Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

• the invention relates to compositions and methods for treatment of patients with seizure-related disorders, especially epilepsy. BACKGROUND OF INVENTION
• Epilepsy is a common but devastating disorder that affects millions of people worldwide.
• Epilepsy is a chronic neurological condition characterized by transient but recurring excessive or abnormal disruptions to neural activity. These disruptions can be manifested as motor, convulsion, sensory or psychic symptoms, particularly in the form of seizures and loss of consciousness.
• Epilepsy syndromes have been classified into more than 40 distinct types based upon characteristic symptoms, types of seizure, cause, age of onset and EEG patterns.
• Seizure sufferers are frequently limited in the kinds of activities they may participate in. Seizures can prevent people from driving, working or otherwise participating in much of what society has to offer. Some sufferers have serious seizures so frequently that they are effectively incapacitated. Furthermore, these are often progressive and can be associated with degenerative disorders and conditions. Over time, seizures often become more frequent and more serious, and in particularly severe cases, are likely to lead to deterioration of other brain functions as well as physical impairments.
• the present invention relates to therapeutic and/or prophylactic uses of pyridazine compounds and to pharmaceutical compositions containing one or more of these compounds as an active component for treating Seizure-Related Disorders, including Epilepsy.
• the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating a Seizure-Related Disorder in a subject.
• the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating Epilepsy in a subject.
• the compositions of the invention generally comprise a pyridazine compound in a pharmaceutically acceptable carrier, excipient, or vehicle.
• a pharmaceutical composition of the invention comprises a therapeutically effective amount of a pyridazine compound to provide a beneficial effect, in particular a sustained beneficial effect following treatment.
• a pharmaceutical composition comprises a pyridazine compound with a favorable pharmacological profile which makes the compounds particularly suitable in patients with enhanced need of safety and tolerability such as pediatric patients and/or patients subject to long term treatment.
• the invention further provides methods for preparing a composition of the invention.
• the invention provides a method of preparing a pharmaceutical composition comprising a pyridazine compound adapted for use in a disorder disclosed herein.
• a method can comprise mixing one or more pyridazine compound 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).
• compositions After compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a composition of the invention, such labeling would include amount, frequency, and method of administration.
• the invention provides methods to make commercially available pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) suppositories, sterile injectable solutions, and/or sterile packaged powders, which contain a pyridazine compound adapted for use in a disorder disclosed herein.
• the invention also contemplates the use of one or more pyridazine compound or method of the invention to prevent and/or ameliorate disorder severity, disorder symptoms, and/or reduce periodicity of recurrence of a disorder disclosed herein.
• the invention contemplates the prevention and treatment, in a subject, of a disorder disclosed herein, using a pyridazine compound or a composition of the invention.
• the invention provides a method for treating a disorder disclosed herein in a subject comprising administering to the subject a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.
• a method of the invention can be used therapeutically or prophylactically in a subject susceptible to or having a predisposition to a disorder disclosed herein.
• the invention provides a method for the prevention and/or intervention of a disorder disclosed herein in a subject comprising administration of at least one pyridazine compound or composition of the invention to the subject.
• the invention provides a method of treating a disorder disclosed herein comprising administering at least one pyridazine compound or a composition of the invention to a subject in need thereof to thereby produce beneficial effects, in particular sustained beneficial effects following treatment.
• the compound or composition is administered orally or systemically.
• the invention provides a method for ameliorating progression of a disorder or obtaining a less severe stage of a disorder disclosed herein in a subject suffering from such disorder comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.
• the 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 compound or a composition of the invention.
• the invention also relates to a method of increasing survival of a subject suffering from a disorder disclosed herein comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.
• the invention relates to a method of improving the lifespan of a subject suffering from a disorder disclosed herein comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.
• the compositions and methods are useful in the prevention, palliation, and/or treatment of Seizure-Related Disorders (e.g. seizures, conduction disturbances, and electroconvulsive disorders) and their manifestations irrespective of the origin of the condition in a subject.
• the invention provides methods for the prevention, palliation and/or treatment of epilepsy in a pediatric patient comprising inhibiting glial activation.
• the invention provides methods for the prevention, palliation and/or treatment of epilepsy in a pediatric patient comprising reducing pro-inflammatory cytokines (e.g. IL- ⁇ and SlOOB) following early-life seizures.
• a treatment method of the invention may be sustained over several days, weeks, months or years thereby having a major beneficial impact on the severity of a disorder or and its complications.
• the invention also contemplates the use of one or more pyridazine compound as a medicament or for the preparation of a medicament for preventing and/or treating a disorder disclosed herein.
• the invention additionally provides uses of a pharmaceutical composition of the invention as a medicament or in the preparation of medicaments for the prevention and/or treatment of a disorder disclosed herein.
• the medicaments provide beneficial effects, preferably sustained beneficial effects following treatment.
• a medicament may be in a form suitable for consumption by a subject, for example, a pill, tablet, caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap, liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium) suppository, sterile injectable solution, and/or sterile packaged powder.
• a composition or method of the invention may be administered to a healthy subject or a subject suffering from a disorder disclosed herein. Accordingly, in an embodiment, a pyridazine compound or a composition of the invention is to be administered before or after the onset of symptoms in a subject.
• the invention also provides a kit comprising a pyridazine compound or a pharmaceutical composition of the invention in kit form.
• the invention provides a kit comprising one or more pyridazine compound or composition of the invention, a container, and instructions for use in treating and/or preventing a disorder disclosed herein.
• FIG. 1 Latency to seizure onset; (B), survival and; (C, D), quantification of neuronal injury following kainic acid (KA)-induced seizures in the immature and adult rat.
• A Latency of seizure onset (minutes ⁇ SEM) on postnatal day (P) 15 (KA-PBS) is reduced compared to adult (P45) seizures (PBS-KA).
• FIG. 3 (A) KA-induced seizures in newborns result in impairment in hippocampal-linked-task. Serial measurement of spontaneous alternation of rats in Y-maze after early-life seizures (KA-PBS) shows reduction compared to controls (PBS-PBS) over 40-day recovery. (B-F) KA-induced seizures on Pl 5 result in prolonged increase in hippocampal expression of GFAP on P55. Representative photomicrographs illustrating GFAP immunostaining in the CAl field of the hippocampus of controls (B, PBS-PBS), early-life seizures (C, KA-PBS), adult seizures (D, PBS-KA), and 'two-hit' (E, KA-KA) animals.
• B PBS-PBS
• C early-life seizures
• D PBS-KA
• E 'two-hit'
• G-J Representative photomicrographs illustrating SlOOB immunostaining in the CAl field of the hippocampus of PBS-PBS (G), KA-PBS (H), PBS-KA (I), and KA-KA (J) animals.
• K Quantification of SlOOB-immunoreactive cells in combined regions of the hippocampi in the four groups. All three KA-treated groups showed a significant increase in SlOOB expression compared to controls. Counterstain is hematoxylin.
• Insets (B-E; G-J) represent higher magnification photomicrographs of CAl. ***p ⁇ 0.001 TO PBS-PBS; **p ⁇ 0.01 TO PBS-PBS by ANOVA. Scale bars, (B) 200 ⁇ m; Inset (B) 100 ⁇ m.
• FIG. 4 KA-induced microglial activation in adult animals is enhanced by early- life seizures.
• A-D Representative photomicrographs illustrating Ibal immunostaining in the CAl field of the hippocampus of PBS-PBS (A), KA-PBS (B), PBS-KA (C) and KA- KA (D) animals. Insets (A-D) are higher magnification photomicrographs of CAl.
• E Quantification of Ibal-immunoreactive cells in combined regions of the hippocampi in the four groups shows no long-term increase in microglial activation following early-life seizures (KA-PBS).
• the 'two-hit' (KA-KA) group showed significantly greater microglial activation compared to the adult seizure group (PBS-KA). Values in both groups were increased compared to controls (PBS-PBS). ***p ⁇ 0.001 TO PBSPBS; **p ⁇ 0.01 TO PBS- PBS by ANOVA. Scale bars (A) 200 ⁇ m; Insets (A-D) 100 ⁇ m.
• FIG. 1 Hippocampal factor H (FH) and clusterin levels following KA exposure.
• A Western blot micrographs and relative quantification of FH blot density demonstrate no significant changes in FH protein levels 24-hr following KA-induced seizures in newborns and adults.
• B Representative photomicrograph of FH immunostaining in the CAl field of the hippocampus of 'two-hit' (KA-KA) animals on P55.
• B inset Photomicrograph showing a FH-immunoreactive astrocyte.
• C Quantification of FH- immunoreactive cells on P55 in combined regions of the hippocampi in the long-term recovery groups shows no significant intergroup differences.
• E-G Representative photomicrographs demonstrating clusterin immunostaining in the CAl field of the hippocampus of long-term recovery groups, controls (E inset, PBS-PBS), early-life seizures (E, KA-PBS), adult seizures (F, PBS-KA; Inset, higher power view of clusterin- immunoreactive cells in CAl), and 'two-hit' (G, KA-KA) animals.
• Inset (C) shows higher power view of GLAST-immunoreactive cells in CAl.
• D Quantification of GLAST- immunoreactive cells on P55 in combined regions of the hippocampi in the long-term recovery groups demonstrates increased expression in PBS-KA and KA-KA compared to controls (PBS-PBS). PBS-KA and KA-KA are not significantly different from each other. GLT-I results were similar to GLAST (data not shown). **p ⁇ 0.01 TO PBS-PBS; *p ⁇ 0.05 TO PBS-PBS by ANOVA. Scale bars 200 ⁇ m; (Inset C) 100 ⁇ m.
• FIG. 7 Timeline of Minozac (Mzc) administration and Y-maze testing. Following intraperitoneal (ip) administration of either PBS or kainic acid (KA) on Pl 5, animals were treated with Mzc (5 mg/kg, ip) or Saline diluent (Sal), at 3 hr and 9 hr recovery. One cohort of animals from each group (PBS-SaI, KA-SaI and KA-Mzc) was sacrificed at 12 hr for assessment of changes in hippocampal pro-inflammatory cytokines. Remaining animals were allowed to recover for 30 days (P45).
• FIG. 8 Effect of Minozac (Mzc) on acute increase in proinflammatory cytokines following KA-induced seizures on Pl 5 (A-D) and glial activation after 30 day recovery (E- L).
• A Administration of Mzc following early-life seizures suppressed the acute increase in IL-l ⁇ seen in untreated animals (KA-SaI). Similar results were seen for IL-6 (B), TNF- ⁇ (C), and SlOOB (D). Tissues for brain homogenates were collected at 12 hr following KA injection.
• E-L Minozac (Mzc) suppresses long-term glial activation response to KA- induced early-life seizures after 30 day recovery from KA exposure on Pl 5.
• E-G Representative photomicrographs of GFAP immunostaining in the CAl field of control (E, PBS-SaI), early-life seizure (F, KA-SaI) and Mzc-treated (G, KA-Mzc) animals.
• H Quantification of GFAP-positive cells in the hippocampus shows Mzc-treated animals (KA-Mzc) have significantly less glial activation compared to untreated animals (KA-SaI).
• I-L Representative photomicrographs of SlOOB immunostaining in the CAl field of PBS- SaI (I), KA-SaI (J) and KA-Mzc (K) animals.
• FIG. 9 Proposed schema for the role of astrocyte and microglial activation in enhanced seizure susceptibility. Summary of effects of kainate administration on postnatal (P) day 15 (A), and P45 (B) including 'two-hits' (P15 and 45) (B). On P15, a transient increase in proinflammatory cytokines is followed by microglial activation and sustained (40 day) astrocyte activation. A similar pattern of cytokine and microglial activation occurs on P45 when astrocyte glutamate transporters also increase. Importantly, the 'two-hit' group exposed to kainate on Pl 5 and P45 show enhanced microglial activation (B, green dashed line).
• Figure 10 depicts a production scheme for synthesis of 2-(4-(4-methyl-6- phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine dihydrochloride salt (MWOl -9-034WH, also referred to herein as "Minozac”).
• 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) l-(2-pyrimidyl) piperazine, water, reflux, (e) HCl, isopropanol.
• administering and “administration” refer to a process by which a therapeutically effective amount of a compound or composition contemplated herein is delivered to a subject for prevention and/or treatment purposes.
• Compositions are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, patient age, sex, body weight, and other factors known to physicians.
