WO2007127475A2 - Pyridazines for demyelinating diseases and neuropathic pain - Google Patents

Pyridazines for demyelinating diseases and neuropathic pain Download PDF

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Publication number
WO2007127475A2
WO2007127475A2 PCT/US2007/010464 US2007010464W WO2007127475A2 WO 2007127475 A2 WO2007127475 A2 WO 2007127475A2 US 2007010464 W US2007010464 W US 2007010464W WO 2007127475 A2 WO2007127475 A2 WO 2007127475A2
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Prior art keywords
substituted
compound
alkyl
hydrogen
aryl
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PCT/US2007/010464
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French (fr)
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WO2007127475A3 (en
Inventor
Martin Watterson
Linda Van Eldik
Wenhui Hu, Ph.D.
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Northwestern University
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Publication of WO2007127475A2 publication Critical patent/WO2007127475A2/en
Publication of WO2007127475A3 publication Critical patent/WO2007127475A3/en

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    • 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
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/505—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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to compositions and methods for use in treatment for patients with Demyelinating Diseases and Conditions including Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke.
  • the compositions and methods can also be used for Stroke Rehabilitation and the treatment of pain disorders including Neuropathic Pain and Chemokine-Induced Pain.
  • BACKGROUND OF INVENTION The treatment of neurological disorders is of great importance in medicine and there is a need for new drugs and treatments to prevent progression and reverse the impairments of neurological disorders such as demyelinating diseases, demyelinating conditions, traumatic brain injury, stroke, cerebral ischemia, craniocerebral trauma and spinal cord injury, as well as to treat pain disorders, including neuropathic pain disorders.
  • Demyelinating diseases comprise disorders that are characterized by damage to the myelin sheath that coats and insulates nerve fibers. Those afflicted with these diseases suffer neurologial deficits due to impaired transmission of nerve impulses caused by myelin being stripped from nerve fibers. Multiple Sclerosis, the most common of these diseases, is a demyelinating disease of the central nervous system (CNS) and a leading cause of nontraumatic neurological disability among young adults in North America.
  • CNS central nervous system
  • Neuropathic pain is a complex disorder resulting from injury to the nerves, spinal cord or brain. Neuropathic pain has developed into a major health problem requiring treatments that are sensitive to the causes behind the pain whether it is an underlying disease or the mechanistic pathway over which it manifests. ' ' . .
  • 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.
  • the pyridazine compounds are suited for use in compositions and methods for treating Demyelinating Diseases and Conditions including Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke.
  • pyridazine compounds are suited for use in compositions and methods for treating pain disorders including Neuropathic Pain and Chemokine-Induced Pain, and for Stroke Rehabilitation.
  • the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating a Demyelinating Disease or a Demyelinating Condition in a subject.
  • the invention also provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating pain disorders including Neuropathic Pain and Chemokine-Induced Pain in a subject.
  • the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating a subject requiring Stroke Rehabilitation.
  • 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 stable pharmaceutical composition comprising a pyridazine compound adapted for use in Stroke Rehabilitation and in treating a Demyelinating Disease, a Demyelinating Condition, or pain disorders including Neuropathic Pain, and Chemokine-Induced Pain.
  • 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 Stroke Rehabilitation and in treating a Demyelinating Disease, a Demyelinating Condition, and pain disorders including Neuropathic Pain, and Chemokine-Induced Pain.
  • the invention also contemplates the use of one or more pyridazine compound and or method of the invention to prevent, and/or ameliorate disease severity, disease symptoms, and/or periodicity of recurrence of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain, or for Stroke Rehabilitation. Therefore, the invention contemplates the prevention and treatment, in a subject, of a
  • the invention provides a method for treating a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain 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 Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain, " or Chemokine-Induced Pain.
  • the invention provides a method for the prevention and/or intervention of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain 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 Demyelinating Disease, a Demyelinating Condition, a pain disorder including Neuropathic Pain, or Chemokine-Induced Pain, or for Stroke Rehabilitation, 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 the treatment of nerve injury and neuropathic pain by the use of one or more pyridazine compound.
  • the invention in particular contemplates a method for protection of the peripheral nervous system and the treatment of neuropathic pain comprising the systemic administration of a therapeutic dose of a pyridazine compound.
  • Treatment may be short or long term depending on the nature of the nerve injury or source of neuropathic pain.
  • Pyridazine compounds can be used for the protection and treatment of peripheral nerve injury caused by any injury or insult and is not limited for use for treatment of injuries resulting from nerve crush or other traumatic, acute injury and neuropathic pain caused by disease.
  • the invention provides a method for amelioriating progression of a disease or obtaining a less severe stage of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain, or Chemokine-Induced Pain in a subject suffering from such disease or condition 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 Demyelinating Disease or a Demyelinating Condition comprising administering a therapeutically effective amount or 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 Demyelinating Disease or a Demyelinating Condition 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 Demyelinating Disease or a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.
  • 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 disease or condition and its complications.
  • the invention also contemplates the use of one or more pyridazine compound for the preparation of a medicament for preventing and/or treating a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine- Induced Pain, or for use in Stroke Rehabilitation.
  • the invention additionally provides uses of a pharmaceutical composition of the invention in the preparation of medicaments for the prevention and/or treatment of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain, or for use in Stroke Rehabilitation.
  • 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 disease or condition disclosed herein. Accordingly, in an embodiment, a pyridazine compound or a composition of the invention is 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 Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain, or Chemokine- Induced Pain, or for use in Stroke Rehabilitation.
  • FIGURES Figure 1 depicts a synthetic scheme for MWOl -3-183 WH.
  • Figure 2 depicts a synthetic scheme for MWO 1-2-151 SRM.
  • Figure 3 is a synthetic- scheme for MWO 1-2-15 ISRM.
  • Figure 4 is a synthetic scheme for MWOl -2-15 ISRM.
  • Figure 5 is a synthetic scheme for MWO 1-2-151 SRM.
  • Figure 6 is a synthetic scheme for MWO 1-5- 188WH.
  • Figure 7 is a synthetic scheme for MW01-5-188WH.
  • Figure 8 is a synthetic scheme for MWO 1-5- 188WH.
  • Figure 9A and 9B are synthetic schemes for MWO 1-6- 189WH.
  • Figure 10 is a synthetic scheme for MWO 1 -7-084 WH.
  • Figure 11 is a synthetic scheme for MWO 1-7-085 WH.
  • Figure 12 is a synthetic scheme for MW01-7-057WH. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
  • 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 disease, or one or more symptoms of such disease, to which such term applies.
  • the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease.
  • a treatment may be .either performed in an acute or chronic way.
  • the term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease.
  • Such prevention or reduction of the severity of a disease 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 disease.
  • Preventing also refers, to preventing the recurrence of a disease or of one or more symptoms associated with such disease.
  • Treatment and “therapeutically,” refer to the act of treating, as “treating” is defined above.
  • The. purpose of prevention and intervention is to combat the disease, condition, or 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 disease, condition, or disorder.
  • 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.
  • a mammal of the present invention can be Canis familiaris (dog), Felis catus (cat), Elephas maximus (elephant), Equus caballus (horse), Sus domesticus (pig), Camelus dromedarious (camel), Cervus axis (deer), Giraffa camelopardalis (giraffe), Bos taurus (cattle/cows), Copra hircus (goat), Ovis aries (sheep), Mus musculus (mouse), Lepus brachyurus ⁇ (rabbit), Mesocricetus auratus (hamster), . Cavia por.cellus .(guinea pig), Meriones unguiculatus
  • 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 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.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • 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 disease disclosed herein.
  • Typical subjects for treatment include persons afflicted with or suspected of having or being pre-disposed to a disease disclosed herein, or persons susceptible to, suffering from or that have suffered a disease disclosed herein.
  • a subject may or may not have a genetic predisposition for a disease disclosed herein such as MS.
  • a subject may be a healthy subject.
  • the term "healthy subject” means a subject, in particular a mammal, having no diagnosed disease, 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 coadministration can be readily determined by one skilled in the art.
  • agents/therapies are co-administered, 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.
  • a beneficial effect can be a statistically significant effect in terms of statistical analysis of an effect of a pyridazine compound and a composition 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.
  • 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 disease 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 disease 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.
  • 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.
  • R 1 , R 2 , and R 3 are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano,.
  • R 7 Js substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl,- acyloxy, sulfonyi, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioary
  • a compound of the Formula Ia or Ib is employed wherein: (a) R 1 is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, cyano, amino, cycloalkyl, sulfonyl, sulfinyl, sulfenyl, thioaryl, thioalkyl, carbonyl, silyl, piperazinyl, piperidinyl, pyrrolidinyl,'. morpholinyl, -SR 20 wherein R 20 ..
  • R 2 is optionally substituted hydroxyl, alkyl, alkenyl, alkoxy, carbonyl, carboxyl, phenyl, benzyl, amino, aryl, cyano, - COH, piperazinyl,.
  • 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, halo, or nitro;
  • R 5 is optionally substituted hydrogen, halo, alkoxy, or amido;
  • R 7 is substituted or unsubstituted hydrogen halo, hydroxyl, alkyl, alkenyl, alkoxy, carboxy, • m ⁇ rpholino, imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl or R 7 is absent and there is a double bond between N at position
  • 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 3 -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 is employed wherein R 3 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(CHs) 3 ), carboxyl, or substituted carboxyl; hydroxyl; or nitro.
  • R 3 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(CHs) 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(CHa) 3 , or -OCH 3 .
  • a compound of the Formula Ia or Ib is employed wherein 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.
  • R 2 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 is pyridinyl, and R is an N-substituted piperzinyl.
  • a compound of the Formula Ib is employed wherein R 1 is amino substituted with alkyl or cycloalkyl and R 2 is pyridinyl.
  • a compound of the Formula Ia or Ib is employed wherein R 3 is hydrogen; hydroxyl; alkyl which may be substituted (e.g., halo); amino which may be substituted; -COR 31 wherein R 31 is hydrogen, hydroxyl, alkoxy (e.g. — OCH 3 ); or, aryl (e.g. phenyl) which may be substituted (e.g., alkyl).
  • a compound of the Formula Ia or Ib is employed wherein R 4 is hydrogen or halo; R 5 is hydrogen or halo; R 6 is hydrogen or halo.
  • a compound of the Formula Ia or Ib is employed wherein 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 and R 7 form a pyrimidinyl ring which may optionally be substituted with alkyl, aryl, halo, or hydroxyl.
  • R 1 is
  • R 34 is hydrogen or alkyl
  • 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, Cj-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 8 wherein R 8 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,
  • 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 45 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 47 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 is halo especially chloro or bromo, R 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 is employed 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 2 is a substituted amino, in particular amino substituted with alkyl or substituted alkyl, in particular alkyl substituted with alkoxy carbonyl, and optionally R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
  • R 1 is halo, especially bromo or chloro
  • R 2 and R 3 form an unsaturated ring, in particular phenyl
  • R 5 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 4 , R 6 and R 7 are hydrogen.
  • R 1 is halo, especially bromo or chloro
  • R 4 is nitro
  • R 2 , R 3 , R 5 , R 6 , and R 7 are hydrogen.
  • the invention employs a compound of the Formula Ia wherein R 1 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 1 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 7 is alkyl, and R 3 , R 4 , R 5 , and R 6 are hydrogen.
  • R 1 is cyano and R 2 is aryl or alkyl, and optionally R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
  • a compound of the Formula Ia is employed wherein one or both.
  • R and R are a saturated 3 to 6-membered heteromonocyclic group containing l .to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially a substituted morpholinyl, and optionally R 3 , 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. pyrrolidinyl], which may be substituted with substituted or unsubstituted carboxyl; R 2 is alkyl or halo, 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. pyrrolidinyl], which may be substituted with substituted or unsubstituted carboxyl;
  • R 2 is alkyl or halo, 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 hydroxyl; R 2 is alkyl or substituted alkyl or R 3 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
  • 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 6 , and R 7 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 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
  • a compound of the Formula Ia is employed wherein.
  • R 1 and R 7 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 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
  • a compound of the Formula Ia is employed wherein R 1 is silyl which may be substituted, in particular substituted with alkyl, R 2 is alkyl, and R 3 , R 4 , R 5 , R 6 , and R 7 are hydrogen.
  • R 2 is hydrogen or methyl
  • R 3 , R 4 , R 5 , and R 6 are hydrogen
  • g) a compound wherein when R is chloro or bromo, R is C 1 -C 3 alkyl, phenyl, amino, benzyl, morpholinyl, chloro, -C( O)NH 2 , -NH 2 , C 1 -C 3 alkylphenyl,
  • R 3 , R 4 , R 5 and R 6 ' are hydrogen; h) a compound wherein when R 1 is chloro or bromo, R 3 is hydroxyl, chloro, bromo, Ci -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 1 is chloro, R 2 is methyl, R 5 is hydroxyl, and R 3 ,
  • R 4 , and R 6 are hydrogen; j) a compound wherein when R 1 is chloro, R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; k) a compound wherein when R 1 is hydroxyl, R 2 is Q-C 4 alkyl, and R 3 , R 4 , R 5 and R 6 are hydrogen; 1) a compound wherein when R 1 is -CpC 4 alkoxy, or C 1 -C 4 alkoxy substituted with -N(CH 3 ) 2 , morpholinyl, or piperidinyl substituted with benzyl, R 2 is
  • R 3 , R 4 , R 5 and R 6 are hydrogen; u) a compound wherein R 1 is cyano substituted with -CH(OH)(CH B ) 2 ,
  • R 1 is -NH 2 CH 2 N(CHs) 2 and R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; bb) a, compound wherein R 1 is -NH 2 , R 3 is -NH 2 , and R 3 , R 4 , R 5 and R 6 are hydrogen; cc) a compound wherein R 1 is -NH 2 , R 5 and R 6 are methoxy, and R 3 and R 4 are hydrogen; dd) a compound wherein R 1 is -NH 2 , R 3 is methyl and R 4 , R 5 and R 6 are hydrogen; ee) a compound wherein R 1 is -NH 2 , R 5 is chloro, and R 3 , R 4 and R 6 are hydrogen; ff) a compound wherein R is -NH-chlorophenyl, and R and R form a phenyl group, and R 4 , R 5 and R 6 are hydrogen; gg) a compound wherein R 1 is -NH 2
  • R 2 is hydrogen, methyl, ethyl, -CHO, -CH 2 OH, -COOH, chloro, -CH 2 CH 2 NH 2 ,
  • 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;
  • R 1 is -NHR 56 wherein R 56 is -CH 2 CH 2 N(CH 2 CH 3 ) 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 is hydrogen, alkyl, or phenyl, and 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 1 is -NHR 58 wherein R 58 is heptyl, phenyl, benzyl, or ethylphenyl, R 2 is hydrogen, methyl, or chlorophenyl, R 4 , R 5 and R 6 are hydrogen; qq) a compound wherein R 1 is -NR 9 wherein R 9 is phenyl and R 2 , R 3 , R 4 , R 5 and
  • R are hydrogen; rr) a compound wherein R 1 is morpholinyl and R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; ss) a compound wherein R 1 is methylpiperazinyl and R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen; tt) .
  • R 3 , R 4 , R 5 and R 6 are hydrogen; ww) a compound wherein R 1 is • -CHCH 2 CH 2 -isoquinolinyl,
  • R 1 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:
  • a compound of the Formula II is employed wherein 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); -NR 36 R 37 wherein R 36 is hydrogen or alkyl, and R 37 is phenyl which may be substituted or alkyl which may be substituted (e.g.
  • a compound of the Formula II is employed wherein R !0 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(CHa) 3 .
  • a compound of the Formula II is employed wherein R 1 ' is hydrogen, halo, optionally substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl, or phenyl.
  • a compound of the Formula II is employed wherein both of R 10 and R 1 ' are not hydrogen.
  • R 10 and R 11 are alkyl, in particular CpC 6 alkyl and the other of R 10 and R 1 ' is hydrogen.
  • one or more of 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, MWOl- 2-069SRM/ MW01-2-151SRM, MW01-5-188WH, MWO 1-6- 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
  • 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 Ci-Cg alkyl, more particularly methyl or dimethyl, or -N-R 40 R 41 wherein R 40 is hydrogen or alkyl, in particular Ci-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 Ci-C 6 alkyl, ' more particularly methyl and R 43 is C]-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 pyridin
  • a compound of the Formula V may comprise compound MWO 1-7-057 WH, 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, HI, IV, or V can be found in U.S. Patent Application No. 20030176437 (herein incorporated by reference in its entirety for all purposes).
  • the 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, HI, IV, or
  • the invention employs a compound of the Formula III with the proviso that compounds depicted in Table 1 are excluded. . In further particular aspects 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 diseases disclosed herein.-
  • the compounds employed are those depicted in the Figures and Table 2, 3; 4, and/or 5 or derivatives thereof.
  • 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 MWOl- 2-15 ISRM, or isomers or pharmaceutically acceptable salts thereof.
  • the invention employs one or more of the compounds designated herein as MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MWOl -2- 189WH and MWO 1-2-151 SRM, 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 MWOl-I-OIrL-DOV, and/or related derivatives, in particular, heterocyclic derivatives, of these compounds.
  • MWO 1-2- 15 ISRM an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed in the invention.
  • MWO 1-5- 188WH an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed iri 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-IrOl-L- DlO, MW01-1-01-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-l- yl)pyridazine(5) shown in Figure 1 is employed.
  • a pharmaceutically acceptable salt employed in the invention is a chloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine(5) shown in
  • a pharmaceutically acceptable salt is a hydrochloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine (5) shown in Figure 1, more particularly the di-hydrochloride hydrate salt shown below (i.e., MW01-9-034WH)(6).
  • 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.
  • the 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. In certain instances, 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. In general, 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, H 5 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.
  • 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. For example, 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. However, 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. By varying the form of a drug, it is possible to vary the physical properties thereof.
  • crystalline polymo ⁇ hs 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 3 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.
  • 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. The methods 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.
  • all physical forms of compounds of the formula I 5 II, III, IV or V are intended
  • 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-acrylarnido-2- methyl- 1-propanesulfonic acid); poly(2-acrylamido-2-methyl,-l-propanesulfonic acid- coacrylonitrile, pory(2-acrylamido-2-methyl- 1 -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 polyvinyl alcohol).
  • a "carbohydrate” as used herein refers to a polyhydroxyaldehyde, or polyhydroxyketone and derivatives thereof.
  • the term includes monosaccharides such as erythrpse, 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, oligosaccharides, 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 alky I, 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.
  • carbohydrate also includes glycoproteins such as lectins (e.g. concanavalin
  • A wheat germ agglutinin, peanutagglutinin, seromucoid, and orosomucoid
  • 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 Ci-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, sulfmyl, 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.
  • the term ''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.).
  • Examples of such groups include, but are not limited to, 1-chloroethyl and the like.
