydrate salt may further have one or more of the following characteristics: yellow powder, about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, Or a purity greater than 99%, a molecular weight of 433.3395, soluble in DMSO, a melting point higher than 488K, an acid dissociation constant (pKa of 2.55, 1.46, 0.84, and -4.31 (calculated)) ), Having a log P of 2.29 measured from the octanol / water partition coefficient, having a log S of 2.5 (experimental) /4.08 (calculated), and / or about 100-400 mg / ml, about 100- 350 mg / ml, about 150~350mg / ml, solubility about 200~350mg / ml or about 300~350mg / ml of water, particularly in water than _{322mg / ml (2HCl · H 2} O salt) Having heard solubility.

  In some embodiments, amorphous or crystalline forms of the compound of formula V are used that have high absorption rates. In certain embodiments, in certain embodiments, the absorption rate is increased by at least 2, 3, 4 or 5 fold.

  Pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, may contain one or more asymmetric centers, such as enantiomers, diastereomers, and (R)-or (S)- Other stereoisomers may be generated that can be defined in terms of absolute stereochemistry. Thus, pyridazine compounds include all possible diastereomers and enantiomers, as well as racemic and optically pure forms. Optically active (R)-and (S) -isomers may be prepared using chiral synthesis elements or chiral reagents, or resolved using conventional techniques. If a pyridazine compound contains a geometrically asymmetric center and is not otherwise specified, the compound is meant to include both E and A geometric isomers. All tautomers are also included within the scope of the pyridazine compounds used in the present invention.

  Compounds of formula I, II, III, IV or V include crystalline forms that may exist as polymorphs. Solvates of compounds formed with water or common organic solvents are also intended to be encompassed within the polymorphic terms. As a result, pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, are in unsolvated and solvated forms with pharmaceutically acceptable solvents (eg, water, ethanol, etc.) Can exist in The solvated form can be considered equivalent to the unsolvated form for the purposes of the present invention. Furthermore, hydrate forms of the compounds and their salts are included within the scope of the invention. Furthermore, prodrugs of compounds of formula I, II, III, IV or V are encompassed within the term.

  The term “solvate” is a variable formed by a physical association or solute (eg, a compound of the invention) of a compound with one or more solvent molecules and a solvent (eg, water, ethanol, or acetic acid). Means a stoichiometric complex. This physical association can involve different degrees of ionic and covalent bonding, including hydrogen bonding. In one example, a solvate could be isolated, for example, when one or more solvent molecules are incorporated into the crystalline lattice of a crystalline solid. In general, the solvent chosen does not interfere with the biological activity of the solute. Solvates include both liquid phases and separable solvates. Representative solvates include hydrates, ethanol solvates, methanol solvates and the like.

  Also included are dehydrates, co-crystals, anhydrides or amorphous forms of the compounds of the invention. The term “hydrate” refers to solvates in which the solvent molecule (s) is water, including its monohydrate, dihydrate, and various polyhydrates. Solvates can be formed using methods known in the art.

  Crystalline compounds of formula I, II, III, IV or V can exist in the form of isolated bases, salts, or co-crystals. The isolated base compound can be crystallized in the presence of a suitable solvent to form a solvate. Acid salt compounds of compounds of formula I, II, III, IV or V (eg HCl, HBr, benzoic acid) can also be used in the preparation of solvates. For example, solvates can be formed using acetic acid or ethyl acetate. Solvate molecules can form crystal structures by hydrogen bonding, van der Waals forces, or dispersion forces, or any combination of two or all three forces.

The amount of solvent used to make the solvate can be determined by routine testing. For example, a monohydrate of a compound of formula I, II, III, IV or V will be about 1 equivalent of solvent (H ₂ O) for each equivalent of a compound of the invention. However, more or less solvent can be used depending on the choice of desired solvate.

  Compounds of formula I, II, III, IV or V may be amorphous or possibly have different crystalline polymorphs that exist in different solvated or hydrated states. By changing the dosage form of the drug, it is possible to change its physical properties. For example, crystalline polymorphs generally have different solubilities that the more thermodynamically stable polymorphs are less soluble than the less thermodynamically stable polymorphs. Pharmaceutical polymorphs can also differ in properties such as shelf life, bioavailability, morphology, vapor pressure, density, color, and compressibility.

Compounds of formula I, II, III, IV, or V may be in the form of a prodrug that is converted in vivo to the active compound. In compounds of Formula I, one or more of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are cleaved and active after administration to a subject (eg, therapeutically Active) compounds or subsequently cleavable groups which give intermediate compounds which produce the active compounds. The cleavable group can be an ester that is removed either enzymatically or non-enzymatically.

  The term “prodrug” means a covalently bonded derivative or carrier of a parent compound or active drug that undergoes at least some biotransformation before exhibiting its pharmacological effect (s). In general, such prodrugs have metabolically cleavable groups that are rapidly transformed in vivo to yield the parent compound, for example by hydrolysis in blood, and are generally analogous to the esters and amides of the parent compound. Including the body. Prodrug has improved chemical stability, improved patient acceptance and consent, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation ( For example, it may be formulated for the purpose of increasing water solubility) and / or reducing side effects (eg, toxicity). In general, the prodrug itself has weak biological activity or no activity at all and is stable under normal conditions. Prodrugs can be readily manufactured using methods known in the art, such as those described below: A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.M. Bundgaard (eds.), Gordon & Breach, 1991, in particular Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. et al. Wilder et al. (Eds.), Vol. 42, Academic Press, 1985, especially pp. 309 396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed. , M.M. Wolff (ed.), John Wiley & Sons, 1995, especially Vol. 1 and pp. 172 178 and pp. 949 982; Pro-Drugs as Novel Delivery Systems, T .; Higuchi and V. Stella (eds.), Am. Chem. Soc. Bioreversible Carriers in Drug Design, E., 1975; B. Roche (ed.), Elsevier, 1987.

  Examples of prodrugs include, but are not limited to, esters of hydroxy functionality of compounds of formula I, II, III, IV or V (eg, acetate, formate, and benzoate derivatives), carbamates (eg, , N, N-dimethylaminocarbonyl), and others.

  One of the compounds of formula I, II, III, IV or V can comprise a pharmaceutically acceptable co-crystal or co-crystal salt. The pharmaceutically acceptable co-crystal is suitable for use in contact with the subject or patient tissue without undue toxicity, irritation, allergic reaction, and has the desired pharmacokinetic properties It is a co-crystal.

  As used herein, the term “co-crystal” means a crystalline material composed of two or more unique solids at room temperature, each containing unique physical properties such as structure, melting point, and heat of fusion. . Co-crystals can be formed by active pharmaceutical ingredients (APIs) and co-crystal formers by hydrogen bonding or other non-covalent interactions such as pie stacking and van der Waals interactions. One aspect of the present invention provides a co-crystal and the co-crystal former is a second API. In another aspect, the co-crystal former is not an API. In another aspect, the co-crystal comprises two or more co-crystal formers. For example, two, three, four, five, or more co-crystal formers can be incorporated into the co-crystal with the API. Pharmaceutically acceptable co-crystals are described, for example, in “Pharmaceutical co-crystals”, Journal of Pharmaceutical Sciences, Volume 95 (3) Pages 499-516, 2006. A method for producing co-crystals is discussed in US Patent Application No. 2007026078.

  In general, co-crystal formers that are pharmaceutically acceptable compounds include, for example, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, acetic acid, formic acid, butyric acid, trimesic acid, 5-nitroisophthalic acid, adamantane-1,3, 5,7-tetracarboxylic acid, formamide, succinic acid, fumaric acid, tartaric acid, malic acid, malonic acid, benzamide, mandelic acid, glycolic acid, fumaric acid, maleic acid, urea, nicotinic acid, piperazine, p-phthalaldehyde, It may be 2,6-pyridinecarboxylic acid, 5-nitroisophthalic acid, citric acid, and alkane- and allene sulfonic acids (eg methane sulfonic acid and benzene sulfonic acid).

  In general, all physical forms of the compounds of formula I, II, III, IV, or V are intended to be within the scope of the present invention.

Pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, may include one or more groups in the compound, such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R in formula I. A carrier that interacts with ⁶ or R ⁷ may optionally be included. The carrier can be a polymer, carbohydrate, or peptide, or derivative or a combination thereof, optionally substituted, for example, with one or more alkyl, halo, hydroxyl, halo, or amino. The carrier may be covalently bound to the pyridazine compound directly or indirectly. Carriers include, but are not limited to, one or more alkyl groups, amino groups, nitro groups, halogen groups, thiol groups, thioalkyl groups, sulfate groups, sulfonyl groups, sulfinyl groups, sulfoxide groups, and hydroxyl groups herein. It may be substituted with the described substituents. In aspects of the invention, the carrier is an amino acid comprising alanine, glycine, praline, methionine, serine, threonine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl. The carrier can also include molecules that target pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, to specific tissues or organs. Thus, the carrier can facilitate or facilitate transport of pyridazine compounds, particularly compounds of formula I, II, III, IV or V, to a targeted treatment site, eg, the brain.

  “Polymer” means a molecule comprising repeating subunits of two or more monomers that may be the same repeating subunit or different repeating subunits. Monomers generally include low molecular weight molecules of simple structure including carbon. The polymer may be optionally substituted. Polymers that can be used in the present invention include vinyl, acrylic, styrene, carbohydrate-derived polymers, polyethylene glycol (PEG), polyoxyethylene, polymethylene glycol, poly-trimethylene glycol, polyvinyl pyrrolidone, polyoxyethylene- Examples include, but are not limited to, polyoxypropylene block polymers, and copolymers, salts and derivatives thereof. In an embodiment of the present invention, the polymer is poly (2-acrylamido-2-methyl-1-propanesulfonic acid); poly (2-acrylamido-2-methyl-1-propanesulfonic acid-coacrylonitrile), poly (2- Acrylamido-2-methyl-1-propanesulfonic acid-co-styrene), poly (vinyl sulfonic acid); poly (sodium 4-styrene sulfonic acid); and sulfates and sulfonates derived therefrom; poly (acrylic acid); Poly (methyl acrylate), poly (methyl methacrylate), and poly (vinyl alcohol).

  As used herein, “carbohydrate” means polyhydroxy aldehyde, or polyhydroxy ketone and derivatives thereof. The term includes monosaccharides such as erythrose, arabinose, allose, altrose, glucose, mannose, threose, xylose, gulose, idose, galactose, talose, aldohexose, fructose, ketohexose, ribose, and aldpentose. The term also includes carbohydrates composed of monosaccharide units, including disaccharides, oligosaccharides, or polysaccharides. Examples of disaccharides are sucrose, lactose, and maltose. Oligosaccharides generally contain 3-9 monosaccharide units and polysaccharides contain more than 10 monosaccharide units. The carbohydrate group may be substituted at one, two, three or four positions other than the position of attachment to the pyridazine compound. For example, a carbohydrate can be optionally substituted with one or more alkyl groups, amino groups, nitro groups, halo groups, thiol groups, carboxyl groups, or hydroxyl groups. Exemplary substituted carbohydrates are glucosamine or galactosamine. In an embodiment of the invention, the carbohydrate is a saccharide, in particular a hexose or pentose, and may be an aldose or ketose. The saccharide may be of the D or L series and can include amino sugars, deoxy sugars, and their uronic acid derivatives. In embodiments of the invention where the carbohydrate is a hexose, the hexose is glucose, galactose, or mannose, or a substituted hexose sugar residue, such as an amino sugar residue (eg, hexosamine, galactosamine, glucosamine, particularly D- Such as glucosamine (2-amino-2-deoxy-D-glucose) or D-galactosamine (2-amino-2-deoxy-D-galactose), etc. Exemplary pentose sugars include arabinose, fucose and ribose. It is done.

The sugar residue may be linked to the pyridazine compound by 1,1 bond, 1,2 bond, 1,3 bond, 1,4 bond, 1,5 bond, or 1,6 bond. The bond may be through the oxygen atom of the pyridazine compound. The oxygen atom can be substituted one or more times with a —CH ₂ — or —S— group.

  The term “carbohydrate” also includes glycoproteins such as lectins (eg, concanavalin A, wheat germ agglutinin, peanut agglutinin, cellomucoid, and orosomucoid) and glycolipids (eg, cerebroside and ganglioside).

  “Peptide” carriers include 1, 2, 3, 4, or 5 or more amino acids covalently linked by peptide bonds. A peptide can include one or more natural amino acids, and analogs, derivatives and homologues thereof. Peptides can be modified to increase their stability, bioavailability, solubility, and the like. As used herein, “peptide analogs” and “peptide derivatives” include molecules that mimic the chemical structure of a peptide and maintain the functionality of the peptide. The carrier can be an amino acid such as alanine, glycine, proline, methionine, serine, threonine, histidine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl. The carrier can be a polypeptide such as albumin, antitrypsin, macroglobulin, haptoglobin, ceruloplasm, transferrin, α- or β-lipoprotein, β- or γ-globulin or fibrinogen. Peptides can be attached to pyridazine compounds via functional groups on the side chain of certain amino acids (eg, serine) or other suitable functional groups. The carrier may comprise 4 or more amino acids having groups attached to 3 or more amino acids via functional groups on the side chains. In one aspect, the carrier is an amino acid, particularly a sulfonate derivative of an amino acid, such as cysteic acid.