• treating refers to reversing, alleviating, or inhibiting the progress of a disorder, or one or more symptoms of such disorder, to which such term applies.
• the term also refers to preventing a disorder, and includes preventing the onset of a disorder, or preventing the symptoms associated with a disorder.
• a treatment may be either performed in an acute or chronic way.
• the term also refers to reducing the severity of a disorder or symptoms associated with such disorder prior to affliction with the disorder.
• Such prevention or reduction of the severity of a disorder prior to affliction refers to administration of a compound or composition of the present invention to a subject that is not at the time of administration afflicted with the disorder.
• Preventing also refers to preventing the recurrence of a disorder or of one or more symptoms associated with such disorder.
• Treatment and “therapeutically,” refer to the act of treating, as “treating” is defined above.
• the purpose of prevention and intervention is to combat the disorder and includes the administration of an active compound to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disorder.
• treatment may comprise (i) partial or complete reversal of epileptogenesis, (ii) prevention of, or decrease or slowing of the rate of epileptogenesis, (iii) inhibition or slowing of the rate of biochemical processes which take place during epileptogenesis; and/or (iv) prevention, slowing, halting and/or reversing the process of epileptogenesis.
• subject refers to an animal preferably a warm-blooded animal such as a mammal.
• Mammal includes without limitation any members of the Mammalia.
• a mammal, as a subject or patient in the present disclosure can be from the family of Primates, Carnivora, Proboscidea, Perissodactyla, Artiodactyla, Rodentia, and Lagomorpha.
• the mammal is a human.
• animals can be treated; the animals can be vertebrates, including both birds and mammals.
• the terms include domestic animals bred for food or as pets, including equines, bovines, sheep, poultry, fish, porcines, canines, felines, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.
• the terms refer to organisms to be treated by the methods of the present invention.
• the term "subject” generally refers to an individual who will receive or who has received treatment (e.g., administration of a pyridazine compound(s) or compositions) for a disorder disclosed herein.
• Typical subjects for treatment include persons afflicted with or suspected of having or being pre-disposed to a disorder disclosed herein, or persons susceptible to, suffering from or that have suffered a disorder disclosed herein.
• a subject may or may not have a genetic predisposition for a disorder disclosed herein, such as Epilepsy.
• the subject is a pediatric patient.
• a subject may be a healthy subject.
• the term "healthy subject” means a subject, in particular a mammal, having no diagnosed disorder, infirmity, or ailment disclosed herein.
• co-administration refers to the administration of one or more pyridazine compound and additional therapeutic agent or therapies to a subject.
• the administration of two or more agents/therapies is concurrent.
• a first agent/therapy is administered prior to a second agent/therapy.
• each component may be administered separately, but sufficiently close in time to provide the desired effect, in particular a beneficial, additive, or synergistic effect.
• the formulations, routes of administration and the appropriate dosage for co-administration can be readily determined by one skilled in the art.
• the respective agents/therapies are administered at lower dosages than appropriate for their administration alone.
• co-administration is especially desirable in embodiments where the co-administration of the agents/therapies lowers the requisite dosage of a known potentially harmful (e.g., toxic) agent(s).
• a “beneficial effect” refers to an effect of a pyridazine compound or a composition of the invention, including favorable pharmacological and/or therapeutic effects, and improved biological activity.
• the beneficial effects include without limitation enhanced stability, a longer half life, and/or enhanced uptake.
• the beneficial effects include one or more of the following: (a) reduction or amelioration of neuronal dysfunction or injury following early-life seizures; (b) reduction or suppression of pro-inflammatory cytokines; (c) reduction in astrocyte activation; (d) reduction in GFAP immunoreactive cells; (e) reduction in microglial activation and (f) reduction in glial activation and impairment of hippocampal-dependent behavior.
• a beneficial effect can be a statistically significant effect in terms of statistical analysis of an effect of a pyridazine compound or a composition of the invention, versus the effects without the compound or composition that is not within the scope of the invention.
• Statistically significant" or "significantly different" effects or levels may represent levels that are higher or lower than a standard. In aspects of the invention, the difference may be 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 50 times higher or lower compared with the effect obtained without a pyridazine compound or a composition of the invention.
• the beneficial effect is a "sustained beneficial effect" where the beneficial effect is sustained for a prolonged period of time after termination of treatment.
• a treatment can be sustained over several days, weeks, months or years thereby having a major beneficial impact on the severity of the disorder and its complications.
• a beneficial effect may be sustained for a prolonged period of at least about 1 to 3 days, 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or several years following treatment.
• the period of time a beneficial effect is sustained may correlate with the duration and timing of the treatment.
• a subject may be treated continuously for about or at least about 1 to 3 days, 1 week, 2 to 4 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 14 weeks, 2 to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or several years, periodically or continuously.
• pharmaceutically acceptable carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
• a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
• carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.
• “Therapeutically effective amount” relates to the amount or dose of an active pyridazine compound or composition of the invention that will lead to one or more desired effects, in particular, one or more beneficial effects, more particularly therapeutic effects.
• a therapeutically effective amount of a substance can vary according to factors such as the disorder state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject.
• a dosage regimen may be adjusted to provide the optimum therapeutic response (e.g. sustained beneficial effects). For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• an effective amount of compound or composition is that amount sufficient to pass across the blood-brain barrier of the subject to interact with relevant receptor sites in the brain of the subject.
• a "pyridazine compound” refers to a compound of the formula I, II, III, IV, or V, or a compound depicted in Table 1, 2, 3, 4, or 5, in particular Table 2, 3, 4, or 5.
• a pyridazine compound refers to a pyridazinyl radical pendant with an aryl or substituted aryl, a heteroaryl or substituted heteroaryl.
• the term includes the structures disclosed in US Patent Application Serial Numbers 20030176437 and 20060073472.
• a pyridazine compound that demonstrates beneficial effects, in particular statistically significant beneficial effects is selected for use in the present invention.
• 1 9 1 1 9 ⁇ independently hydrogen, alkyl, alkoxy, halo, or nitro; or R and R , R and R , or R and R may form a heteroaryl or heterocyclic ring; or an isomer or a pharmaceutically acceptable salt thereof.
• a compound of the Formula Ia or Ib wherein: (a) R is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, cyano, amino, cycloalkyl, sulfonyl, sulfinyl, sulfenyl, thioaryl, thioalkyl, carbonyl, silyl, piperazinyl, piperidinyl,
• R is optionally substituted alkyl, carbonyl, carboxyl, carbamoyl, aryl, heterocylic, or heteroaryl
• R 2 is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, carbonyl, carboxyl, phenyl, benzyl, amino, aryl, cyano, -COH, piperazinyl, alcohol, piperidinyl, morpholinyl, or naphthyl
• R 3 is optionally substituted hydrogen, halo, hydroxyl, alkyl, alkenyl, alkoxy, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiol, sulfenyl, sulfonyl, sulfinyl, or nitro
• R 4 is hydrogen,
• a compound of the Formula Ia or Ib is employed wherein R 2 is carbonyl, piperazinyl, morpholinyl, sulfonyl, sulfinyl, sulfenyl, or phenyl, -
• CN -COH, -CH 2 OH, -OCH 2 CH 3 , or alkyl which may be optionally substituted with alkyl, alkoxy, amino, halo, phenyl, substituted phenyl, benzyl, hydroxyl, amino, piperidinyl, or morpholinyl.
• a compound of the Formula Ia or Ib wherein R is piperazinyl; substituted piperzinyl; alkyl which may optionally be substituted with amino; phenyl; substituted phenyl; amino which may be optionally substituted with alkyl or alkylamine (e.g., NHCOOC(CH 3 ) 3 ), carboxyl, or substituted carboxyl; hydroxyl; or nitro.
• R is piperazinyl; substituted piperzinyl; alkyl which may optionally be substituted with amino; phenyl; substituted phenyl; amino which may be optionally substituted with alkyl or alkylamine (e.g., NHCOOC(CH 3 ) 3 ), carboxyl, or substituted carboxyl; hydroxyl; or nitro.
• a compound of the Formula Ia or Ib is employed wherein R 5 is hydrogen, halo, -OCH 2 CH 2 CH 2 NHCOOC(CH 3 ) 3 , or -OCH 3 .
• R 7 is absent and there is a double bond between N at position 1 and C at position 6.
• a compound of the Formula Ia is employed wherein 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 of the Formula Ia or Ib is employed wherein R 1 is a piperazinyl which may be substituted (e.g., with a pyrimidinyl moiety); halo; amino which may be substituted; cyano; - SR 22 wherein R 22 is alkyl or aryl (e.g.
• a compound of the Formula Ia or Ib wherein R is hydrogen; morpholinyl; piperazinyl which may be substituted (e.g., with a pyrimidinyl moiety); phenyl; alkyl; alkoxy (e.g. CH(OCH 3 ) 2 ); substituted alkyl; substituted aryl (e.g., phenyl); cyano; or hydroxyl.
• R is hydrogen; morpholinyl; piperazinyl which may be substituted (e.g., with a pyrimidinyl moiety); phenyl; alkyl; alkoxy (e.g. CH(OCH 3 ) 2 ); substituted alkyl; substituted aryl (e.g., phenyl); cyano; or hydroxyl.
• a compound of the Formula Ib is employed wherein R 1 is pyridinyl, and R 2 is an N-substituted piperzinyl.
• a compound of the Formula Ib is employed wherein R is amino substituted with alkyl or cycloalkyl and R is pyridinyl.
• a compound of the Formula Ia or Ib is employed wherein R is hydrogen; hydroxyl; alkyl which may be substituted (e.g., halo); amino which may be substituted; -COR wherein R is hydrogen, hydroxyl, alkoxy (e.g. -OCH 3 ); or, aryl (e.g. phenyl) which may be substituted (e.g., alkyl).
• R is hydrogen or halo; R is hydrogen or halo; R is hydrogen or halo.
• a compound of the Formula Ia is employed wherein R is hydrogen; alkyl which may be substituted (e.g. with phenyl);
• R 1 and R 2 form a piperidinyl ring which may optionally be substituted with a carboxyl.
• a compound of the Formula Ia is employed wherein R 1 and R 7 form a pyrimidinyl ring which may optionally be substituted with alkyl, aryl, halo, or hydroxyl.
• a compound of the formula Ia or Ib is employed wherein R 1 is -NR 34 R 35 wherein R 34 is hydrogen or alkyl, and R 35 is hydrogen, alkyl, carbonyl, aryl, amino, cycloalkane, heterocylic, or heteroaryl which may be substituted.
• R 35 may comprise or be selected from the group consisting of hydrogen, C 1 -C 6 alkyl (e.g.
• methyl or ethyl which may be substituted with optionally substituted hydroxyl, alkyl, amino, carbonyl, carboxyl, morpholinyl, isoquinolinyl, or an amino which may be substituted with one or more of optionally substituted alkyl, benzyl, carboxyl, alcohol group, heteroaryl or heterocyclic, a propanol group, phenyl which may be optionally substituted with halo, benzyl which may be substituted with alkoxy, cyclohexyl, piperidinyl which may be substituted with optionally substituted phenyl, pyrrolidinyl or pyrrolidinylalkyl which may be substituted with alkyl, -COOR wherein R is alkyl which may be substituted, or [CH 2 ] m -piperidinyl wherein m is 1 to 4, in particular 1 to 3 and the piperidinyl is optionally substituted with optionally substituted alkyl, pheny
• R 35 is -R 44 R 45 wherein R 44 is -NH[CH 2 ] W NH wherein w is 1 to 4, in particular 2 or 3, and R is piperazinyl substituted with pyrimidinyl which may be substituted, in particular substituted with alkyl.
• R 35 is -R 46 R 47 wherein R 46 is -[CH 2 ] W N(CH 3 ) wherein w is 1 to 4, in particular 2 or 3, and R is piperazinyl substituted with pyrimidinyl which may be substituted, in particular substituted with alkyl.
• a compound of the Formula Ia or Ib is employed wherein R 1 is halo, especially chloro or bromo, R 2 is alkyl which may be substituted, in particular substituted with alkoxy (e.g., methoxy, dimethoxy), substituted aryl which may be substituted with alkyl, alkoxy, (e.g., benzyl, methoxy phenyl), halo (e.g.