  • the term "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.
  • the term “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. Examples of such 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-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), and prop-2-en-2-yl), buten-1-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l- yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
  • propenyl e.g., prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), and prop-2-en-2-yl
  • 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.
  • 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-l-yl and prop-2-yn-l-yl, butynyls such as but-1-yn-l-yl, but-l-yn- 3-yl, and but-3-yn-l-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, and 3-methylbutyn-l-yl, hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and 3,3- dimethylbutyn-1-yl radicals and the like.
  • 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.
  • alkylene refers to a linear or branched radical having from about 1 to 1O 5 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.
  • an 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.
  • 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 Cj-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.
  • 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, tolulyi, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexyl, acenapththylenyl, anthracenyl, biphenyl, bibenzylyl, and related bibenzylyl homologs, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyi, 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, cyc.opentyl, 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.
  • 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). Examples of such groups include, but are not limited to, 1-chlorodecalyl and the like.
  • cycloalkenyl refers to radicals comprising about 4 to 16, 2 to
  • cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms.
  • examples of 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 alone or in combination, 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.
  • Illustrative "aryl" radicals includes without limitation aromatic radicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indahyl, bip ' henyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl.
  • aryl radical may be optionally substituted 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,
  • 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,
  • 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 limitiation a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g.
  • 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 arylsulfmyl, refers to the divalent radicals -S(O)-.
  • sulfonate is art recognized and includes a group represented by the formula:
  • R 18 is an electron pair, hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, heterocyclic, carbohydrate, peptide, or peptide derivative.
  • 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 38 R 39 where R 38 and R 39 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, cycloh ' exylamino, piperidinyl, hydrazinyl, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert.-butylsilylamino, which may or
  • 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 26 where R 26 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 where R is an alkoxy group which may be substituted.
  • a "thioalkoxy group” may have 1-6 carbon atoms i.e. a -S-(O)-Ci-C 6 alkyl group wherein Ci -C 6 alkyl have the meaning as defined above.
  • Illustrative examples of a straight or branched thioalkoxy group or radical having from 1 to 6 carbon atoms, also known as a Cj -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, diphenylmethoxy-carbonyl, benzhydroxycarbonyl, di-(4-methoxyphenyl-methoxycarbonyl, 2- bromoethoxycarbonyl, 2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2- triphenyl
  • 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. methoxy), and/or halo (e.g. chlorine).
  • Examples of silicon substituents include trimethylsilyl and dimethyltert.butylsilyl.
  • 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 64 , where R 64 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 64 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 64 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 64 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • examples include, but are not limited to formy
  • phosphonate refers to a C-PO(OH) 2 or C-PO(OR 65 ) 2 group wherein R 65 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 1 ' 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, may be prepared by reacting a compound with a structure of formula II wherein R i0 is halo, in particular chloro, and R 1 ' 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-
  • a compound of the formula II wherein R 1 ' is hydrogen and R 10 is a substituted aryl is prepared by reacting a compound with the structure of formula II wherein R 10 is halo, in particular chloro, and R 11 is hydrogen, with a substituted aryl boronic acid under suitable conditions.
  • a compound of the formula II wherein R 10 is hydrogen and R 11 is alkyl is prepared by reacting a compound with the structures of formula II wherein R 11 is halo, in particular chloro, and R 10 is hydrogen, with an alkyl boronic acid under suitable conditions.
  • R 1 ' is lower alkyl, in particular methyl or ethyl
  • a compound of the formula II wherein R 11 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 1 ' 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-4- yloxy)pyrimidine under suitable conditions to prepare a compound of the formula II wherein R 10 is hydrogen and R u is an alkyl.
  • R 1 ' 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 1 ' is phenyl.
  • a compound of the formula II is prepared wherein R 10 is hydrogen and R 11 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 1 ' is halo, in particular chloro, and R 10 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,
  • a compound of the formula II is prepared wherein R 10 is hydrogen and R 11 is pyridinyl by reacting a compound of the formula II wherein R 11 is halo, in particular chloro, and R 10 is hydrogen, with a pyridinyl boronic acid under suitable conditions.
  • 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 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-pyr
  • 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-4-yloxy)pyrimidine under suitable conditions to prepare a compound of the formula II wherein R 10 is hydrogen and
  • R 1 ' is pyridinyl
  • R 1 ' is piperidinyl or substituted piperidinyl by reacting a compound of the formula II wherein R 11 is halo, in particular chloro, and R is hydrogen with piperazinyl or substituted piperazinyl under suitable conditions.
  • a compound of the formula I is prepared wherein R 1 is piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R 2 is aryl, R 3 , R 4 , R 5 and R 6 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 1 is piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, 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, more particularly 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 and at the C4 position with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms,
  • a compound of the formula I is prepared wherein R 1 is substituted amino in particular amino substituted with substituted morpholinyl, in particular morpholinoethyl, R 2 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
  • a compound of the formula V is prepared wherein R 50 is aryl, R 51 is hydrogen, and R is alkyl by reacting a pyridazine substituted at position C3 with halo, at position C4 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 1 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 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 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,- and at the C6 position with phenyl, and a substituted amino under suitable conditions. . . . .
  • a precursor (see, for example, Figure 1) that may be. utilized can be. obtained commercially and used directly for the synthesis of the illustrated compound MW01-3-183WH 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 1 a synthetic scheme is shown, for synthesis of MW01-3-183WH with unconstrained aromatic ring at position 6 and no modification at position 5. . .
  • 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.
  • Demyelinating Diseases refers to diseases in which myelin is the primary target. These diseases can be divided into two groups: Acquired Diseases and Hereditary Metabolic Disorders. Acquired Demyelinating Diseases include Multiple sclerosis (MS) including its alternating relapsing/remitting phases. Hereditary Metabolic Disorders includes the leukodystrophies such as metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus- Merzbacher disease and Alexander's disease.
  • MS Multiple sclerosis
  • Hereditary Metabolic Disorders includes the leukodystrophies such as metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus- Merzbacher disease and Alexander's
  • Demyelinating Conditions refers to conditions that result in deficient myelination. Such conditions include, but are not limited to, Spinal Cord Injury, Traumatic Brain Injury and Stroke.
  • SCI Spinal Cord Injury
  • SCI Spinal Cord Injury
  • TBI Traumatic Brain Injury
  • a head injury may be a closed head injury or penetrating head injury.
  • a closed head injury may occur when the head is hit by a blunt object causing the brain to interact with the hard bony surface inside the skull.
  • a closed head injury may also occur without direct external trauma to the head if the brain undergoes a rapid forward or backward movement, (e.g. whiplash).
  • a penetrating head injury may occur when a fast moving object such as a bullet pierces the skull.
  • a closed or penetrating head injury may result in localized and widespread, or diffuse, damage to the brain which may manifest as memory loss, emotional disturbances, motor difficulties, including paralysis, damage to the senses, and death.
  • the term also includes secondary damage that follows an injury including swelling and fluid buildup and the accumulation of substances toxic to surrounding neurons such as the neurotransmitter glutamate.
  • Stroke refers to a sudden loss of brain function caused by the interruption of the flow of blood to the brain (an ischemic stroke) or the rupture of blood vessels in the brain (a hemorrhagic stroke). The interruption of the blood flow or the rupture of blood vessels causes neurons in the affected area to die.
  • Pain disorder refers to a disorder or condition involving pain and includes without limitation acute pain, persistent pain, chronic pain, inflammatory pain, neuropathic pain, neurogenic pain, and chemokine-induced pain.
  • a pain disorder includes without limitation pain resulting from soft tissue and peripheral damage such as acute trauma; complex regional pain syndrome also referred to as reflex sympathetic dystrophy; postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; pain associated with osteoarthritis and rheumatoid arthritis; musculoskeletal pain such as pain associated with strains, sprains and trauma such as broken bones; spinal pain, central nervous system pain such as pain due to spinal cord or brain stem damage; lower back pain, sciatica, dental pain, myofascial pain syndromes, episiotomy pain, gout pain, and pain resulting from burns; deep and visceral pain, such as heart pain; muscle pain, eye pain, inflammatory pain, orofacial pain, for example, odontalgia; abdominal pain, and gynecological pain, for example, dysmenorrhoea
  • Neuroneuropathic pain refers to pain initiated or caused by a primary lesion or dysfunction in the nervous system.
  • Neuroogenic Pain which is defined as pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system.
  • the uses of the present invention include central or peripheral neuropathic pain or neurogenic pain.
  • neuropathic pain includes the pain caused by either mononeuropathy or polyneuropathy.
  • Peripheral neuropathic pain refers to a pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system and "peripheral neurogenic pain” refers to a pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral nervous system.
  • a peripheral neuropathic pain can be allodynia (i.e., a pain due to a stimulus which does not normally provoke pain); causalgia (i.e.; a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes); hyperalgesia (i.e., an increased response to a stimulus which is normally painful); hyperesthesia (i.e., increased sensitivity to stimulation, excluding the senses); hyperpathia (i.e., a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold); neuritis (i.e., inflammation of a nerve or nerves); or neuropathy (i.e., a disturbance of function or pathological change in a nerve).
  • IASP Classification of chronic pain, 2nd Edition, IASP Press (2002), for detailed definitions of these categories of neuropathic pain and neurogenic pain).
  • neuropathic pain examples include infective (e.g., post herpetic neuralgia and HIV neuropathy), metabolic (e.g., diabetic neuropathy and Fabry's disease), toxic (e.g., from lead or chemotherapy), traumatic/stretch injury (e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia), and idiopathic (e.g., trigeminal neuralgia/tic douloureux).
  • infective e.g., post herpetic neuralgia and HIV neuropathy
  • metabolic e.g., diabetic neuropathy and Fabry's disease
  • toxic e.g., from lead or chemotherapy
  • traumatic/stretch injury e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia
  • idiopathic e.g.
  • Neuropathic Pain include post-herpetic neuralgia, painful diabetic neuropathy, phantom limb pain, central post-stroke pain, HIV neuropathy, Fabry's disease, peripheral neuropathy; trigeminal neuralgia, post incisional neuropathic pain, phantom limb pain, reflex sympathetic dystrophy, causalgia, anesthesia dolorosa, intercoastal neuralgia, post-traumatic localized pain, atypical facial neuralgia pain after tooth extraction and the like, complex regional pain syndrome, neuropathic pain caused by trauma, lead, or . chemotherapy, cancer pain resistant to narcotic analgesics such as morphine.
  • Treatment of neuropathic pain may be defined as administration of a therapeutic dose of a pyridazine compound to reduce' and preferably eliminate pain that results from, nerve injury.
  • Treatment of nerve injury may be defined as administration of a therapeutic dose of a pyridazine to ameliorate injury and to increase the rate of recovery.
  • An increased rate of recovery is defined as a reduction of indications of pain from peripheral nerve injury, such as thermal hyperalgesia and mechanical allodynia, more quickly than would be accomplished without pharmacological or other medical intervention.
  • “Chemokine?Induced Pain” refers to pain that occurs in response, in whole or in part, to chemokines, in particular pro-inflammatory cytokines (e.g. fractalkine, CCL2, and CCL5).
  • An example of chemokirie-induced pain is arthritic pain. . .
  • One or more pyridazine compound in particular a compound of the Formula I, II, III, rV, or V, may be formulated into a pharmaceutical composition for administration ' to a subject.
  • Pharmaceutical 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 (21 st Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999.
  • 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. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes
  • lubricants e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride
  • disintegrating agents e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum
  • flavoring agents, and coloring agents may also be combined in the compositions.
  • Compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.
  • 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.
  • a composition of the invention is a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the 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.
  • a pharmaceutical composition is provided for oral administration of one or more pyridazine compounds for treatment of a disease.
  • 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 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, glucoronic, 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),
  • 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 compound of the formula I 5 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. After pharmaceutical 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.
  • kits comprising 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, H 3 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 simultaneous, separate or sequential 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 therapeutic effect.
  • 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 therapeutic effect.
  • containers 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 disease disclosed herein.
  • An article of manufacture may comprise a container with a label.
  • 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 disease disclosed herein.
  • the label on the container indicates that the compounds of the formula I, 11, III, IV or V or formulations of the invention are used for treating a disease 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.
  • kits comprising one or more of compounds of the formula I, II, III, IV or V.
  • 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 ⁇ ihy methods disclosed herein (e.g., methods for treating a disease 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 Alzheimer's disease.
  • 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 abeneficial effect, in particular ' a sustained beneficial effect.
  • a pyridazine compound or 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 abeneficial effect, in particular ' a sustained beneficial effect.
  • 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, disease or condition to provide effects, in particular beneficial effects, more particularly sustained beneficial effects, will " depend on the nature of the disease, 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 disease, 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 the pyridazine compound are generally about 0.01 rag 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.
  • 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 (a) to (t) 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.
  • 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 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 diseases disclosed herein as well as agents that are used for the treatment of complications resulting from or associated with a disease disclosed herein, or general medications that treat or prevent side effects.
  • Figure 1 depicts a synthetic scheme for the preparation of 2-(4-(6-phenylpyridazin-3- yl)piperazin-l-yl)pyrimidine (MW01-3-183WH).
  • Reagent and condition (a) 1-BuOH, NH 4 Cl, and 2-( piperazin-l-yl)pyrimidine.
  • a typical reaction mixture of comprised about 0.01 mol of 3- chloro-6-phenylpyridazine by 2-(piperazin-l- yl)pyrimidine, about 0.05 mol of 2-(piperazin-l- yl)pyrimidine and about 0.01 mol of ammonium hydrochloride was prepared in about 15ml of 1- BuOH.
  • a NaOH solution is used to absorb the HCl that escapes from the dry tube.
  • the reaction mixture is heated to reflux, and the color of the reaction suspension changes to dark green upon heating.
  • the reaction is complete (after refluxing for 2 h)
  • the flask is removed from the oil bath and cooled to ambient temperature.
  • the reaction is cooled in an ice-water bath and 150 mL of ice- water is added to quench the reaction.
  • the mixture is stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride.
  • the precipitate is collected by filtration (pH of the filtrate is 0 - 1) and washed with 100 mL of IN HCl solution, then 100 mL of water 5 times. To remove remaining copper by-products that are trapped in the solid, the filter cake is stirred in 150 mL of IN HCl solution for 0.5 h and filtered. The filter cake is subsequently washed with Milli-Q water until the filtrate is at pH 7 (approximately 7 washes). The solid is dried over a medium frit sintered glass funnel in vacuo to give 3 as a light gray powder in 93.8% yield. [See Eddy, S et al. Synthetic Communications, 2000, 30(1), l-7.Csende, F et al Synthesis, 1995, 1240-1242.] 3-chloro-4-methyl-6-phenylpyridazine (4)
  • Ice water (150 mL) is slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into HCl and HsPO 4, resulting in formation of a pink solid.
  • the solid is collected by filtration and washed three times with 50 mL of MiIH-Q water.
  • the solid is transferred to a 250 mL beaker, followed by addition of 100 mL of water to form a suspension.
  • the solid is filtered and washed 3 times with 100 mL of water to wash out the excess base.
  • 6-phenyl-3 -(4-f ⁇ yrimidin-2- vDpiperazin- 1 -yr)pyridazin-4-ol MWO 1-7-121 WH
  • the compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14g, 68mmol).
  • a mixture of 3-chloro-4,6-diphenylpyridazine (267mg, l.Ommol), l-(2-pyrimidyl)piperazine (656mg, 4.0mmol) in 3ml of 1-BuOH was heated with stirring at 130 0 C for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension.
  • a reflux condenser was connected to the flask and a dry tube filled with CaCl 2 was fitted to the top of the condenser.
  • the reaction mixture was heated to reflux in an oil bath (110 0 C) for 3 h.
  • the color of the reaction suspension changed to dark yellow once the reflux started.
  • the flask was removed from the oil bath and cooled to ambient temperature.
  • the mixture was poured on to 200 g of crushed ice and stirred vigorously for 10 minutes to give a gray precipitate and blue liquid.
  • the precipitate was then collected by filtering (pH of the filtrate was 1.5-2.0), and washed with 50 ml of a IN HCl solution to rid the solid of any remaining copper byproducts.
  • 3-chloro-6-phenyl-4-phenylpyridazine 2.O g (8 mmole) of 6-phenyIpyridazinone obtained above and 10 ml (54 mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed in a 50 ml single-necked round bottom flask. The flask was connected with a reflux condenser and a dry tube filled with CaCl 2 was fitted to the top of the condenser. (HCl gas is formed in the reaction so a basic solution such as NaOH may be needed to absorb HCl in a large-scale synthesis).
  • MWO 1-6-189 WH 4-pyridyl-6-phenyl-3 -(4-pyrimidin-2-ylpiperazin- 1 -y l)pyridazine
  • the mixture was poured on to 200 g of crushed ice and stirred vigorously for 10 minutes to give a gray precipitate and blue, liquid.
  • the precipitate was then collected by filtering (pH of the filtrate was 1.5-2.0), and washed with 50 ml of a IN HCl solution to rid the solid of any remaining copper byproducts. This is followed by washing with 100 ml of Milli-Q water to get rid of the acid in the solid, and is monitored by checking the pH value of the filtrate.
  • the solid was washed until the filtrate shows a pH of 7, after approximately 5 washes.
  • the solid was dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of a blue gray solid. Yield was 90%, confirmed by ESI-MS.
  • the protected pyridazinone MWOl -7-053 WH (l.Oequiv.) was mixed with arylboronic acid (1.37equiv.), Pd(PPh 3 ) 4 (0.05 equiv.) and K 2 CO 3 (3.1equiv) and 200 mL of DME in a 350ml of pressure vessel, flushed with argon for 3 min, and the mixture was then stirred and refluxed (oil bath, 12O 0 C) until the starting material had disappeared. After cooling, the solution was concentrated to dryness under reduced pressure, the residue was treated with water and filtered off. The filter cake was washed with water over filter funnel and then used for next step directly.
  • CCI chronic constriction injury
  • SNC spinal nerve crush
  • NRC nerve root crush
  • a model for lumbar radiculopathy/sensory loss may be used to investigate the effects of pyridazine compounds in the peripheral nervous system.
  • L5/6 facectomy and L5 hemilaminectomy using care to avoid trauma to the tissue.
  • the L5 nerve proximal to (in nerve root crush) or just distal (2 mm) from (in spinal nerve crush) the DRG will be crushed once for 2 s, by using a smooth surface forceps. Some nerve- fibers should survive the crush so that sensory function will not be blocked completely.
  • This form of proximal nerve injury should produce a transient hyperalgesia and neuronal apoptosis.
  • Other animals, in which the spinal nerve is exposed but not crushed, will be used for controls (sham surgery). Chronic constriction injury. Under barbiturate anesthesia, the sciatic nerve will be exposed uniaterally at the midthigh level.