  Methods for representing peptide analogs, derivatives and mimetics are known in the art. For example, Farmer, P .; S. in Drug Design (EJ Aliens, ed.) Academic Press, New York, 1980, vol. 10, pp. 119-143; Ball. J. et al. Band Alewood, P.A. F. (1990) J. MoI. Mol. Recognition 3:55; Morgan, B .; A. and Gainor, J. et al. A. (1989) Ann. Rep. Med. Chem. 24: 243; and Freidinger, R .; M.M. (1989) Trends Pharmacol. Sci. 10: 270. Sawyer, T .; K. (1995) “Peptidomimetic Design and Chemical Approaches to Peptide Metabolism”, in Taylor, M .; D. and Amidon, G .; L. (Eds.) Peptide-Based Drug Design: Controlling Transport and Metabolism, Chapter 17; Smith, A. et al. B. 3rd et al. (1995) J. MoI. Am. Chem. Soc. 117: 11113-11123; Smith, A .; B. 3rd et al. (1994) J. MoI. Am. Chem. Soc. 116: 9947-9996, and Hirschman, R .; (1993) J. et al. Am. Chem. Soc. 115: 12550-12568.

The term “alkyl” refers to a monovalent saturated hydrocarbon group that may be straight-chain (ie, linear) or branched, alone or within other terms such as “thioalkyl” and “arylalkyl”. means. Alkyl groups for use in the present invention generally have about 1-20 carbon atoms, especially about 1-10, 1-8 or 1-7, more particularly about 1-6 or Contains 3 to 6 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl. , N-octyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like Examples include a branch-like deformed body. In some embodiments of the invention, the alkyl group is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert. -C ₁ -C ₆ lower alkyl, including or selected from the group consisting of -pentyl, and n-hexyl. The alkyl group is optionally substituted with a substituent as defined herein at a position that does not significantly interfere with the preparation of the compound of Formula I, II, III, IV, or V and does not significantly reduce the effectiveness of the compound. It's okay. In some embodiments of the invention, the alkyl group is a substituent, particularly halo, lower alkoxy, lower aliphatic, substituted lower aliphatic, hydroxy, cyano, nitro, thio, amino, keto, aldehyde, ester, amide, substituted amino Carboxyl, sulfonyl, sulfinyl, sulfenyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (eg, CF ₃ ), halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, Substituted with 1 to 5 substituents including cycloaliphatic, substituted cycloaliphatic, or aryl (eg, phenylmethyl (ie, benzyl)). A substituent on an alkyl group may itself be substituted.

  As used herein with respect to certain embodiments of the invention, the term “substituted aliphatic” means that at least one of the aliphatic hydrogen atoms is halogen, amino, hydroxy, nitro, thio, ketone, aldehyde, ester, amide, lower By alkyl, alkane having less than 10 carbons substituted with aliphatic, substituted lower aliphatic, or ring (such as aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such groups include, but are not limited to, 1-chloroethyl and the like.

  The term “amino-substituted lower alkyl” as used herein with respect to certain embodiments of the present invention is any arbitrary containing up to 8 and 8 carbon atoms in which one of the aliphatic hydrogen atoms is replaced with an amino group. Means an alkyl unit. Examples of such include, but are not limited to, ethylamino and the like.

  The term “halogen-substituted lower alkyl” as used herein with respect to certain embodiments of the present invention, is any arbitrary containing up to 8 and 8 carbon atoms, wherein one of the aliphatic hydrogen atoms is substituted with a halogen. The alkyl chain of Examples of such include, but are not limited to, chloroethyl and the like.

  The term “acetylamino” as used herein refers to any primary or secondary amino that is acetylated. Examples of such include, but are not limited to, acetamide and the like.

  The term “alkenyl” as used herein refers to an unsaturated acyclic branched or straight hydrocarbon group containing at least one double bond. An alkenyl group has about 2 to 24, 2 to 15, or 2 to 10 carbon atoms, in particular about 3 to 8 carbon atoms, more particularly about 3 to 6 or 2 to 6 carbon atoms. It may contain carbon atoms. Suitable alkenyl groups include ethenyl, propenyl (eg, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2. -En-2-yl), buten-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but- 2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, heptene-1 -Yl, octen-1-yl, and the like, but are not limited to these. Alkenyl groups, like alkyl, may be optionally substituted.

  In embodiments of the present invention, “substituted alkenyl” includes, for example, alkenyl groups substituted with 1 to 3 substituents, preferably 1 to 2 substituents, including alkyl, alkoxy, halo Alkoxy, alkylalkoxy, haloalkoxyalkyl, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxyalkyl, Carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamide, thioalkoxy, aryl, nitro and the like can be mentioned.

  As used herein, the term “alkynyl” refers to an unsaturated branched or straight chain hydrocarbon group containing one or more triple bonds. Alkynyl groups may contain about 1-20, 1-15, or 2-10 carbon atoms, in particular about 3-8 carbon atoms, more particularly about 3-6 carbon atoms. Good. Suitable alkynyl groups include butynyl (eg, but-1-in-1-yl, but-1-in-, such as ethynyl, prop-1-in-1-yl, and prop-2-yn-1-yl. 3-yl, and but-3-yn-1-yl), pentynyl (eg, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, and 3-methylbutyn-1- Hexyl), and the like (for example, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl and 3,3-dimethylbutyn-1-yl groups) and the like. Alkynyl may be optionally substituted similar to alkyl. The term “cycloalkynyl” means a cyclic alkynyl group.

  In embodiments of the invention, “substituted alkynyl” includes, for example, alkyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano , Alkynyl groups substituted by substituents such as halogen, hydroxyl, carboxyl, carboxyalkyl, carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamido, thioalkoxy, aryl, nitro and the like.

  As used herein, the term “alkylene” has about 1-10, 1-8, 1-6, or 2-6 carbon atoms for two or more covalent bonds. Means a linear or branched group having the following points of attachment. Examples of such groups are methylene, ethylene, propylene, butylene, pentylene, hexylene, ethylidene, methylethylene, and isopropylidene. When an alkenylene group is present as a substituent on another group, it is generally regarded as a single substituent rather than a group formed by two substituents.

The term “alkenylene” as used herein refers to about 2-10, 2-8, or 2-6 carbon atoms, having at least one double bond, and two or more covalent bonds. Means a linear or branched group having a point of attachment for Examples of alkenylene groups include 1,1-vinylidene (—CH ₂ ═C—), 1,2-vinylidene (—CH═CH—), and 1,4-butadienyl (—CH═CH—CH═CH—). ).

  The term “halo” as used herein means a halogen such as a fluorine, chlorine, bromine or iodine atom.

  The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

  As used herein, the term “cyano” refers to a carbon group in which three of the four covalent bonds are shared by a nitrogen atom, in particular —C≡N. The cyano group may be substituted with the substituents described herein.

The term “alkoxy” as used herein refers to a linear or branched oxy-containing group having an alkyl moiety of 1 to about 10 carbon atoms, such as an optionally substituted methoxy group. . In aspects of the invention, the alkoxy group may contain about 1-10, 1-8, 1-6, or 1-3 carbon atoms. In an embodiment of the present invention, alkoxy groups contain about 1-6 carbon atoms, include _C 1 -C ₆ alkyl -O- group as an example, _wherein, C 1 -C ₆ alkyl, the Has the meaning indicated in the description. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isopropoxy and t-butoxyalkyl. An “alkoxy” group is an alkyl atom to give an “alkylalkoxy” group; a “haloalkoxy” group (eg, fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, Pentafluoroethoxy, and fluoropropoxy) and “haloalkoxyalkyl” groups (eg, fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl) to give fluorine, chlorine, or It may be optionally substituted with one or more substituents disclosed herein, including halo atoms such as bromine.

  The term “alkenyloxy” as used herein refers to a linear or branched oxy-containing group having an alkenyl moiety of about 2 to 10 carbon atoms, such as an ethenyloxy or propenyloxy group. An alkenyloxy group may be a “lower alkenyloxy” group having about 2 to 6 carbon atoms. Examples of alkenyloxy groups include, but are not limited to, ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxyalkyl. An “alkenyloxy” group is a halo atom such as fluorine, chlorine or bromine to give a “haloalkenyloxy” group (eg, trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy) And may be substituted with one or more substituents disclosed herein.

  “Carbocyclic” refers to a saturated or unsaturated substituted or unsubstituted 5 to 14 membered, 5 to 12 membered or 5 to 10 membered organic nucleus in which the atoms forming the ring (other than hydrogen) are only carbon. Contains derived groups. Examples of carbocyclic groups are cycloalkyl, cycloalkenyl, aryl, in particular phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xyenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexyl, acenaphthylenyl, anthracenyl, Biphenyl, bibenzylyl, and related bibenzylyl homologues, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl and the like.

The term “cycloalkyl” as used herein has about 3-15, 3-10, 3-8, or 3-6 carbon atoms, 1, 2, 3 One or four rings, wherein such rings refer to groups that may be linked in a pendant manner or may be fused. In certain embodiments of the invention, “cycloalkyl” contains from ₃ to ₇ carbon atoms per 1 to 2 rings and rings (which may be further fused with an unsaturated C _{3 to} C ₇ carbocycle). Means an optionally substituted saturated hydrocarbon ring system. Examples of the cycloalkyl group include a monocyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and cyclododecyl, and a polycyclic structure such as adamantyl. In some embodiments of the invention, the cycloalkyl group is a “lower cycloalkyl” having about 3-10, 3-8, 3-6, or 3-4 carbon atoms, particularly cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes radicals where a cycloalkyl group is fused to an aryl or heterocyclyl group. A cycloalkyl group can be optionally substituted with the groups disclosed herein.

  In embodiments of the invention, “substituted cycloalkyl” includes, but is not limited to, alkyl, alkenyl, alkoxy, cycloalkyl, substituted cycloalkyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, 1 to 5 (especially 1 to 3) including halogen, hydroxyl, carboxyl, carboxyalkyl, keto, thioketo, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, nitro and the like A cycloalkyl group having a substituent.

  The term “cycloaliphatic” as used herein with respect to certain embodiments of the invention means a fused ring system consisting of a cycloalkane having less than 8 carbons or no more than 3 fused cycloaliphatic rings. Examples of such include, but are not limited to, decalin and the like.

  The term “substituted cycloaliphatic” as used herein with respect to certain embodiments of the present invention is a fused ring system consisting of a cycloalkane having less than 8 carbons or no more than 3 fused rings, At least one hydrogen atom is halogen, nitro, thio, amino, hydroxy, ketone, aldehyde, ester, amide, lower aliphatic, substituted lower aliphatic, or ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic) Means a group substituted with a group. Examples of such include, but are not limited to, 1-chlorodecalyl and the like.

  As used herein, the term “cycloalkenyl” refers to about 4-16, 2-15, 2-10, 2-8, 4-10, 3-8, 3-7. 3-6, or 4-6 carbon atoms, one or more carbon-carbon double bonds, and one, two, three, or four rings, wherein such rings are pendant It means a group which may be bonded in a form or may be condensed. In certain embodiments of the invention, cycloalkenyl groups are “lower cycloalkenyl” groups having 3-7 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Cycloalkenyl groups may be optionally substituted with groups disclosed herein, particularly with one, two, or three substituents that may be the same or different.

  As used herein, the term “cycloalkoxy” refers to a cycloalkyl group attached to an oxy group (particularly a cycloalkyl group having 3 to 15, 3 to 8, or 3 to 6 carbon atoms). means. Examples of cycloalkoxy groups include cyclohexoxy and cyclopentoxy. Cycloalkoxy groups may be optionally substituted with groups disclosed herein.

  As used herein, the term “aryl”, alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings, wherein such rings are pendant. May be bonded together or may be condensed. In an embodiment of the invention, the aryl group contains 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms. Examples of “aryl” groups include phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentarenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acethyrenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl. An aromatic group is mentioned, However, It is not limited to these. Aryl groups may be optionally substituted with groups disclosed herein, in particular hydroxyl, alkyl (“arylalkyl”), carbonyl, carboxyl, thiol (“thioalkyl”), amino, and / or halo, In particular, substituted aryl includes, but is not limited to, arylamines and arylalkylamines.

  As used herein with respect to certain embodiments of the invention, the term “substituted aryl” includes aromatic rings or fused aromatic ring systems consisting of up to three fused rings, at least one of which is aromatic, At least one of the above hydrogen atoms is halogen, amino, hydroxy, nitro, thio, alkyl, ketone, aldehyde, ester, amide, lower aliphatic, substituted lower aliphatic, or ring (aryl, substituted aryl, cycloaliphatic, Or a substituted cycloaliphatic group). Examples of such include, but are not limited to, hydroxyphenyl, chlorophenyl, and the like.

  In embodiments of the invention, the aryl group may be optionally substituted with 1 to 4 substituents, such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl Substituted aryl, aralkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aralkyloxy, amino, alkylamino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, Alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkylsulfonyl, Hon'amido, an aryloxy and the like. Substituents may be further substituted with hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or aralkyl. In aspects of the invention, the aryl group is substituted with hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and / or halo. The term “aralkyl” means an aryl or substituted aryl group attached directly through an alkyl group, for example benzyl. Other specific examples of substituted aryl groups include chlorobenzyl and aminobenzyl.