• morpholinyl in particular a substituted morpholinyl, piperazinyl,or piperazinyl substituted with a heteroaryl in particular an 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, or pyridazinyl, especially pyrimidinyl, and optionally R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• a compound of the Formula Ia wherein R 1 is halo especially chloro or bromo, and R 3 is a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g., piperidinyl, and piperazinyl] or a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
• morpholinyl in particular a substituted morpholinyl, piperazinyl, or piperazinyl substituted with alkyl or a heteroaryl in particular an 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, or pyridazinyl, especially pyrimidinyl, or R is a substituted amino, in particular amino substituted with alkyl or substituted alkyl, in particular alkyl substituted with alkoxy carbonyl, and optionally R , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• R is halo, especially bromo or chloro, and R and R form an unsaturated ring, in particular phenyl
• R is a heteroaryl, in particular a substituted or unsubstituted unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, especially imidazolyl, and optionally R , R and R are hydrogen.
• R is halo, especially bromo or chloro, and R is nitro, and optionally R , R , R , R , and R are hydrogen.
• the invention employs a compound of the Formula Ia wherein R is a thiol substituted with alkyl (thioalkyl); substituted alkyl, in particular alkyl substituted with a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl] or a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
• morpholinyl sydnonyl
• aryl substituted aryl
• carboxyl which may be substituted with substituted or unsubstituted aryl
• R 2 is alkyl, in particular lower alkyl
• optionally R 3 is alkyl, in particular lower alkyl or nitro
• optionally R 5 is alkoxy
• optionally R 7 is alkyl
• optionally R 4 , R 5 , and R 6 are hydrogen.
• a compound of the Formula Ia is employed wherein R 1 is sulfonyl which may be substituted with substituted or unsubstituted aryl, in particular substituted phenyl, and optionally R 2 is alkyl and R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• a compound of the Formula Ia is employed wherein R is substituted or unsubstituted alkyl or alkynyl, in particular alkyl substituted with aryl, substituted aryl, halo, cyano, or alkynyl substituted with alkyl; and optionally R 2 is alkyl, R is alkyl, and R , R , R , and R are hydrogen.
• a compound of the Formula Ia is employed wherein R is cyano and R is aryl or alkyl, and optionally R , R , R , R , and R are hydrogen.
• a compound of the Formula Ia is employed wherein one or both of R 1 and R 2 are a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially a substituted morpholinyl, and optionally R , R , R , R , and R are hydrogen.
• a compound of the Formula Ia is employed wherein R is a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl], which may be substituted with substituted or unsubstituted carboxyl; R is alkyl or halo, and optionally R , R , R , R , and R are hydrogen.
• R is a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl], which may be substituted with substituted or unsubstituted carboxyl;
• R is alkyl or halo, and optionally R , R , R , R , and R are hydrogen.
• a compound of the Formula Ia wherein R is hydroxyl; R is alkyl or substituted alkyl or R is a saturated 3 to 6- membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. piperidinyl, and piperazinyl] which may optionally be substituted with a heteroaryl [e.g., pyrimidinyl], and the other of R 2 or R 3 is hydrogen, and optionally R 4 , R 5 , R 6 , and R 7 are hydrogen.
• a compound of the Formula Ia is employed wherein R 1 is a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g., piperidinyl and piperazinyl] which may be substituted with carboxyl or carboxyl substituted with alkyl or alkoxy or with purinyl or substituted purinyl; R 2 is alkyl or substituted alkyl, in particular alkylaryl, and optionally R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• R 1 is a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g., piperidinyl and piperazinyl] which may be substituted with carboxyl or carboxyl substituted with alkyl or alkoxy or with purinyl or substituted purinyl
• R 2 is alkyl or substituted alkyl, in particular alkylaryl, and optionally R 3 , R
• a compound of the Formula Ia is employed wherein R 1 is alkoxy, R 2 is alkyl, substituted alkyl, or alkoxy, and optionally R 3 , R 4 , R 5 , R , and R are hydrogen.
• a compound of the Formula Ia is employed wherein R 1 and R 2 form a heterocyclic, in particular a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms, in particular a 6-membered ring comprising 1 or 2 nitrogen atoms [e.g., piperidinyl and piperazinyl] which may be substituted for example with alkyl, halo, carboxyl, or alkoxy carbonyl, and optionally R , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• R 1 and R 2 form a heterocyclic, in particular a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms, in particular a 6-membered ring comprising 1 or 2 nitrogen atoms [e.g., piperidinyl and piperazinyl] which may be substituted for example with alkyl, halo, carboxyl, or alkoxy carbonyl, and optionally R ,
• a compound of the Formula Ia is employed wherein R 1 and R 2 form a heteroaryl, in particular an 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, or pyridazinyl, R 2 is hydrogen or alkyl, and R , R , R , R , R , and R are hydrogen.
• a compound of the Formula Ia is employed wherein R is silyl which may be substituted, in particular substituted with alkyl, R is alkyl, and R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
• R 3 , R 4 , R 5 and R 6 are hydrogen; h) a compound wherein when R is chloro or bromo, R is hydroxyl, chloro, bromo, C 1 -C 3 alkyl, phenyl, or -N(CH 3 ) 2 , and R 2 , R 4 , R 5 and R 6 are hydrogen; i) a compound wherein when R is chloro, R is methyl, R is hydroxyl, and
• R and R are hydrogen; w) a compound wherein R is methyl, and R , R , R , R and R are hydrogen; x) a compound wherein R is methyl, and R , R , R , R and R are hydrogen; y) a compound wherein R is methoxycarbonyl, R is hydrogen, and R , R , R and R are hydrogen; z) a compound wherein R 1 is -NH 2 , R 2 is methyl, chlorophenyl, methoxyphenyl, ethylphenyl, ethylmethoxyphenyl, propylphenyl, or -CH(CH 3 ) 2 , R 4 , R 5 and R 6 are hydrogen, and R 7 is absent or -CH 2 CH 2 CH 2 COOH; aa) a compound wherein R 1 is -OR 29 wherein R 29 is ethylmorpholinyl or -CH 2 CH 2 N(CH 3 ) 2 and R 2 , R 3
• R 3 , R 4 , R 5 and R 6 are hydrogen; jj) a compound wherein R 1 is -NHR 49 wherein R 49 is ethanol, methylpiperidinylbenzyl, ethylpiperidinyl, ethylpiperidinylbenzyl, or butylpiperidinylbenzyl, R 2 is hydrogen, methyl, or -C(CH 3 ) 2 , and R 3 , R 4 , R 5 and R 6 are hydrogen; kk) a compound wherein R 1 is -NHR 55 wherein R 55 is hydrogen, and R 3 , R 4 , R 5 and R 6 are hydrogen; 11) a compound wherein R 1 is -NHR 56 wherein R 56 is -CH 2 CH 2 N(CH 2 CHs) 2 or ethylmorpholinyl, R 3 is ethyl, and R 4 , R 5 and R 6 are hydrogen; mm) a compound wherein R 1 is -NHNH 2 , R 3
• R 3 , R 4 , R 5 and R 6 are hydrogen; nn) a compound wherein R 1 is -NHR 57 wherein R 57 is NH 2 , -CH 2 CH 2 OH,
• R 2 is methyl, and R 3 , R 4 , R 5 and
• R 1 is -NHR R 58 wherein R 58 is heptyl, phenyl, benzyl, or ethylphenyl, R is hydrogen, methyl, or chlorophenyl, R , R and R are hydrogen; qq) aa ccoommppoouurnd wherein R is -NR wherein R is phenyl and R , R , R , R and R are hydrogen; rr) a compound wherein R is morpholinyl and R , R , R , R and R are hydrogen; ss) a compound wherein R is methylpiperazinyl and R , R , R , R and R are hydrogen; tt) a compound wherein R 1 is -NHCH 2 CH 2 OH
• R 1 is -CHCH 2 CH 2 -isoquinolinyl
• R , R and R are hydrogen; and ccc) a compound wherein 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.
• a compound of the formula Ia or Ib is employed wherein R is a piperazinyl or substituted piperazinyl, in particular a piperazinyl substituted with a pyrimidinyl of Formula A below.
• a pyridazine compound for use in the present invention includes compounds of the Formula II: wherein R and R are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, phosphonate, cyano, halo, silyl, sil
• R 10 is hydrogen; hydroxyl; alkyl; aryl [e.g. phenyl which is optionally substituted (e.g., halide)]; piperazinyl which may be substituted (e.g. substituted with a pyrimidinyl);
• R 36 is hydrogen or alkyl
• R 37 is phenyl which may be substituted or alkyl which may be substituted (e.g. amino, in particular -CH 2 CH 2 NH 2 ; CH 2 CH 2 NHCOOC(CH 3 ) S ); morpholinyl which may be substituted; or -SR 23 wherein R 23 is phenyl which may be substituted; and R 11 is hydrogen, or aryl (e.g. phenyl) which may be substituted.
• a compound of the Formula II is employed wherein R is hydrogen, halo, optionally substituted hydroxyl, alkyl, pyridinyl, phenyl, benzyl, piperazinyl, amino, morpholinyl, or -SR 24 wherein R 24 is alkyl or aryl.
• R 10 is -NH[CH 2 ] m NR 61 R 62 wherein m is 1 to 6, in particular 2 to 4, R 61 is hydrogen, R 62 is a carboxyl, in particular -COOC(CH 3 ) 3 .
• R is hydrogen, halo, optionally substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl, or phenyl.
• a compound of the Formula II is employed wherein both of R and R are not hydrogen.
• one or more of R 10 and R 11 are alkyl, in particular C 1 -C 6 alkyl and the other of R 10 and R 11 is hydrogen.
• R 10 and R 11 are aryl in particular phenyl or benzyl and the other of R 10 and R 11 is hydrogen.
• a compound of the Formula II is a compound in Table 3, more particularly a compound designated MW01-2-065LKM, MW01-2-069SRM, MW01-2-151SRM, MW01-5-188WH, MW01-6-127WH, MW01-6- 189WH, or MWO 1-7- 107WH, and pharmaceutically acceptable salts, and derivatives thereof.
• the invention employs a compound of the Formula III:
• the invention employs a compound of the Formula IV:
• R 70 is a heterocylic, in particular a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms more particularly, pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl, especially piperazinyl or piperidinyl, which may be substituted with alkyl especially methyl, dimethyl, cycloalkyl especially cyclohexyl, aryl especially phenyl, a substituted or unsubstituted unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl, quinolizidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, phen
• a compound of the Formula IV is employed wherein R 70 is amino or substituted amino, and optionally R 71 is aryl, in particular phenyl.
• R 70 is -N- R 63 wherein R 63 is hydrogen or alkyl, in particular C 1 -C 6 alkyl, more particularly methyl or dimethyl, or -N-R 40 R 41 wherein R 40 is hydrogen or alkyl, in particular C 1 -C 6 alkyl, more particularly methyl and R 41 is alkyl substituted with amino or substituted amino, heterocyclic, substituted heterocylic, or cycloalkyl.
• R 70 is -N-R 42 R 43 wherein R 42 is hydrogen or alkyl, in particular C 1 -C 6 alkyl, more particularly methyl and R 43 is C 1 -C 6 alkyl, especially methyl or ethyl substituted with a cycloalkyl especially cyclopropyl, a heterocyclic especially piperidinyl, pyrrolidinyl, or morpholinyl which may be substituted in particular substituted with aryl, especially benzyl.
• R 42 is hydrogen or alkyl, in particular C 1 -C 6 alkyl, more particularly methyl and R 43 is C 1 -C 6 alkyl, especially methyl or ethyl substituted with a cycloalkyl especially cyclopropyl, a heterocyclic especially piperidinyl, pyrrolidinyl, or morpholinyl which may be substituted in particular substituted with aryl, especially benzyl.
• a compound of the Formula IV may comprise a structure designated as compound 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, or 139 in Table 5 or pharmaceutically acceptable salts, isomers, or derivatives thereof.
• the invention employs a compound of the Formula V:
• a compound of the Formula V is employed wherein R 50 is substituted or unsubstituted hydrogen, alkyl, aryl, or heterocyclic; R 51 is substituted or unsubstituted hydrogen or alkyl, and R 52 is substituted or unsubstituted hydrogen, alkyl, cycloalkyl, heteroaryl or halo.
• a compound of the Formula V is employed wherein R 50 is hydrogen, C 1 -C 6 alkyl which may be substituted with alkyl, especially methyl or trimethyl, phenyl, or a 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms more particularly, piperidinyl or morpholinyl, R 51 is hydrogen or alkyl especially methyl, and R 52 is hydrogen, alkyl especially methyl, dimethyl, ethyl, or propyl, cyclohexyl, chloro, or an 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, or pyridazinyl, especially pyridiny
• R is aryl
• R is hydrogen
• R is C 1 -C 6 alkyl.