  • ligatures chromic gut 4.0
  • the ligatures will be tied until they constrict, just slightly, the diameter of the nerve and a brief twitch is seen in the respective hind limb.
  • a number of animals will be studied per timepoint while contralateral and uninjured nerves will serve as controls.
  • the wound will be closed in layers. Thermal hyperalgesia is a reliable indicator of pain-related behavior in this model.
  • thermal hyperalgesia The thermal nociceptive threshold will be measured in each hindpaw of the experimental animals before surgery and at regular intervals from day 1 after surgery using a thermal testing device and protocol that allows each animal to serve as its own control (Hargreaves et al., Pain 32:77-78, 1988).
  • This technique uses a light source to selectively heat one foot at a time.
  • the method is suitable for investigations of neuropathic pain involving unilateral lesions to peripheral nerves. Both the left (injured) and right (uninjured) footpads will be tested as described by Wagner R. Myers R R., Neuroreport 7:2897-901, 1996). All animals will be tested for three consecutive days prior to surgery to acclimate the animals to the testing procedure.
  • the potential of preventing or reducing CNS injury using a pyridazine compound may be evaluated in animal models described in US Patent No. 6833237, the description of which is generally reproduced below.
  • the models represent varying levels of complexity, and they can be evaluated by comparison of control animals to the treated animals.
  • the efficacy of such treatment may be evaluated in respect to clinical outcome, neurological deficit, dose- response and therapeutic window.
  • CHI Closed Head Injury
  • Transient middle cerebral artery occlusion A 90 to 120 minutes transient focal ischemia may be performed in adult, male Sprague Dawley rats, 300-370 g.
  • the intraluminal suture MCAO method described by Longa et al.(Stroke, 30, 84, 1989) and Dogan et al. (J. Neurochem. 72, 765, 1999) may be employed.
  • a 3-0-nylon suture material coated with Poly-L-Lysine is inserted into the right internal- carotid artery (ICA) through a hole in the external carotid artery.
  • the nylon thread is pushed into the ICA to the right MCA origin (20-23 mm), 90-120 minutes later the thread is pulled off, and the animal is closed and allowed to recover.
  • EAE chronic EAE animal model
  • This model is a well accepted experimental model for MS.
  • EAE can be induced in female C57BL/6 mice using the protocol described by Mendel et al. (Eur. J. Immunol. 25:1951-59, 1995). Briefly, disease is induced by immunizing mice with a MOG35-55 peptide derived from rat myelin oligodendrocyte glycoprotein (Mendel et al., 1995).
  • mice in a second experiment are given an intravenous injection of 500 ng pertussis toxin administered 48 hours after they receive the dose of MOG35-55.
  • the mice in Experiment 1 receive no pertussis toxin; therefore disease onset in Experiment 2 is accelerated as compared with Experiment 1
  • a pyridazine compound or placebo may be initiated on the day after the MOG35-55 is administered (day 1) and it may be continued through day 11.
  • Each mouse is injected intraperitoneally every other day with pyrogen-free phosphate-buffered saline (PBS) or 0.2 ml PBS containing a suitable dose of a pyridazine compound.
  • Mice are monitored daily for 35 days (Experiment 1) or 30 days (Experiment 2) for. weight loss, disease onset and severity of clinical signs of EAE by an independent observer blinded to the treatment groups. The severity of EAE is assessed using a standard EAE index system in which "0" is used to indicate an asymptomatic mouse and clinical scores ranging from 0.5 to 4 are used to indicate varying degrees of ascending paralysis.
  • mice will be treated with 5.0 mg/kg MWOl -2-151 SRM or MW01-5-188WH per day, beginning two days prior to induction of EAE by active immunization with PLP139-151 peptide in CFA, for a total of 14 days and they will be compared to an equal number of control-treated animals.
  • the mice will be observed for presentation of clinical signs of disease; immunologic parameters (peripheral and CNS cytokine expression patterns), CNS histology, and CNS flow cytometric analysis of inflammatory cell populations will be analyzed.
  • the time points that will be examined will correspond to peak clinical disease, remission, and first relapse.
  • MWO 1-2-15 ISRM also referred to herein as Minozac

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Abstract

The invention relates to compositions and methods for treating patients with Demyelinating Diseases and Conditions including Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke. The compositions and methods may also be used for Stroke Rehabilitation and the treatment of pain disorders including Neuropathic Pain and Chemokine-Induced Pain. The compositions comprise one or more pyridazine compounds having a pyridazinyl radical pendant with an aryl or substituted aryl, a heteroaryl or substituted heteroaryl.

Description

COMPOSITIONS AND TREATMENTS FOR DEMYELINATING DISEASES AND PAIN DISORDERS FIELD OF INVENTION
The invention relates to compositions and methods for use in treatment for patients with Demyelinating Diseases and Conditions including Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke. The compositions and methods can also be used for Stroke Rehabilitation and the treatment of pain disorders including Neuropathic Pain and Chemokine-Induced Pain. BACKGROUND OF INVENTION The treatment of neurological disorders is of great importance in medicine and there is a need for new drugs and treatments to prevent progression and reverse the impairments of neurological disorders such as demyelinating diseases, demyelinating conditions, traumatic brain injury, stroke, cerebral ischemia, craniocerebral trauma and spinal cord injury, as well as to treat pain disorders, including neuropathic pain disorders. Demyelinating diseases comprise disorders that are characterized by damage to the myelin sheath that coats and insulates nerve fibers. Those afflicted with these diseases suffer neurologial deficits due to impaired transmission of nerve impulses caused by myelin being stripped from nerve fibers. Multiple Sclerosis, the most common of these diseases, is a demyelinating disease of the central nervous system (CNS) and a leading cause of nontraumatic neurological disability among young adults in North America.
The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" [IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210)]. Neuropathic pain is a complex disorder resulting from injury to the nerves, spinal cord or brain. Neuropathic pain has developed into a major health problem requiring treatments that are sensitive to the causes behind the pain whether it is an underlying disease or the mechanistic pathway over which it manifests. ' ' . .
SUMMARY OF INVENTION
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. The pyridazine compounds are suited for use in compositions and methods for treating Demyelinating Diseases and Conditions including Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke. In addition, pyridazine compounds are suited for use in compositions and methods for treating pain disorders including Neuropathic Pain and Chemokine-Induced Pain, and for Stroke Rehabilitation.
Therefore, the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating a Demyelinating Disease or a Demyelinating Condition in a subject. The invention also provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating pain disorders including Neuropathic Pain and Chemokine-Induced Pain in a subject. Further, the invention provides a composition comprising a pyridazine compound in a therapeutically effective amount for treating a subject requiring Stroke Rehabilitation. The compositions of the invention generally comprise a pyridazine compound in a pharmaceutically acceptable carrier, excipient, or vehicle. In aspects, 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.
In other aspects, 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. In an aspect, the invention provides a method of preparing a stable pharmaceutical composition comprising a pyridazine compound adapted for use in Stroke Rehabilitation and in treating a Demyelinating Disease, a Demyelinating Condition, or pain disorders including Neuropathic Pain, and Chemokine-Induced Pain. 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). 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.
In some aspects 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 Stroke Rehabilitation and in treating a Demyelinating Disease, a Demyelinating Condition, and pain disorders including Neuropathic Pain, and Chemokine-Induced Pain. The invention also contemplates the use of one or more pyridazine compound and or method of the invention to prevent, and/or ameliorate disease severity, disease symptoms, and/or periodicity of recurrence of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain, or for Stroke Rehabilitation. Therefore, the invention contemplates the prevention and treatment, in a subject, of a
Demyelinating Disease, a Demyelinating Condition, a pain disorder including Neuropathic Pain, or Chemokine-Induced Pain, using a pyridazine compound or a composition of the invention. In particular, the invention provides a method for treating a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine- Induced Pain 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 Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain," or Chemokine-Induced Pain. In an aspect, the invention provides a method for the prevention and/or intervention of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain 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 Demyelinating Disease, a Demyelinating Condition, a pain disorder including Neuropathic Pain, or Chemokine-Induced Pain, or for Stroke Rehabilitation, 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. In an embodiment, the compound or composition is administered orally or systemically. In an aspect, the invention provides a method for the treatment of nerve injury and neuropathic pain by the use of one or more pyridazine compound. The invention in particular contemplates a method for protection of the peripheral nervous system and the treatment of neuropathic pain comprising the systemic administration of a therapeutic dose of a pyridazine compound. Treatment may be short or long term depending on the nature of the nerve injury or source of neuropathic pain. Pyridazine compounds can be used for the protection and treatment of peripheral nerve injury caused by any injury or insult and is not limited for use for treatment of injuries resulting from nerve crush or other traumatic, acute injury and neuropathic pain caused by disease.
In an aspect, the invention provides a method for amelioriating progression of a disease or obtaining a less severe stage of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain, or Chemokine-Induced Pain in a subject suffering from such disease or condition 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 Demyelinating Disease or a Demyelinating Condition comprising administering a therapeutically effective amount or 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 Demyelinating Disease or a Demyelinating Condition comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention.-
In an embodiment, the invention relates .to a method of improving the lifespan of a subject suffering from a Demyelinating Disease or a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain comprising administering a therapeutically effective amount of one or more pyridazine compound or a composition of the invention. 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 disease or condition and its complications.
The invention also contemplates the use of one or more pyridazine compound for the preparation of a medicament for preventing and/or treating a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine- Induced Pain, or for use in Stroke Rehabilitation.
The invention additionally provides uses of a pharmaceutical composition of the invention in the preparation of medicaments for the prevention and/or treatment of a Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain or Chemokine-Induced Pain, or for use in Stroke Rehabilitation.
In aspects of the invention, 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 disease or condition disclosed herein. Accordingly, in an embodiment, a pyridazine compound or a composition of the invention is 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. In an aspect, 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 Demyelinating Disease, a Demyelinating Condition, or a pain disorder including Neuropathic Pain, or Chemokine- Induced Pain, or for use in Stroke Rehabilitation.
These, and other aspects, features, and advantages of the present invention should, be apparent to those skilled in the art from the following detailed description. DESCRIPTION OF THE FIGURES Figure 1 depicts a synthetic scheme for MWOl -3-183 WH.
Figure 2 depicts a synthetic scheme for MWO 1-2-151 SRM.
Figure 3 is a synthetic- scheme for MWO 1-2-15 ISRM.
Figure 4 is a synthetic scheme for MWOl -2-15 ISRM. Figure 5 is a synthetic scheme for MWO 1-2-151 SRM.
Figure 6 is a synthetic scheme for MWO 1-5- 188WH.
Figure 7 is a synthetic scheme for MW01-5-188WH.
Figure 8 is a synthetic scheme for MWO 1-5- 188WH.
Figure 9A and 9B are synthetic schemes for MWO 1-6- 189WH. Figure 10 is a synthetic scheme for MWO 1 -7-084 WH.
Figure 11 is a synthetic scheme for MWO 1-7-085 WH.
Figure 12 is a synthetic scheme for MW01-7-057WH. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
For convenience, certain terms employed in the specification, examples, and appended claims are collected here.
Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term "about." The term "about" means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made. Further, it is to be understood that "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition comprising "a compound" includes a mixture of two or more compounds.
As used herein the terms "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. The term "treating" refers to reversing, alleviating, or inhibiting the progress of a disease, or one or more symptoms of such disease, to which such term applies. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease. A treatment may be .either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease 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 disease. "Preventing" also refers, to preventing the recurrence of a disease or of one or more symptoms associated with such disease. "Treatment" and "therapeutically," refer to the act of treating, as "treating" is defined above. The. purpose of prevention and intervention is to combat the disease, condition, or 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 disease, condition, or disorder.
The terms "subject", "individual", or "patient" are used interchangeably herein and refer 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. Among other specific embodiments a mammal of the present invention can be Canis familiaris (dog), Felis catus (cat), Elephas maximus (elephant), Equus caballus (horse), Sus domesticus (pig), Camelus dromedarious (camel), Cervus axis (deer), Giraffa camelopardalis (giraffe), Bos taurus (cattle/cows), Copra hircus (goat), Ovis aries (sheep), Mus musculus (mouse), Lepus brachyurus ■ (rabbit), Mesocricetus auratus (hamster), . Cavia por.cellus .(guinea pig), Meriones unguiculatus
(gerbil), or Homo sapiens (human). In a particular embodiment, the mammal is a human. In other embodiments, animals can be treated; the animals can be vertebrates, including both birds and mammals. In aspects of the invention, 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. In aspects of the invention 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.
In aspects of the invention, the terms refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. In the context of particular aspects of the 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 disease disclosed herein. Typical subjects for treatment include persons afflicted with or suspected of having or being pre-disposed to a disease disclosed herein, or persons susceptible to, suffering from or that have suffered a disease disclosed herein. A subject may or may not have a genetic predisposition for a disease disclosed herein such as MS. In certain aspects, a subject may be a healthy subject. As utilized herein, the term "healthy subject" means a subject, in particular a mammal, having no diagnosed disease, disorder, infirmity, or ailment disclosed herein.
As used herein, the terms "co-administration", "combination treatment", and "administering in combination" refer to the administration of one or more pyridazine compound and additional therapeutic agent or therapies to a subject. In aspects, the administration of two or more agents/therapies is concurrent. In other aspects, a first agent/therapy is administered prior to a second agent/therapy. In this aspect, 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 coadministration can be readily determined by one skilled in the art. hi some embodiments, when agents/therapies are co-administered, the respective agents/therapies are administered at lower dosages than appropriate for their administration alone. Thus, 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. In aspects of the invention, the beneficial effects include without limitation enhanced stability, a longer half life, and/or enhanced uptake. A beneficial effect can be a statistically significant effect in terms of statistical analysis of an effect of a pyridazine compound and a composition 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. In aspects, 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 disease and its complications. In aspects of the invention, 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.
The term "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. Examples of 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 disease 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.
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. In aspects of the invention a pyridazine compound refers to a pyridazinyl radical pendant with an aryl or substituted aryl, a heteroaryl or substituted heteroaryl. In some aspects the term includes the structures disclosed in US Patent Application Serial Numbers 20030176437 and 20060073472.
In aspects, a pyridazine compound that demonstrates beneficial effects, in particular statistically significant beneficial effects is selected for use in the present invention.
In aspects of the invention, a compound of the following formula I is employed.
Figure imgf000011_0001
wherein R1, R2, and R3 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, cyano,. halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; R7 Js substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl,- acyloxy, sulfonyi, sulfinyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide or R7 may be absent and there is a double bond between N at position 1 and C at position 6; R4, R5, and R6 are independently hydrogen, alkyl, alkoxy, halo, or nitro; or R1 and R2, R1 and R7, or R2 and R3 may form a heteroaryl or heterocyclic ring; or an isomer or a pharmaceutically acceptable salt thereof.
In an aspect, a compound of the Formula Ia or Ib is employed wherein: (a) R1 is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, cyano, amino, cycloalkyl, sulfonyl, sulfinyl, sulfenyl, thioaryl, thioalkyl, carbonyl, silyl, piperazinyl, piperidinyl, pyrrolidinyl,'. morpholinyl, -SR20 wherein R20.. is optionally substituted alkyl, carbonyl, carboxyl, carbamoyl, aryl, heterocylic, or heteroaryl; (b) R2 is optionally substituted halo, hydroxyl, alkyl, alkenyl, alkoxy, carbonyl, carboxyl, phenyl, benzyl, amino, aryl, cyano, - COH, piperazinyl,. alcohol, piperidinyl, morpholinyl, or naphthyl;(c) R3 is optionally substituted hydrogen, halo, hydroxyl, alkyl, alkenyl, alkoxy, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiol, sulfenyl, sulfonyl, sulfinyl, or nitro; (d) R4 is hydrogen, halo, or nitro; (e) R5 is optionally substituted hydrogen, halo, alkoxy, or amido;(f) R7 is substituted or unsubstituted hydrogen halo, hydroxyl, alkyl, alkenyl, alkoxy, carboxy, • mόrpholino, imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl or R7 is absent and there is a double bond between N at position 1 and C at position 6; and/or (g) R1 and R2, R1 and R7 or R2 and R3 may form a substituted or unsubstituted heteroaryl or heterocyclic ring. .
In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R1 is Cl or Br, -NH2, alkyl,- -CN, =S, silyl, sulfonyl, thioalkyl, thioaryl, piperazinyl, piperidinyl, morpholinyl, pyrrolyl, or pyrrolidinyl, which may be optionally substituted with halo, =0, alkoxy, alkenyl, alkyl, substituted alkyl, -CN, -SR21 wherein R21 is optionally substituted methyl, ethyl, phenyl, heterocylic, or heteroaryl, or -CO substituted with phenyl or substituted phenyl.
In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R2 is carbonyl, piperazinyl, morpholinyl, sulfonyl, sulfinyl, sulfenyl, or phenyl, -CN, -COH, -CH2OH3 -OCH2CH3, or alkyl which may be optionally substituted with alkyl, alkoxy, amino, halo, phenyl, substituted phenyl, benzyl, hydroxyl, amino, piperidinyl, or morpholinyl.
In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R3 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(CHs)3), carboxyl, or substituted carboxyl; hydroxyl; or nitro.
In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R4 is nitro or hydrogen.
In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R5 is hydrogen, halo, -OCH2CH2CH2NHCOOC(CHa)3, or -OCH3. In another aspect of the invention a compound of the Formula Ia or Ib is employed wherein R7 is alkyl, morpholinyl, benzyl, imidazolyl, -CH2COOCH2CHa, CH2C=COOCH2CH3, CH2CH2CH2SO2OH, CH2CH2CH2SO3 ", CH2CH2CH2CH2PO(OH)2, or CH2CH2CH2PO(OH)2.
In another, aspect of the invention a compound of the Formula Ia or Ib is employed wherein R7 is absent and there is a double bond between N at position 1 and C at position 6.
In a further aspect, a compound of the Formula Ia is employed wherein R1, R2, R3, and R7 are independently substituted aliphatic, lower alkyl substituted amino, lower alkyl substituted halogen, cycloaliphatic, or substituted cycloaliphatic.
In a still further aspect of the invention a compound of the Formula Ia or Ib is employed wherein R1 is a piperazinyl which may be substituted (e.g., with a pyrimidinyl moiety); halo; amino which, may be substituted; cyano; - SR22 wherein R22 is alkyl or aryl (e.g. phenyl) which may be substituted (e.g., halo); substituted alkyl [e.g., alkyl substituted with halogen, such as CH(Br)2]; morpholinyl; pyrrolyl which may be substituted; hydroxyl; -OR28 wherein R28 is alkyl; -C= CHR30 wherein R30 is alkyl; or pyrrolidinyl. In a still further aspect of the invention a compound of the Formula Ia or Ib is employed wherein R2 is hydrogen; morpholinyl; piperazinyl which may be substituted (e.g., with a pyrimidinyl moiety); phenyl; alkyl; alkoxy (e.g. CH(OCH3)2); substituted alkyl; substituted aryl (e.g., phenyl); cyano; or hydroxyl. In another aspect of the invention a compound of the Formula Ib is employed wherein
R is pyridinyl, and R is an N-substituted piperzinyl.