  The term “aryloxy” as used herein means an aryl group, as defined above, attached to an oxygen atom. Examples of the aryloxy group include naphthyloxy, quinolyloxy, isoquinolidinyloxy and the like.

  The term “arylalkoxy” as used herein means an aryl group attached to an alkoxy group. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.

  The term “aroyl” as used herein refers to an aryl group as defined above attached to a carbonyl group as defined herein, including but not limited to benzoyl and toluoyl. An aroyl group may be optionally substituted with a group disclosed herein.

  The term “heteroaryl” as used herein means a fully unsaturated heteroatom-containing cyclic aromatic group having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen. A heteroaryl group may contain one, two or three rings, which may be linked in a pendant manner or may be fused. In aspects of the invention, the term is a complete having 3-15, 3-10, 3-8, 5-15, 5-10, or 5-8 ring members selected from carbon, nitrogen, sulfur and oxygen. Represents an unsaturated heteroatom-containing cyclic aromatic group in which at least one ring atom is a heteroatom. Examples of “heteroaryl” groups are unsaturated 5-6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, in particular pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl, quinolizinyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, carbazolyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, indazolyl Benzotriazolyl, tetrazolopyridazinyl, etc .; unsaturated 3-6 membered monocyclic heterocyclic groups containing oxygen atoms, especially 2-furyl, 3-furyl, pyranyl, etc .; unsaturated containing sulfur atoms A 5- to 6-membered monocyclic heterocyclic group, in particular thienyl, 2-thienyl, 3-thienyl and the like; an unsaturated 5-6-membered monocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Cyclic heterocyclic groups, in particular furazanyl, benzofurazanyl, oxazolyl, isoxazolyl and oxadiazolyl; unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in particular benzoxazolyl An unsaturated 5-6 membered monocyclic heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, etc .; 1 Two fused heterocyclic group unsaturation containing a sulfur atom and 1 to 3 nitrogen atoms, for example benzothiazolyl, although such benzothiadiazolyl include, but are not limited to. The term also includes groups in which a heterocyclic group is fused with an aryl group, in particular bicyclic groups such as benzofuranyl, benzothiophenyl, phthalazinyl, chromenyl, xanthenyl. A heteroaryl group can be optionally substituted with groups disclosed herein, for example, alkyl, amino, halogen, and the like, particularly heteroarylamines.

  In an embodiment of the invention, the term includes an unsaturated 5-6 membered heteromonocyclyl group, especially containing 1 to 4 nitrogen atoms, in particular pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, It means 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like.

  A heteroaryl group may be optionally substituted with a group disclosed herein, for example, alkyl, amino, halogen, etc., and in particular a substituted heteroaryl group is a heteroarylamine.

  The term “heterocycle” means saturated and partially saturated heteroatom-containing cyclic groups having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen. Heterocyclic groups may contain one, two or three rings, such rings may be linked in a pendant manner or may be fused. In one aspect, the term includes saturated and partially saturated heteroatoms having 3-15, 3-10, 5-15, 5-10, or 3-8 ring members selected from carbon, nitrogen, sulfur and oxygen. Means a containing cyclic group, wherein at least one ring atom is a heteroatom. Examples of saturated heterocyclic groups include saturated 3-6 membered monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms (eg, pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl); 1 to 2 oxygen atoms And saturated 3 to 6 membered monocyclic heterocyclic groups containing 1 to 3 nitrogen atoms (eg morpholinyl; sydnonyl); and saturated containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Examples thereof include, but are not limited to, 3 to 6-membered monocyclic heterocyclic groups (for example, thiazolidinyl). Examples of partially saturated heterocyclyl groups include, but are not limited to, dihydrothiophene, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of the heterocyclic group include aziridinyl, azetidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, azepinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, pyrazolinyl, 1,4-dithianyl, thiomorpholinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiopyranyl, thioxanyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3H-indolyl, quinu Lysinyl, although such quinolizinyl include, but are not limited to.

  As used herein with respect to certain embodiments of the invention, the term “heterocycle” refers to a ring carbon atom consisting of a cycloalkane and / or aryl ring system, or 3 or fewer fused rings, having less than 8 carbons. Means a fused ring system in which at least one of is substituted with oxygen, nitrogen or sulfur. Examples of such include, but are not limited to, morpholino and the like.

  As used herein with respect to certain embodiments of the invention, the term “substituted heterocycle” refers to a cycloalkane and / or aryl ring system having less than 8 carbons, or a fused ring system comprising no more than 3 fused rings. Wherein at least one of the ring carbon atoms is substituted with oxygen, nitrogen or sulfur and at least one of the aliphatic hydrogen atoms is halogen, hydroxy, thio, nitro, amino, ketone, aldehyde, ester, amide , Lower aliphatic, substituted lower aliphatic, or ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such include, but are not limited to, 2-chloropyranyl.

  The aforementioned heteroaryl and heterocyclic groups may be C-linked or N-linked (if possible).

The term “sulfonyl” as used herein, alone or in combination with other terms such as alkylsulfonyl or arylsulfonyl, refers to the divalent group —SO ₂ —. In an embodiment of the present invention, the sulfonyl group is substituted or unsubstituted hydroxyl, alkyl group, ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, heterocyclic group, carbohydrate, It may be bound to a peptide or peptide derivative.

  The term “sulfinyl” used alone or in conjunction with other terms such as alkylsulfinyl (ie, —S (O) -alkyl) or arylsulfinyl is the divalent group —S (O). -Means.

  The term “sulfonate” is art-recognized and has the formula:

Wherein R ¹⁸ is an electron pair, hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, heterocycle, carbohydrate, peptide, or peptide derivative.

  The term “sulfate” is an art-recognized term used alone or linked to other terms and has the formula:

Wherein R ¹⁹ is an electron pair, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, carbohydrate, peptide, or peptide derivative. Including.

  The term “sulfoxide” refers to the group —S═O.

The term “amino” as used herein, alone or in combination, means that the nitrogen atom (N) is hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, heterocyclic, or a general chemical formula. , —NR ³⁸¹ R ³⁹ heteroaryl, wherein R ³⁸ and R ³⁹ may be unsubstituted or substituted, hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, carbonyl , Carboxyl, amino, silyl, heteroaryl, or any combination of heterocycles) means a group that binds to three substituents present in any combination. Optionally, one substituent on the nitrogen atom may be a hydroxyl group (—OH) to give an amine known as hydroxylamine. Specific examples of the amino group may not be substituted, amino (-NH _2), alkylamino, acylamino, cycloalkyl amino, acyclic alkyl amino, aryl amino, aryl alkyl amino, and lower alkyl Silylamino, especially methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino, cyclohexylamino, piperidinyl, hydrazinyl, benzylamino, diphenylmethylamino , Tritylamino, trimethylsilylamino, and dimethyl-tert-butylsilylamino.

  As used herein, the term “thiol” means —SH. A thiol may be substituted with a substituent as disclosed herein, particularly alkyl (thioalkyl), aryl (thioaryl), alkoxy (thioalkoxy) or carboxyl.

The term “sulfenyl” used alone or in conjunction with other terms such as alkylsulfenyl, refers to a —SR ²⁵ group, where R ²⁵ is not hydrogen. In aspects of the invention, R ²⁵ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, silylalkyl, heterocycle, heteroaryl, carbonyl, carbamoyl, alkoxy, or carboxyl.

  The term “thioalkyl”, as used herein, alone or in combination, means a chemical functional group in which a sulfur atom (S) is attached to an optionally substituted alkyl. Examples of thioalkyl groups are thiomethyl, thioethyl, and thiopropyl. A thioalkyl may be substituted with a substituted or unsubstituted carboxyl, aryl, heterocycle, carbonyl, or heterocycle.

As used herein, alone or in combination, the term “thioaryl” refers to a sulfur atom (S) where the —SR ²⁶ group of the general chemical formula (where R ²⁶ is an optionally substituted aryl). ) Means a chemical functional group bonded to an aryl group. Specific examples of thioaryl groups and substituted thioaryl groups are thiophenyl, chlorothiophenyl, para-chlorothiophenyl, thiobenzyl, 4-methoxy-thiophenyl, 4-nitro-thiophenyl, and para-nitrothiobenzyl.

As used herein, alone or in combination, the term “thioalkoxy” refers to an —SR ²⁷ group of the general chemical formula (where R ²⁷ is an optionally substituted alkoxy group). Is a chemical functional group bonded to an alkoxy group. A “thioalkoxy group” is 1 to 6 carbon atoms, ie, —S— (O) —C ₁ -C ₆ alkyl group (wherein C ₁ -C ₆ alkyl is the same as defined above) May have a meaning). Specific examples of linear or branched thioalkoxy groups or radicals (also known as C ₁ -C ₆ thioalkoxy) having 1 to 6 carbon atoms include thiomethoxy and thioethoxy.

  Thiols are substituted or unsubstituted heteroaryl or heterocycles, in particular substituted or unsubstituted saturated 3-6 membered monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms (eg pyrrolidinyl, imidazolidinyl, Piperidinyl, and piperazinyl) or saturated 3-6 membered monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg morpholinyl, sydnolyl), in particular substituted morpholinyl or piperidinyl May be substituted.

  As used herein, the term “carbonyl” refers to a carbon group that shares two of the four covalent bonds with an oxygen atom.

The term “carboxyl” as used herein, alone or in combination, refers to —C (O) OR ¹⁴ or —C (═O) OR ^14, where R ¹⁴ is optionally substituted. Which is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl, thioalkyl, thioaryl, thioalkoxy, heteroaryl, or heterocycle. In certain aspects of the invention, —C (O) OR ¹⁴ provides an ester or amino acid derivative. Esterified forms are also specifically referred to herein as “carboxylic esters”. In embodiments of the invention, “carboxyl” may be substituted, in particular substituted with alkyl, amino, halo, alkylamino, aryl, carboxyl or heterocycle, optionally substituted with one or more amino. You can. Examples of carboxyl groups are methoxycarbonyl, butoxycarbonyl, tert-alkoxycarbonyl (eg, tert-butoxycarbonyl), one or two aryl groups (including, but not limited to, lower alkyl, lower alkoxy, hydroxyl, halo, and / Or phenyl optionally substituted with nitro), for example, benzyloxycarbonyl, methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl tert-butylcarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy-carbonyl, benzhydroxycarbonyl, di- (4-methoxyphenyl-methoxycarbonyl, 2-bromo Examples include ethoxycarbonyl, 2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-triphenylsilylethoxycarbonyl, etc. Further carboxyl groups in the esterified form are silyloxycarbonyl groups including organic silyloxycarbonyl. The silicon substituent of such compounds may be substituted with lower alkyl (eg, methyl), alkoxy (eg, methoxy), and / or halo (eg, chlorine) Examples of silicon substituents include trimethylsilyl In an embodiment of the invention, the carboxyl group is an alkoxycarbonyl, in particular methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl. t- pentyloxycarbonyl or heptyloxycarbonyl, in particular, may be a methoxycarbonyl or ethoxycarbonyl.

  As used herein, alone or in combination, the term “carbamoyl” refers to an amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkyl, attached to one of the two non-covalent bonds in the carbonyl group. Means cycloalkylamino and dicycloalkylamino groups;

  The term “carboxamide” as used herein refers to the group —CONH—.

The term “nitro” as used herein, means —NO ₂ —.

  The term “acyl” as used herein, alone or in combination, includes, for example, optionally substituted hydride, alkyl (eg, haloalkyl), alkenyl, alkynyl, alkoxy (acetyloxy, butyryloxy, iso- “Acyloxy”, including valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy, such as alkoxyalkyl and haloalkoxy, aryl, halo, heterocyclyl, heteroaryl, sulfinyl (eg, alkylsulfinylalkyl) ), Sulfonyl (eg alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (eg alkylamino or dialkyl) Mino), and means the bound carbonyl or thiocarbonyl group to a group selected from aralkoxy. Specific examples of “acyl” groups are formyl, acetyl, 2-chloroacetyl, 2-bromoacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl and the like.

In aspects of the invention, “acyl” refers to the group —C (O) R ⁶⁴ where R ⁶⁴ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, And heteroarylalkyl). Examples include but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

The term “phosphonate” as used herein means C—PO (OH) ₂ or C—PO (OR ⁶⁵ ) ₂ , where R ⁶⁵ is an optionally substituted alkyl or aryl. It is.

  The term “ureido” as used herein, means a “—NHCONH—” group. Examples of the ureido group include ureido substituted with alkyl, and in particular, alkylureido including ureido in which a lower alkyl is bonded to the terminal nitrogen of the ureido group. Examples of alkylureido include, but are not limited to, N'-methylureido, N'-ethylureido, N'-n-propylureido, N'-i-propylureido and the like. Also, as ureido groups, N ′, including —NHCON groups, wherein the terminal nitrogen is bound to two optionally substituted groups, including alkyl, aryl, heterocycle, and heteroaryl. N'-dialkylureido groups are mentioned.