• a compound of the Formula V may comprise compound MW01-7-057WH, or structure 32, 34, 36, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 63, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81, or 82 in Table 5 or pharmaceutically acceptable salts, isomers or derivatives thereof
• the pyridazine compound is an isolated and pure, in particular, substantially pure, compound of the Formula I, II, III, IV, or V, or an isomer or a pharmaceutically acceptable salt thereof.
• pure in general means better than 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure, and "substantially pure” means a compound synthesized such that the compound, as made or as available for consideration into a composition or dosage form described herein, has only those impurities that can not readily nor reasonably be removed by conventional purification processes.
• a pyridazine compound employed in the invention includes derivatives, in particular derivatives of a compound of the Formula I, II, III, IV, or V.
• the term "derivative" of a compound, as used herein, refers to a chemically modified compound wherein the chemical modification takes place either at a functional group of the compound or on the aromatic ring.
• Non-limiting examples of derivatives of compounds of the Formula I, II, III, IV, or V may include N-acetyl, N-methyl, N-hydroxy groups at any of the available nitrogens in the compound.
• Derivative groups that may be used to modify the compounds of the Formula I, II, III, IV, or V can be found in U.S. Patent Application No. 20030176437 (herein incorporated by reference in its entirety for all purposes).
• organic compounds, and/or heterocyclic derivatives thereof depicted in Tables 1, 2, 3, 4 or 5 are employed, in particular Tables 2, 3, 4, or 5.
• the invention employs a compound of the Formula I, II, III, IV, or V as defined herein, with the proviso that compounds depicted in Table 1 are excluded.
• the invention employs a compound of the Formula II with the proviso that the compounds depicted in Table 1 are excluded.
• the invention employs a compound of the Formula III with the proviso that compounds depicted in Table 1 are excluded.
• the invention employs compounds of the Formula IV with the proviso that compounds depicted in Table 1 are excluded.
• the invention employs compounds of the Formula V with the proviso that compounds depicted in Table 1 are excluded.
• pyridazine compounds and/or related heterocyclic derivatives thereof are employed in the treatment or prevention of disorders disclosed herein.
• the compounds employed are those depicted in Table 2, 3, 4, and/or 5 or derivatives thereof.
• the invention employs one or more of the compounds designated herein as MWO 1-3-
• the invention employs one or more of the compounds designated herein as MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2- 184WH, MW01-2-189WH and MW01-2-151SRM, or isomers or pharmaceutically acceptable salts thereof.
• the invention employs one or more of the compounds designated MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MW01-2-151SRM, MW01-2-189WH, and MW01-1-01-L-D07, and/or related derivatives, in particular, heterocyclic derivatives, of these compounds.
• MW01-2-151SRM an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed in the invention.
• MW01-5-188WH an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed in the invention.
• a pyridazine compound also includes "pharmaceutically acceptable salt(s)".
• pharmaceutically acceptable salts are meant those salts which are suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1.
• salts include the compounds designated herein as MWOl-I-Ol-L-DlO, MWOl-I -01 -L-E02, MW01-1-01-L-E08, MW01-1-03-L-A05, MW01-1-16-L-D09, and MW01-1-17-L-G04.
• an acid addition salt in particular a halide salt, more particularly a chloride salt, most particularly a hydrochloride salt of a compound of the formula II is employed.
• a pharmaceutically acceptable halide salt of the pyridazine compound 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1- yl)pyridazine(5) shown in Figure 10 is employed.
• a pharmaceutically acceptable salt employed in the invention is a chloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine(5) shown in Figure 10.
• a pharmaceutically acceptable salt is a hydrochloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (5) shown in Figure 10, more particularly the di -hydrochloride hydrate salt shown below (i.e., MW01-9-034WH)(16)(i.e., 2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl) pyrimidine dihydrochloride salt)(6).
• a di-hydrochloride hydrate salt of a compound of the Formula V in particular 2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine dihydrochloride salt (6) shown in Figure 10, characterized by enhanced solubility is utilized in the present invention.
• the di-hydrochloride hydrate salt may be further characterized by one or more of the following: a yellow powder, having a purity of greater than about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, molecular weight of 423.3395, soluble in DMSO, melting point of greater than 488K, acid dissociation constants (pKa) of 2.55, 1.46, 0.84 and -4.31 (calculated), logP of 2.29 determined from octanol/water partition coefficient, logS of 2.5 (experimental)/4.08 (calculated), and/or having an aqueous solubility at 37°C of about 100 to 400 mg/ml, about 100 to 350 mg/ml, about 150 to 350 mg/ml, about 200 to 350 mg/ml, or about 300 to 350 mg/ml, in particular a solubility of greater than 322 mg/ml in water (2HCL»H 2 O) salt).
• a yellow powder having a purity
• a compound of the Formula V in amorphous or crystalline form that has an enhanced resorption rate is utilized.
• the resorption rate is increased by a factor of at least 2, 3, 4 or 5.
• a pyridazine compound in particular a compound of the Formula I, II, III, IV, or V, may contain one or more asymmetric centers and may give rise to enantiomers, diasteriomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
• pyridazine compounds include all possible diasteriomers and enantiomers as well as their racemic and optically pure forms.
• Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• a pyridazine compound contains centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. All tautomeric forms are also included within the scope of a pyridazine compound employed in the present invention.
• a compound of the formula I, II, III, IV or V includes crystalline forms which may exist as polymorphs. Solvates of the compounds formed with water or common organic solvents are also intended to be encompassed within the term.
• a pyridazine compound in particular a compound of the Formula I, II, III, IV, or V, can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• solvated forms may be considered equivalent to the unsolvated forms for the purposes of the present invention.
• hydrate forms of the compounds and their salts are encompassed within this invention.
• Further prodrugs of compounds of the formula I, II, III, IV or V are encompassed within the term.
• solvate means a physical association of a compound with one or more solvent molecules or a complex of variable stoichiometry formed by a solute (for example, a compound of the invention) and a solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding.
• the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• the solvents selected do not interfere with the biological activity of the solute.
• Solvates encompass both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
• hydrate means a solvate wherein the solvent molecule(s) is/are H 2 O, including, mono-, di-, and various poly-hydrates thereof. Solvates can be formed using various methods known in the art.
• Crystalline compounds of the formula I, II, III, IV or V can be in the form of a free base, a salt, or a co-crystal. Free base compounds can be crystallized in the presence of an appropriate solvent in order to form a solvate.
• Acid salt compounds of the formula I, II, III, IV or V e.g. HCl, HBr, benzoic acid
• solvates can be formed by the use of acetic acid or ethyl acetate.
• the solvate molecules can form crystal structures via hydrogen bonding, van der Waals forces, or dispersion forces, or a combination of any two or all three forces.
• the amount of solvent used to make solvates can be determined by routine testing.
• a monohydrate of a compound of the formula I, II, III, IV or V would have about 1 equivalent of solvent (H 2 O) for each equivalent of a compound of the invention.
• solvent H 2 O
• more or less solvent may be used depending on the choice of solvate desired.
• Compounds of the formula I, II, III, IV or V may be amorphous or may have different crystalline polymorphs, possibly existing in different solvation or hydration states.
• crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
• Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility.
• a compound of the Formula I, II, III, IV, or V may be in the form of a prodrug that is converted in vivo to an active compound.
• one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 may comprise a cleavable group that is cleaved after administration to a subject to provide an active (e.g., therapeutically active) compound, or an intermediate compound that subsequently yields the active compound.
• a cleavable group can be an ester that is removed either enzymatically or non-enzymatically.
• prodrug means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
• prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds.
• the prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
• prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
• Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard- Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly 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. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309 396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M.
• prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g. N,N-dimethylaminocarbonyl) of hydroxy functional groups on compounds of the formula I, II, III, IV or V, and the like.
• esters e.g., acetate, formate, and benzoate derivatives
• carbamates e.g. N,N-dimethylaminocarbonyl
• a compound of the formula I, II, III, IV or V compound can include a pharmaceutically acceptable co-crystal or a co-crystal salt.
• a pharmaceutically acceptable co-crystal includes a co-crystal that is suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and has the desired pharmacokinetic properties.
• co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point, and heats of fusion.
• Co-crystals can be formed by an active pharmaceutical ingredient (API) and a co-crystal former either by hydrogen bonding or other non-covalent interactions, such as pi stacking and van der Waals interactions.
• API active pharmaceutical ingredient
• An aspect of the invention provides for a co-crystal wherein the co- crystal former is a second API.
• the co-crystal former is not an API.
• the co-crystal comprises more than one co-crystal former.
• co-crystal formers can be incorporated in a co-crystal with an API.
• pharmaceutically acceptable co-crystals are described, for example, in “Pharmaceutical co-crystals," Journal of Pharmaceutical Sciences, Volume 95 (3) Pages 499 - 516, 2006. Methods for producing co-crystals are discussed in the United States Patent Application 20070026078.
• a co-crystal former which is generally a pharmaceutically acceptable compound, may be, 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, 2,6-pyridinecarboxylic acid, 5-nitroisophthalic acid, citric acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benezenesulfonic acid.
• a pyridazine compound in particular a compound of the Formula I, II, III, IV, or V, may optionally comprise a carrier interacting with one or more radicals in the compound, for example R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 in Formula I.
• a carrier may be a polymer, carbohydrate, or peptide, or derivatives or combinations thereof, and it may be optionally substituted, for example, with one or more alkyl, halo, hydroxyl, halo, or amino.
• a carrier may be directly or indirectly covalently attached to a pyridazine compound.
• a carrier may be substituted with substituents described herein including without limitation one or more alkyl, amino, nitro, halogen, thiol, thioalkyl, sulfate, sulfonyl, sulfinyl, sulfoxide and hydroxyl groups.
• the carrier is an amino acid including alanine, glycine, praline, methionine, serine, threonine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl.
• a carrier can also include a molecule that targets a pyridazine compound, in particular a compound of the Formula I, II, III, IV, or V, to a particular tissue or organ.
• a carrier may facilitate or enhance transport of a pyridazine compound, in particular a compound of the Formula I, II, III, IV or V, to a target therapeutic site, for example the brain.
• a “polymer” refers to molecules comprising two or more monomer subunits that may be identical repeating subunits or different repeating subunits.
• a monomer generally comprises a simple structure, low-molecular weight molecule containing carbon. Polymers may optionally be substituted. Polymers that can be used in the present invention include without limitation vinyl, acryl, styrene, carbohydrate derived polymers, polyethylene glycol (PEG), polyoxyethylene, polymethylene glycol, poly-trimethylene glycols, polyvinylpyrrolidone, polyoxyethylene-polyoxypropylene block polymers, and copolymers, salts, and derivatives thereof.
• 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-l -propanesulfonic acid- co-styrene), poly(vinylsulfonic acid); poly(sodium 4-styrenesulfonic acid); and sulfates and sulfonates derived therefrom; poly(acrylic acid), poly(methylacrylate), poly(methyl methacrylate), and poly(vinyl alcohol).
• a “carbohydrate” as used herein refers to a polyhydroxyaldehyde, or polyhydroxyketone 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 aldopentose.
• the term also includes carbohydrates composed of monosaccharide units, including disaccharides, ogliosaccharides, or polysaccharides. Examples of disaccharides are sucrose, lactose, and maltose.
• Oligosaccharides generally contain between 3 and 9 monosaccharide units and polysaccharides contain greater than 10 monosaccharide units.
• a carbohydrate group may be substituted at one two, three or four positions, other than the position of linkage to a pyridazine compound.
• a carbohydrate may be substituted with one or more alkyl, amino, nitro, halo, thiol, carboxyl, or hydroxyl groups, which are optionally substituted.
• Illustrative substituted carbohydrates are glucosamine, or galactosamine.
• the carbohydrate is a sugar, in particular a hexose or pentose and may be an aldose or a ketose.
• a sugar may be a member of the D or L series and can include amino sugars, deoxy sugars, and their uronic acid derivatives.
• the carbohydrate is a hexose
• the hexose is glucose, galactose, or mannose, or substituted hexose sugar residues such as an amino sugar residue such as hexosamine, galactosamine, glucosamine, in particular D-glucosamine (2-amino-2-doexy- D-glucose) or D-galactosamine (2-amino-2-deoxy-D-galactose).