In another embodiment a compound of the Formula Ib is employed wherein R1 is amino substituted with alkyl or cycloalkyl and R2 is pyridinyl.
In a still further aspect of the invention a compound of the Formula Ia or Ib is employed wherein R3 is hydrogen; hydroxyl; alkyl which may be substituted (e.g., halo); amino which may be substituted; -COR31 wherein R31 is hydrogen, hydroxyl, alkoxy (e.g. — OCH3); or, aryl (e.g. phenyl) which may be substituted (e.g., alkyl).
In a still further aspect of the invention a compound of the Formula Ia or Ib is employed wherein R4 is hydrogen or halo; R5 is hydrogen or halo; R6 is hydrogen or halo. In a still further aspect of the invention a compound of the Formula Ia is employed wherein R7 is hydrogen; alkyl which may be substituted (e.g. with phenyl); -CH2CH2COOR32 wherein R32 is alkyl, -CH2C=COOR33 wherein R33 is alkyl, CH2CH2CH2S(O)2OH, morpholinyl, benzyl, imidazolyl, or [CH2]nPO(OH)2 wherein n is 1 to 6, in particular 3 or 4.
In a still further aspect of the invention a compound of the Formula Ia or Ib is employed wherein R1 and R2 form a piperidinyl ring which may optionally be substituted with a carboxyl.
In a still further aspect of the invention a compound of the Formula Ia is employed wherein R and R7 form a pyrimidinyl ring which may optionally be substituted with alkyl, aryl, halo, or hydroxyl. In a particular aspect, a compound of the formula Ia or Ib is employed wherein R1 is
-NR34R35 wherein R34 is hydrogen or alkyl, and R35 is hydrogen, alkyl, carbonyl, aryl, amino, cycloalkane, heterocylic, or heteroaryl which may be substituted. In embodiments R35 may comprise or be selected from the group consisting of hydrogen, Cj-C6 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, -COOR8 wherein R8 is alkyl which may be substituted, or [CH2]m-piperidinyl wherein m is 1 to 4, in particular 1 to 3 and the piperidinyl is optionally substituted with optionally substituted alkyl, phenyl, or benzyl.
In embodiments, R35 is -R44R45 wherein R44 is -NH[CH2]WNH wherein w is 1 to 4, in particular 2 or 3, and R45 is piperazinyl substituted with pyrimidinyl which may be substituted, in particular substituted with alkyl.
In embodiments, R35 is -R46R47 wherein R46 is -[CH2]WN(CH3) wherein w is 1 to 4, in particular 2 or 3, and R47 is piperazinyl substituted with pyrimidinyl which may be substituted, in particular substituted with alkyl.
In an aspect of the invention, a compound of the Formula Ia or Ib is employed wherein R is halo especially chloro or bromo, R 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. bromo or chloro), or carbonyl, 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; sydnonyl], 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 R3, R4, R5, R6, and R7 are hydrogen.
In another aspect of the invention, a compound of the Formula Ia is employed wherein R1 is halo especially chloro or bromo, and R3 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; sydnonyl], 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 R2 is a substituted amino, in particular amino substituted with alkyl or substituted alkyl, in particular alkyl substituted with alkoxy carbonyl, and optionally R2, R4, R5, R6, and R7 are hydrogen.
In further aspect R1 is halo, especially bromo or chloro, and R2 and R3 form an unsaturated ring, in particular phenyl, R5 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 R4, R6 and R7 are hydrogen.
In a further aspect, R1 is halo, especially bromo or chloro, and R4 is nitro, and optionally R2, R3, R5, R6, and R7 are hydrogen.
In a further aspect, the invention employs a compound of the Formula Ia wherein R1 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], especially a substituted morpholinyl or piperidinyl; aryl; substituted aryl; carboxyl which may be substituted with substituted or unsubstituted aryl; optionally R2 is alkyl, in particular lower alkyl; optionally R3 is alkyl, in particular lower alkyl or nitro; optionally R5 is alkoxy; optionally R7 is alkyl; and optionally R4, R5, and R6, are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is =S, and optionally R2 is alkyl, in particular lower alkyl, R5 is alkoxy, and R3, R4, R6 and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is sulfonyl which may be substituted with substituted or unsubstituted aryl, in particular substituted phenyl, and optionally R2 is alkyl and R3, R4, R5, R6, and R7 are hydrogen. In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is substituted or unsubstituted alkyl or alkynyl, in particular alkyl substituted with aryl, substituted aryl, halo, cyano, or alkynyl substituted with alkyl; and optionally R2 is alkyl, R7 is alkyl, and R3, R4, R5, and R6 are hydrogen. In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is cyano and R2 is aryl or alkyl, and optionally R3, R4, R5, R6, and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein one or both. of R and R are a saturated 3 to 6-membered heteromonocyclic group containing l .to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially a substituted morpholinyl, and optionally R3, R4, R5, R6, and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 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; R2 is alkyl or halo, and optionally R3, R4, R5, R6, and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is hydroxyl; R2 is alkyl or substituted alkyl or R3 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 R2 or R3 is hydrogen, and optionally R4, R5, R6, and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 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; R2 is alkyl or substituted alkyl,. in particular alkylaryl, and optionally R3, R4, R5, R6, and R7 are hydrogen.
In a further aspect of the' invention, a compound of the Formula Ia is employed wherein R is =0, and R is alkyl, alkylaryl, cyano, alkoxy, or substituted alkoxy, and ' optionally R3, R4, R5, R6, and R7' are hydrogen. In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is alkoxy, R2 is alkyl, substituted alkyl, or alkoxy, and optionally R3, R4, R5, R6, and R7 are hydrogen.
In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 and R2 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 R3, R4, R5, R6, and R7 are hydrogen. In a further aspect of the invention, a compound of the Formula Ia is employed wherein. R1 and R7 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, R2 is hydrogen or alkyl, and R3, R4, R5, R6, and R7 are hydrogen. In a further aspect of the invention, a compound of the Formula Ia is employed wherein R1 is silyl which may be substituted, in particular substituted with alkyl, R2 is alkyl, and R3, R4, R5, R6, and R7 are hydrogen.
In some aspects, one or more of the following compounds are not within the scope of a pyridazine compound of the formula Ia or Ib employed in the present invention: a) a compound wherein when R1 is =0, R3 is -COOCH3, CH=CHCOOCH3,
-CH=CHC(=O)-phenyl, -CH=CH(C(=O)OCH3)2, -S-phenyl,
-CH=CH(COCH3)(COOCH3), CH=CH(COOCH2CH3);., -phenyl-COOCHj, -CH=CHCO-phenyl, -CH2CH(Cl)(CH2OH), -methylphenyl, R7 is hydrogen or -CH2OCH3, and R1, R2, R4, R5 and R6 are hydrogen; b) a compound wherein when R1 is =0, R2 is cyano, R3 is -C(=O)OCH3, and R3,
R4, R5, and R6 are hydrogen; c) a compound wherein when R1 is =0, R2 is -methylthiophene or benzyl, R3, R4, R5, R6, and R7 are hydrogen; d) a compound wherein when R1 is =0, R2 is methyl, R5 is hydrogen, hydroxyl, chloro, or bromo, R7 is hydrogen or ethylmorpholinyl, and R3, R4, and R6 are hydrogen; e) a compound wherein when R2 is methyl, R5 is chloro, bromo, or hydrogen, R7 is hydrogen or -CHbCEb-morpholinyl, and R1, R3, R4, and R6 are hydrogen; f) a compound wherein when R1 is piperazinyl, piperazinyl substituted with pyridinyl. phenyl, or methyl, R2 is hydrogen or methyl, and R3, R4, R5, and R6 are hydrogen; g) a compound wherein when R is chloro or bromo, R is C1-C3 alkyl, phenyl, amino, benzyl, morpholinyl, chloro, -C(=O)NH2, -NH2, C1-C3 alkylphenyl,
-CH(CHs)2, -CH2CH(CH3)2, -benzylchloro, and R3, R4, R5 and R6 ' are hydrogen; h) a compound wherein when R1 is chloro or bromo, R3 is hydroxyl, chloro, bromo, Ci -C3 alkyl, phenyl, or -N(CH3)2, and R2, R4, R5 and R6 are hydrogen; i) a compound wherein when R1 is chloro, R2 is methyl, R5 is hydroxyl, and R3,
R4, and R6 are hydrogen; j) a compound wherein when R1 is chloro, R2, R3, R4, R5 and R6 are hydrogen; k) a compound wherein when R1 is hydroxyl, R2 is Q-C4 alkyl, and R3, R4, R5 and R6 are hydrogen; 1) a compound wherein when R1 is -CpC4 alkoxy, or C1-C4 alkoxy substituted with -N(CH3)2, morpholinyl, or piperidinyl substituted with benzyl, R2 is
. ' hydrogen or methyl, R3, R4, R5 and R6 are hydrogen, R7 is absent, hydrogen, or methyl; m) a compound wherein when R1 is -SH, -SCH3, or -SCH2C(=O)CH3, R2 is hydrogen or methyl, and R3, R4, R5 and R6 are hydrogen; n) . a compound wherein when R1 is =S, R2 is hydrogen or methyl, R7 is methyl or benzyl, and R3, R4, arid R6 are hydrogen; o) a compound wherein when R1 is =S, R2 is methyl and R5 is chloro or R7 is methyl, and R3, R4, and R6 are hydrogen; p) a compound wherein when R is hydroxyl, R is hydrogen, methyl, or butyl, and R3, R4, Rs and R6 are hydrogen; q) a compound wherein when R1 is methoxy, R2, R3, R4, R5 and R6 are hydrogen; r) a compound wherein when R1 is Ci-C2 alkoxy or C1-C4 alkoxy substituted with morpholinyl, -N(CHs)2, or piperidinyl substituted with benzyl, R2 is methyl, and R3, R4, R5 and R6 are hydrogen; s) a compound wherein R , R3, R4, R5 and R are hydrogen; t) a compound wherein R1 is cyano or cyano substituted with -C(OCH2CHs)2,
-CH(OH)(CH3), -Si(CH2CH3)2, cyclohexol, -CH2O-trimethyldiphenylsilyl or cyclohexyl substituted with hydroxyl, and R3, R4, R5 and R6 are hydrogen; u) a compound wherein R1 is cyano substituted with -CH(OH)(CHB)2,
-Si(CH2CH3)2, morpholinyl, trimethyldiphenylsilyl, or -CH(OCH2CH3)2, R2 is methyl, and R3, R4, R5 and R6 are hydrogen; v) a compound wherein R7 is oxy, and R2 is hydrogen or methyl, and R3, R4, R5 and R6 are hydrogen; w) a compound wherein R1 is methyl, and R2, R3, R4, R5 and R6 are hydrogen; x) a compound wherein R2 is methyl, and R1, R3, R4, R5 and R6 are hydrogen; y) a compound wherein R1 is methoxycarbonyl, R3 is hydrogen, and R2, R4, R5 and R6 are hydrogen; z) a compound wherein R1 is -NH2, R2 is methyl, chlorophenyl, methoxyphenyl, ethylphenyl, ethylmethoxyphenyl, propylphenyl, or -CH(CH3)2, R4, R5 and R6 are hydrogen, and R7 is absent or -CH2CH2CH2COOH; aa) a compound wherein R1 is -OR29 wherein R29 is ethylmoφholinyl or
-CH2CH2N(CHs)2 and R2, R3, R4, R5 and R6 are hydrogen; bb) a, compound wherein R1 is -NH2, R3 is -NH2, and R3, R4, R5 and R6 are hydrogen; cc) a compound wherein R1 is -NH2 , R5 and R6 are methoxy, and R3 and R4 are hydrogen; dd) a compound wherein R1 is -NH2 , R3 is methyl and R4, R5 and R6 are hydrogen; ee) a compound wherein R1 is -NH2 , R5 is chloro, and R3, R4 and R6 are hydrogen; ff) a compound wherein R is -NH-chlorophenyl, and R and R form a phenyl group, and R4, R5 and R6 are hydrogen; gg) a compound wherein R1 is -NH2, R4 and R5 is methoxy, and R2, R3 and R6 are hydrogen; hh) a compound wherein R1 is -NH2, R2 is ethylmethoxyphenyl, R7 is carboxyethyl or carboxypropyl, and R3, R4 and R6 are hydrogen; ii) a compound wherein R1 is -NHR48 wherein R48 is ethylmorpholinyl, ethylmorpholinyl substituted with =0, -CH2CH2OCH3, -CH2CH2CH2CH2CH2
CH2CH2CH3, -CH2CH2CH2CH2OH, -CH2CH2OH, or -CH2CH2OCH3, R2 is hydrogen, methyl, ethyl, -CHO, -CH2OH, -COOH, chloro, -CH2CH2NH2,
-NO2, -C=N, -C(=O)OCH2CH3, or -C(O)NH2, and R3, R4, R5 and R6 are hydrogen; jj) a compound wherein R1 is -NHR49 wherein R49 is ethanol, methylpiperidinylbenzyl, ethylpiperidinyl, ethylpiperidinylbenzyl, or butylpiperidinylbenzyl, R2 is hydrogen, methyl, or -C(CH3)2} and R3, R4, R5 and R6 are hydrogen; kk) a compound wherein R1 is -NHR55 wherein R55 is hydrogen, and R3, R4, R5 and R6 are hydrogen;
11) a compound wherein R1 is -NHR56 wherein R56 is -CH2CH2N(CH2CH3)2 or ethylmorpholinyl, R3 is ethyl, and R4, R5 and R6 are hydrogen; mm) a compound wherein R1 is -NHNH2, R3 is hydrogen, alkyl, or phenyl, and R3,
R4, R5 and R6 are hydrogen; nn) a compound wherein R1 is -NHR57 wherein R57 is NH2, -CH2CH2OH,
CH2CH(OH)(CH3), ethylmorpholinyl, ethylmorpholinyl substituted with O, ethylphenyl, -CH2CH2NHCH3, -CH2CH2N(-CH2CH2CH3)2, ethylpiperidinyl, or ethylpiperidinylbenzyl, R2 is methyl, and R3, R4, R5 and R6 are hydrogen; oo) a compound wherein R is morpholinyl, R is -C(F)3, -C(=O), -CH2OH,
-C(=O)H, -COOH5 chloro, -NO2, or cyano, and R3, R4, R5 and R6 are hydrogen; pp) a compound wherein R1 is -NHR58 wherein R58 is heptyl, phenyl, benzyl, or ethylphenyl, R2 is hydrogen, methyl, or chlorophenyl, R4, R5 and R6 are hydrogen; qq) a compound wherein R1 is -NR9 wherein R9 is phenyl and R2, R3, R4, R5 and
R are hydrogen; rr) a compound wherein R1 is morpholinyl and R2, R3, R4, R5 and R6 are hydrogen; ss) a compound wherein R1 is methylpiperazinyl and R2, R3, R4, R5 and R6 are hydrogen; tt) . a compound wherein R1 is -NHCH2CH2OH or NHCH2CH2OCH3, R2 is phenyl and R3, R4, R5 and R6 are hydrogen; uu) a compound wherein R1 is -NHR59 wherein R59 is ethylamino, butylamino, ethylaminomethyl, and R2 is hydrogen, methyl, or -C(=0)NH2, and R3, R4, R5 and R6 are hydrogen; w) a compound wherein R1 is -NHR60 wherein R60 is ethylpiperidinyl, methylpiperidinylbenzyl, piperidinylbenzyl, ethylpiperidinylbenzyl, methylpyrrolidinylmethyl, ethylpiperazinylbenzyl, -CH2C(=O)- piperazinylbenzyl, -C(=O)-methylnaphthyl,
-CH2CH2CH2CH2CH2N(CH3)(C7H7), -CH2C(=O)-piperidinylbenzyl, -C(O)- methylpiperidinylbenzyl, or -CH(CHB)2, and R3, R4, R5 and R6 are hydrogen; ww) a compound wherein R1 is • -CHCH2CH2-isoquinolinyl,
-NHCH2CH2N(CH2CH2CH3)2, propyl substituted with piperidinyl fused to phenyl, -NHCH2CH2, or -NHCH2CH2CH2CH2CH2 substituted with a piperidinyl fused to two adjacent carbon atoms of a phenyl moiety; xx) a compound wherein R1 is -NH substituted with two pyrrolidinyl groups; R3 is methyl, and R2, R4, R5 and R6 are hydrogen; yy) a compound wherein R1 is -COOCH3, R3 is methyl, and R2, R4, R5 and R6 are hydrogen; zz) a compound wherein R1 is hydrogen, R2 is methyl, R7 is oxygen; aaa) a compound wherein R7 is methyl or oxygen, and R1, R2, R4, R5 and R6 are hydrogen; bbb) a compound wherein R1 is -NHCH2CH2N(CH2CHS)25 R3 is ethyl, and R2, R4, R5 and R6 are hydrogen; and ccc) a compound wherein R1 is -NHCH2CH(OH)(CH3) or -NHCH2CH2NHCH2CH2OH,- R2 is methyl, and R3, R4, R5 and R6 are hydrogen.
In aspects of the invention a compound of the formula Ia or Ib is employed wherein R1 is a piperazinyl or substituted piperazinyl, in particular a piperazinyl substituted with a pyrimidinyl of Formula A below.
Figure imgf000023_0001
Thus, a pyridazine compound for use in the present invention includes compounds of the Formula II:
Figure imgf000023_0002
wherein R10 and R11 are independently substituted or unsubstituted hydrogen, hydroxy., 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, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof. In an aspect of the invention, a compound of the Formula II is employed wherein R10 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); -NR36R37 wherein R36 is hydrogen or alkyl, and R37 is phenyl which may be substituted or alkyl which may be substituted (e.g. amino, in particular - CH2CH2NH2; CH2CH2NHCOOC(CH3)3); morpholinyl which may be substituted; or -SR23 wherein R23 is phenyl which may be substituted; and R1 ' is hydrogen, or aryl (e.g. phenyl) which may be substituted.
In a particular aspect of the invention a compound of the Formula II is employed wherein R!0 is hydrogen, halo, optionally substituted hydroxyl, alkyl,- pyridinyl, phenyl,. benzyl, piperazinyl, amino, morpholinyl, • or -SR24 wherein R24 is alkyl or aryl. In an embodiment, R10 is -NH[CH2]mNR61R62 wherein m is 1 to 6, in particular 2 to 4, R61 is hydrogen, R62 is a carboxyl, in particular -COOC(CHa)3.
In an aspect of the invention, a compound of the Formula II is employed wherein R1 ' is hydrogen, halo, optionally substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl, or phenyl.