  The terms used herein for groups including “alkyl”, “alkoxy”, “alkenyl”, “alkynyl”, “hydroxyl” and the like refer to both unsubstituted and substituted groups. As used herein, the term “substituted” refers to a specified atom (eg, hydrogen) when the substitution results in a stable compound without exceeding the normal valence of the specified atom. ) Is replaced with one selected from the groups disclosed herein. Substituents and / or combinations of groups are possible only if such combinations result in stable compounds. By “stable compound” is meant a compound that is sufficiently robust to withstand isolation from the reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent.

  The groups in the pyridazine compound are alkyl, alkoxy, alkenyl, alkynyl, alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene, haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl, alkylaryl, haloalkoxy Haloalkenyloxy, heterocycle, heteroaryl, alkylsulfonyl, sulfinyl, sulfonyl, sulfenyl, alkylsulfinyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, amino, oxy, halo, azide, Thio, = O, = S, cyano, hydroxyl, phosphonate, phosphinate, thioalkyl, alkylamino, Reelamino, arylsulfonyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino, heteroaryloxy, heteroaryloxylalkyl, arylacetamidoyl, aryloxy, aroyl, aralkanoyl, aralkoxy, A person skilled in the art including, but not limited to aryloxyalkyl, haloaryloxyalkyl, heteroaroyl, heteroaralkanoyl, heteroaralkoxy, heteroaralkoxyalkyl, thioaryl, arylthioalkyl, alkoxyalkyl, and acyl groups It may be substituted with one or more substituents apparent in These substituents may themselves be substituted.

  A chemical substituent is a “pendant” from a group when it is attached to an atom of the group. In this context, substituents can be dangling from a group carbon atom, a carbon atom bonded to a group carbon atom with a chain extender, or a group heteroatom. The term “fused” means that the second ring is present (ie, bonded or formed) with two adjacent atoms in common or shared with the first ring.

  Pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, are prepared using reactions and methods generally known to those skilled in the art in light of the present disclosure, including their knowledge and examples. can do. The reaction is performed in a solvent suitable for the reagents and materials used and suitable for the reaction to be carried out. One skilled in the art of organic synthesis will understand that the functionality present in the compound should be consistent with the proposed reaction steps. This will sometimes require a change in the order of the synthetic steps or selection of one particular method scheme relative to the other in order to obtain the desired compounds of the invention. It will also be appreciated that another major consideration in the development of synthetic routes is the choice of protecting groups used for the protection of reactive functional groups present in the compound. An authoritative report that describes many options for the expert is Green and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

  Starting materials and reagents used to prepare pyridazine compounds are available from the manufacturer, or Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.A. Y. , 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supplies. Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N .; Y. , 1991; March J .; : Advanced Organic Chemistry, 4th ed. , John Wiley and Sons, New York, N .; Y. And by procedures well known to those skilled in the art according to procedures described in references such as Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

  Starting materials, intermediates, and pyridazine compounds may be isolated and purified using conventional methods such as precipitation, filtration, distillation, crystallization, chromatography and the like. Pyridazine compounds may be characterized using conventional methods, including physical constants and spectroscopic methods, particularly HPLC.

  Pyridazine compounds that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. In practice, first the pyridazine compound is isolated from the reaction mixture as a pharmaceutically unacceptable salt, then the salt is converted to the free base compound by treatment with an alkaline reagent, after which the free base is converted as a pharmaceutically agent. It is desirable to convert to an acceptable acid addition salt. Acid addition salts of base compounds of pyridazine compounds are obtained by treating the base compound in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol with a substantially equivalent amount of the selected inorganic or organic acid. Easy to prepare. Upon careful evaporation of the solvent, the desired solid salt is obtained.

  Pyridazine compounds that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. These salts are prepared by conventional treatment by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution preferably to dryness under reduced pressure. It may be prepared by a method. Alternatively, they may be prepared by mixing together a lower alkanol solution of an acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In either case, the stoichiometric amount of the reagent is typically used to ensure completeness of reaction and maximum product yield.

In certain embodiments, the present invention provides compounds of Formula II wherein R ¹¹ is hydrogen and R ¹⁰ is an unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms, particularly pyrrolyl, A process for the preparation of pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl, more particularly pyridinyl, which comprises formula II (formula And R ¹⁰ is substituted with an unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms and a compound having the structure of R ¹⁰ is halo, especially chlorine and R ¹¹ is hydrogen. Boronic acid (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, Pyridazinyl, triazolyl, or tetrazolyl, and more particularly boronic acid substituted with pyridinyl, is reacted under suitable conditions to form Formula II where R ¹¹ is hydrogen and R ¹⁰ is 1-4. Unsaturated 5- to 6-membered heteromonocyclyl groups containing 1 nitrogen atom, in particular pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, Or tetrazolyl, more particularly pyridinyl). In one embodiment, R ¹⁰ is phenyl substituted with halo.

In another embodiment, a compound of formula II wherein R ¹¹ is hydrogen and R ¹⁰ is substituted aryl is a compound of formula II wherein R ¹⁰ is halo, especially chlorine, and R ¹¹ is hydrogen In a suitable condition under a suitable condition.

In another embodiment, a compound of formula II wherein R ¹⁰ is hydrogen and R ¹¹ is alkyl is a compound of formula II wherein R ¹¹ is halo, especially chlorine and R ¹⁰ is hydrogen A compound having a structure of (a) is reacted with an alkylboronic acid under suitable conditions. In one embodiment, R ¹¹ is lower alkyl, especially methyl or ethyl, and the compound of formula II (wherein R ¹¹ is chlorine), under suitable conditions, is a lower alkyl boronic acid, especially React with methyl or ethyl boronic acid.

In another embodiment, the preparation of a compound of formula II wherein R ¹⁰ is hydrogen and R ¹¹ is alkyl, wherein the C3 position is halo (eg, chlorine), the C4 position is alkyl, And pyridazine substituted at the 6-position with phenyl and 2- (piperidin-4-yloxy) pyrimidine under the appropriate conditions to give a compound of formula II wherein R ¹⁰ is hydrogen and R ¹¹ is Compound) which is alkyl). In one embodiment, R ¹¹ is methyl or ethyl.

In another embodiment, the compound of formula II (wherein R ¹⁰ is hydrogen and R ¹¹ is aryl) is a compound of formula II (wherein R ¹⁰ is hydrogen and R ¹¹ is halo (eg, chlorine A pyridazine substituted at the C3 position with halo (eg, chlorine), at the C4 position with aryl, and at the 6 position with phenyl, and 2- (piperidin-4-yloxy) pyrimidine Is reacted under suitable conditions. In one embodiment, R ¹¹ is phenyl.

In another embodiment, Formula II wherein R ¹⁰ is hydrogen and R ¹¹ is an unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms (particularly pyrrolyl, pyrrolinyl, imidazolyl, Pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl)) compounds of formula II (wherein R ¹¹ is halo) , in particular chlorine, R ¹⁰ is a compound of hydrogen), boronic acid (especially substituted unsaturated 5- to 6-membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, pyrrolyl, pyrrolinyl, Imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, Or tetrazolyl, more specifically boronic acid substituted with pyridinyl) under suitable conditions.

In one embodiment, a compound of formula II (wherein R ¹⁰ is hydrogen and R ¹¹ is pyridinyl) is a compound of formula II (wherein R ¹¹ is halo, in particular chlorine, and R ¹⁰ is hydrogen). Of the compound) with a pyridinylboronic acid under suitable conditions.

In another embodiment, Formula II wherein R ¹⁰ is hydrogen and R ¹¹ is an unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms (particularly pyrrolyl, pyrrolinyl, imidazolyl, Pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, and more particularly pyridinyl))) compound is a halo at the C3 position and a 1 at the C4 position. An unsaturated 5-6 membered heteromonocyclyl group containing -4 nitrogen atoms (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, Triazolyl or tetrazolyl, more particularly pyridinyl) and phenyl in position 6 Pyridazine substituted, a 2- (piperidin-4-yloxy) pyrimidine, are prepared by reacting under suitable conditions.

In one embodiment, the preparation of a compound of formula II wherein R ¹⁰ is hydrogen and R ¹¹ is pyridinyl, wherein the C3 position is halo, the C4 position is pyridinyl, and the 6 position is phenyl. The compound of formula II (wherein R ¹⁰ is hydrogen and R ¹¹ is pyridinyl) is obtained by reacting pyridazine substituted with a 2- (piperidin-4-yloxy) pyrimidine under appropriate conditions. Manufactured.

In another embodiment, the compound of formula II (wherein R ¹⁰ is hydrogen and R ¹¹ is piperidinyl or substituted piperidinyl) is a compound of formula II (wherein R ¹¹ is halo, especially chlorine, R ¹⁰ Is hydrogen) and is reacted with piperazinyl or substituted piperazinyl under suitable conditions.

In another embodiment, formula I wherein R ¹ is piperazinyl, or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R ² is aryl, R ³ , R ⁴ , R ⁵ and R ⁶ Is hydrogen and R ⁷ is not present) is a compound of pyridazine substituted with halo at C3 and aryl at C4 with piperazinyl substituted with piperazinyl or alkyl, aryl or cycloalkyl It is produced by reacting under

In another embodiment, Formula I wherein R ¹ is piperazinyl, or piperazinyl substituted with alkyl, aryl, or cycloalkyl, and R ² is an unsaturated 5-6 containing 1-4 nitrogen atoms A membered heteromonocyclyl group (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl, more particularly pyridinyl) , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen and R ⁷ is not present) is an unsaturated compound containing 1 to 4 nitrogen atoms in the C5 position with halo and the C4 position. 6-membered heteromonocyclyl group (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl Or pyridazine substituted with pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl) with piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl under suitable conditions Manufactured by.

In another embodiment, formula I wherein R ¹ is substituted amino (especially amino substituted with substituted morpholinyl, especially amino substituted with morpholinoethyl) and R ² is aryl or 1-4 nitrogens Unsaturated 5- to 6-membered heteromonocyclyl groups containing atoms (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, In particular, R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, and R ⁷ is not present) is a compound in which the C3 position is halo and the C4 position is aryl or 1-4 nitrogens Unsaturated 5- to 6-membered heteromonocyclyl groups containing atoms (especially pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl) Pyridazines substituted with ru, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl, can be substituted with a substituted amino (especially substituted morpholinyl substituted amino, especially , Amino substituted with morpholinoethyl) under suitable conditions.

In another embodiment, Formula V (in ^{formula, R 50} represents ^{aryl, R 51} is ^{hydrogen, R 52} is alkyl) compounds of, with _{halo, C 3} position, with aryl and _{C 4} position, And 6-alkyl substituted pyridazines by reacting with 1- (2-pyrimidyl) piperazine under suitable conditions.

In another embodiment, formula I wherein R ¹ is substituted amino and R ² is an unsaturated 5-6 membered heteromonocyclyl group containing 1-4 nitrogen atoms (particularly pyrrolyl, pyrrolinyl, imidazolyl). , pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl, especially, ^{pyridinyl), R 3, R 4,} R 5 and ^{R 6} are hydrogen , R7 compounds of not present), with _halo, C ₃ position, the C ₄ position unsaturated 5- to 6-membered heteromonocyclyl group containing 1 to 4 nitrogen atoms (in particular, pyrrolyl, pyrrolinyl, imidazolyl, Pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl Le, inter alia, pyridinyl), and a pyridazine the C ₆ position is substituted by phenyl, are prepared by reacting a substituted amino under suitable conditions.

  Precursors that may be utilized in the preparation of compounds of formula II (see, eg, FIG. 10, compound (15)) are commercially available and are illustrated without further purification. It can be used directly for the synthesis of compound MW01-3-183WH. The compound can be synthesized in 81-96% yield. All purified compounds can be characterized by HPLC, mass spectrometry and NMR to confirm the synthesis. In FIG. 10, a synthesis scheme for the synthesis of MW01-3-183WH is shown.

Thus, in one embodiment, a substituted 6-phenylpyridazine and 2- (piperazin-1-yl) pyrimidine are reacted to produce a compound of formula II, wherein R ¹⁰ and R ¹¹ are hydrogen. To produce a compound of formula II. A compound of formula II (wherein R ¹⁰ and R ¹¹ are hydrogen) is reacted with a suitable reagent under suitable conditions to give groups R ¹⁰ and R ¹¹ (independently hydrogen, hydroxyl, alkyl , Alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino , Azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, = O, = S, carboxyl, carbonyl, carbamoyl, or carboxamide) It is possible.

  The term “disorder” refers to a disorder associated with abnormalities in normal nerve electrical activity and / or function, including but not limited to central nervous system (CNS) conduction disorders, particularly seizure-related disorders. . The disorder may be of unknown cause, either the acute or chronic nature of the genetic cause, or both, or it may be, for example, surgery or treatment of the brain by radiation; alcohol, benzodiazepines, barbiturates or other drugs or Chemical withdrawal symptoms; exposure to epilepsy-inducing agents; injury or trauma, stroke, cerebrovascular stroke, fever, CNS inflammation or infection (eg meningitis), secondary to metabolic disorders or ect It may be. The term also includes emotional, cognitive, and motor symptoms resulting from these disorders.