• Illustrative pentose sugars include arabinose, fucose, and ribose.
• a sugar residue may be linked to a pyridazine compound from a 1,1 linkage, 1,2 linkage, 1,3 linkage, 1,4 linkage, 1,5 linkage, or 1,6 linkage.
• a linkage may be via an oxygen atom of a pyridazine compound.
• An oxygen atom can be replaced one or more times by -CH 2 - or -S- groups.
• glycoproteins such as lectins (e.g. concanavalin A, wheat germ agglutinin, peanutagglutinin, seromucoid, and orosomucoid) and glycolipids such as cerebroside and ganglioside.
• a "peptide” carrier includes one, two, three, four, or five or more amino acids covalently linked through a peptide bond.
• a peptide can comprise one or more naturally occurring amino acids, and analogs, derivatives, and congeners thereof.
• a peptide can be modified to increase its stability, bioavailability, solubility, etc.
• Peptide analogue and “peptide derivative” as used herein include molecules which mimic the chemical structure of a peptide and retain the functional properties of the peptide.
• a carrier can be an amino acid such as alanine, glycine, proline, methionine, serine, threonine, histidine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl.
• a carrier can be a polypeptide such as albumin, antitrypsin, macroglobulin, haptoglobin, caeruloplasm, transferring, ⁇ - or ⁇ - lipoprotein, ⁇ - or ⁇ - globulin or fibrinogen.
• a peptide can be attached to a pyridazine compound through a functional group on the side chain of certain amino acids (e.g. serine) or other suitable functional groups.
• a carrier may comprise four or more amino acids with groups attached to three or more of the amino acids through functional groups on side chains.
• the carrier is one amino acid, in particular a sulfonate derivative of an amino acid, for example cysteic acid.
• alkyl either alone or within other terms such as “thioalkyl” and "arylalkyl”, means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain.
• An alkyl radical for use in the present invention generally comprises from about 1 to 20 carbon atoms, particularly from about 1 to 10, 1 to 8 or 1 to 7, more particularly about 1 to 6 carbon atoms, or 3 to 6 carbon atoms.
• Illustrative alkyl radicals include 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, along with branched variations thereof.
• an alkyl radical is a C 1 -C 6 lower alkyl comprising or selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec -butyl, tert-butyl, tert-pentyl, and n-hexyl.
• An alkyl radical may be optionally substituted with substituents as defined herein at positions that do not significantly interfere with the preparation of compounds of the Formula I, II, III, IV, or V and do not significantly reduce the efficacy of the compounds.
• an alkyl radical is substituted with substituents, in particular one to five substituents, including halo, lower alkoxy, lower aliphatic, a 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 (e.g.
• CF 3 halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, cycloaliphatic, substituted cycloaliphatic, or aryl (e.g., phenylmethyl (i.e. benzyl)). Substituents on an alkyl group may themselves be substituted.
• substituted aliphatic refers to an alkyl or an alkane possessing less than 10 carbons where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, an amino, a hydroxy, a nitro, a thio, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic, etc.).
• groups include, but are not limited to, 1 -chloroethyl and the like.
• lower-alkyl- substituted-amino refers to any alkyl unit containing up to and including eight carbon atoms where one of the aliphatic hydrogen atoms is replaced by an amino group. Examples of such groups include, but are not limited to, ethylamino and the like.
• lower-alkyl- substituted-halogen refers to any alkyl chain containing up to and including eight carbon atoms where one of the aliphatic hydrogen atoms is replaced by a halogen.
• groups include, but are not limited to, chlorethyl and the like.
• acetylamino shall mean any primary or secondary amino that is acetylated. Examples of such groups include, but are not limited to, acetamide and the like.
• alkenyl refers to an unsaturated, acyclic branched or straight-chain hydrocarbon radical comprising at least one double bond.
• An alkenyl radical may contain from about 2 to 24, 2 to 15, or 2 to 10 carbon atoms, in particular from about 3 to 8 carbon atoms and more particularly about 3 to 6 or 2 to 6 carbon atoms.
• Suitable alkenyl radicals include without limitation ethenyl, propenyl (e.g., 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, hepten-1-yl, and octen-1-yl, and the like.
• An alkenyl radical may be optionally substituted similar to alkyl.
• substituted alkenyl includes an alkenyl group substituted by, for example, one to three substituents, preferably one to two substituents, such as alkyl, alkoxy, haloalkoxy, alkylalkoxy, haloalkoxyalkyl, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamido, thioalkoxy, aryl, nitro, and the like.
• substituents such as alkyl, alkoxy, haloalkoxy, alkylalkoxy, haloalkoxy
• alkynyl refers to an unsaturated, branched or straight- chain hydrocarbon radical comprising one or more triple bonds.
• An alkynyl radical may contain about 1 to 20, 1 to 15, or 2-10 carbon atoms, particularly about 3 to 8 carbon atoms and more particularly about 3 to 6 carbon atoms.
• Suitable alkynyl radicals include without limitation ethynyl, such as prop-1-yn-1-yl and prop-2-yn-1-yl, butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, and 3-methylbutyn-1-yl, hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and 3,3-dimethylbutyn-1-yl radicals and the like.
• An alkynyl may be optionally substituted similar to alkyl.
• cycloalkynyl refers to cyclic alkynyl groups.
• substituted alkynyl includes an alkynyl group substituted by, for example, a substituent, such as, alkyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamido, thioalkoxy, aryl, nitro, and the like.
• a substituent such as, alkyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino,
• alkylene refers to a linear or branched radical having from about 1 to 10, 1 to 8, 1 to 6, or 2 to 6 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, propylene, butylene, pentylene, hexylene, ethylidene, methylethylene, and isopropylidene.
• alkenylene radical is present as a substituent on another radical it is typically considered to be a single substituent rather than a radical formed by two substituents.
• alkenylene refers to a linear or branched radical having from about 2 to 10, 2 to 8, or 2 to 6 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds.
• halo refers to a halogen such as fluorine, chlorine, bromine or iodine atoms.
• hydroxyl or “hydroxy” refers to an -OH group.
• cyano refers to a carbon radical having three of four covalent bonds shared by a nitrogen atom, in particular -C ⁇ N. A cyano group may be substituted with substituents described herein.
• alkoxy refers to a linear or branched oxy-containing radical having an alkyl portion of one to about ten carbon atoms, such as a methoxy radical, which may be substituted. In aspects of the invention an alkoxy radical may comprise about 1-10, 1-8, 1-6, or 1-3 carbon atoms.
• an alkoxy radical comprises about 1-6 carbon atoms and includes a C 1 -C 6 alkyl-O-radical wherein C 1 -C 6 alkyl has the meaning set out herein.
• alkoxy radicals include without limitation methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls.
• An "alkoxy" radical may optionally be substituted with one or more substitutents disclosed herein including alkyl atoms to provide "alkylalkoxy” radicals; halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals (e.g.
• fluoromethoxy chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropox
• haloalkoxyalkyl radicals e.g. fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
• alkenyloxy refers to linear or branched oxy-containing radicals having an alkenyl portion of about 2 to 10 carbon atoms, such as an ethenyloxy or propenyloxy radical.
• An alkenyloxy radical may be a "lower alkenyloxy” radical having about 2 to 6 carbon atoms. Examples of alkenyloxy radicals include without limitation ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls.
• alkenyloxy radical may be substituted with one or more substitutents disclosed herein including halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy” radicals (e.g. trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy).
• haloalkenyloxy e.g. trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy.
• a “carbocylic” includes radicals derived from a saturated or unstaturated, substituted or unsubstituted 5 to 14, 5 to 12, or 5 to 10 member organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon.
• carbocyclic radicals are cycloalkyl, cycloalkenyl, aryl, in particular phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexyl, acenapththylenyl, anthracenyl, biphenyl, bibenzylyl, and related bibenzylyl homologs, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl and the like.
• cycloalkyl refers to radicals having from about 3 to 15, 3 to 10, 3 to 8, or 3 to 6 carbon atoms and containing one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused.
• cycloalkyl refers to an optionally substituted, saturated hydrocarbon ring system containing 1 to 2 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 -C 7 carbocylic ring.
• cycloalkyl groups include single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclododecyl, and the like, or multiple ring structures such as adamantanyl, and the like.
• the cycloalkyl radicals are "lower cycloalkyl” radicals having from about 3 to 10, 3 to 8, 3 to 6, or 3 to 4 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• the term "cycloalkyl” also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals.
• a cycloalkyl radical may be optionally substituted with groups as disclosed herein.
• substituted cycloalkyl includes cycloalkyl groups having from 1 to 5 (in particular 1 to 3) substituents including without limitation alkyl, alkenyl, alkoxy, cycloalkyl, substituted cycloalkyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, and nitro.
• cycloaliphatic refers to a cycloalkane possessing less than 8 carbons or a fused ring system consisting of no more than three fused cycloaliphatic rings. Examples of such groups include, but are not limited to, decalin and the like.
• substituted cycloaliphatic refers to a cycloalkane possessing less than 8 carbons or a fused ring system consisting of no more than three fused rings, and where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, a nitro, a thio, an amino, a hydroxy, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic).
• cycloalkenyl refers to radicals comprising about 4 to 16, 2 to 15, 2 to 10, 2 to 8, 4 to 10, 3 to 8, 3 to 7, 3 to 6, or 4 to 6 carbon atoms, one or more carbon-carbon double bonds, and one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused.
• the cycloalkenyl radicals are "lower cycloalkenyl” radicals having three to seven carbon atoms.
• cycloalkenyl radicals include without limitation cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
• a cycloalkenyl radical may be optionally substituted with groups as disclosed herein, in particular 1, 2, or 3 substituents which may be the same or different.
• cycloalkoxy refers to cycloalkyl radicals (in particular, cycloalkyl radicals having 3 to 15, 3 to 8 or 3 to 6 carbon atoms) attached to an oxy radical.
• examples of cycloalkoxy radicals include cyclohexoxy and cyclopentoxy.
• a cycloalkoxy radical may be optionally substituted with groups as disclosed herein.
• aryl refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused.
• an aryl radical comprises 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms.
• aryl radicals includes without limitation aromatic radicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl.
• aromatic radicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl.
• aryl radical may be optionally subsitituted with groups as disclosed herein, in particular hydroxyl, alkyl ("arylalkyl”), carbonyl, carboxyl, thiol ("thioalkyl”), amino, and/or halo, in particular a substituted aryl includes without limitation arylamine and arylalkylamine.
• substituted aryl includes an aromatic ring, or fused aromatic ring system consisting of no more than three fused rings at least one of which is aromatic, and where at least one of the hydrogen atoms on a ring carbon has been replaced by a halogen, an amino, a hydroxy, a nitro, a thio, an alkyl, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such groups include, but are not limited to, hydroxyphenyl, chlorophenyl and the like.
• an aryl radical may be optionally subsitituted with one to four 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, alkysulfonyl, s
• a substituent may be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or aralkyl.
• an aryl radical is substituted with hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo.
• aralkyl refers to an aryl or a substituted aryl group bonded directly through an alkyl group, such as benzyl.
• substituted aryl radicals include chlorobenyzl, and amino benzyl.
• aryloxy refers to aryl radicals, as defined above, attached to an oxygen atom.
• exemplary aryloxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
• arylalkoxy refers to an aryl group attached to an alkoxy group.
• Representative examples of arylalkoxy groups include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
• aroyl refers to aryl radicals, as defined above, attached to a carbonyl radical as defined herein, including without limitation benzoyl and toluoyl.
• An aroyl radical may be optionally substituted with groups as disclosed herein.
• heteroaryl refers to fully unsaturated heteroatom- containing ring-shaped aromatic radicals having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen.
• a heteroaryl radical may contain one, two or three rings and the rings may be attached in a pendant manner or may be fused.
• the term refers to fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 3 to 15, 3 to 10, 3 to 8, 5 to 15, 5 to 10, or 5 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
• heteroaryl radicals include without limitation, an 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, tetrazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl, quinolizidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, phenanthridinyl, a
• heterocyclic radicals are fused with aryl radicals, in particular bicyclic radicals such as benzofuranyl, benzothiophenyl, phthalazinyl, chromenyl, xanthenyl, and the like.