In another aspect of the invention, a compound of the Formula II is employed wherein both of R10 and R1 ' are not hydrogen.
In particular embodiments of the invention, one or more of R10 and R11 are alkyl, in particular CpC6 alkyl and the other of R10 and R1 ' is hydrogen. In particular embodiments of the invention, one or more of R10 and R11 are aryl in particular phenyl or benzyl and the other of R10 and R11 is hydrogen.
In particular embodiments of the invention, a compound of the Formula II is a compound in Table 3, more particularly a compound designated MW01-2-065LKM, MWOl- 2-069SRM/ MW01-2-151SRM, MW01-5-188WH, MWO 1-6- 127WH, MW01-6-189WH, or MWO 1-7-107WH, and pharmaceutically acceptable salts, and derivatives thereof. In aspects, the invention employs a compound of the Formula III:
Figure imgf000025_0001
wherein R15 and R16 are independently su stituted 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof.
In other aspects, the invention employs a compound of the Formula IV:
Figure imgf000025_0002
wherein R70 and R71 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, cyano, halo, silyl, silyloxy, silyalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, or carbamoyl, or an isomer or pharmaceutically acceptable salt thereof.
In other aspects, a compound of the formula IV is employed wherein R70 is substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, carbonyl, carbamoyl, or carboxamide, especially heterocyclic, heteroaryl, amino, and substituted amino and R71 is aryl or substituted aryl; or an isomer or a pharmaceutically acceptable salt thereof.
In another aspect, a compound of the Formula IV is employed wherein R70 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, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, carbazolyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, or indazolyl, especially benzimidazolyl substituted with oxy.
In other aspects, a compound of the Formula IV is employed wherein R70 is amino or •substituted amino, and optionally R71 is aryl, in particular phenyl. In an aspect R70 is -N-R63 wherein R63 is hydrogen or alkyl, in particular Ci-Cg alkyl, more particularly methyl or dimethyl, or -N-R40R41 wherein R40 is hydrogen or alkyl, in particular Ci-C6 alkyl, more particularly methyl and R41 is alkyl substituted with amino or substituted amino, heterocyclic, substituted heterocylic, or cycloalkyl. In an embodiment, R70 is -N-R42R43 wherein R42 is hydrogen or alkyl, in particular Ci-C6 alkyl,' more particularly methyl and R43 is C]-C6 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.
In further aspects, the invention employs a compound of the Formula V:
Figure imgf000027_0001
wherein R50, R51, and R52 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof.
In aspects of the invention a compound of the Formula V is employed wherein R50 is substituted or unsubstituted hydrogen, alkyl, aryl, or heterocyclic; R51 is substituted or unsubstituted hydrogen or alkyl, and R52 is substituted or unsubstituted hydrogen, alkyl, cycloalkyl, heteroaryl or halo. In an aspect, a compound of the Formula V is employed wherein R50 is hydrogen, C1-C6 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, R51 is hydrogen or alkyl especially methyl, and R52 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 pyridinyl. In an embodiment, R50 is aryl, R51 is hydrogen, and R52 is CpC6 alkyl.
A compound of the Formula V may comprise compound MWO 1-7-057 WH, 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
In aspects of the invention 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. As used herein, the term "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 (e.g., • pyridazine derivatives of the present invention) 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, HI, IV, or V can be found in U.S. Patent Application No. 20030176437 (herein incorporated by reference in its entirety for all purposes).
In some embodiments, the 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. In particular aspects the invention employs a compound of the Formula I, II, HI, IV, or
V as defined herein, with the proviso that compounds depicted in Table 1 are excluded.
• In other particular aspects the invention employs a compound of the Formula II with the proviso that the compounds depicted in Table 1 are excluded. ■ :
In further particular aspects the invention employs a compound of the Formula III with the proviso that compounds depicted in Table 1 are excluded. . In further particular aspects the invention employs compounds of the Formula IV with the proviso that compounds depicted in Table 1 are excluded.
In still further particular aspects the invention employs compounds of the Formula V with the proviso that compounds depicted in Table 1 are excluded. . In accordance with aspects of the invention pyridazine compounds and/or related heterocyclic derivatives thereof (see, for example, the Figures and Tables herein, in particular Table 2, 3, 4 and/or 5 or heterocyclic derivatives thereof), are employed in the treatment or prevention of diseases disclosed herein.- In some embodiments, the compounds employed are those depicted in the Figures and Table 2, 3; 4, and/or 5 or derivatives thereof. In some ' embodiments, 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 MWOl- 2-15 ISRM, or isomers or pharmaceutically acceptable salts thereof.
In some embodiments, the invention employs one or more of the compounds designated herein as MW01-3-183WH, MW01-5-188WH, MW01-2-065LKM, MW01-2-184WH, MWOl -2- 189WH and MWO 1-2-151 SRM, or isomers or pharmaceutically acceptable salts thereof.
In some embodiments, 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 MWOl-I-OIrL-DOV, and/or related derivatives, in particular, heterocyclic derivatives, of these compounds. In another particular embodiment of the invention, MWO 1-2- 15 ISRM, an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed in the invention. In a particular embodiment of the invention, MWO 1-5- 188WH, an isomer, a pharmaceutically acceptable salt, or derivative thereof is employed iri the invention.
A pyridazine compound also includes' "pharmaceutically acceptable salt(s)". By pharmaceutically acceptable salts is 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. Examples of salts include the compounds designated herein as MWOl-IrOl-L- DlO, MW01-1-01-L-E02, MW01-1-01-L-E08, MW01-1-03-L-A05, MW01-.1-16-L-D09, and MW01-1-17-L-G04. . . • . In aspects of the invention, 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. In a particular embodiment, a pharmaceutically acceptable halide salt of the pyridazine compound 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l- yl)pyridazine(5) shown in Figure 1 is employed.
In an embodiment, a pharmaceutically acceptable salt employed in the invention is a chloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine(5) shown in
Figure 1. In a particular embodiment, a pharmaceutically acceptable salt is a hydrochloride salt of 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine (5) shown in Figure 1, more particularly the di-hydrochloride hydrate salt shown below (i.e., MW01-9-034WH)(6).
Figure imgf000030_0001
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)-. Thus, 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. When 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. Thus, 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. The solvated forms may be considered equivalent to the unsolvated forms for the purposes of the present invention. In addition, 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.
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. In certain instances, 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. In general, 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.
Dehydrate, co-crystals, anhydrous, or amorphous forms of the compounds of the invention are also included. The term "hydrate" means a solvate wherein the solvent molecule(s) is/are H2O, 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, H5 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) can also be used in the preparation of solvates. For example, 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. For example, a monohydrate of a compound of the formula I, II, III, IV or V would have about 1 equivalent of solvent (H2O) for each equivalent of a compound of the invention. However, 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. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymoφhs 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. IV3 or V may be in the form of a prodrug that is converted in vivo to an active compound. In a compound of the Formula I one or more of R1, R2, R3, R4, R5, R6, and R7 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.
The term "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). In general, such 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). In general, 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. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172 178 and pp. 949 982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc, 1975; and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987.
Examples of 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.
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.
The term "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. An aspect of the invention provides for a co-crystal wherein the co-crystal former is a second API. In another aspect, the co-crystal former is not an API. In another aspect, the co-crystal comprises more than one co-crystal former. For example, two, three, four, five, or more 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. The methods 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. In general, all physical forms of compounds of the formula I5 II, III, IV or V are intended to be within the scope of the present invention.
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 R1, R2, R3, R4, R5, R6 or R7 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. In aspects of the invention 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. Thus, 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. In aspects of the invention, the polymer is poly(2-acrylarnido-2- methyl- 1-propanesulfonic acid); poly(2-acrylamido-2-methyl,-l-propanesulfonic acid- coacrylonitrile, pory(2-acrylamido-2-methyl- 1 -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 polyvinyl alcohol). A "carbohydrate" as used herein refers to a polyhydroxyaldehyde, or polyhydroxyketone and derivatives thereof. The term includes monosaccharides such as erythrpse, 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, oligosaccharides, 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. For example, a carbohydrate may be substituted with one or more alky I, amino, nitro, halo, thiol, carboxyl, or hydroxyl groups, which are optionally substituted. Illustrative substituted carbohydrates are glucosamine, or galactosamine. In aspects of the invention, 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. In embodiments of the invention where 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 -CH2- or -S- groups. The term "carbohydrate" also includes 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, α- or β- lipoprotein, β- or γ- 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. In an aspect, the carrier is one amino acid, in particular a sulfonate derivative of an amino acid, for example cysteic acid.
Approaches to designing peptide analogues, derivatives and mimetics are known in the art. For example, see Farmer, P. S. in Drug Design (E. J. Ariens, ed.) Academic Press, New York, 1980, vol. 10, pp. 119-143; Ball. J. B. and Alewood, P. F. (1990) J MoI. Recognition 3:55; Morgan, B. A. and Gainor, J. A. (1989) Ann. Rep. Med. Chem. 24:243; and Freidinger, R. M. (1989) Trends Pharmacol. Sci. 10:270. See also Sawyer, T. K. (1995) "Peptidomimetic Design and Chemical Approaches to Peptide Metabolism" in Taylor, M. D. and Amidon, G. L. (eds.) Peptide-Based Drug Design: Controlling Transport and Metabolism, Chapter 17; Smith, A. B. 3rd, et al. (1995) J. Am. Chem. Soc. 117:11113-11123; Smith, A. B. 3rd, et al. (1994) J. Am. Chem. Soc. 116:9947-9962; and Hirschman, R., et al. (1993) J. Am. Chem. Soc. 115:12550-12568.
The term "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. In certain aspects of the invention an alkyl radical is a Ci-C6 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. In certain aspects of the invention, 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, sulfmyl, sulfenyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g. CF3), 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. As used herein in respect to certain aspects of the invention, the term ''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.). Examples of such groups include, but are not limited to, 1-chloroethyl and the like.
As used herein in respect to certain aspects of the invention, the term "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. As used herein in respect to certain aspects of the invention, the term "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. Examples of such groups include, but are not limited to, chlorethyl and the like.
As used herein, the term "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. As used herein the term "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-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), and prop-2-en-2-yl), buten-1-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l- yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,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. In aspects of the invention, "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.
As used herein, the term "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-l-yl and prop-2-yn-l-yl, butynyls such as but-1-yn-l-yl, but-l-yn- 3-yl, and but-3-yn-l-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, and 3-methylbutyn-l-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. The term "cycloalkynyl" refers to cyclic alkynyl groups. In aspects of the invention, "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. As used herein the term "alkylene" refers to a linear or branched radical having from about 1 to 1O5 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. When an 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.
As used herein the term "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. Examples of alkenylene radicals include 1,1- vinylidene (-CH2=C-), 1 ,2-vinylidehe (-CH=CH-), and 1 ,4-butadienyl (-CH=CH-CH=CH-).
As used herein the term "halo" refers to a halogen such as fluorine, chlorine, bromine or iodine atoms.
As used herein the term "hydroxyl" or "hydroxy" refers to an -OH group. As used herein the term "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.
As used herein the term "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. In embodiments of the invention, an alkoxy radical comprises about 1-6 carbon atoms and includes a Cj-C6 alkyl-O-radical wherein C1-C6 alkyl has the meaning set out herein. Examples of 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) and "haloalkoxyalkyl" radicals (e.g. fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl). As used herein the term "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. An "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).
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. Examples of carbocyclic radicals are cycloalkyl, cycloalkenyl, aryl, in particular phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyi, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexyl, acenapththylenyl, anthracenyl, biphenyl, bibenzylyl, and related bibenzylyl homologs, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyi, dimethoxytetrahydronaphthyl and the like.
As used herein, the term "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. In aspects of the invention, "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 C3-C7 carbocylic ring. Examples of 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. In certain aspects of the invention 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, cyc.opentyl, 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. In aspects of the invention, "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.
As used herein in respect to certain aspects of the invention, the term "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.
As used herein in respect to certain aspects of the invention, the term "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). Examples of such groups include, but are not limited to, 1-chlorodecalyl and the like.
A used herein, the term "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. In certain aspects of the invention the cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms.. Examples of 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.
As used herein the term "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. As used herein, the term "aryl", alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings wherein, such rings may be attached together, in a pendant manner or may be fused. In aspects of the invention an aryl radical comprises 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms. Illustrative "aryl" radicals includes without limitation aromatic radicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indahyl, bip'henyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl. An aryl radical may be optionally substituted 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.
As used herein in respect to certain aspects of the invention, the term "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.
In. aspects of the invention, 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, sulfonamido, aryloxy and the like..A substituent may be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or aralkyl. In aspects of the invention an aryl radical is substituted with hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo. The term "aralkyl" refers to an aryl or a substituted aryl group bonded directly through an alkyl group, such as benzyl. Other particular examples of substituted aryl radicals include chlorobenyzl, and amino benzyl. As used herein, the term "aryloxy" refers to aryl radicals, as defined above, attached to an oxygen atom. Exemplary aryloxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
As used herein the term "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.
As used herein, the term "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. As used herein the term "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. In aspects of the invention 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. Examples of "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, acridinyl, phenanthrolinyl, phenazinyl, carbazolyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl and the like; an unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, in particular, 2-furyl, 3-furyl, pyranyl, and the like; an unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, in particular, thienyl, 2-thienyl, 3-thienyl, and the like; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in particular, furazanyl, benzofurazanyl, oxazolyl, isoxazolyl, and oxadiazolyl; an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in particular benzoxazolyl, benzoxadiazolyl and the like; an unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl, benzothiadiazolyl and the like. The term also includes radicals where 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. In aspects of the invention, 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.
The term "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. In an aspect, 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 limitiation 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]; and, a saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl] etc. Examples of partially saturated heterocyclyl radicals include without limitation dihydrothiophene, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl. Illustrative 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, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3H-indolyl, quinuclidinyl, quinolizinyl, and the like.
As used herein in respect to certain aspects of the invention, the term "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. Examples of such groups include, but are not limited to, morpholino and the like.
As used herein in respect to certain aspects of the invention, the term "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.
The foregoing heteroaryl and heterocyclic groups may be C-attached or N-attached (where such is possible).
As used herein the term "sulfonyl", used alone or linked to other terms such as alkylsulfonyl or arylsulfonyl, refers to the divalent radicals -SO2 ". In aspects of the invention, 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.
The term "sulfinyl", used alone or linked to other terms such as alkylsulfinyl (i.e. -S(O)-alkyl) or arylsulfmyl, refers to the divalent radicals -S(O)-. The term "sulfonate" is art recognized and includes a group represented by the formula:
Figure imgf000046_0002
wherein R18 is an electron pair, hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, heterocyclic, carbohydrate, peptide, or peptide derivative.
The term "sulfate", used alone or linked to other terms, is art recognized and includes a group that can be represented by the formula:
Figure imgf000046_0001
wherein R19 is an electron pair, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, carbohydrate, peptide or peptide derivative. The term "sulfoxide" refers to the radical -S=O. As used herein the term "amino", alone or in combination, 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 -NR38R39 where R38 and R39 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. Optionally one substituent on the nitrogen atom may be a hydroxyl group (-OH) to provide an amine known as a hydroxylamine. Illustrative examples of amino groups are amino (?NH2), alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino, arylalkylamino, and lower alkylsilylamino, in particular methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino, cycloh'exylamino, piperidinyl, hydrazinyl, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert.-butylsilylamino, which may or may not be substituted.
As used herein the term "thiol" means -SH. A thiol may be substituted with a substituent disclosed herein, in particular alkyl (thioalkyl), aryl (thioaryl), alkoxy (thioalkoxy) or carboxyl.
The term "sulfenyl" used alone or linked to other terms such as alkylsulfenyl, refers to the radical -SR25 wherein R25 is not hydrogen. In aspects of the invention R25 is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, silylalkyl, heterocyclic, heteroaryl, carbonyl, carbamoyl, alkoxy, or carboxyl. As used hererin, the term "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. Examples of thioalkyl groups are thiomethyl, thioethyl, and thiopropyl. A thioalkyl may be substituted with a substituted or unsubstitute carboxyl, aryl, heterocylic, carbonyl, or heterocyclic. As used herein the term "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 -SR26 where R26 is aryl which may be substituted. Illustrative examples of thioaryl groups and substituted thioaryl groups are thiophenyl, chlorothiophenyl, para- chlorothiophenyl, thiobenzyl, 4-methoxy-thiophenyl, 4-nitro-thiophenyl, and para- nitrothiobenzyl.
As used herein the term "thioalkoxy", alone or in combination, refers to a chemical functional group where a sulfur atom (S) is bonded to an alkoxy. group with the general chemical formula -SR where R is an alkoxy group which may be substituted. A "thioalkoxy group" may have 1-6 carbon atoms i.e. a -S-(O)-Ci-C6 alkyl group wherein Ci -C6 alkyl have the meaning as defined above. Illustrative examples of a straight or branched thioalkoxy group or radical having from 1 to 6 carbon atoms, also known as a Cj -C6 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.
As used herein, the term "carbonyl" refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom.
As used hererin, the term "carboxyl", alone or in combination, refers to -C(O)OR14- or -C(=O)OR14 wherein R14 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl, thioalkyl, thioaryl, thioalkoxy, a heteroaryl, or a heterocyclic, which may optionally be substituted. In particular aspects of the invention, -C(O)OR14 provides an ester or an amino acid derivative. An esterified form is also particularly referred to herein as a "carboxylic ester". In aspects of the invention 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. Examples of 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, diphenylmethoxy-carbonyl, 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. methoxy), and/or halo (e.g. chlorine). Examples of silicon substituents include trimethylsilyl and dimethyltert.butylsilyl. In aspects of the invention, 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.
As used herein, the term "carbamoyl", alone or in combination, refers to amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. As used herein, the term "carboxamide" refers to the group -CONH-.
As used herein, the term "nitro" means -NO2-.
As used herein, the term "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. Illustrative examples of "acyl" radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
In aspects of the invention, "acyl" refers to a group -C(O)R64, where R64 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl. Examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
As used herein the term "phosphonate" refers to a C-PO(OH)2 or C-PO(OR65)2 group wherein R65 is alkyl or aryl which may be substituted.
As used herein, "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. Examples of an 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. The terms used herein for radicals including "alkyl", "alkoxy", "alkenyl", "alkynyl",
"hydroxyl" etc. refer to both unsubstituted and substituted radicals. The term "substituted," as used herein, 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, azido, thio, =0, =S, cyano, hydroxyl, phosphonato, phosphinato, thioalkyl, alkylamino, arylamino, arylsulfonyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heteroarylsulfϊnyl, heteroarylsulfony, heteroarylamino, heteroaryloxy, heteroaryloxylalkyl, arylacetamidoyl, aryloxy, aroyl, aralkanoyl, aralkoxy, aryloxyalkyl, haloaryloxyalkyl, heteroaroyl, heteroaralkanoyl, heteroaralkoxy, heteroaralkoxyalkyl, thioaryl, arylthioalkyl, alkoxyalkyl, and acyl groups. These substitutents may themselves be substituted.