  The term “seizure-related disorder” means a disorder characterized by conduction disorders, electric shock convulsions and / or seizures, particularly recurrent and / or excessive seizures. A “seizure” is a sudden abnormality of the brain's normal electrical activity associated with altered consciousness and / or other neurological and behavioral symptoms. Seizures can be partial or general. In some aspects of the invention, the seizure-related disorder includes epilepsy, seizure occurrence, epileptogenic, non-epileptic convulsions, eclampsia and convulsions from administration of convulsants or trauma to a subject.

  Seizure occurrence refers to an acute, well-defined electrical / chemical event that occurs over seconds or minutes. Epileptogenicity is the slowness involved in transforming a normal brain into a state that is prone to spontaneous, occasional, timed, recurrent seizures over months and years. Refers to a biochemical or histological process. Epileptogenicity occurs before the first seizure and often includes a first early phase that results from stroke, disease, trauma (eg, due to head trauma or surgery). In the second phase of epilepsy, the brain that is already prone to seizures is more susceptible to more frequent and severe seizures.

  The term "epilepsy" is a transient but recurrent, excessive or abnormal, with or without consciousness and loss of consciousness and abnormal movement, perception or behavior in certain seizures It refers to a chronic disorder of the brain characterized by disturbances in the electrical function of the brain. The term includes epileptic syndromes characterized by specific symptoms including epileptic seizures. Such syndromes include absence seizures, psychomotor epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, occipital lobe epilepsy, parietal lobe epilepsy, Lennox-Gastaut syndrome, Rasmussen encephalitis, childhood absence epilepsy, Ramsey Hunt syndrome type II, Benign epilepsy syndrome, infantile benign encephalopathy, neonatal benign convulsions, early myoclonic encephalopathy, progressive and infantile epilepsy, medial temporal lobe epilepsy, infantile benign juvenile myoclonic epilepsy, juvenile myoclonic epilepsy, childhood generalized tonic-clones Including, but not limited to, epilepsy with seizures, infantile convulsions (West syndrome), epilepsy with persistent slow waves during slow wave sleep (ESES), Laudau Keffner syndrome and Rasmussen syndrome). A subject may suffer from any combination of these syndromes. In aspects of the invention, the subject suffers from a partial seizure. In other aspects of the invention, the subject suffers from a generalized seizure.

  In aspects of the invention, the disorder is epileptogenic. In another aspect of the invention, the disorder is epilepsy. In other aspects of the invention, the disorder is infantile seizures or childhood epilepsy.

Compositions and Kits One or more pyridazine compounds, particularly compounds of formula I, II, III, IV, or V, can be formulated into a pharmaceutical composition for administration to a subject. Accordingly, the present invention is not limited to pills, tablets, caplets, soft gelatin capsules and hard gelatin capsules, lozenges, sachets, veggie caps, droplets, elixirs, suspensions, emulsions , Syrups, syrups, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, and / or sterile packaged powders, which contain pyridazine compounds, particularly pure or Contains substantially pure pyridazine compounds.

  The pharmaceutical composition of the present invention or a portion thereof includes suitable pharmaceutically acceptable carriers, excipients and vehicles selected on the basis of the intended form of administration and consistent with normal pharmaceutical practice. Certain compositions of the present invention can include pure or substantially pure pyridazine compounds. Suitable pharmaceutical carriers, excipients and vehicles can be found in the standard textbooks Remington: The Science and Practice of Pharmacy (21st Edition. 2005, University of the Sciences, USA) : Described in The National Formula (USP 24 NF19) published in 1999.

  The composition of the present invention may comprise at least one buffer or buffer solution. Suitable buffers include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, glucaronic acid, maleic acid, furonic acid, citric acid, glutamic acid , Benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid, stearic acid, sulfanilic acid, argenic acid, galacturonic acid And mixtures thereof, but are not limited thereto. Additives that may be included include pregelatinized corn starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose, calcium hydrogen phosphate, magnesium stearate, talc, silica, potato starch, sodium starch glycolate, lauryl sulfate Sodium, sorbitol syrup, cellulose derivative, hydrogenated edible fat, lecithin, acacia, almond oil, oily ester, ethyl alcohol, fractionated vegetable oil, methyl, propyl-p-hydroxybenzoate, sorbic acid and mixtures thereof. Buffers include one or more dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, poly (N-vinyl pyrrolidone), poly (methyl methacrylate), polylactide, polyglycolide and mixtures thereof. May be included. In some embodiments, the buffer may be formulated as at least one vehicle including, but not limited to, a suspension, solution, or emulsion. In other embodiments, the buffering agent may further include pharmaceutical substances including, but not limited to, pharmaceutically acceptable carriers, excipients, suspending agents, stabilizers or dispersing agents.

  In aspects of the invention, a pharmaceutical composition is provided for oral administration of one or more pyridazine compounds to treat a disorder. For example, for oral administration in the form of a capsule or tablet, the active ingredient may be an oral non-oral such as lactose, starch, sucrose, methylcellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital. It can be combined with a toxic pharmaceutically acceptable inert carrier. For oral administration in liquid form, the drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerin, water and the like. Suitable binders (eg gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums and waxes), lubricants (eg sodium oleate, sodium stearate, magnesium stearate, benzoic acid) Sodium, sodium acetate, and sodium chloride), disintegrants (eg, starch, methylcellulose, agar, bentonite, and xanthan gum), fragrances, and colorants may also be incorporated into the composition. The compositions disclosed herein can further comprise a wetting or emulsifying agent, or a pH buffering agent.

  In aspects of the invention, the composition of the invention is a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Various delivery systems are known, such as, for example, encapsulation in liposomes, microparticles, microcapsules, and can be used to administer the compounds of the present invention.

  Formulations for parenteral administration may include aqueous or oleaginous suspensions and emulsions with edible oils such as aqueous solutions, syrups, cottonseed oil, coconut oil or peanut oil. Dispersants or suspending agents that can be used for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone. .

  Compositions for parenteral administration are for sterile parenteral administration of sterile aqueous or non-aqueous solvents such as water, isotonic saline, isotonic glucose solutions, buffer solutions, or therapeutically active agents. Other solvents that are conveniently used may also be included. Compositions intended for parenteral administration may also contain conventional or similar additives such as stabilizers, buffers, or preservatives, eg, antioxidants such as methyl hydroxybenzoate.

  The compositions of the present invention can be formulated as pharmaceutically acceptable salts described herein.

  The compounds or compositions of formula I, II, III, IV, or V of the present invention can be obtained, for example, by filtration through a bacteria-retaining filter, addition of a sterilant to the compound or composition, irradiation of the compound or composition, or compound Or it may be sterilized by heating the composition. Alternatively, the compounds or compositions of the invention may be provided as a sterile solid formulation, eg, a lyophilized powder that is readily soluble in a sterile solvent immediately prior to use.

  After the pharmaceutical composition is prepared, they may be placed in a suitable container and labeled for the treatment of indications. For administration of the compositions of the invention, such labels can include dosage, frequency of administration, and method of administration.

  According to the present invention, a kit is provided. In one aspect, the kit comprises a compound of formula I, II, III, IV, or V or a composition of the invention in kit form. The kit can be a package containing a container containing a compound or formulation of formula I, II, III, IV, or V of the present invention and containing instructions for administration of the compound or formulation to a subject. . The present invention further relates to a commercial package comprising a compound or formulation of formula I, II, III, IV or V of the present invention together with instructions for its use. In particular, the label may include dosage, frequency of administration, and method of administration.

  The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the composition of the present invention to provide beneficial effects including therapeutic effects. . Along with such container (s) various labels, eg instructions for use, or labels, manufactures, medicinal products or biology that show the certification of the manufacture, use or sale agency for human administration Accompanied by a precautionary statement ordered by a government agency that regulates the use or sale of the product.

  The present invention also relates to products and kits containing materials useful for the treatment of the disorders disclosed herein. The product may include a labeled container. Examples of suitable containers are bottles, vials, and test tubes, which can be formed from a variety of materials including glass and plastic. The container holds a compound or formulation of formula I, II, III, IV, or V of the present invention useful for the treatment of the disorders disclosed in the present invention. The label on the container indicates that the compound or formulation of formula I, II, III, IV, or V of the present invention is used for the treatment of the disorders disclosed herein and is also used A method can also be shown. In aspects of the invention, the medicament or formulation in the container may comprise a medicament or formulation disclosed herein.

  In an embodiment of the invention, the kit of the invention comprises a container as described herein. In certain embodiments, the kits of the invention comprise a container described herein and a second container comprising a buffer. The kit may further include other materials desirable from a commercial or user standpoint, for example, buffers, diluents, filters, needles, syringes, and for performing any method disclosed herein. A package insert with instructions (for example, but not limited to, a method of treating a disorder disclosed herein). The medicament or formulation in the kit of the present invention may include any of the formulations or compositions disclosed herein.

  In aspects of the invention, the kit is useful for any of the methods disclosed herein, including but not limited to treating a subject suffering from epilepsy. Kits of the invention can include instructions for performing any of the methods disclosed herein.

Administration The pyridazine compounds and compositions of the present invention allow the active agent to contact the site of action of the active agent in the subject or patient's body to provide a therapeutic effect, particularly a beneficial effect, especially a sustained beneficial effect. Administration can be by any means that results. The pyridazine compounds and compositions of the invention can be formulated for sustained release, for local or systemic delivery. Selecting a dosage form and route that optimizes the composition and the therapeutic effect of the present invention to provide a therapeutic effect, particularly a beneficial effect, and more particularly a sustained beneficial effect, is accomplished by a skilled physician. Or within the veterinary abilities.

  Pyridazine compounds and compositions are tablets, capsules (each of which includes a sustained or timed release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and It may be administered in an oral dosage form such as an emulsion. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all utilizing dosage forms well known to those skilled in the pharmaceutical arts. The pyridazine compounds and compositions of the present invention may be administered by the intranasal route by topical use of a suitable intranasal vehicle or by a transdermal route such as a conventional transdermal skin patch. Dosage protocols for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen. Sustained release formulations can also be used for therapeutic agents.

  In aspects of the invention, the pyridazine compounds and compositions of the invention are administered by peripheral administration, particularly intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transmucosal, or pulmonary administration. Be administered.

  In order to provide an effect, particularly a beneficial effect, and more particularly a sustained beneficial effect, a therapeutically effective dosage of the pyridazine compounds and compositions of the present invention for the treatment of a particular disorder or condition is the nature of the disorder. And can be determined by standard clinical methods. The exact dosage used in the formulation will also depend on the route of administration, and the severity of the disorder, and should be determined by the judgment of the practitioner and the environment of each patient.

  Appropriate dosage ranges for administration are finely selected to provide therapeutic effects, particularly beneficial effects, and more particularly sustained beneficial effects. Dosage ranges are generally effective in causing the desired biological response. The dosage range for pyridazine compounds is generally about 0.01 mg to about 3 g / kg per kg body weight of the subject once, twice or more daily, preferably once a day. 0.01 mg to about 2 g / kg, 0.5 mg to about 2 g / kg, about 1 mg to about 1 g / kg, about 1 mg to about 500 mg / kg, about 1 mg to about 200 mg / kg, about 1 mg to about 100 mg / kg From about 1 mg to about 50 mg / kg, from about 10 mg to about 100 mg / kg, or from about 30 mg to about 70 mg / kg.

  In aspects of the invention, the dosage range is about 0.01 to 3000 mg / kg, 0.01 to 2000 mg / kg, 0.5 to 2000 mg / kg, about 0.5, twice or less per day. -1000 mg / kg, 0.1-1000 mg / kg, 0.1-500 mg / kg, 0.1-400 mg / kg, 0.1-300 mg / kg, 0.1-200 mg / kg, 0.1-100 mg / Kg, 0.1-50 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 0.1-6 mg / kg, 0.1-5 mg / kg, 0.1-3 mg / kg 0.1 to 2 mg / kg, 0.1 to 1 mg / kg, 1 to 1000 mg / kg, 1 to 500 mg / kg, 1 to 400 mg / kg, 1 to 300 mg / kg, 1 to 200 mg / kg, 1 to 100 mg / Kg, 1-50 g / kg, 1-20 mg / kg, 1-10 mg / kg, 1-6 mg / kg, 1-5 mg / kg, or 1-3 mg / kg, or 1-2.5 mg / kg, or about 10 mg / kg or Less than that, 5 mg / kg, 2.5 mg / kg, 1 mg / kg, or 0.5 mg / kg.

  In embodiments of the invention, the dosage range is about 0.1 to 1000 mg / kg, 0.1 to 500 mg / kg, 0.1 to 400 mg / kg, 0.1 to 300 mg / kg, 0.1 to 200 mg. / Kg, 0.1-100 mg / kg, 0.1-75 mg / kg, 0.1-50 mg / kg, 0.1-25 mg / kg, 0.1-20 mg / kg, 0.1-15 mg / kg 0.1-10 mg / kg, 0.1-9 mg / kg, 0.1-8 mg / kg, 0.1-7 mg / kg, 0.1-6 mg / kg, 0.1-5 mg / kg, 0 .1-4 mg / kg, 0.1-3 mg / kg, 0.1-2 mg / kg, or 0.1-1 mg / kg.

  A composition or treatment of the present invention may comprise a unit dosage of a pyridazine compound to provide a beneficial effect, particularly one or more beneficial effects described herein. A “unit dosage” or “dosage unit” can be administered to a patient and the active agent can be administered as is or in admixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles. Means a unit that can be easily handled and filled, i.e., a single dose, while leaving a physically and chemically stable unit dose.