• a heteroaryl radical may be optionally substituted with groups as disclosed herein, for example with an alkyl, amino, halogen, etc., in particular a heteroarylamine.
• the term refers to an 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, tetrazolyl and the like.
• a heteroaryl radical may be optionally substituted with groups disclosed herein, for example with an alkyl, amino, halogen, etc., in particular a substituted heteroaryl radical is a heteroarylamine.
• heterocyclic refers to saturated and partially saturated heteroatom- containing ring-shaped radicals having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen.
• a heterocylic radical may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
• the term refers to a saturated and partially saturated heteroatom-containing ring-shaped radicals having from about 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 3 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
• Examplary saturated heterocyclic radicals include without limitation a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl] ; a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
• morpholinyl sydnonyl
• a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl] etc.
• partially saturated heterocyclyl radicals include without limitation dihydrothiophene, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.
• heterocyclic radicals include without limitation 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
• heterocyclic refers to a cycloalkane and/or an aryl ring system, possessing less than 8 carbons, or a fused ring system consisting of no more than three fused rings, where at least one of the ring carbon atoms is replaced by oxygen, nitrogen or sulfur.
• groups include, but are not limited to, morpholino and the like.
• substituted heterocyclic refers to a cycloalkane and/or an aryl ring system, possessing less than 8 carbons, or a fused ring system consisting of no more than three fused rings, where at least one of the ring carbon atoms is replaced by oxygen, nitrogen or sulfur, and where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, hydroxy, a thio, nitro, an amino, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such groups include, but are not limited to 2-chloropyranyl.
• heteroaryl and heterocyclic groups may be C-attached or N-attached (where such is possible).
• sulfonyl used alone or linked to other terms such as alkylsulfonyl or arylsulfonyl, refers to the divalent radicals -SO 2 -.
• the sulfonyl group may be attached to a substituted or unsubstituted hydroxyl, alkyl group, ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, heterocyclic group, carbohydrate, peptide, or peptide derivative.
• sulfinyl used alone or linked to other terms such as alkylsulfinyl (i.e. -S(O)-alkyl) or arylsulfinyl, refers to the divalent radicals -S(O)-.
• R is an electron pair, hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, heterocyclic, carbohydrate, peptide, or peptide derivative.
• sulfate used alone or linked to other terms, is art recognized and includes a group that can be represented by the formula:
• R 19 is an electron pair, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, carbohydrate, peptide or peptide derivative.
• amino refers to a radical where a nitrogen atom (N) is bonded to three substituents being any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, heterocyclic, or heteroaryl with the general chemical formula -NR R where R and R can be any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, carbonyl carboxyl, amino, silyl, heteroaryl, or heterocyclic which may or may not be substituted.
• one substituent on the nitrogen atom may be a hydroxyl group (-OH) to provide an amine known as a hydroxylamine.
• amino groups are amino (-NH 2 ), alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino, arylalkylamino, and lower alkylsilylamino, in particular methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino, cyclohexylamino, piperidinyl, hydrazinyl, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert.-butylsilylamino, which may or may not
• thiol means -SH.
• a thiol may be substituted with a substituent disclosed herein, in particular alkyl (thioalkyl), aryl (thioaryl), alkoxy (thioalkoxy) or carboxyl.
• sulfenyl used alone or linked to other terms such as alkylsulfenyl, refers to the radical -SR 25 wherein R 25 is not hydrogen.
• R 25 is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, silylalkyl, heterocyclic, heteroaryl, carbonyl, carbamoyl, alkoxy, or carboxyl.
• thioalkyl alone or in combination, refers to a chemical functional group where a sulfur atom (S) is bonded to an alkyl, which may be substituted.
• thioalkyl groups are thiomethyl, thioethyl, and thiopropyl.
• a thioalkyl may be substituted with a substituted or unsubstitute carboxyl, aryl, heterocylic, carbonyl, or heterocyclic.
• thioaryl alone or in combination, refers to a chemical functional group where a sulfur atom (S) is bonded to an aryl group with the general chemical formula -SR where R is aryl which may be substituted.
• thioaryl groups and substituted thioaryl groups are thiophenyl, chlorothiophenyl, para-chlorothiophenyl, thiobenzyl, 4-methoxy-thiophenyl, 4-nitro-thiophenyl, and para-nitrothiobenzyl.
• thioalkoxy refers to a chemical functional group where a sulfur atom (S) is bonded to an alkoxy group with the general chemical formula -SR 27 where R 27 is an alkoxy group which may be substituted.
• thioalkoxy group may have 1-6 carbon atoms i.e. a -S-(O)- C 1 -C 6 alkyl group wherein C 1 -C 6 alkyl have the meaning as defined above.
• -C 6 thioalkoxy include thiomethoxy and thioethoxy.
• a thiol may be substituted with a substituted or unsubstituted heteroaryl or heterocyclic, in particular a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl] or a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially a substituted morpholinyl or piperidinyl.
• a substituted or unsubstituted heteroaryl or heterocyclic in particular a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and pipe
• carbonyl refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom.
• -C(O)OR 14 provides an ester or an amino acid derivative.
• An esterified form is also particularly referred to herein as a "carboxylic ester".
• a "carboxyl” may be substituted, in particular substituted with alkyl which is optionally substituted with one or more of amino, amino, halo, alkylamino, aryl, carboxyl or a heterocyclic.
• carboxyl groups are methoxycarbonyl, butoxycarbonyl, tert.alkoxycarbonyl such as tert.butoxycarbonyl, arylmethyoxycarbonyl having one or two aryl radicals including without limitation phenyl optionally substituted by for example lower alkyl, lower alkoxy, hydroxyl, halo, and/or nitro, such as benzyloxycarbonyl, methoxybenxyloxycarbonyl, diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl,
• 2-iodoethoxycarbonyltert.butylcarbonyl 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, benzhydroxycarbonyl, di-(4-methoxyphenyl-methoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2-triphenylsilylethoxycarbonyl.
• Additional carboxyl groups in esterified form are silyloxycarbonyl groups including organic silyloxycarbonyl.
• the silicon substituent in such compounds may be substituted with lower alkyl (e.g. methyl), alkoxy (e.g.
• the carboxyl group may be an alkoxy carbonyl, in particular methoxy carbonyl, ethoxy carbonyl, isopropoxy carbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, or heptyloxy carbonyl, especially methoxy carbonyl or ethoxy carbonyl.
• carbamoyl refers to amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
• carboxyamide refers to the group -CONH-.
• nitro means -NO 2 -.
• acyl alone or in combination, means a carbonyl or thiocarbonyl group bonded to a radical selected from, for example, optionally substituted, hydrido, alkyl (e.g. haloalkyl), alkenyl, alkynyl, alkoxy ("acyloxy” including acetyloxy, butyryloxy, iso-valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo, heterocyclyl, heteroaryl, sulfinyl (e.g.
• alkylsulfinylalkyl sulfonyl (e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (e.g alkylamino or dialkylamino), and aralkoxy.
• acyl radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
• acyl refers to a group -C(O)R , where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
• R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
• R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
• R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
• examples include, but are not limited to formyl, acet
• phosphonate refers to a C-PO(OH) 2 or C-PO(OR 65 ) 2 group wherein R is alkyl or aryl which may be substituted.
• ureido refers to the group "-NHCONH-".
• a ureido radical includes an alkylureido comprising a ureido substituted with an alkyl, in particular a lower alkyl attached to the terminal nitrogen of the ureido group.
• alkylureido include without limitation N'-methylureido, N'-ethylureido, N'-n-propylureido, N'-i- propylureido and the like.
• a ureido radical also includes a N',N'-dialkylureido group containing a radical -NHCON where the terminal nitrogen is attached to two optionally substituted radicals including alkyl, aryl, heterocylic, and heteroaryl.
• radicals including "alkyl”, “alkoxy”, “alkenyl”, “alkynyl”,
• hydroxyl etc. refer to both unsubstituted and substituted radicals.
• substituted means that any one or more moiety on a designated atom (e.g., hydrogen) is replaced with a selection from a group disclosed herein, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or radicals are permissible only if such combinations result in stable compounds.
• “Stable compound” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• a radical in a pyridazine compound may be substituted with one or more substituents apparent to a person skilled in the art including without limitation alkyl, alkoxy, alkenyl, alkynyl, alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene, haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl, alkylaryl, haloalkoxy, haloalkenyloxy, heterocyclic, heteroaryl, alkylsulfonyl, sulfinyl, sulfonyl, sulfenyl, alkylsulfinyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, amino, oxy, halo, azi
• a chemical substituent is "pendant" from a radical if it is bound to an atom of the radical.
• the substituent can be pending from a carbon atom of a radical, a carbon atom connected to a carbon atom of the radical by a chain extender, or a heteroatom of the radical.
• the term “fused” means that a second ring is present (i.e, attached or formed) by having two adjacent atoms in common or shared with the first ring.
• Pyridazine compounds in particular compounds of the Formula I, II, III, IV, or V can be prepared using reactions and methods generally known to the person of ordinary skill in the art, having regard to that knowledge and the disclosure of this application including the Examples.
• the reactions are performed in a solvent appropriate to the reagents and materials used and suitable for the reactions being effected.
• the functionality present on the compounds should be consistent with the proposed reaction steps. This will sometimes require modification of the order of the synthetic steps or selection of one particular process scheme over another in order to obtain a desired compound of the invention.
• another major consideration in the development of a synthetic route is the selection of the protecting group used for protection of the reactive functional groups present in the compounds.
• An authoritative account describing the many alternatives to the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
• the starting materials and reagents used in preparing the pyridazine compounds are either available from commercial suppliers or are prepared by methods well known to a person of ordinary skill in the art, following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., 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 Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
• the starting materials, intermediates, and pyridazine compounds may be isolated and purified using conventional techniques, such as precipitation, filtration, distillation, crystallization, chromatography, and the like.
• the pyridazine compounds may be characterized using conventional methods, including physical constants and spectroscopic methods, in particular HPLC.
• Pyridazine compounds which are basic in nature can form a wide variety of different salts with various inorganic and organic acids.
• a pyridazine compound from the reaction mixture as a pharmaceutically unacceptable salt and then convert the latter to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the base compounds of the pyridazine compounds are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
• Pyridazine compounds which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• These salts may be prepared by conventional techniques by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.
• they may be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are typically employed to ensure completeness of reaction and maximum product yields.
• a compound of the formula II wherein R 11 is hydrogen and R 10 is an 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, more particularly pyridinyl, may be prepared by reacting a compound with a structure of formula II wherein R 10 is halo, in particular chloro, and R 11 is hydrogen, with boronic acid substituted with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl
• a compound of the formula II wherein R is hydrogen and R is a substituted aryl is prepared by reacting a compound with the structure of formula II wherein R is halo, in particular chloro, and R is hydrogen, with a substituted aryl boronic acid under suitable conditions.
• a compound of the formula II wherein R is hydrogen and R is alkyl is prepared by reacting a compound with the structures of formula II wherein R is halo, in particular chloro, and R is hydrogen, with an alkyl boronic acid under suitable conditions.
• R is lower alkyl, in particular methyl or ethyl
• a compound of the formula II wherein R is chloro is reacted with lower alkyl boronic acid, in particular methyl or ethyl boronic acid under suitable conditions.
• a compound of the formula II is prepared wherein R 10 is hydrogen and R 11 is an alkyl by reacting a pyridazine substituted at the C3 position with halo (e.g., chloro), at the C4 position with alkyl, and at the 6 position with phenyl, with 2-(piperidin-
• R 10 is hydrogen and R 11 is an alkyl.
• R 11 is methyl or ethyl.
• a compound of the formula II wherein R 10 is hydrogen and R 11 is aryl is prepared by reacting a compound with the structure of formula II wherein R 10 is hydrogen and R 11 is halo (e.g., chloro), with pyridazine substituted at the C3 position with halo (e.g., chloro), at the C4 position with aryl, and at the 6 position with phenyl, with 2- (piperidin-4-yloxy)pyrimidine under suitable conditions.
• R 11 is phenyl.
• a compound of the formula II is prepared wherein R 10 is hydrogen and R is an 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, more particularly pyridinyl by reacting a compound of the formula II wherein R 11 is halo, in particular chloro, and R is hydrogen, with a boronic acid substituted with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyri
• a compound of the formula II is prepared wherein R is hydrogen and R is pyridinyl by reacting a compound of the formula II wherein R is halo, in particular chloro, and R is hydrogen, with a pyridinyl boronic acid under suitable conditions.