A chemical substituent is "pendant" from a radical if it is bound to an atom of the radical. In this context, 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. It will be understood by those skilled in the art of organic synthesis that 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. It will also be recognized that 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. In practice is it desirable to first isolate 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. Alternatively, 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.
In particular aspects, a compound of the formula II wherein R1 ' 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, may be prepared by reacting a compound with a structure of formula II wherein Ri0 is halo, in particular chloro, and R1 ' 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, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl, under suitable conditions to prepare a compound of the formula II wherein R11 is hydrogen and R10 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. In an' embodiment, R10 is phenyl substituted with halo.
In another aspect, a compound of the formula II wherein R1 ' is hydrogen and R10 is a substituted aryl is prepared by reacting a compound with the structure of formula II wherein R10 is halo, in particular chloro, and R11 is hydrogen, with a substituted aryl boronic acid under suitable conditions. In another aspect, a compound of the formula II wherein R10 is hydrogen and R11 is alkyl is prepared by reacting a compound with the structures of formula II wherein R11 is halo, in particular chloro, and R10 is hydrogen, with an alkyl boronic acid under suitable conditions. In an embodiment, R1 ' is lower alkyl, in particular methyl or ethyl, and a compound of the formula II wherein R11 is chloro is reacted with lower alkyl boronic acid, in particular methyl or ethyl boronic acid under suitable conditions. In another aspect, a compound of the formula II is prepared wherein R10 is hydrogen and
R1 ' 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-4- yloxy)pyrimidine under suitable conditions to prepare a compound of the formula II wherein R10 is hydrogen and Ru is an alkyl. In an embodiment, R1 ' is methyl or ethyl.
In another aspect, a compound of the formula II wherein R10 is hydrogen and R11 is aryl is prepared by reacting a compound with the structure of formula II wherein R10 is hydrogen and R11 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. In an embodiment, R1 ' is phenyl.
In another aspect, a compound of the formula II is prepared wherein R10 is hydrogen and R11 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 R1 ' is halo, in particular chloro, and R10 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-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl; or tetrazolyl, more particularly pyridinyl, under suitable conditions. In an embodiment, a compound of the formula II is prepared wherein R10 is hydrogen and R11 is pyridinyl by reacting a compound of the formula II wherein R11 is halo, in particular chloro, and R10 is hydrogen, with a pyridinyl boronic acid under suitable conditions.
In another aspect, a compound of the formula II is prepared wherein R10 is hydrogen and Rπ 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl, and at the 6 position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine under suitable conditions.
In an embodiment, a compound of the formula II is prepared wherein R10 is hydrogen and R11 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-4-yloxy)pyrimidine under suitable conditions to prepare a compound of the formula II wherein R10 is hydrogen and
R1 ' is pyridinyl.
In another aspect, a compound of the formula II is prepared wherein R10 is hydrogen and
R1 ' is piperidinyl or substituted piperidinyl by reacting a compound of the formula II wherein R11 is halo, in particular chloro, and R is hydrogen with piperazinyl or substituted piperazinyl under suitable conditions.
In another aspect, a compound of the formula I is prepared wherein R1 is piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R2 is aryl, R3, R4, R5 and R6 are hydrogen and R7 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.
In another aspect, a compound of the formula I is prepared wherein R1 is piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl, R2 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, R3, R4, R5 and R6 are hydrogen and R7 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, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl, with piperazinyl or piperazinyl substituted with alkyl, aryl, or cycloalkyl under suitable conditions.
In another aspect, a compound of the formula I is prepared wherein R1 is substituted amino in particular amino substituted with substituted morpholinyl, in particular morpholinoethyl, R2 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, R3, R4, R5 and R6 are hydrogen and R7 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 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, with substituted amino in particular amino substituted with substituted morpholinyl, in particular morpholinoethyl, under suitable conditions. In another aspect, a compound of the formula V is prepared wherein R50 is aryl, R51 is hydrogen, and R is alkyl by reacting a pyridazine substituted at position C3 with halo, at position C4 with aryl and at position 6 with alkyl, with l-(2-pyrimidyl)piperazine under suitable conditions..
In another aspect, a compound of the formula I is prepared wherein R1 is substituted amino, R2 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, R3,
. R4, R5 and R6 are hydrogen and R7 is absent 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, in particular pyridinyl,- and at the C6 position with phenyl, and a substituted amino under suitable conditions. . . . .
In. the preparation of compounds of the Formula II, a precursor (see, for example, Figure 1) that may be. utilized can be. obtained commercially and used directly for the synthesis of the illustrated compound MW01-3-183WH 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. In Figure 1, a synthetic scheme is shown, for synthesis of MW01-3-183WH with unconstrained aromatic ring at position 6 and no modification at position 5. . . ' ' Thus, in an aspect, 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 R10 and R11 are hydrogen. A compound of the formula H wherein R10 and Rn are hydrogen can be reacted under suitable conditions and with suitable reagents to introduce the radicals R10 and R11 which are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfϊnyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, carbonyl, carbamoyl, or carboxamide. The term "Demyelinating Diseases" refers to diseases in which myelin is the primary target. These diseases can be divided into two groups: Acquired Diseases and Hereditary Metabolic Disorders. Acquired Demyelinating Diseases include Multiple sclerosis (MS) including its alternating relapsing/remitting phases. Hereditary Metabolic Disorders includes the leukodystrophies such as metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus- Merzbacher disease and Alexander's disease.
The term "Demyelinating Conditions" refers to conditions that result in deficient myelination. Such conditions include, but are not limited to, Spinal Cord Injury, Traumatic Brain Injury and Stroke. The term "Spinal Cord Injury (SCI)" refers to an injury to the spinal cord which results in loss of function such as mobility or feeling.
The term "Traumatic Brain Injury (TBI)" refers to an injury which results in damage to the brain. A head injury may be a closed head injury or penetrating head injury. A closed head injury may occur when the head is hit by a blunt object causing the brain to interact with the hard bony surface inside the skull. A closed head injury may also occur without direct external trauma to the head if the brain undergoes a rapid forward or backward movement, (e.g. whiplash). A penetrating head injury may occur when a fast moving object such as a bullet pierces the skull. A closed or penetrating head injury may result in localized and widespread, or diffuse, damage to the brain which may manifest as memory loss, emotional disturbances, motor difficulties, including paralysis, damage to the senses, and death. The term also includes secondary damage that follows an injury including swelling and fluid buildup and the accumulation of substances toxic to surrounding neurons such as the neurotransmitter glutamate.
The term "Stroke" refers to a sudden loss of brain function caused by the interruption of the flow of blood to the brain (an ischemic stroke) or the rupture of blood vessels in the brain (a hemorrhagic stroke). The interruption of the blood flow or the rupture of blood vessels causes neurons in the affected area to die.
The term "Stroke Rehabilitation" refers to the intervention that results in the full or partial recovery of functions that have been lost due to stroke. A "pain disorder" refers to a disorder or condition involving pain and includes without limitation acute pain, persistent pain, chronic pain, inflammatory pain, neuropathic pain, neurogenic pain, and chemokine-induced pain. In aspects of the invention, a pain disorder includes without limitation pain resulting from soft tissue and peripheral damage such as acute trauma; complex regional pain syndrome also referred to as reflex sympathetic dystrophy; postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; pain associated with osteoarthritis and rheumatoid arthritis; musculoskeletal pain such as pain associated with strains, sprains and trauma such as broken bones; spinal pain, central nervous system pain such as pain due to spinal cord or brain stem damage; lower back pain, sciatica, dental pain, myofascial pain syndromes, episiotomy pain, gout pain, and pain resulting from burns; deep and visceral pain, such as heart pain; muscle pain, eye pain, inflammatory pain, orofacial pain, for example, odontalgia; abdominal pain, and gynecological pain, for example, dysmenorrhoea, labour pain and pain associated with endometriosis; somatogenic pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment, brachial plexus avulsions, and peripheral neuropathies; pain associated with limb amputation, tic douloureux, neuroma, or vasculitis; diabetic neuropathy, chemotherapy-induced-neuropathy, acute herpetic and postherpetic neuralgia; atypical facial pain, nerve root damage, neuropathic lower back pain, HFV related neuropathic pain, cancer related neuropathic pain, diabetes related neuropathic pain and arachnoiditis, trigeminal neuralgia, occipital neuralgia, segmental or intercostal neuralgia, HIV related neuralgias and AIDS related neuralgias and other neuralgias; allodynia, hyperalgesia, idiopathic pain, pain caused by chemotherapy; occipital neuralgia, psychogenic pain, brachial plexus avulsion, pain associated with restless legs syndrome; pain associated with gallstones; pain caused by chronic alcoholism or hypothyroidism or uremia or vitamin deficiencies; neuropathic and non-neuropathic pain associated with carcinoma, often referred to as cancer pain, phantom limb pain, functional abdominal pain, headache, including migraine with aura, migraine without aura and other vascular headaches, acute or chronic tension headache, sinus headache and cluster headache; temperomandibular pain and maxillary sinus pain; pain resulting from ankylosing spondylitis and gout; pain caused by increased bladder contractions; pain associated with gastrointestinal (GI) disorders, disorders caused by helicobacter pylori and diseases of the GI tract such as gastritis, proctitis, gastroduodenal ulcers, peptic ulcers, dyspepsia, disorders associated with the neuronal control of viscera, ulcerative colitis, chronic pancreatitis, Crohn's disease and emesis; post operative pain, scar pain, and chronic non-neuropathic pain such as pain associated with HlV, anthralgia and myalgia, vasculitis and fibromyalgia. "Neuropathic pain" refers to pain initiated or caused by a primary lesion or dysfunction in the nervous system. For the purpose of this invention included under this heading or to be treated as synonymous is "Neurogenic Pain" which is defined as pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system. In aspects, the uses of the present invention include central or peripheral neuropathic pain or neurogenic pain. In other aspects, neuropathic pain includes the pain caused by either mononeuropathy or polyneuropathy.
"Peripheral neuropathic pain" refers to a pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system and "peripheral neurogenic pain" refers to a pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral nervous system. A peripheral neuropathic pain can be allodynia (i.e.,a pain due to a stimulus which does not normally provoke pain); causalgia (i.e.; a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes); hyperalgesia (i.e., an increased response to a stimulus which is normally painful); hyperesthesia (i.e., increased sensitivity to stimulation, excluding the senses); hyperpathia (i.e., a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold); neuritis (i.e., inflammation of a nerve or nerves); or neuropathy (i.e., a disturbance of function or pathological change in a nerve). [See IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), for detailed definitions of these categories of neuropathic pain and neurogenic pain).
Exemplary types of neuropathic pain include infective (e.g., post herpetic neuralgia and HIV neuropathy), metabolic (e.g., diabetic neuropathy and Fabry's disease), toxic (e.g., from lead or chemotherapy), traumatic/stretch injury (e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia), and idiopathic (e.g., trigeminal neuralgia/tic douloureux).
Particular examples of Neuropathic Pain include post-herpetic neuralgia, painful diabetic neuropathy, phantom limb pain, central post-stroke pain, HIV neuropathy, Fabry's disease, peripheral neuropathy; trigeminal neuralgia, post incisional neuropathic pain, phantom limb pain, reflex sympathetic dystrophy, causalgia, anesthesia dolorosa, intercoastal neuralgia, post-traumatic localized pain, atypical facial neuralgia pain after tooth extraction and the like, complex regional pain syndrome, neuropathic pain caused by trauma, lead, or . chemotherapy, cancer pain resistant to narcotic analgesics such as morphine.
Treatment of neuropathic pain may be defined as administration of a therapeutic dose of a pyridazine compound to reduce' and preferably eliminate pain that results from, nerve injury. Treatment of nerve injury may be defined as administration of a therapeutic dose of a pyridazine to ameliorate injury and to increase the rate of recovery. An increased rate of recovery is defined as a reduction of indications of pain from peripheral nerve injury, such as thermal hyperalgesia and mechanical allodynia, more quickly than would be accomplished without pharmacological or other medical intervention. • "Chemokine?Induced Pain", refers to pain that occurs in response, in whole or in part, to chemokines, in particular pro-inflammatory cytokines (e.g. fractalkine, CCL2, and CCL5). An example of chemokirie-induced pain is arthritic pain. . .
COMPOSITIONS AND KITS
One or more pyridazine compound, in particular a compound of the Formula I, II, III, rV, or V, may be formulated into a pharmaceutical composition for administration' to a subject. Pharmaceutical 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 NF 19) published in 1999. By way of example for oral administration in the form of a capsule or tablet, 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. For oral administration in a liquid form, 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. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes), lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride), disintegrating agents (e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum), flavoring agents, and coloring agents may also be combined in the compositions. Compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.
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.
In aspects of the invention, a composition of the invention is a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The 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. In aspects of the invention, a pharmaceutical composition is provided for oral administration of one or more pyridazine compounds for treatment of a disease.
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 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, glucoronic, 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. In some aspects, a buffering agent may be formulated as at least one medium including without limitation a suspension, solution, or emulsion. In other aspects, 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 compound of the formula I5 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. Alternatively, 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. After pharmaceutical 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.
According to the invention, a kit is provided. In an aspect, 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, H3 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 simultaneous, separate or sequential use. In particular 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 therapeutic effect. Associated with such containers) 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 disease 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 disease disclosed herein. The label on the container indicates that the compounds of the formula I, 11, III, IV or V or formulations of the invention are used for treating a disease disclosed herein and may also indicate directions for use. In aspects of the invention, a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
The invention also contemplates kits comprising one or more of compounds of the formula I, II, III, IV or V. In aspects of the invention, a kit of the invention comprises a container described herein. In particular aspects, 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 εihy methods disclosed herein (e.g., methods for treating a disease disclosed herein). A medicament or formulation in a kit of the invention may comprise any of the formulations or compositions disclosed herein. ' ' .
In aspects of the invention, the kits may be useful for any of the methods disclosed herein, including, without limitation treating a subject suffering from Alzheimer's disease. 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 abeneficial 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.
In aspects of the invention 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, disease or condition to provide effects, in particular beneficial effects, more particularly sustained beneficial effects, will" depend on the nature of the disease, 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 disease, 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 the pyridazine compound are generally about 0.01 rag 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.
In aspects of the invention 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 than or about lOmg/kg, 5mg/kg, 2.5mg/kg, lmg/kg, or 0.5 mg/kg twice daily or less.
In embodiments of the invention, 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 (a) to (t) 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.
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.
Thus, 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 or continuously. However, 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 diseases disclosed herein as well as agents that are used for the treatment of complications resulting from or associated with a disease disclosed herein, or general medications that treat or prevent side effects.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. EXAMPLES Example 1 Synthesis of Exemplary Pyridazine Compounds A. Preparation of 2-(4-(6-phenvIpyridazin-3-vπpiperazin-l-yl)pyriniid-ne (MW01-3- 183WH).