  The pyridazine compound is about 50 to about 10,000 mg, 50 to about 2000 mg, 70 to about 7000 mg, 70 to about 6000 mg, 70 to about 5500 mg, 70 to about 5000 mg, 70 to about once a day, twice a day. 4500 mg, 70 to about 4000 mg, 70 to about 3500 mg, 70 to about 3000 mg, 150 to about 2500 mg, 150 to about 2000 mg, 200 to about 2500 mg, 200 to about 2000 mg, 200 to about 1500 mg, 700 to about 1200 mg, 70 mg to 1000 mg , 70 mg to 500 mg, in particular 200 to 2000 mg, 70 to 1200 mg, or 1000 mg can be provided in single or multiple dosage units (ie tablets or capsules).

  The dosage regimes of the present invention include the pharmacodynamic characteristics of the drug and the method and route of administration; patient species, age, sex, health, medical condition and weight, nature and range of symptoms, type of combination treatment, frequency of treatment, administration It will vary depending on known factors such as route, patient kidney and liver function, and the desired effect.

  Thus, a subject can be treated with a pyridazine compound or composition of the invention on virtually any desired schedule. The pyridazine compounds or compositions of the invention may be administered one or more times per day, in particular once or twice a day, once a week, once a month, twice a month or continuously. Good. However, the subject may be treated less frequently, such as every other day or once a week, or more frequently. The pyridazine compounds or compositions of the invention may be approximately or at least about 24 hours, 2 days, 3 days, 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks. 2 weeks-12 weeks, 2 weeks-14 weeks, 2 weeks-16 weeks, 2 weeks-6 months, 2 weeks-12 months, 2 weeks-18 months, or 2 weeks-24 months, periodic Or may be administered to the subject continuously.

  The pyridazine compounds, compositions and methods of treatment described herein are indicated for their indication as therapeutic agents or methods alone or in combination with other therapeutic agents or other forms of treatment. These may be combined or formulated together with one or more therapies or agents used to treat the conditions described herein. The compositions of the present invention may be administered together with other therapeutic agents or therapies, simultaneously, separately or sequentially. Accordingly, a compound of formula I, II, III, IV, and / or V results from one or more additional agents for treating the disorders described herein, as well as the disorders described herein. Or may be co-administered with drugs used for the treatment of complications associated with the disorder, or general medicines for treating or preventing side effects.

  In embodiments, the additional therapeutic agent is phenobarbital, valproate, levetiracetam, tiagabine, N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) Antagonists, and neurotrophic factors, and their receptors.

  The invention is described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way.

Summary Infant seizures increase vulnerability to later nerve injury. The hypothesis that infantile seizures increase susceptibility to subsequent nerve injury by causing chronic glial activation was tested. To determine the mechanism by which glial activation can modulate nerve damage, acute changes in pro-inflammatory cytokines and activation of astrocytes and microglia and stars in a “two-hit” model in kainic acid (KA) -induced seizures Both long-term changes in dendritic cell glutamate transporters were tested. Method: Male rats at 15 days of age (P) were administered KA or phosphate buffered saline (PBS). At P45, the animals received a second treatment with KA or PBS. In P55, control (PBS-PBS), infantile seizures (KA-PBS), adult seizures (PBS-KA), and “two-hit” (KA-KA) groups were treated with astrocytes and microglia activation, glutamate We tested for changes in transporters and expression of glial proteins, clusterins. Results: P15 seizures resulted in an acute increase in hippocampal levels of IL-10 and S100B, followed by behavioral disorders and long-term increases in GFAP and S100B. The animals in the “two-hit” group showed greater susceptibility to microglial activation, nerve damage, and stroke compared to the adult stroke group. The glutamate transporter increased after seizures, but there was no difference between these two groups. Treatment with Minozaku (a small molecule inhibitor of pro-regulatory cytokine upregulation) after an infantile attack prevented both long-term increases in activated glia and associated behavioral disorders. Conclusion: These data suggest that glial activation after infantile seizures increases susceptibility to adult seizures, in part by priming microglia and enhanced glial activation. Glial activation can be a new therapeutic target for pediatric epilepsy.

  The following materials and methods were used in the study described in this example.

Materials and methods:
Animals Used A total of 195 male Sprague-Dawley rats (Charles River, Cambridge, Mass.) Were used in these experiments. The animals were divided into experimental groups as summarized in Tables 6 and 7. If multiple outcomes were required within each group, surviving animals were randomly selected for each endpoint. All procedures were approved by the Institutional Animal Care and Use Committee of Children's Memory Research Center, Chicago, IL.

At either 15 or 45 days after kainic acid mediated induction (P), rats were given KA (Ocean Product International, Nova Scotia), or an equivalent amount of vehicle, phosphate buffered saline (PBS, pH 7.4). Any of (2) was administered. The KA dosage at P15 (5 mg / kg) and P45 (15 mg / kg) was based on the difference in age-dependent threshold for KA-induced seizures (22). All injections were intraperitoneal (ip).

“Two-hit” model of kainic acid-induced seizures In order to determine the long-term effects of infantile seizures occurring in P15, animals were allowed to recover for 30 days. At P45, rats were administered KA as previously described for the “two-hit” model of KA-induced neuropathy (2). Control animals received PBS and all animals were allowed to recover for an additional 10 days before being sacrificed at P55. Four experimental groups were tested including controls (PBS-PBS), neonatal seizures (KA-PBS), adult seizures (PBS-KA), and “two-hit” animals. Rats were cardiac perfused with PBS and fixed with 4% paraformaldehyde (PFA) in 0.1 M PBS (pH 7.4). The brain was excised and postfixed in 4% PFA overnight. The brain was cut with paraffin embedded for immunohistochemistry. A biaxial cross section representing the hippocampus (Bregma-7.34 mm, Paxinos plate 99 and Bregma-5.60 mm, Paxinos plate 106) was selected for each outcome determination (23).

Determination of seizure onset and seizure severity grade All animals were continuously monitored for 3 hours after administration of KA or PBS. Latency to first seizure onset (defined as onset of forelimb clonic spasm) and seizure severity were quantified as previously described (2). Only animals with grade IV seizures were included in this study.

Assessment of neuronal cell damage Neuronal cell damage was measured in 5 μm paraffin-embedded sections using Fluoro-Jade B (FJB) (Chemicon International, Temecula, Calif.) (24, 25). Cell nuclei were counterstained and identified using the nuclear dye 4,6-diamidino-2-phenylindole (DAPI, Sigma, St. Louis, Missouri). Hippocampal CA1, CA2, CA3, dentate gyrus (DG) and polymorphic dentate gyrus (PoDG) were taken at 10x magnification and images were grayscale (black and white tones) for quantification of FJB positive cells Converted to. The percentage of positive cells in designated hippocampal areas was measured by thresholding on lightly stained or FJB positive cells (Metamorph, Universal Imaging Corporation, Sunnyvale, CA). In addition to staining specific to the hippocampal region, total FJB positive cells in the hippocampus were obtained for each sample.

Preparation of Brain Homogenate and Determination of Protein Concentration Hippocampal homogenate is a protease inhibitor cocktail (1 μg leupeptin (Sigma, St. Louis, MO), 0.001 M 4-dithio-L-threitol (DTT, Iml PBS). Sigma), 0.002 M sodium orthovanadate (Sigma) and 0.001 M phenylmethanesulfonyl fluoride (PMSF, FLUKA, Switzerland)). Total protein concentration was measured using commercially available reagents (BCA, Pierce, Rockford, IL).

Measurement of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α levels were determined by enzyme immunoassay using commercially available plates and reagents (ELISA; MesoScale Discovery, MSD, Gaithersburg, Maryland). Measured in homogenate. The S100B level was measured as described in (26). Samples were analyzed twice and compared to known concentrations of protein. Plates were analyzed using a SECTOR Imager 2400 (MSD).

Hippocampal-related task test The Y-maze test of voluntary alternation was used to evaluate hippocampal-dependent spatial learning (26, 27). The test began at P27 when the animal was first able to determine either the left or right arm of the maze. The test was conducted every other day until P55 by a blinded observer. Each animal started with the vertical arm of the Y-maze. If the animal selected a different arm on the second run in the maze, it was scored as an alternating action. The alternation rate over the duration of the study was calculated for each animal.

Western blot analysis of factor H and clusterin concentrations after kainic acid-induced seizures Changes in factor H and clusterin levels in the hippocampus after KA-induced seizures were measured using commercially available antibodies (1: 2000 goat polyclonal anti-FH antibody, Quidel Corporation, San Diego). (Diego, CA; 1: 1000 goat polyclonal anti-clusterin antibody, Santa Cruz Biotech, Santa Cruz, CA). Proteins were separated by conventional methods using polyacrylamide gels. After incubation with secondary antibodies (1: 1000 anti-goat IgG-HRP against FH; 1: 2000 anti-goat IgG-HRP against clusterin), protein bands were detected by electrochemiluminescence detection (ECL Western Blotting Detection Reagents, Amersham) Biosciences, Piscataway, NJ). Appropriately sized bands were quantified by relative densitometry using digitized images and OpenLab software (Improvision line, Lexington, Mass.). Values for FH and clusterin were normalized to GAPDH and β-tubulin, respectively, and data were expressed as the ratio of two bands (1: 4000 GAPDH, Ambion, Austin, Tx; 1: 1000 β-tubulin). It was. The E7 anti-β-tubulin antibody developed by Michael Klymkowski was obtained from the Developmental Studies Hybridoma Bank developed by NICHD, and the University of Census of Biotechnology, and the University of Clinic.

Immunohistochemistry Hippocampal markers of glial activation and immunohistochemical detection of the astrocytic glutamate transporter were performed using 5 μm paraffins using Vectastein Elite ABC immunodetection kit and diaminobenzidine substrate (DAB) ((Vector Laboratories, Burlingame CA). The following primary antibodies were used: GFAP (1: 1500, mouse monoclonal, Sigma); S100B (1: 1500, rabbit polyclonal, DAKO Cytomation, Carpinteria, CA); Ibal (1: 400) , Goat polyclonal, Abcam, Cambridge, MA); FH (1: 400, goat polyclonal, Quidel); β-clusterin (1: 100, goat police) GLAST (1: 5000, guinea pig polyclonal, Chemicon International, Temecula, Calif.) And GLT-1 (1: 5000, guinea pig polyclonal, Chemicon) Control sections were replaced with normal serum or primary antibody. Incubated with PBS To determine antibody specificity, selected slides were incubated with pre-adsorbed IgG instead of primary antibody (rabbit IgG against S100B; mouse IgG against GFAP) clusterin, GLAST. And for GLT-1, the control peptide was used in place of the primary antibody to determine specific immunoreactivity, and sections were prepared with the appropriate biotinylated secondary antibody (1: 400 dilution). Incubated for 1 hour at 38 ° C. with Ector).

Immunofluorescent double labeling of clusterin positive cells Double labeling of clusterin immunoreactive cells can be performed using either the astrocytic marker GFAP (1: 1000) or the neuronal marker NeuN (1:50, Chemicon). It was done using. After 20 minutes of rehydration and incubation in standard horse serum (NHS), sections were incubated with either primary antibody for 1 hour at room temperature. Following a 30 minute incubation with a biotinylated secondary antibody (anti-mouse IgG, 1: 400), the tissue was incubated with fluorescent avidin D (Vector) for 45 minutes and blocked with avidin and biotin solution and 10% NHS. The tissue was then incubated for 1 hour with a second primary antibody (clusterin, 1:50 dilution). Sections were incubated with biotinylated anti-goat IgG secondary antibody (1: 400) for 20 minutes followed by 45 minutes with Texas Red Avidin (Vector). After washing with PBS, the cover glass was sealed with a Vectashield mounting medium (Vector) containing DAPI.

Peroxidase double labeling of clusterin immunoreactive cells Double labeling of clusterin immunoreactive cells was also performed using Ibal, a microglia marker, or NeuN, a neuronal marker. Standard immunohistochemical methods continued, but VIP (Vector) instead of DAB was used as a substrate for visualization. Following development with VIP, the tissue was blocked and then incubated overnight at 4 ° C. with Ibal antibody (1: 400 dilution). After 1 hour incubation with biotinylated anti-goat IgG, the tissue was treated with ABC solution (Vector) and developed with SG substrate (Vector) before encapsulation. A similar method was used for double labeling of clusterin with NeuN (1:50).

Image acquisition and quantification of immunoreactive cells. Sections were examined with two blind observers with a bright field microscope (Nikon Eclipse E800). For GFAP, S100B, Ibal, FH, clusterin, GLAST and GLT-1 sections, CAI, CA2, CA3, DG and PoDG were taken at 10X magnification and the images were gray for quantification of immunoreactive cells. Converted to scale. The percentage of positive cells in a particular hippocampal region was measured by thresholding against dark objects that show immunoreactive cells (Metamorph, Universal Imaging Corporation, Sunnyvale, CA). Total hippocampal immunoreactivity as well as immunoreactivity specific to the hippocampal region was obtained for each sample. Changes in the morphology of immunoreactive cells were not evaluated.