• a compound of the formula II is prepared wherein R is hydrogen and R is an 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, more particularly pyridinyl by reacting a pyridazine substituted at the C3 position with halo, at the C4 position with an 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,
• a compound of the formula II is prepared wherein R 10 is hydrogen and R 11 is pyridinyl by reacting a pyridazine substituted at the C3 position with halo, at the C4 position with pyridinyl, and at the 6 position with phenyl, with 2-(piperidin-
• a compound of the formula II is prepared wherein R 10 is hydrogen and R 11 is piperidinyl or substituted piperidinyl by reacting a compound of the formula II wherein R 11 is halo, in particular chloro, and R 10 is hydrogen with piperazinyl or substituted piperazinyl under suitable conditions.
• a compound of the formula I is prepared wherein R i i •s piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R is aryl, R , R , R and R are hydrogen and R 7 is absent, by reacting a pyridazine substituted at the C3 position with halo and at the C4 position with aryl, with a piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl under suitable conditions.
• a compound of the formula I is prepared wherein R is piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R is an 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, more particularly pyridinyl, R , R , R and R are hydrogen and R is absent, by reacting a pyridazine substituted at the C3 position with halo and at the C4 position with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular,
• a compound of the formula I is prepared wherein R is substituted amino in particular amino substituted with substituted morpholinyl, in particular morpholinoethyl, R is aryl or an 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, in particular pyridinyl, R 3 , R 4 , R 5 and R 6 are hydrogen and R 7 is absent, by reacting a pyridazine substituted at the C3 position with halo, at the C4 position with aryl or an unsaturated 5 to 6 membered heteromonocyclyl group containing 1
• a compound of the formula V is prepared wherein R 50 is aryl, R 51 is hydrogen, and R 52 is alkyl by reacting a pyridazine substituted at position C 3 with halo, at position C 4 with aryl and at position 6 with alkyl, with l-(2-pyrimidyl)piperazine under suitable conditions.
• a compound of the formula I is prepared wherein R is substituted amino, R 2 is an 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, in particular pyridinyl, R , R , R and R are hydrogen and R is absent by reacting a pyridazine substituted at the C 3 position with halo, at the C 4 position with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-
• a precursor (see, for example, Figure 10, compound (15)) that may be utilized can be obtained commercially and used directly for the synthesis of the illustrated compound MWO 1-3- 183WH without further purification.
• Compounds may be synthesized with yields of 81 - 96%. All purified compounds may be characterized by HPLC, mass spectrometry and NMR in order to confirm syntheses.
• Figure 10 a synthetic scheme is shown, for synthesis of MW01-3- 183WH.
• a compound of the Formula II is prepared wherein a substituted 6-phenylpyridazine is reacted with 2-(piperazin-lyl)pyridmidine to produce a compound of the Formula II wherein R 10 and R 11 are hydrogen.
• disorder refers to disorders involving disruptions to normal neural electrical activity and/or function including without limitation conduction disturbances of the central nervous system (CNS), more particularly Seizure-Related Disorders.
• a disorder may be either or both of an acute or chronic nature of unknown origin, hereditary origin or it may be secondary to, for example, manipulation of the brain such as by surgery or radiation; alcohol, benzodiazepine, barbiturates or other drugs or chemical withdrawal; exposure to epileptogenic drugs; injury or trauma, stroke, cerebrovascular accident, fever, CNS inflammation or infection (e.g. meningitis), metabolic disturbance, or electroconvulsive therapy.
• the term also includes the emotional, cognitive, and motor symptoms resulting from these disorders.
• Seizure-Related Disorders refers to a disorder characterized by conduction disturbances, electroconvulsions and/or seizures, in particular recurrent and/or excessive seizures.
• a “seizure” is a sudden disruption of the brain's normal electrical activity accompanied by altered consciousness and/or other neurological and behavioral manifestations.
• a seizure may be partial or generalized.
• a Seizure-Related Disorder includes Epilepsy, Ictogenesis, epileptogenesis, non-epileptic convulsions, eclampsia and convulsions due to administration of a convulsive agent or trauma to a subject.
• Ictogenesis refers to the rapid and definitive electrical/chemical event which occurs over seconds or minutes.
• Epileptogenesis refers to a slow biochemical or histological process occurring over months to years involving transformation of the normal brain to a state susceptible to spontaneous, episodic, time-limited, recurrent seizures.
• Epileptogenesis involves a first initiation phase which occurs prior to the first seizure and often results from stroke, disease, trauma (e.g. caused by head injury or surgery).
• the brain which is already susceptible to seizures, becomes more susceptible to more frequent and severe seizures.
• Epilepsy refers to a chronic disorder of the brain characterized by transient but recurrent, excessive, or abnormal, disturbances to the electrical functions of the brain that may or may not associate with impairment or loss of consciousness and abnormal movements, sensation or behavior, in particular seizures.
• the term encompasses epileptic syndromes that are characterized by specific symptoms that include epileptic seizures.
• Such syndromes include but are not limited to, absence epilepsy, psychomotor epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, occipital lobe epilepsy, parietal lobe epilepsy, Lennox-Gastaut syndrome, Rasmussen's encephalitis, childhood absence epilepsy, Ramsay Hunt Syndrome type II, benign epilepsy syndrome, benign infantile encephalopathy, benign neonatal convulsions, early myoclonic encephalopathy, progressive epilepsy and infantile epilepsy, mesial temporal lobe epilepsy, benign myoclonic epilepsy in infants, juvenile myoclonic epilepsy, juvenile absence epilepsy, epilepsy with generalized tonic clonic seizures in childhood, infantile spasms (West syndrome), epilepsy with continuous spike and waves in slow wave sleep (ESES), Laudau Kleffner syndrome, and Rasmussen's syndrome.
• a subject may suffer from any combination of these syndromes.
• a disorder is epileptogenesis. In other aspects of the invention, the disorder is epilepsy. In other aspects of the invention, the disorder is early- life seizures or pediatric epilepsy. COMPOSITIONS AND KITS
• One or more pyridazine compound in particular a compound of the Formula I, II, III, IV, or V, may be formulated into a pharmaceutical composition for administration to a subject. Therefore, the invention provides formulations including without limitation pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) suppositories, sterile injectable solutions, and/or sterile packaged powders, which contain a pyridazine compound in particular a pure or substantially pure pyridazine compound.
• compositions of the present invention or fractions thereof comprise suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices.
• Particular compositions of the invention may contain a pyridazine compound that is pure or substantially pure.
• Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21st Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States Pharmacopeia: The National Formulary (USP 24 NFl 9) published in 1999.
• a composition of the invention may include at least one buffering agent or solution.
• Suitable buffering agents include, but are not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, citric, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic, pamoic, methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, galacturonic acid and mixtures thereof.
• Additional agents that may be included are one or more of pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose, calcium hydrogen phosphate, magnesium stearate, talc, silica, potato starch, sodium starch glycolate, sodium lauryl sulfate, sorbitol syrup, cellulose derivatives, hydrogenated edible fats, lecithin, acacia, almond oil, oily esters, ethyl alcohol, fractionated vegetable oils, methyl, propyl-p-hydroxybenzoates, sorbic acid and mixtures thereof.
• Buffering agents may additionally comprise one or more of dichlorodifluoromethane, trichloro fluoromethane, dichlorotetra fluoroethane, carbon dioxide, poly (N-vinyl pyrrolidone), poly (methylmethacrylate), polyactide, polyglycolide and mixtures thereof.
• a buffering agent may be formulated as at least one medium including without limitation a suspension, solution, or emulsion.
• a buffering agent may additionally comprise a formulatory agent including without limitation a pharmaceutically acceptable carrier, excipient, suspending agent, stabilizing agent or dispersing agent.
• a pharmaceutical composition for oral administration of one or more pyridazine compounds for treatment of a disorder.
• the active component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
• the drug component may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• Suitable binders e.g.
• compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.
• a composition of the invention is a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
• compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
• Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
• Various delivery systems are known and can be used to administer a composition of the invention, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like.
• Formulations for parenteral administration may include aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oil such as cottonseed oil, coconut oil or peanut oil.
• Dispersing 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 may include sterile aqueous or nonaqueous solvents, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration of therapeutically active agents.
• a composition intended for parenteral administration may also include conventional additives such as stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives.
• compositions of the invention can be formulated as pharmaceutically acceptable salts as described herein.
• a compound of the formula I, II, III, IV or V or a composition of the invention may be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the compounds or composition, irradiation of the compounds or composition, or heating the compounds or composition.
• the compounds or compositions of the present invention may be provided as sterile solid preparations e.g. lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.
• kits are provided.
• the kit comprises a compound of the formula I, II, III, IV or V or a formulation of the invention in kit form.
• the kit can be a package which houses a container which contains compounds of the formula I, II, III, IV or V or formulations of the invention and also houses instructions for administering the compounds or formulations to a subject.
• the invention further relates to a commercial package comprising compounds of the formula I, II, III, IV or V or formulations of the invention together with instructions for their use.
• a label may include amount, frequency, and method of administration.
• the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a composition of the invention to provide a beneficial effect including a therapeutic effect.
• Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
• the invention also relates to articles of manufacture and kits containing materials useful for treating a disorder disclosed herein.
• An article of manufacture may comprise a container with a label. Examples of suitable containers include bottles, vials, and test tubes which may be formed from a variety of materials including glass and plastic.
• a container holds compounds of the formula I, II, III, IV or V or formulations of the invention which are effective for treating a disorder disclosed herein.
• the label on the container indicates that the compounds of the formula I, II, III, IV or V or formulations of the invention are used for treating a disorder disclosed herein and may also indicate directions for use.
• a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
• a kit of the invention comprises a container described herein.
• a kit of the invention comprises a container described herein and a second container comprising a buffer.
• a kit may additionally include other materials desirable from a commercial and user standpoint, including, without limitation, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein (e.g., methods for treating a disorder disclosed herein).
• a medicament or formulation in a kit of the invention may comprise any of the formulations or compositions disclosed herein.
• kits may be useful for any of the methods disclosed herein, including, without limitation treating a subject suffering from Epilepsy.
• Kits of the invention may contain instructions for practicing any of the methods described herein. ADMINISTRATION
• a pyridazine compound and composition of the present invention can be administered by any means that produces contact of the active agent(s) with the agent's sites of action in the body of a subject or patient to produce a therapeutic effect, in particular a beneficial effect, in particular a sustained beneficial effect.
• a pyridazine compound or composition of the invention can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the compositions and treatments of the present invention to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects.
• Pyridazine compounds and compositions may be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular forms, all utilizing dosage forms well known to those of ordinary skill in the pharmaceutical arts. Pyridazine compounds and compositions of the invention may be administered by intranasal route via topical use of suitable intranasal vehicles, or via a transdermal route, for example using conventional transdermal skin patches.
• a dosage protocol for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen.
• a sustained release formulation can also be used for the therapeutic agents.
• the pyridazine compounds or compositions of the invention are administered by peripheral administration, in particular by intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, oral administration, topical administration, transmucosal administration, or pulmonary administration.
• a therapeutically effective dose of a pyridazine compound or composition of the invention for the treatment of a particular disorder or condition to provide effects, in particular beneficial effects, more particularly sustained beneficial effects, will depend on the nature of the disorder, and can be determined by standard clinical techniques. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
• Suitable dosage ranges for administration are particularly selected to provide therapeutic effects, in particular beneficial effects, more particularly sustained beneficial effects.
• a dosage range is generally effective for triggering the desired biological responses.
• the dosage ranges for a pyridazine compound are generally about 0.01 mg to about 3 g per kg, 0.01 mg to about 2 g per kg, 0.5 mg to about 2 g per kg, about 1 mg to about 1 g per kg, about lmg to about 500 mg per kg, about 1 mg to about 200 mg per kg, about 1 mg to about 100 mg per kg, about 1 mg to about 50 mg per kg, about 10 mg to about 100 mg per kg, or about 30 mg to 70 mg per kg of the weight of a subject, once, twice, or more per day, preferably once daily.