Figure 1 depicts a synthetic scheme for the preparation of 2-(4-(6-phenylpyridazin-3- yl)piperazin-l-yl)pyrimidine (MW01-3-183WH). Reagent and condition: (a) 1-BuOH, NH4Cl, and 2-( piperazin-l-yl)pyrimidine. A typical reaction mixture of comprised about 0.01 mol of 3- chloro-6-phenylpyridazine by 2-(piperazin-l- yl)pyrimidine, about 0.05 mol of 2-(piperazin-l- yl)pyrimidine and about 0.01 mol of ammonium hydrochloride was prepared in about 15ml of 1- BuOH. The mixture was stirred at about 13O0C for about 48h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded light yellow crystals, yield 96.4%; HPLC: 97.4% purity; HRMS calculated 318.1587, found 318.1579; 1H NMR (CDCl3): δ 8.356 (d, J=4.5, 2H), 8.01 l(d, J=7.5, 11 2H), 7.692 (d, J=9.5, 1H), 7.468 (t, J=6.0, 2H), 7.417 (d, J=7.5, 1H), 7.047 (d, J=9.5, 1H), 6.546 (t, J=4.5, 1H), 4.013 (t, J=5.0, 4H), 3.826 (t, J=5.0, 4H). B. Preparation of 4-methyl-6-phenyI-3-(4-pyrimidin-2-yIpiperazin-l-yl)pyridazine (MW01-2-151SRM)
4-methyl-6-phenyl-3 -(4-pyrimidin-2-ylpiperazin- 1 -yl)pyridazine (MWO 1-2-151 SRM) was prepared by several synthetic schemes as depicted in Figure 2 (Scheme 1), Figure 3 (Scheme 2), Figure 4 (Scheme 3), and Figure 5 (Scheme, 4), which were carried out as described in detail herein. The various reaction schemes (Schemes 1, 2, and 3) are generally applicable to the compounds of the present invention and are not restricted in utility only to the preparation of MWO 1-2-15 ISRM. Scheme 1 (Figure 2) 4,5-dihydro-4-methyl-6-phenylpyridazin-3(2H)-one (2) A 250 mL three-neck round bottom flask fit with a temperature probe and condenser is charged with 7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid 1 and 20 ml of ethanol (95%). The suspension is cooled to below 1O0C and 2.2 ml (42 mmole, 1.05 equiv.) of hydrazine monohydrate in 10 mL of ethanol is added dropwise at a rate that maintains the solution temperature at below 200C. Upon addition, the suspension changes to a pale yellow solution. After addition, the reaction mixture is heated to reflux and stirred for 2 h, and after 20 minutes of heating, a solid is seen in the mixture. Once the reaction is completed, the flask is removed from the oil bath and cooled to ambient temperature. Upon cooling, white crystals form in the flask, which are collected by filtration. The solid is washed first with 30 mL of 2N NaHCO3, followed by 60 mL Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give the desired product 2 in 96.1% yield. [See Hansen, KB et al. Organic process research & development, 2005, 9, 634-639; Nelson, DA. US 20050137397A1. Coudert, P et al. Journal of Heterocyclic Chemistry, 1988, 25(3), 799-802.] 4-methyl-6-phenylpyridazin-3(2H)-one (3) 7.0 g (35 mmole) of 2 is placed in a 250 ml single-necked round bottom flask followed by 30 mL of acetonitrile. The mixture is stirred to allow 2 to dissolve. 11.3 g (84 mmole, 2.4 equiv.) of anhydrous copper (II) chloride is added to the solution to give a green-yellow suspension. A reflux condenser is connected to the flask and a dry tube filled with anhydrous CaCl2 is fitted to the top of the condenser. To control the HCl gas that forms during the course of the reaction, a NaOH solution is used to absorb the HCl that escapes from the dry tube. The reaction mixture is heated to reflux, and the color of the reaction suspension changes to dark green upon heating. When the reaction is complete (after refluxing for 2 h), the flask is removed from the oil bath and cooled to ambient temperature. The reaction is cooled in an ice-water bath and 150 mL of ice- water is added to quench the reaction. The mixture is stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride. The precipitate is collected by filtration (pH of the filtrate is 0 - 1) and washed with 100 mL of IN HCl solution, then 100 mL of water 5 times. To remove remaining copper by-products that are trapped in the solid, the filter cake is stirred in 150 mL of IN HCl solution for 0.5 h and filtered. The filter cake is subsequently washed with Milli-Q water until the filtrate is at pH 7 (approximately 7 washes). The solid is dried over a medium frit sintered glass funnel in vacuo to give 3 as a light gray powder in 93.8% yield. [See Eddy, S et al. Synthetic Communications, 2000, 30(1), l-7.Csende, F et al Synthesis, 1995, 1240-1242.] 3-chloro-4-methyl-6-phenylpyridazine (4)
6.0 g (32 mmole) of 3 is placed in a 250 mL single neck round bottom flask and 30 mL of acetonitrile is added to create a pale yellow slurry. 6.0 ml (64 mmole, 2 equiv.) of phosphorus oxychloride is added changing the slurry to a darker color. The flask is fitted with a reflux condenser and a dry tube filled with anhydrous CaCl2 is fitted to the top of the condenser. The reaction mixture is heated at reflux and becomes a dark red liquid. After the reaction is completed (2.5 h), the mixture is cooled to ambient temperature and placed in an ice water bath. Ice water (150 mL) is slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into HCl and HsPO4, resulting in formation of a pink solid. The solid is collected by filtration and washed three times with 50 mL of MiIH-Q water. The solid is transferred to a 250 mL beaker, followed by addition of 100 mL of water to form a suspension. Subsequently, IN NaOH is added until the aqueous suspension is at pH = 8, and the mixture is stirred for 5 minutes to remove all trace starting material contaminants. The solid is filtered and washed 3 times with 100 mL of water to wash out the excess base. The solid is dried over a medium frit sintered glass funnel in vacuo to provide 4 as a light pink powder in 96% yield. [See Contreras, JM et al. Journal of Medicinal Chemistry, 2001, 44(17), 2707-2718; Nelson, DA. US 20050137397A1:] 2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-l-yl)pyrimidine (5) 7.5 g (36.6 mmole) of 4 is. placed in a 250 mL single neck round bottom flask and suspended in 125 mL of water. 60.17 g (366.0 mmole, 10 equiv.) of 2-(piperazine-l-yl)pyrimidine is added and the flask fit with a condenser: The reaction mixture is heated at reflux with rapid stirring for 60 h, with continuous amine addition possible to boost reaction rates. When complete, the reaction mixture is cooled to ambient temperature and two layers are observed in the flask consisting of an orange aqueous layer and a brown oil that settles to the bottom of the flask. The water is decanted off, leaving the oil, which is the product 5. The oil is then dissolved in minimal volume of isopropanol and heated to reflux. After 10 minutes of reflux, the solution is cooled to ambient temperature, and cooled to 0 0C to induce crystallization. Pale yellow crystals are filtered from isopropanol and rinsed with minimal cold ether to provide 5. Recovery of the crystals is 50%, but may be increased by recursive crystallization of compound. [Contreras, JM et al. Journal of Medicinal Chemistry, 1999, 42(4), 730-741. Chayer, S et al Tetrahedron Letters, 1998, 39, 841 -844.] Scheme 2 (Figure 3) 3 -chloro-ό-phenylpyridazin^-ol was synthesized according to the procedure described by Coudert, P., et al., supra. 6-ρhenyl-3-(4-(pyrimidm-2-vnpiperazin-l -vDpyridazin-4-ol (MWO 1-7-121 WHQ This compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14g, 68mmol) in the same manner as described below, yielding white solid (22.1g, 66mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR (DMSO): 1H NMR (DMSO): d 8.406 (d, 3=6.5, 2H), 7.740 (d, J=4.0, 2H), 7.558 (s, 3H), 6.686 (t, J=4.8, J=4.4, 1H), 6.841 (s, 1H), 3.881 (s, 4H), 3.620 (s, 4H), 3.776 (s, 4H).
4-chloro-6-phenyl-3-(4-pyrimidm-2-yrpiperazin- 1 -vPpyridazine (MWOl -6-127WH) 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazin-4-ol (22.Og, 66mmol) was suspended in 75ml phosphorus oxychloride and heated with stirring at 1000C for 3h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3g, 60.3mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR (CDCl3): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672 (t, J=4.0, J=4.5, 4H). 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-vnpyridazine (MW01-2-151SRM)
Into a reaction tube were added MW01-6-127WH (1.4g, 4.0mmol), K2CO3 powder (1.7g, 12.4mmol),- Pd(dppf)C12 (326mg, 0.4mmol), silver oxide (2.3g, lOmmol), methylboronic acid (324mg, 5.4mmol) and 20ml of THF. Argon was then flushed through the tube for 3min. The tube was then sealed tightly and heated with stirring at 80 degree for 12h. After cooled down, the mixture was quenched with 10% NaOH solution and extracted with ethyl acetate. The organic phase was concentrated in vacuo and the residue was purified by column chromatography eluting with 1:4, Ethyl Acetate: Petroleum, ether. White powder solid was obtained (0.6Og, 1.8mmol,. yield 45.2%). ESI-MS: m/z 333.4 (M+H+). 1H NMR (CDCl3): d 8.380 (d, J=5.0, 2H), 7.065 (d, J=7.0, 2H), 7.626 (s, 1H), 7.473 (m, 3H), 6.567 (t, J=4.5, J=5.0, 1H), 4.056 (t, J=5.0, 4H), 3.475 (t, J=5.0, 4H), 2.456 (s, 3H).
Scheme 3 (Figure 4) Into a reaction tube were added MW01-6-127WH (1.4g, 4.0mmol), K2CO3 powder (1.7g, 12.4mmol), Pd(PPh3)4 (240mg, 0.2mmol), silver oxide (2.3g, lOmmol), methylboronic acid (324mg, 5.4mmol) and 20ml of DME. Argon was then flushed through the tube for 3min. The tube was then sealed tightly and heated with stirring at 12O0C for 24h. After cooled down, the mixture was filter through acelite earth, the filtrate was then concentrated and the residue was purified by column chromatography eluting with 1:4, Ethyl Acetate: Petroleum ether. White powder solid was obtained (0.64g, 1.93mmol, yield 48.1%). ESI-MS: m/z 333.4 (M+H+). 1H NMR (CDCl3): d 8.380 (d, J=5.0, 2H), 7.065 (d, J=7.0, 2H), 7.626 (s, 1H), 7.473 (m, 3H), 6.567 (t, J=4.5, J=5.0. 1H), 4.056 (t, J=5.0, 4H), 3.475 (t, J=5.0, 4H), 2.456 (s, 3H). Scheme 4 (Figure 5)
4.5-dihvdro-4-methyl-6-ρhenylρyridazin-3(2HVone (MW01-8-004WH>) 7.7 g (40 mmole) of 2-methyl-4-oxo-4-phenylbutanoic acid was added to a 100 ml single- necked round bottom flask followed by 3.0 ml (60 mmole) of hydrazine monohydrate and then 20 ml of reagent grade ethanol (100%, 95% of ethanol should be fine also). The flask was fitted with a reflux condenser and the reaction mixture was heated to reflux in an oil bath at 1100C (temperature of oil bath) and stirred for 2 h. The flask was then removed from the oil bath and the reaction mixture cooled to ambient temperature. The stir bar was removed and the solvent was evaporated in vacuo in a water bath at 450C. The residue was then treated with 50 ml of Milli-Q water and stirred for 10 minutes to give a suspension. The precipitate was collected by filtering, washed with 100 ml of 2N NaHCC«3, then washed with 60 ml Milli-Q water three times, and dried over a medium frit sintered glass funnel in vacuo to give 7.15 g of white crystals (Syn. ID, WH-8-004). Yield, 95%, confirmed by ESI-MS. ESI-MS: m/z 189.2 (M+H+). 4-methyl-6-phenylpyridazin-3(2H)-one (MW01-8-008WH)
7.0 g (35 mmole) of MW01-8-004WH was placed in a 100 ml single-necked round bottom flask followed by 9.4 g (70 mmole) of anhydrous copper (II) chloride and then 30 ml of acetonitrile to give a brown yellow suspension. A reflux condenser was connected to the flask and a dry tube filled with CaCl2 was fitted to the top of the condenser. The reaction mixture was heated to reflux in an oil bath (HO0C) for 3 h. The color of the reaction suspension changed to dark yellow once the reflux started. After the completion of the reaction (monitored by HPLC), the flask was removed from the oil bath and cooled to ambient temperature. The mixture was poured on to 300g of crushed ice and stirred vigorously for 10 minutes to give a gray precipitate and blue liquid. The precipitate was then collected by filtering (pH of the filtrate was 1.5-2.0), and washed with 100 ml of a IN HCl solution to rid the solid of any remaining copper byproducts. This is followed by washing with 100 ml of Milli-Q water to get rid of the acid in the solid, and is monitored by checking the pH value of the filtrate. The solid was washed until the filtrate shows a pH of 7, after approximately 5 washes. The solid was dried over a medium frit sintered glass funnel in vacuo to give 6.3 g of a blue gray solid. Yield was 96.7% and confirmed by ESI-MS. ESI-MS: m/z 187.3 (M+H+). 3-chloro-4-methyl-6-phenylpyridazinef MWO 1-8-012 WH)
6.0 g (32 mmole) of MWO1-8-0O8WH and 30 ml (320 mmole) of phosphorus oxychloride were placed in a 100 ml single-necked round bottom flask. The flask was connected with a reflux condenser and a dry tube filled with anhydrous CaCl2 was fitted to the top of the condenser. (HCl gas is formed in the reaction so a basic solution such as NaOH may be needed to absorb HCl in a large-scale synthesis). The reaction mixture was stirred in an oil bath (9O0C) for 2 h, then cooled to ambient temperature and poured onto crushed ice (phosphorus oxychloride can be decomposed by water to give HCl and H3PO4). The mixture was then stirred vigorously for 10 minutes to give a white suspension. The suspension was neutralized with a 2N NaOH solution until the pH of the suspension was pH = 7. The precipitate was filtered, washed three times with 100 ml of Milli-Q water and dried over a medium frit sintered glass funnel in vacuo to provide 5.9 g of a light pink powder (Syn. ID, WH-8-012). Yield was 89.4% and confirmed by ESI-MS. ESI-MS: m/z 205.4 (M+H+). • 2-('4-(4-methyl-6-phenylpyridazin-3-yl')pipera2in-l-yl')pyrimidine (MW01-2-151SRM) 0.82 g (4.0mmole) of WH-8-012 was placed in a 30 ml pressure vessel followed by addition of 2.6 g (16.0mmole) of l-(2-pyrimidyl) piperazine and then 15 ml of 1-BuOH. The vessel was sealed tightly and placed into an oil bath and stirred at 130°C (temperature of oil bath) for 2.5 days. The reaction mixture was then cooled to ambient temperature and transferred to a single-necked flask for evaporation under reduced pressure. Removal of solvent gave rise to a brown-red residue that was treated with 30 ml of water to give a brown sticky oil. The mixture was kept at ambient temperature overnight while the oil solidified gradually. The formed solid was then broken into small pieces with a steel spatula. The solid was collected by filtering and washed with 50 ml of Milli-Q water three times and dried, over a filter funnel in vacuo to provide 1.25 g of light yellow solid (Syn. ID, WH-8-020). Yield was 94%. (Alternative separation is to use precipitation procedure instead of solidification process. Solidification is a simple and cheap operation, yet time-consuming. Precipitation is time efficient, yet more costly than the former one. So it is up to the process chemist to decide which procedure to pick for the manufacture. The precipitation process is below: The oil product was dissolved completely in 10 ml of reagent grade ethanol or acetone to form a solution. The solution was then added dropwise to 150 ml of ice water under vigorous stirring. Light yellow suspension was then formed gradually. The solid was collected by filtering, washed with Milli-Q water, dried over filter funnel in vacuo to give the desired product.) The final compound was confirmed by ESI-MS and NMR. ESI-MS: m/z 333.8 (M+H+). 1H NMR (CDCl3): d 8.380 (d, J=5.0, 2H)3 7.065 (d, J=7.0, 2H), 7.626 (s, 1H), 7.473 (m, 3H), 6.567 (t, J=4.5, J=5.0, 1H), 4.056 (t, J=5.0, 4H)5 3.475 (t, J=5.0, 4H)5 2.456 (s, 3H).
C. Preparation of 4,6-diphenyl-3-(4-pyrimidϊa-2-ylpiperazip-l-vDpyridazϊne (MW01-5-
188WH).
4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine (MW01-5-188WH) was prepared by several synthetic schemes as depicted in Figure 6 (Scheme 1), Figure 7 (Scheme 2), and Figure 8 (Scheme 3), which were carried out as described in detail herein. The various reaction schemes (Schemes I5 2, and 3) are generally applicable to the compounds of the present invention and are not restricted in utility only to the preparation of MWO 1-2- 188WH. Scheme 1 (Figure 6) 3 -chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al.supra.
6-phenyl-3 -(4-f ρyrimidin-2- vDpiperazin- 1 -yr)pyridazin-4-ol (MWO 1-7-121 WH) The compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14g, 68mmol). A mixture of 3-chloro-4,6-diphenylpyridazine (267mg, l.Ommol), l-(2-pyrimidyl)piperazine (656mg, 4.0mmol) in 3ml of 1-BuOH was heated with stirring at 1300C for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid yielding white solid (22.1g, 66mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR (DMSO): 1H NMR (DMSO): d 8.406 (d, 1=6.5, 2H), 7.740 (d, J=4.0, 2H), 7.558 (s, 3H)3 6.686 (t, J=4.8, J=4.4, 1H)5 6.841 (s, 1H), 3.881 (s, 4H), 3.620 (s, 4H), 3.776 (s, 4H). 4-chloro-6-phenyl-3-(4-pyrimidin-2-ylpiperazin- 1 -vDpyridazine (MWO 1 -6- 127WH) 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazin-4-ol (22.Og, 66mmol) was suspended in 75ml phosphorus oxychloride and heated with stirring at 1000C for 3h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3g, 60.3mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR (CDC13): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672 (t, J=4.0, J=4.5, 4H). 4,6-diρhenyl-3-(4-pyrimidin-2-ylpiperazin-l -yPpyridazine (MWOl -5-188WH) A mixture of 3-chloro-4,6-diphenylpyridazine (267mg, l.Ommol), l-(2-pyrimidyl)piperazine (656mg, 4.0mmol) in 3ml of 1-BuOH was heated with stirring at 13O0C for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid. (320mg, 0.81mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979, found 395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1E), 7.509 (m, 6H), 6.530 (t, J=4.5, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H). Scheme 2 (Figure 7) 4,5-dihvdro-6-phenyl-4-phenylpyridazin-3(2H)-one 135 ml (135 mmole) of a solution of phenylmagnesium bromide (IM) in THF was added to a hot suspension of 6-phenylpyridazinone compound 7.8g (45 mmole) in dry toluene (50 ml). The mixture was-refluxed for 8h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 250.1 (M+H+). 6-phenyl-4-phenylpyridazin-3(2H)-one 4.4 g (17.5 mmole) of 6-pyridazinone obtained above was placed in a 50 ml single-necked round bottom flask followed by 4.7 g (35 mmole) of anhydrous copper (II) chloride and then 20 ml of acetonitrile to give a brown yellow' suspension. A reflux condenser was connected to the flask and a dry tube filled with CaCl2 was fitted to the top of the condenser. The reaction mixture was heated to reflux in an oil bath (1100C) for 3 h. The color of the reaction suspension changed to dark yellow once the reflux started. After the completion of the reaction (monitored by HPLC), the flask was removed from the oil bath and cooled to ambient temperature. The mixture was poured on to 200 g of crushed ice and stirred vigorously for 10 minutes to give a gray precipitate and blue liquid. The precipitate was then collected by filtering (pH of the filtrate was 1.5-2.0), and washed with 50 ml of a IN HCl solution to rid the solid of any remaining copper byproducts. This is followed by washing with 100 ml of Milli-Q water to get rid of the acid in the solid, and is monitored by checking the pH value of the filtrate. The solid was washed until the filtrate shows a pH of 7, after approximately 5 washes. The solid was dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of a blue gray solid. Yield was 90%, confirmed by ESI-MS. ESI-MS: m/z 248.1 (M+H+). 3-chloro-6-phenyl-4-phenylpyridazine 2.O g (8 mmole) of 6-phenyIpyridazinone obtained above and 10 ml (54 mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed in a 50 ml single-necked round bottom flask. The flask was connected with a reflux condenser and a dry tube filled with CaCl2 was fitted to the top of the condenser. (HCl gas is formed in the reaction so a basic solution such as NaOH may be needed to absorb HCl in a large-scale synthesis). The reaction mixture was stirred in an oil bath (9O0C) for 2 h, then cooled to ambient temperature and poured onto crushed ice. (phosphorus oxychloride can be decomposed by water to give HCl and H3PO4). The mixture was then stirred vigorously for 10 minutes to give a white suspension. The suspension was neutralized with a 2N NaOH solution until the pH of the suspension was pH = 7. The precipitate was filtered, washed three times with 100 ml of water and dried over a medium frit sintered glass funnel in vacuo to provide 1.8 g of a light pink powder. Yield was 85%, confirmed by ESI-MS. ESI-MS: m/z 266.4 (M+H+). 2-(4-(6-phenyl-4-phenylρyridazin-3-yl)piperazin-l-yl)pyrirnidine
1.1 g (4.0mmole) of 3-chloropyridazine obtained above was placed in a 30 ml pressure vessel followed by addition of 2.6 g (16.0mmole) of l-(2-pyrimidyl) piperazine and then 15 ml of 1- BuOH (reagent grade). The vessel was sealed tightly and placed into an oil bath and stirred at 13O0C (temperature of oil bath) for 3 days. The reaction mixture was then cooled to ambient temperature and transferred to a single-necked flask for evaporation under reduced pressure. Removal of solvent gave rise to a brown-red residue that was treated with 30 ml of water to give a brown suspension. The solid was collected by filtering and washed with 50 mL of water three times and dried over a filter funnel in vacuo to provide 0.96 g of light yellow solid. Yield was 90%, ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979, found 395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, J=4.5, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H). Scheme 3 (Figure 8) 3-chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al, supra.
4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin- 1 -vDpyridazine (MWO 1-5-188 WH) A mixture of 3-chloro-4,6-diphenylpyridazine (267mg, l.Ommol), l-(2-pyrimidyl)piperazine (656mg, 4.0mmol) in 3ml of 1-BuOH was heated with stirring at 13O0C for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid. (320mg, 0.81mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979, found 395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H)3 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2R), 7.655 (s, 1H), 7.509 (m, 6H)5 6.530 (t, J=4.5, 1H)5 3.836 (t, J=4.5, J=5.05 4H)5 3.394 (t, J=5.0, J=4.55 4H).