Decreased pro-inflammatory cytokine increase after kainic acid treatment Determines whether suppression of early cytokine increase prevents long-term glial activation and improves neurobehavioral outcome after seizures in infancy To do so, P15 rats were administered Minozaku (Mzc). Mzc (2- (4- (4-methyl-6-phenylpyridazin-3-yl) piperazin-1-yl) pyrimidine dihydrochloride monohydrate) is biologically available and is Is a CNS permeable small molecule inhibitor of up-regulation of pro-inflammatory cytokines (19). Mzc was purified from a lead compound synthesized by chemical diversification of an inactive pyridazine fragment (26). Mzc (5 mg / kg) or diluent (saline) was administered by intraperitoneal injection at 3 and 9 hours after KA injection at P15 (FIG. 7). Control animals were injected with an equal volume of saline (Sal). At 12 hours, the animals were sacrificed and the tissues were processed for analysis of pro-inflammatory cytokines by ELISA as described above. Another group of animals was allowed to recover for 30 days for Y-maze testing and immunohistochemical analysis of glial activation. Details of experimental groups and results determination are summarized in Table 7.

Statistical analysis Values are expressed as mean ± SEM for each group. A normality test was performed on each data set. Student t test was used to compare two groups, and a one-way analysis of variance (ANOVA) was performed to compare three or more groups. Tukey's multiple comparison test was used for parametric measurements and Dunn's post-test was applied to nonparametric data. Fisher's exact test was used to determine differences in seizure severity. Kaplan-Meier survival analysis and log rank tests were performed to analyze differences in mortality between groups. Significance was defined as p <0.05 for all tests. Prism 4.0 (GraphPad Software Inc., San Diego, Calif.) Was used for statistical analysis.

Results Comparison of kainic acid-induced seizures of P15 and P45 Seizure latency (min ± SEM; data expressed as n) compared to P45 (P45 KA and PBS-KA; 34.3 ± 3.3; n = 32) Thus, there was a significant decrease in rats exposed to KA at P15 (P15 KA and KA-PBS; 16.7 ± 1.2; n = 30) (FIG. 1A). There was no difference in seizure severity between age groups. In P15, the majority of animals (P15 KA and KA-PBS; 27/31, 87%) experienced a grade IV seizure, while the P45 treatment group (P45 KA and PBS-KA; 28/32, 88%) There was no significant difference in the frequency of seizures of grade IV in The survival rate of immature rats exposed to KA (KA-P13S, 16/19, 84%) was not significantly different from the P45 group (PBS-KA, 13/20, 65%) (FIG. 1B).

Increased susceptibility of infantile seizures to adult seizures For seizure susceptibility (FIG. 1), in the “two-hit” group exposed to KA at both P15 and P45 (KA-KA), at P45 (PBS-KA) Compared to rats initially exposed to KA. The seizure latency was compared to the “two-hit” group (KA-KA, 18 .8 ± 3.8; n = 12) significantly decreased (FIG. 1A). Survival (FIG. 1B) was significantly reduced in the “two-hit” group (6/12, 50%) compared to PBS-KA animals (13/20, 65%). There were no significant differences between groups in seizure severity. Grade IV seizures occurred in 88% (28/32) of animals exposed to KA at P45 (P45 KA and PBS-KA) and 100% (12/12) in “two-hit” KA-KA animals . P55 (PBS-PBS, 316.7 ± 6.1; KA-PBS, 327.7 ± 8.4; PBS-KA, 292.6 ± 9.0; KA-KA, 326.0 ± 21.2) There was no significant difference in body weight (g ± SEM) between the groups at the time of sacrifice.

Increased neuronal damage resulting from stroke after “second hit” Data representing the extent of hippocampal neuronal damage (FIGS. 1C and D) in adult stroke (PBS-KA) as fluorescent dye FJB (% FJB positive cells ± SEM) ) Was used to compare with the “two-hit” (KA-KA) group. An overview of regions of interest for FJB and other immunohistochemical outcome determination is shown in FIG. 1E. Nerve cell damage was not detected in either the control group (PBS-PBS; n = 9) or the immature seizure group (KA-PBS; n = 5). Compared to littermates that initially received KA as an adult (PBS-KA, 6.4 ± 0.8; n = 7), the “two-hit” group had a significantly greater neuronal damage (29.2 ± 3). .6; n = 5). The majority of FJB positive cells from both groups were present in the CA3 layer of the hippocampus. CAI, CA2 and DG also showed a significant increase in labeled cells compared to the control. FJG positive cells were also observed in these groups of olfactory cortex and frontal cortex, lateral septal nucleus, piriform cortex, and periolfactory cortex. Values in these areas were not different between groups.

Seizures that result in an acute increase in hippocampal IL-1β and S100B levels To determine whether seizures result in an increase in pro-inflammatory cytokine levels and glial activation (data expressed as pg / ml ± SEM; n) KA At 24 hours after administration, changes in the levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and S100) in hippocampal brain homogenates were measured (FIG. 2). This response in immature brain (P15) and adult brain (P45) was compared. In neonates, KA exposure resulted in a significant increase in IL-1β (37.0 ± 4.0; n = 7) compared to PBS-treated controls (20.5 ± 3.0; n = 6). (FIG. 2A). A similar increase was observed in P45 animals (45.8 ± 9.3; n = 9) treated with KA compared to age-matched controls (21.1 ± 4.8; n = 4). There was no significant difference between immature and adult levels of IL-1β. IL-6 showed the same change tendency as IL-β but did not reach statistical significance (FIG. 2B). There was no change in the level of TNF-α in group 4 (FIG. 2C). In contrast, S100B levels (FIG. 2D) are compared to PBS-treated controls (1123 ± 130.7, n = 4) compared to KA-treated neonates (2664.0 ± 225.8, n = 7) significantly increased. A similar increase was observed in KA-treated P45 animals (5508 ± 304.3, n = 10) compared to PBS-treated P45 controls (3678.0 ± 529.3, n = 4). S100B levels were significantly higher in adults compared to neonates in both KA and PBS treated groups.

Infant stage seizures that cause neurobehavioral disorders To determine whether an acute increase in IL-1β and S100B after KA-induced seizures in neonates is associated with abnormal neurobehavioral results, We tested for the ability to perform hippocampal related behavior (data expressed as% alternation ± SEM; n) (Figure 3A). Despite the lack of neuronal damage, animals in the infantile seizure group compared to controls (PBS-1PBS, 73.4 ± 5.3, n = 8) after 40 days of recovery. , Showed significant impairment (KA-PBS, 25.4 ± 3.4, n = 12).

Neonatal brain seizures that cause long-term glial activation Hippocampus using immunohistochemical methods to determine whether immature brain seizures resulted in glial activation despite the absence of neuronal damage Changes in the astrocyte-specific markers GFAP and S100B (FIGS. 3B-K) and the microglia marker Iba1 (FIG. 4) were quantified. Immunostaining in four long-term (P55) recovery groups: control group (PBS-PBS), immature seizure group (KA-PBS), adult seizure group (PBS-KA) and “two-hit” group (KA-KA) (% Immunopositive cells ± SEM; data expressed as n) were compared.

  A single dose of KA at P15 resulted in a significant increase in GFAP immunoreactivity in the hippocampus (FIGS. 3B-F), compared to controls (PBS-PBS, 25.8 ± 3.4, n = 13). And persisted until after 40 days of recovery (KA-PBS, 59.9 ± 4.8, n = 10). The animals in the “two-hit” group showed a significant increase in GFAP (KA-KA, 72.0 ± 15.5, n = 5) compared to the control, but the adult seizure group (PBS-KA, 50 .3 ± 6.5, n = 10) was not significantly different. The GFAP positive astrocytes of the KA-PBS, PBS-KA and KA-KA groups had deeper processing and enhanced staining compared to the controls. These cells also tended to surround nerve cells. For all hippocampal regions examined (CA1, CA2, CA3, DG and PoDG), all three KA treatment groups significantly increased GFAP positive cells compared to the PBS-PBS group. Individual areas did not show a higher percentage of GFAP positive cells compared to the other areas examined.

  Similar responses were observed for the glial derived protein, S100B (FIGS. 3G-K). S100B immunoreactive astrocytes in the hippocampus were exposed to KA at P15 once compared to controls (PBS-PBS, 10.8 ± 1.7, n = 113) (KA-PBS, 35.0 It increased significantly 40 days after ± 7.3, n = 10). On the other hand, animals in the “two-hit” group showed a significant increase in S100B (KA-KA, 39.6 ± 1.9, n = 6) compared to the control, but the adult seizure group (PBS-KA). 31.0 ± 2.6, n = 8) was not significantly different. In animals exposed to KA, the morphology of these cells was generally that of activated astrocytes (FIGS. 3H-J).

Transient microglial activation and increase by “second hit” Notably, the “two-hit” group of animals compared to the adult seizure group (PBSKA, 17.4 ± 4.3, n = 5) , Iba1 immunoreactive microglia (KA-KA, 34.0 ± 5.0, n = 6) showed a significant increase (FIG. 4). Ibal expression in both these groups (FIGS. 4C, D) was also significantly increased (FIG. 4A) compared to controls (PBS-PBS, 4.0 ± 0.6, n = 6). In contrast to the sustained increase in GFAP and S100B, activated microglia increased in the long-term recovery group (KA-PBS, 8.7 ± 0.8, n = 8) after the infancy attack Did not (Figure 4B).

Increased clusterin levels involved in microglial activation in a “two-hit” model FH and clusterin regulate microglia activation and astrocyte-dependent cell death following brain injury (16-18, 28). Changes in both proteins in the hippocampus at 24 hours post-seizure in newborns (FIGS. 5A, D) were measured using Western blotting (relative density ± SEM; data expressed as n). There was no difference in FH levels between the control group at P15 or P45 and the KA treatment group (FIG. 5A). Next, immunohistochemical methods were used to determine whether infantile seizures resulted in persistent changes in FH in the adult hippocampus (FIGS. 5B, C). There was no significant difference in values for FH in the long-term recovery group. FH immunoreactive cells had astrocyte morphology and were also present in the frontal cortex, striatum and periventricular regions.

  After 24 hours of recovery from KA-induced seizures, hippocampal clusterin levels were as high as the age control group (3.0 ± 0.30, n = 6) and (2.7 ± 0.31, n = 6). In comparison, both P15 (4.5 ± 0.36, n = 8) and P45 (4.3 ± 0.33, n = 5) were significantly higher (FIG. 5D). Infancy seizures did not produce persistent changes in clusterin in the hippocampus (data expressed as immunopositive cells ±% SEM) (FIG. 7E). Animals exposed to KA during adulthood (FIG. 5F) showed a significant increase in clusterin (PBS-KA, 18.9 ± 3.7, n = 7) compared to controls.

  Clusterin levels are both adult seizures (PBS-KA, 18.9 ± 3.7, n = 7) and infantile seizures (KA-PBS, 2.1 ± 0.8, n = 7) As well as significantly increased in the “two-hit” group (KA-KA, 32.9 ± 3.1, n = 6) compared to the control (PBS-PBS, 1.6 ± 1.1, n = 8). (Figure 5G, H). To confirm the cellular origin of clusterin, double labeling studies were performed in a total of 4 experimental groups (n = 4 per group) (FIGS. 5I-L). Quantitative evaluation of clusterin immunostaining showed clusterin positive cells in the entorhinal cortex, cerebral cortex, midbrain and hippocampal layers CAI, CA2, CA3 dentate gyrus and PoDG. Clusterin positive cells were not co-labeled with NeuN (FIG. 5I, J) or GFAP (FIG. 5K), but were co-labeled with Ibal (FIG. 5L) and identified as microglia.

Increased Glitreglutamate Transporters GLAST and GLT-1 After Seizures To determine one potential mechanism that can lead to neurological dysfunction after infancy seizures, using immunohistochemical methods in the hippocampus Changes in the astrocyte glutamate transporters GLAST and GLT-1 were measured (FIG. 6) (13). The expression of these proteins was compared in four long-term experimental groups after exposure to KA or PBS at P15 (data are data expressed as% of immunopositive cells ± SEM; n). GLAST and GLT-1 immunoreactive cells showed similar pericellular staining patterns and distribution in the brain (FIGS. 6A-C). The majority of labeled cells were distributed in the hippocampus, entorhinal cortex and frontal cortex. Neither GLAST nor GLT-1 expression increased significantly in the hippocampus after the infantile attack over a long period of recovery (FIG. 6D). In contrast, animals exposed to KA during adulthood are compared to controls (PBS-PBS; 3.4 ± 0.6, n = 7) with GLAST (PBS-KA, 16.3 ± 3. 8, n = 7) showed a significant increase. GLAST levels were also significantly increased in the “two-hit” group (KA-KA, 22.4 ± 5.0, n = 6) compared to controls. Similar results were observed for GLT-1. Values for GLT-1 in the infantile seizure group (KA-PBS, 5.9 ± 1.9, n = 6) were the controls (PBS-PBS, 7.2 ± 1.1, n = 6). ), But animals exposed to KA during adulthood were significantly more GLT-1 (PBS-KA, 19.4 ± 3.5, n = 10) than controls. Showed an increase. GLT-1 levels were significantly increased in the “two-hit” group (KA-KA, 25.0 ± 4.2, n = 5) compared to the control.