• the dosages ranges are about 0.01 to 3000 mg/kg, 0.01 to 2000 mg/kg, 0.5 to 2000 mg/kg, about 0.5 to 1000 mg/kg, 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 to 100 mg/kg, 0.1 to 50mg/kg, 0.1 to 20 mg/kg, 0.1 to 10 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 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 to 50mg/kg, 1 to 20 mg/kg, 1 to 10 mg/kg, 1 to 6 mg/kg, 1 to 5 mg/kg, or 1 to 3 mg/kg, or 1 to 2.5 mg/kg, or less
• the dosages ranges are 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 to 100 mg/kg, 0.1 to 75 mg/kg, 0.1 to 50 mg/kg, 0.1 to 25 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg/kg, 0.1 to 10 mg/kg, 0.1 to 9 mg/kg, 0.1 to 8 mg/kg, 0.1 to 7 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 4 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, or 0.1 to 1 mg/kg.
• a composition or treatment of the invention may comprise a unit dosage of a pyridazine compound to provide beneficial effects, in particular one or more of the beneficial effects set out herein.
• a "unit dosage” or “dosage unit” refers to a unitary i.e., a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising the active agent as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.
• a pyridazine compound can be provided once daily, twice daily, in a single dosage unit or multiple dosage units (i.e., tablets or capsules) having about 50 to about 10000 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 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, 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.
• the dosage regimen of the invention will vary depending upon known factors such as the pharmacodynamic characteristics of the agents and their mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect.
• a subject may be treated with a pyridazine compound or a composition of the invention on substantially any desired schedule.
• a pyridazine compound or composition of the invention may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month, twice a month or continuously.
• a subject may be treated less frequently, such as every other day or once a week, or more frequently.
• a pyridazine compound or a composition of the invention may be administered to a subject for about 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 to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, or 2 weeks to 24 months, periodically or continuously.
• Pyridazine compounds, compositions and treatment methods described herein are indicated as therapeutic agents or methods either alone or in conjunction with other therapeutic agents or other forms of treatment. They may be combined or formulated with one or more therapies or agents used to treat a condition described herein. Compositions of the invention may be administered concurrently, separately, or sequentially with other therapeutic agents or therapies. Therefore, compounds of the formula I, II, III, IV or V may be co-administered with one or more additional therapeutic agents for treating disorders disclosed herein as well as agents that are used for the treatment of complications resulting from or associated with a disorder disclosed herein, or general medications that treat or prevent side effects.
• the additional therapeutic agents comprise phenobarbital, valproate, levetiracetam, tiagabine, N-methyl-D-aspartate, alpha- amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) antagonists, and neuotrophins and their receptors.
• AMPA alpha- amino-3-hydroxy-5- methylisoxazole-4-propionic acid
• Minozac a small molecule inhibitor of proinflammatory cytokine up-regulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment.
• mice were allowed to recover for 30 days.
• rats were administered KA as previously described for the 'twohit' model of KA-induced neurologic injury (2).
• Control animals were administered PBS, and all animals were allowed to recover for a further 10 days before sacrifice on P55.
• Four experimental groups, including controls (PBS-PBS), newborn seizures (KA-PBS), adult seizures (PBS-KA), and v two-hit' animals (KA-KA) were studied. Rats were perfused transcardially with PBS and fixed with 4% paraformaldehyde (PFA) in 0.1 M PBS, pH 7.4. Brains were excised and post-fixed in 4% PFA overnight.
• PFA paraformaldehyde
• Brains were paraffin-embedded and sectioned for immunohistochemistry. For each outcome measure, two axial sections representing the hippocampus (sections between Bregma -7.34 mm, Paxinos plate 99, and Bregma -5.60 mm, Paxinos plate 106) were selected (23).
• FJB Fluoro-Jade B
• DAPI 6-diamidino-2-phenyllindole
• CAl, CA2, CA3, dentate gyrus (DG) and polymorph dentate gyrus (PoDG) of the hippocampus were photographed at 10x magnification, and images were converted to grayscale for quantification of FJB-positive cells.
• the percentage of positive cells in the hippocampal regions specified was measured by thresholding for lightly stained, or FJB-positive cells (Metamorph, Universal Imaging Corporation, Sunnyvale, CA). The total FJB-positive cells in the hippocampus as well as hippocampal region-specific staining were obtained for each sample.
• Hippocampal homogenates were prepared by sonication in protease inhibitor cocktail (1 ⁇ g leupeptin (Sigma, St. Louis, MO), 0.001 M 4-dithio-L-threitol (DTT, Sigma), 0.002 M sodium orthovanadate (Sigma) and 0.001 M phenylmethanesulfonyl fluorid (PMSF, FLUKA, Switzerland) in I ml PBS).
• protease inhibitor cocktail (1 ⁇ g leupeptin (Sigma, St. Louis, MO), 0.001 M 4-dithio-L-threitol (DTT, Sigma), 0.002 M sodium orthovanadate (Sigma) and 0.001 M phenylmethanesulfonyl fluorid (PMSF, FLUKA, Switzerland) in I ml PBS).
• PMSF phenylmethanesulfonyl fluorid
• IL- l ⁇ , IL-6, and TNF- ⁇ were measured in hippocampal homogenates by enzyme linked immunosorbent assay using commercially available plates and reagents (ELISA; MesoScale Discovery, MSD, Gaithersburg, Maryland). SlOOB levels were measured as described (26). Samples were analyzed in duplicates and compared with known concentrations of protein. Plates were analyzed using the SECTOR Imager 2400 (MSD). Hippocampal-linked task testing The Y-maze test of spontaneous alternation was used to evaluate hippocampus- dependent spatial learning (26, 27). Testing began on P27 when animals were first able to decide between the left or right arm of the maze.
• Testing was performed by a blinded observer on alternate days until P55. Each animal started in 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 alternating. The percent alternation over the duration of testing was calculated for each animal.
• the E7 anti- ⁇ -tubulin antibody developed by Michael Klymkowsky was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242). Immunohistochemistry
• GFAP (1:1500, mouse monoclonal, Sigma); SlOOB (1:1500, rabbit polyclonal, DAKO Cytomation, Carpinteria, CA); Ibal (1:400, goat polyclonal, Abeam, Cambridge, MA); FH (1: 400, goat polyclonal, Quidel); ⁇ -clusterin (1:100, goat polyclonal, Santa Cruz); GLAST (1:5000 guinea pig polyclonal, Chemicon International, Temecula, CA) and GLT-I (1:5000, guinea pig polyclonal, Chemicon). Control sections were incubated in normal serum or PBS in place of primary antibody.
• Double-labeling of clusterin-immunoreactive cells was also performed with the microglial marker, Ibal or with the neuronal marker, NeuN. Standard immunohistochemical methods were followed but VIP (Vector) instead of DAB was used as the substrate for visualization. Following development with VIP, tissues were blocked and then incubated with Ibal antibody (1:400 dilution) overnight at 4°C. After incubation with biotinylated anti-goat IgG for 1 hr, tissues were treated with ABC solution (Vector) and developed with SG substrate (Vector) before mounting. A similar approach was used for double labeling of clusterin with NeuN (1:50). Image acquisition and quantification of immunoreactive cells Sections were examined under brightfield microscopy by two blinded observers
• Mzc 2-(4-(4-methyl-6-phenylpyridazin-3- yl)piperazin-1-yl)pyrimidine dihydrochloride monohydrate, is a bioavailable and CNS- penetrant, small molecule suppressor of brain pro-inflammatory cytokine up-regulation (19). Mzc was refined from a lead compound synthesized by chemical diversification of an inactive pyridazine fragment (26).
• Mzc (5 mg/kg) or diluent (saline) was administered via ip injection at 3 and 9 hr following KA injection on P15 (Figure 7).
• Control animals were injected an equal volume of saline (Sal).
• tissues were processed for analysis of pro-inflammatory cytokines by ELISA as above.
• a separate group of animals was allowed to recover for 30 d for Y-maze testing and immunohistochemical analysis of glial activation. Details of experimental groups and outcome measures are summarized in Table 7.
• P15 KA and KA-PBS; 27/31, 87%) experienced Grade IV seizures, which was not significantly different from the frequency of Grade IV seizures in the P45 treatment group (P45 KA and PBS-KA; 28/32, 88%).
• Survival in the immature rats exposed to KA (KA-P13S, 16/19, 84%) was not significantly different from the P45 group (PBS-KA, 13/20, 65%) ( Figure 1 B).
• CAI, CA2 and DG also showed significant increases in labeled cells compared to controls.
• FJG-positive cells were also observed in the entorhinal and frontal cortex, lateral septal nuclei, piriform cortex, perirhinal cortex of these groups. Values in these regions were not different between groups. Seizures result in an acute increase in hippocampal IL-I ⁇ and SlOOB levels
• FH- immunoreactive cells had the morphology of astrocytes, and were also present in the frontal cortex, striatum, and periventricular areas.
• Early-life seizures did not result in persistent changes in clusterin (Figures 7 E) in the hippocampus (data expressed as % of immuno-positive cells + SEM).
• Qualitative assessment of clusterin immunostaining showed clusterin positive cells in the entorhinal cortex, cerebral cortex, midbrain and hippocampal layers CAl, CA2, CA3 dentate gyrus and PoDG. Clusterin- positive cells did not co-label with NeuN ( Figures 51, J), or GFAP (Figure 5K), but did co- label with Ibal ( Figure 5L), identifying them as microglia.
• Glial glutamate transporters GLAST and GLT-I increase following seizures
• the prevention of the long-term increase in glial activation in the Mzc-treated animals demonstrates that glial activation can contribute to neuronal dysfunction (8).
• the threshold for generation of seizures is lower in the immature than the adult brain (6) but the immature hippocampus is resistant to SE-induced structural damage (29). This discrepancy implies that the mechanisms by which early life seizures increase the vulnerability of the adult to seizures and neurologic injury occur at the molecular or subcellular level.
• Previous studies have implicated changes in AMPA receptors (33), glutamate receptor subunits (34), and the neuronal glutamate transporter, EAACl (15).
• glial activation in the v two-hit' group implicates glial (astrocytes and microglial) activation in the mechanisms leading to increased susceptibility to seizures and neurologic injury following early life seizures. This hypothesis is supported by the improved behavioral function and prevention of long-term glial activation in the Mzc-treated animals. The precise mechanisms by which activated astrocytes and microglia cause neurologic injury remain obscure (35, 36).
• Neuroinflammation is a well-established response to central nervous system injury (36) including epilepsy (37) although the potential of this response as a therapeutic target in epilepsy has not been explored in detail.
• central nervous system injury including epilepsy (37)
• epilepsy a well-established response to central nervous system injury (6) including epilepsy (37) although the potential of this response as a therapeutic target in epilepsy has not been explored in detail.
• Precedent from human pathologic, in vitro, and in vivo studies of Alzheimer's disease have implicated a glia-mediated neuroinflammatory response both in the pathophysiology of the disease (8) and as treatment target (19, 26, 38).
• Microglial activation leading to overexpression of IL-I has been proposed as the pivotal step in initiating a self propagating cytokine cycle culminating in neurodegeneration (8, 39).
• Clusterin expression is upregulated in astrocytes following seizures (18).
• the increase in clusterin in the KA-exposed animals is of microglial origin. This result supports the finding that microglial activation is potentiated in the v two-hit' group and may be a mechanism by which activated microglia can lead to cell injury (17).
• the complement inhibitory protein, Factor H (28) acts as a chemotactic factor for activated microglia in amyloid- ⁇ -induced brain injury (16). Lack of change in Factor H levels in response to KA suggests that this signaling pathway is not involved in microglial recruitment after seizures.
• Mzc (19) is a bioavailable, water- soluble, CNS-penetrant, non-toxic compound that inhibits hippocampal pro-inflammatory cytokine upregulation, suppresses synaptic dysfunction, and attenuates hippocampal- dependent behavioral deficits in an Alzheimer's disease mouse model.
• the results presented here and the ability to produce Mzc in large scale under FDA guidelines (19) indicates the need to investigate the potential of this compound as a novel therapeutic in pediatric epilepsy. Efficacy in the present study lends further support to the hypothesis that targeting neuroinflammation may alter progression of central nervous system disorders (19, 20, 38).
• FIG. 9 A model ( Figure 9) is proposed in which an initial rise in pro-inflammatory cytokines following early life seizures, particularly IL- l ⁇ and SlOOB, results in further activation of microglia. This activation is also transient, but is followed by a persistent increase in astrocyte activation. Activated astrocytes result in neurobehavioral impairment, and may increase the susceptibility to a second neurologic insult in part through enhanced microglial activation after the insult. Early-life seizures prime microglia for an exaggerated response to a second neurologic insult (20).

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