Prevention of hippocampal-dependent behavioral disorders by delayed administration of minozaku after KA-induced seizures Remarkably, treatment with the small molecule compound Mzc after KA-induced seizures at P15 (FIG. 7A) was observed in the KA-exposed group (FIG. 7B). Prevented weakening of the behavioral functions seen. After a 30 day recovery period, the turnover rate of KA-exposed animals treated with saline (KA-Sal, 53.3 ± 3.1, n = 21) was the control (PBS-Sal, 83.0 ± 3). .4, n = 10). Animals treated with Mzc after KA-induced seizures showed significantly improved behavior in this study compared to KA-saline treated animals (P <0.001).

Suppression of kainic acid-induced acute increase in pro-inflammatory cytokines by delayed administration of minozaku Next, inhibition of neurobehavioral disturbance after infantile seizures by Mzc is the result of suppression of acute cytokines and long-term glial activation response It was sought to determine if there was. Treatment with Mzc after KA-induced seizures with P15 also prevented an acute increase in pro-inflammatory cytokines in hippocampal brain homogenates (FIGS. 8A-D) (data expressed as% control ± SEM, n). In the Mzc-treated group at 12 hours of recovery after KA exposure, IL-1β (103.7 ± 4.6, n = 12), IL-6 (103.2 ± 3.8, n = 12), TNF− α (98.5 ± 3.9, n = 12) and S100B (89.1 ± 9.7, n = 8) levels were not significantly different from controls, exposed to KA and treated with saline alone Was significantly suppressed compared to the treated animals.

Prevention of KA-induced sustained increase in glial activation by delayed administration of Minozac Treatment with Mzc after KA exposure with P15 also prevented long-term increases in astrocyte activation (FIGS. 8E-L). After 30 days of recovery, glial activation was quantified by immunohistochemical methods. The level of GFAP immunoreactive cells (FIGS. 8E-H) is significantly increased in KA-exposed animals (KA-Sal, 47.8 ± 7.6, n = 8), and this increase is observed in Mzc (KA-Mzc). 20.9 ± 1.8, n = 9) (FIG. 8H) prevented. Similar results for S1008 for both groups (KA-Sal, 15.6 ± 2.0, n = 12; KA-Mzc, 8.1 ± 0.9, n = 13), (FIGS. 8I-L). It was seen.

DISCUSSION This study has two problems: neurobehavioral impairment in animals after infancy attacks contrary to the absence of neuronal cell damage and, secondly, seizures in the immature brain are vulnerable to later seizures. It was described in half as a mechanism that can increase sex (4, 6, 29, 30). The main findings of this study are: (a) increased susceptibility to seizures in “two-hit” animals exposed to KA “second hit” after infancy seizures; (b) infants Long-term increase in glial activation after hippocampal seizures and hippocampal-dependent behavioral deficits; (c) enhanced microglia activation in “two-hit” animals exposed to KA at P15 and P45; and ( d) Prevention of both outcomes by delayed administration of small molecule inhibitors of up-regulation of pro-inflammatory cytokines.

  The lack of neuronal damage in the infantile seizure group and the increased damage in the “two-hit” group are consistent with previous studies (2). Impaired neurobehavioral function after infantile seizures seen in this and other studies (31) suggests vulnerability of hippocampal neuronal function, although other marginal areas may also be impaired (32). Prevention of this disorder by Mzc treatment involves pro-inflammatory cytokines at the start of the process. There has been such a report (22) that there is no difference in the cytokine response between the infantile and adult seizure groups, and these data reflect only one time point, so this initial Age-dependent differences in cytokine responses are not ignored. Prevention of long-term increase in glial activation in Mzc-treated animals demonstrates that glial activation can contribute to neurological dysfunction (8).

  Although the threshold for the occurrence of seizures is lower in the immature brain than in the adult brain (6), the immature hippocampus is resistant to structural damage induced by SE (29). This discrepancy means that the mechanism by which infantile seizures increase vulnerability to adult seizures and neuropathy occurs at the molecular or intracellular level. Previous studies have shown that changes in the AMPA receptor (33), glutamate receptor subunit (34), and the neuronal glutamate transporter, EAAC1 (15), are implicated. Data showing enhanced microglial activation in the “two-hit” group show that glial (astrocytes and microglia) activation leads to increased susceptibility to seizures and neuropathy after infancy attacks Related. This hypothesis is supported by improved behavioral function and prevention of long-term glial activation in Mzc-treated animals. The exact mechanism by which activated astrocytes and microglia cause neuropathy remains unclear (35, 36).

  The possibility of this response as a therapeutic target for epilepsy has not been investigated in detail, but neuroinflammation is an established response to central nervous system disorders (36), including epilepsy (37). A precedent from in vitro and in vivo pathological studies of humans with Alzheimer's disease shows glial-mediated neuroinflammatory responses both in the pathophysiology of the disease (8) and as a therapeutic target (19, 26, 38). Related. Microglial activation leading to overexpression of IL-1 has been proposed as an important step in the initiation of a self-propagating cytokine cycle resulting in neurodegeneration (8, 39). Data showing an early increase in IL-1β is consistent with previous studies on changes in pro-inflammatory cytokine mRNA in response to KA at P15 (22) and P21 (40). The important role of pro-inflammatory cytokines at the start of this cycle is supported by the therapeutic effects provided by the Mzc-treated infantile seizure group with suppressed acute cytokine responses. IL-1β and pro-inflammatory cytokines may also function in epilepsy as seizure-inducing signaling molecules independent of such cycles (41).

  There is evidence for long-term glial activation in the hippocampus of rats exposed to KA at P15, which manifests as increased expression of GFAP and S100B (42, 43) after 40 days of recovery. The astrocyte-derived cytokine S100B increased both rapidly and in the course of the long-term recovery of this study. With the long-term increase in GFAP, this finding means that astrocytes remain activated after the infantile attack. The mechanism by which S100B thereby increases vulnerability to neuropathy remains unclear, but studies of mice that overexpress S100B have demonstrated both increased glial activation and increased susceptibility to neuropathy. (10, 44). The increased S100B level seen in mature control animals is consistent with an increase in S100B with aging (45).

  There was no long-term change in the expression of the astrocyte glutamate transporter (13, 14) responsible for the majority of glutamate uptake in the central nervous system. The increase in both transporters in the “two-hit” group is comparable to that seen in the adult (PBS-KA) seizure group and may be a protective response (46). These data imply that astrocytic glutamate transporters either do not contribute to increased seizure susceptibility after infancy attacks or the functional properties of these transporters are altered.

  Clusterin expression is upregulated in astrocytes after stroke (18). The increase in clusterin in animals exposed to KA is of microglia origin. This result supports the finding that microglial activation may be a mechanism that is enhanced in the “two-hit” group and that activated microglia leads to cell damage (17). Factor H (28), a complement inhibitory protein, acts as a chemotactic factor for activated microglia in amyloid-β-induced brain injury (16). The absence of a change in factor H levels in response to KA suggests that this signaling pathway is not involved in the recruitment of microglia after stroke.

  The small molecule Mzc (19) used in these studies is a bioavailability, water-soluble, CNS-permeable, non-toxic compound that is pro-inflammatory in the hippocampus in an Alzheimer mouse model. Inhibits cytokine upregulation, suppresses synaptic dysfunction, and attenuates hippocampal-dependent behavioral disorders. The results presented herein and the large-scale ability to produce Mzc according to FDA guidelines (19) indicate the need to investigate the potential of this compound as a novel therapeutic agent for childhood epilepsy. The effectiveness of this study leads to further support of the hypothesis (19, 20, 38) that targeted neuroinflammation may alter the progression of central nervous system disease.

  These data relate to neuroinflammation both in the chronic neurological sequelae of infantile seizures and in increased susceptibility to further neuropathy after neonatal seizures. A model (FIG. 9) is proposed in which an initial rise in pro-inflammatory cytokines after infancy attacks, particularly IL-1β and S100B, leads to further activation of microglia. This activation is also transient, but is followed by a sustained increase in astrocyte activation. Activated astrocytes can lead to neurobehavioral impairment, and may increase susceptibility to a second neurological disorder, in part by enhanced microglia activation after the disorder. An infantile seizure irrigates the microglia for an excessive response to a second nerve injury (20). These hypotheses suggest an inhibitory effect on the early pro-inflammatory cytokine response, region specificity of the glial activation response to the hippocampus, and increased susceptibility to neuropathy in transgenic mice (10, 44) overexpressing S100B. Supported by previous data shown and similar models proposed for neurodegeneration in Alzheimer's disease (7, 8, 19, 20).

  Such embodiments are merely illustrative of one aspect of the invention, but any functionally equivalent embodiment is intended to be within the scope of the invention, It is not intended to be limited to the scope according to the specific embodiments described herein. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

  All publications, patents and patent applications referred to herein are individually and individually indicated that each individual publication, patent and patent application is incorporated by reference in its entirety. As is the case, their entire disclosure is incorporated by reference. All publications, patents and patent applications mentioned in this specification are referenced for purposes of describing and disclosing the methods, etc. reported therein that may be used in connection with the present invention. Is incorporated herein by reference. This invention should not be construed herein as an admission that such rights are not granted by such prior disclosure.

P, days after birth; KA, kainic acid; Cyt, cytokine (IL-1β; 1L6; TNF-α, S-100B); FJB, Fluoro-JadeB; FH, H factor; Cl, clusterin; GLAST and GLT-1 , Glutamate transporter; latency, time to onset of seizure; severity, seizure severity after KA

P, days after birth; KA, kainic acid; Mzc, Minozaku; Cyt, cytokine (IL-1β; IL6; TNFα, S-100B)
References The following are references used by publications included in Example 1.

Claims (15)

  A pharmaceutical composition for treating a disorder characterized by conduction disorders, electric shock convulsions and / or seizures, comprising a therapeutically effective amount of a pyridazine compound for treating the disorder, and a pharmaceutically acceptable carrier, A pharmaceutical composition comprising a dosage form or vehicle.   The pharmaceutical composition according to claim 1, wherein the pyridazine compound comprises a pendant pyridazinyl group having aryl or substituted aryl, heteroaryl or substituted heteroaryl.   The pharmaceutical composition according to claim 2, wherein said heteroaryl is piperazinyl substituted with pyrimidinyl or pyridinyl. Said pyridazine compound is of formula Ia or Ib:
Wherein R ¹ , R ² , and R ³ are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, Aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, Ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; ⁷ is a substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, Heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, = O, = S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide, or ^{R 7} is absent, Well it, presence of a double bond between C of 1-position of N and 6-positions; R ^{4, R 5,} and R ⁶ is independently hydrogen, alkyl, alkoxy, halo or nitro, Or R ¹ and R ² , R ¹ and R ⁷ , or R ² and R ³ may form a heteroaryl or heterocycle); or have an isomer or pharmaceutically acceptable salt thereof The pharmaceutical composition according to claim 1. Said pyridazine compound has the formula II:
Wherein R ¹⁰ and R ¹¹ are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy , Arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, phosphonate, Cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, carbonyl, carbamoyl, or carboxamide); Having an isomer or pharmaceutically acceptable salt thereof, pharmaceutical composition according to claim 1. Said pyridazine compound has the formula III:
Wherein R ¹⁵ and R ¹⁶ are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cyclo Alkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, Nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, = O, = S, phosphonate, carboxyl, carbonyl, carbamoyl, or carbo A Samido); or a so isomer or pharmaceutically having acceptable salts, pharmaceutical composition according to claim 1. Said pyridazine compound has the formula IV:
Wherein R ⁷⁰ is a substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, Arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo Silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, carboxyl, phosphonate, carbonyl, carbamoyl, or carboxamide, especially heterocycle, 2. A pharmaceutical composition according to claim 1 having teloaryl, amino, and substituted amino; and ^R71 is aryl or substituted aryl); or an isomer or pharmaceutically acceptable salt thereof. The pyridazine compound has the formula V:
Wherein R ⁵⁰ , R ⁵¹ , and R ⁵² are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, Aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocycle, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate amino, imino, azide, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido , Cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ═O, ═S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide. ); Or with a salt thereof isomer or pharmaceutically acceptable pharmaceutical composition according to claim 1.   2. The pharmaceutical composition of claim 1, wherein the pyridazine compound does not comprise a compound described in Table 1.   The pharmaceutical composition according to claim 1, wherein the pyridazine compound is 2- (4- (4-methyl-6-phenylpyridazin-3-yl) piperazin-1-yl) pyrimidine dihydrochloride.   11. A method for treating and / or preventing a disorder characterized by conduction disturbances, electric shock convulsions and / or seizures in a subject, comprising administering a therapeutically effective amount of a composition according to any of claims 1-10. A method involving that.   The method of claim 11, wherein the disorder is epilepsy.   13. The method according to claim 11 or 12, wherein the subject is a pediatric patient.   Use of a composition according to any of claims 1 to 13 for the treatment and / or prevention of disorders characterized by conduction disorders, electric shock convulsions and / or seizures.   15. Pyridazine compound or composition, container, and instructions for use thereof according to any of claims 1-14 for the treatment and / or prevention of disorders characterized by conduction disorders, electric shock convulsions and / or seizures Including kit.