D. Preparation of 4-pyridyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine (MW01-6-189WH).
4-pyridyl-6-phenyl-3 -(4-pyrimidin-2-ylpiperazin- 1 -y l)pyridazine (MWO 1-6-189 WH) was prepared by two synthetic schemes as depicted in Figure 9A and 9B5 which were carried out as described in detail herein. The various reaction schemes (Schemes 1 and 2) are generally applicable to the compounds of the present invention and are not restricted in utility only to the preparation of MWO 1-2- 189WH.
Scheme 1
3 -chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al., supra. 6-phenyl-3-(4-(pyrimidin-2-vDρiperazin- 1 -vnpyridazin-4-ol (TVTWO 1-7-121 WTD " This compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14g, 68mmol) A mixture of 3-chloro-4,6-diphenylpyridazine (267mg, l.Ommol), l-(2-pyrimidyl)piperazine (656mg, 4.0mmol) in 3ml of 1-BuOH was heated with stirring at 13O0C for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid, yielding white solid (22.1g, 66mmol, 97.3%). ESI-MS: m/z 335.2 (M+H+). 1H NMR (DMSO): 1H NMR (DMSO): d 8.406 (d, J=6.5, 2H), 7.740 (d, J=4.0, 2H), 7.558 (s, 3H), 6.686 (t, J=4.8, J=4.4, 1H), 6.841 (s, 1H), 3.881 (s, 4H), 3.620 (s, 4H), 3.776 (s, 4H).
4-chloro-6-phenyl-3 -(4-pyrimidin-2-ylpiperazin- 1 -vDpyridazine ("MWO 1-6-127WH) 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazin-4-ol Ih (22.Og, 66mmol) was suspended in 75ml phosphorus oxychloride and heated with stirring at 1000C for 3h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3g, 60.3mmol, 91.4%). ESI-MS: m/z 3.53.4 (M+H+). 1H NMR (CDCl3): d 8.377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H)," 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.0, J=4.5, 4H), 3.672 (t, J=4.0, J=4.5, 4H).. . . . 4-pyridyl-6rphenyl-3-(4-pyrimidin-2-ylpiperazin- 1 -vDpyridazine TMWO 1 -6- 189 WH) .
Into a reaction tube were added WH-6-127 (1.4g, 4.0mmol), K2CO3 powder (Ug, 12.4mmol), Pd(PPb.3)4 (240mg, 0.2mmol), 4-pyridineboronic acid (664mg, 5.4mmol) and 20ml of DME. Argon was then flushed through the tube for 3min. The tube was then sealed tightly and heated with stirring at 120 degree for 24h. After cooled down, the mixture was filter through a celite earth, the filtrate was then concentrated and the residue was purified by column chromatography eluting with 1:4, Ethyl Acetate: Petroleum ether.. Light yellow needle crystals were obtained (0.65g, 1.65mmol, yield 41.2%). Confirmed by ESI-MS and NMR. ESI-MS: m/z 3.96.2 (M+H+). 1H NMR (CDCl3): d 8.809 (d, J=6.0, 2H), 8.335 (d, J=5.0, 2H), 8.090 (d, J=7.5, 2H), 7.750 (m5 6H), 6.543 (t, J=4.5, 1H), 3.868 (t, J=5.0, 4H), 3.404 (t, J=5.0, 4H). Scheme 2
4,5-dihvdro-6-phenyl-4-(pyridin-4-yl)pyridazin-3('2H')-one
To a 200 ml, three-necked, round-bottomed flask equipped with a magnetic stir bar, 150 ml pressure-equalizing addition funnel, reflux condenser and a glass stopper, was added 21 g (135 mmole) of 4-bromopyridine and 70 of anhydrous THF. The system was oven-dried and flushed with argon before use. 135 ml (135 mmole) of THF solution of phenylmagnesium bromide (IM) was placed in the pressure-equalizing addition funnel. Then, the grignard solution was added dropwise over a period of 10 minutes. After the addition, the reaction was stirred for 15 minutes for completion. The solution of Grignard reagent was then obtained. A solution of 4-pyridylmagnesium bromide obtained above was added to a hot suspension of 6- phenylpyridazinone compound 7.8g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8h, left overnight at ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by • ESI-MS. ESI-MS: m/z 252.1 (M+H+). β-phenyM-fpyridin^-vDpyridazin-SQHVone
4.4 g (17.5 mmole) of 6-pyridazinone obtained above was placed in a 50 ml single-necked round bottom flask followed by 4.7 g (35 mmole) of anhydrous copper (II) chloride and then 20 ml of acetonitrile to give a brown yellow suspension. A reflux condenser was connected to the flask and a dry tube filled with CaCl2 was fitted to the top of the condenser. The reaction mixture was heated to reflux in an oil bath (HO0C) for 3 h. The color of the reaction suspension changed to dark yellow once the reflux started. After the completion of the reaction (monitored by HPLC), the flask was removed from the oil bath and cooled to ambient temperature. The mixture was poured on to 200 g of crushed ice and stirred vigorously for 10 minutes to give a gray precipitate and blue, liquid. The precipitate was then collected by filtering (pH of the filtrate was 1.5-2.0), and washed with 50 ml of a IN HCl solution to rid the solid of any remaining copper byproducts. This is followed by washing with 100 ml of Milli-Q water to get rid of the acid in the solid, and is monitored by checking the pH value of the filtrate. The solid was washed until the filtrate shows a pH of 7, after approximately 5 washes. The solid was dried over a medium frit sintered glass funnel in vacuo to give 3.9 g of a blue gray solid. Yield was 90%, confirmed by ESI-MS. ESI-MS: m/z 250.1 (M+H+). 3-chloro-6-phenyl-4-(pyridin-4-yl')pyridazine 2.0 g (8 mmole) of 6-phenylpyridazinone obtained above and 10 ml (54 mmole) of phosphorus oxychloride (reagent grade, Aldrich) were placed in a 50 ml single-necked round bottom flask. The flask was connected with a reflux condenser and a dry tube filled with CaCb was fitted to the top of the condenser. (HCl gas is formed in the reaction so a basic solution such as NaOH may be needed to absorb HCl in a large-scale synthesis). The reaction mixture was stirred in an oil bath (9O0C) for 2 h, then cooled to ambient temperature and poured onto crushed ice. (phosphorus oxychloride can be decomposed by water to give HCl and H3PO4). The mixture was then stirred vigorously for 10 minutes to give a white suspension. The suspension was neutralized with a 2N NaOH solution until the pH of the suspension was pH = 7. The precipitate was filtered, washed three times with 100 ml of water and dried over a medium frit sintered glass funnel in vacuo to provide 1.8 g of a light pink • powder. Yield was 85%, confirmed by ESI-MS. ESI-MS: m/z 268.4 (M+H+). 4-pyridyl-6-phenyl-3 -(4-pyrimidin-2-ylpiperazin- 1 -vBpyridazine (MWO 1 -6- 189 WH) 1.1 g (4.0mmole) of 3-chloropyridazine obtained above was placed in a 30 ml pressure vessel followed by addition of 2.6 g (16.0mmole) of l-(2-pyrimidyl) piperazine and then 15 ml of 1- BuOH (reagent grade). The vessel was sealed tightly and placed into an oil bath and stirred at 13O0C (temperature of oil bath) for 3 days. The reaction mixture was then cooled to ambient temperature and transferred to a single-necked flask for evaporation under reduced .pressure. Removal of solvent gave rise to a brown-red residue that was treated with 30 ml of water to give a brown suspension. The solid was collected by filtering and washed with 50 mL of water three times and dried over a filter funnel in vacuo to provide 0.96 g of light yellow solid. Yield was 90%, confirmed by ESI-MS and NMR. ESI-MS: m/z 396.2 (M+H+). 1H NMR (CDCl3): d 8.809 (d, J=6.0, 2H), 8.335 (d, J=5.0, 2H), 8.090 (d, J=7.5, 2H), 7.750 (m, 6H)5 6.543 (t, J=4.5, 1H), 3.868 (t, J=5.0, 4H), 3.404 (t, J=5.0, 4H). E. Preparation of A^-fcvcIopropyImethylV6-phenyI-4"fDyridin-4-vπpyridazin-3-amine (MW01-7-084WH). A synthetic scheme for the prepration of JV-(cyclopropylmethyl)-6-phenyl-4-(pyridin-4- yl)pyridazin-3 -amine (MW01-7-084WH) is depicted in Figure 10, and synthesis was carried out as described herein.
4-chloro-6-phenvbyridazin-3(2H)-one (MWQl-6-093WH) 4-chloro-6-phenylpyridazin-3(2H)-one was synthesized according to the procedure described by Coudert, P. supra.
4-cMoro-2-fmethoxyme1hylV6-phenylpyridazin-3r2H)-one (]VlW01-7-053WH) A mixture of chloropyridazinone 1 (25.5 g, 0.12mol), 4-NJNT-dimemylarninopyridine (0.20 g) and i- Pr2NEt (26.7g, 0.21mol) in anhydrous CH2Cl2 (30OmL) was stirred at O0C (ice bath) for 30 min. Methoxymethyl chloride (25g, 0.31mol) was added and the mixture was stirred at 00C for Ih and then allowed to warm to room termperature. The reaction was strirred at room temperature till complete. The solvent was then removed in vacuo, the residue was treated with water, washed with dilute Na2CO3 solution and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated, the residue was then purified by recrystallization from 95% ethanol to give 20.1 light yellow solid. Yield 66.9%. β-phenvM-foyridin^-vnpyrida-dn-SαH^-one fMWOl^-OόgWH)
The protected pyridazinone MWOl -7-053 WH (l.Oequiv.) was mixed with arylboronic acid (1.37equiv.), Pd(PPh3)4 (0.05 equiv.) and K2CO3 (3.1equiv) and 200 mL of DME in a 350ml of pressure vessel, flushed with argon for 3 min, and the mixture was then stirred and refluxed (oil bath, 12O0C) until the starting material had disappeared. After cooling, the solution was concentrated to dryness under reduced pressure, the residue was treated with water and filtered off. The filter cake was washed with water over filter funnel and then used for next step directly. The residue obtained above was dissolved in 200ml of EtOH, 6 N HCl (200 mL) was added and the reaction mixture was refluxed (oil bath, 1200C) for 6 h, then it was allowed to cool to room termperature, and concentrated to dryness under reduced pressure. The residue was neutralized with dilute NaOH solution. The suspension was then filtered off, washed with water and dried over a filter funnel. Recrystallization from 90% ethanol provided brown yellow solid. Yield 80.4%. ESI-MS: m/z 294.3 (M+H+) 3-chloro-6-phenvl-4-fpvridin-4-vlbvridazine HvTWOl -7-076 WHD 3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-076WH) (66mmol) was suspended in 75ml phosphorus oxychloride and heated with stirring at 1000C for 3h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to yielding a light yellow solid. ESI-MS: m/z 268.4 (M+H+). N-rcyclopropylme1hylV6-phenyl-4-(pyridin-4-vnpwidazin-3-arnine (MWO 1 -7-084 WH) A mixture of N-(cyclopropylmemyl)-6-phenyl-4-(pyridm-4-yl)pyrida2in-3.-aniine (MWO 1-7- 084WH) ( 0.5mmol), C-Cyclopropyl-methylamine (2.0mmol) in 3ml of 1-BuOH was heated with stirring at 1300C for 7 days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, then 1:3, Ethyl Acetate: Petroleum ether, dried over filter funnel in vacuo yielding gray solid. ESI-MS: m/z 330.4 (M+H+).
F. Preparation of 3-(4-methyIpiperazin-l-vI)-6-phenyl-4-(pyridin-4-vI)pyridazine rMW01-7-085WH). A mixture of 3-chloro-6-phenyl-4-(pyridin-4-yl)pyridazine (MWO 1-7-076 WH) (0.5mmol), 1- methyl-piperazine (2.0mmol) in 3ml of IrBuOH was heated with stirring at 13O0C for about 7 days. The solvent was removed by evaporation in vacuo the residue was treated. with water to give a suspension. The solid was then filtered off, washed with water, then 1:3, Ethyl Acetate: Petroleum ether, dried over a filter funnel in vacuo to yield a brown solid. ESI-MS: m/z 332.2 (M+H*). A synthetic reaction scheme for the preparation of 3-(4-methylpiperazinrl-yl)-6- phenyl-4-(pyridin-4-yl)pyridazine (MW01-7-085WH) is depicted in Figure 11.
G. Preparation . of 6-methyI-4-phenyI-3-(4-pyrimidin-2-ylpiperazin-l-yl)pyridazine (MW01-7-057) .
A synthetic reaction scheme for the preparation of 6-methyl-4-phenyl-3-(4-pyrimidin-2- ylpiperazin-l-yl)pyridazine (MWOl-7-057) is depicted in Figure 12, and synthesis was carried out as described herein. A mixture of 3-chloro-6-methyl-4-phenylpyridazine (lOOmg,
0.5mmol), l-(2-pyrimidyl)piperazine (400mg, 2.0rnmol) in 3ml of 1-BuOH was heated with stirring at 1300C for 7days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, Washed with water, then 1:3, Ethyl Acetate: Petroleum ether, dried over a filter ftinnel in vacuo to give light yellow solid. (68mg, 0.20mmol, yield 41.7%). Purity >95%; ESI-MS: m/z 333.1 (M+H+). 1H NMR (CDCl3): d 8.310 (d, J=5.0, 2H), 7.678 (d, J=7.5, 2H), 7.476 (m, 3H), 7.119 (s, H), 6.509 (t, J=4.5, 1H), 3.785 (t, J=4.5, J=5.0, 4H), 3.277 (t, J=4.5, J=5.0, 4H), 2.669 (s, 3H). Example 2 Models of Peripheral Nerve Injury
Three different models of peripheral nerve injury, chronic constriction injury (CCI), a model for chronic neuropathic pain (carpal) tunnel syndrome; a model for spinal nerve crush (SNC), a model for chronic neuopathic pain; a model for nerve root crush (NRC); a model for lumbar radiculopathy/sensory loss, may be used to investigate the effects of pyridazine compounds in the peripheral nervous system. These models are described in detail in US Published Application No. 20050234105 and for completeness the description is generally reproduced below.
Nerve crush. Adult female Sprague-Dawley rats weighing 200 to 250 g may be used in this study (n=4 animals per timepoint). The study generally involves the following protocol. Animals will be anesthetized by intraperitoneal injection of a solution containing sodium pentobarbital (Nembutal, 50 mg/ml; Abbott Laboratories, Chicago, 111.), diazepam (5 mg/ml; Steris Laboratories, Phoenix, Ariz.), and saline (0.9%; Steris Laboratories, Phoenix, Ariz.) in a volume proportion of 1:1:2, respectively. Initially, 0.5 ml will be injected and then supplemented with 0.1 ml injections as needed to produce an adequate level of surgical anesthesia throughout the experiment! Through a midline incision, the thoracolumbar fascia
• will be incised just left of the spinous processes of the fifth and sixth lumbar vertebrae. The sacrospinalis muscle will be gently moved laterally to expose the facet joint between the fifth and sixth lumbar vertebrae. The L5 nerve root, DRG, and spinal nerve will be exposed by
L5/6 facectomy and L5 hemilaminectomy, using care to avoid trauma to the tissue. The L5 nerve proximal to (in nerve root crush) or just distal (2 mm) from (in spinal nerve crush) the DRG will be crushed once for 2 s, by using a smooth surface forceps. Some nerve- fibers should survive the crush so that sensory function will not be blocked completely. This form of proximal nerve injury should produce a transient hyperalgesia and neuronal apoptosis. Other animals, in which the spinal nerve is exposed but not crushed, will be used for controls (sham surgery). Chronic constriction injury. Under barbiturate anesthesia, the sciatic nerve will be exposed uniaterally at the midthigh level. Four ligatures (chromic gut 4.0) will be placed around the nerve with 1-mm spacing. The ligatures will be tied until they constrict, just slightly, the diameter of the nerve and a brief twitch is seen in the respective hind limb. A number of animals will be studied per timepoint while contralateral and uninjured nerves will serve as controls. The wound will be closed in layers. Thermal hyperalgesia is a reliable indicator of pain-related behavior in this model.
Behavioral testing for thermal hyperalgesia. The thermal nociceptive threshold will be measured in each hindpaw of the experimental animals before surgery and at regular intervals from day 1 after surgery using a thermal testing device and protocol that allows each animal to serve as its own control (Hargreaves et al., Pain 32:77-78, 1988). This technique uses a light source to selectively heat one foot at a time. The method is suitable for investigations of neuropathic pain involving unilateral lesions to peripheral nerves. Both the left (injured) and right (uninjured) footpads will be tested as described by Wagner R. Myers R R., Neuroreport 7:2897-901, 1996). All animals will be tested for three consecutive days prior to surgery to acclimate the animals to the testing procedure. All behavior measurements will be made at the same time each day in a quiet room and by an investigator blinded to treatment groups. Behavioral testing for mechanical allodynia. Sensitivity to non-noxious mechanical stimuli will be tested by determining the hindpaw withdrawal response to von Prey hair stimulation of the plantar surface of the footpad (Igarashi et al., Spine 25:2975-80, 2000). Rats will be acclimated to being on a suspended 6-mm wire grid and having the plantar surface of their footpads stimulated with von Prey filaments. Three days prior to surgery, animals will be baselined to acclimate animals to movements and foot poking. After surgery, nine filaments calibrated between 1-15 g force will be applied to the paw surface just until the filament bent, for a total of two applications approximately 2 to 3 seconds apart and varied in location so as to avoid sensitization. If the rat did not withdraw its foot after either of the two applications of a given filament, the next stiffer filament will be tested in the same manner. When a rat withdrews its foot, the measurement will be verified by ensuring that there was an absence of response at the next less stiff filament. The gram force of the filament causing the positive response will be recorded for first reaction. After 5 minutes the same procedure will be performed again. Baseline testing will be performed three days prior to the start of the experiment to accommodate the animals to the testing procedure and to verify that they had normal responses. If the rat withdraws its foot, this gram force will be recorded as a second reaction. A positive responder will be identified as an animal responding to a filament gram force of less than 5 grams. Crush and sham animals will be tested on 1, 3, 7, 11, and 14 days after surgery. Example 3 Animal Models of CNS Injury
The potential of preventing or reducing CNS injury using a pyridazine compound may be evaluated in animal models described in US Patent No. 6833237, the description of which is generally reproduced below. The models represent varying levels of complexity, and they can be evaluated by comparison of control animals to the treated animals. The efficacy of such treatment may be evaluated in respect to clinical outcome, neurological deficit, dose- response and therapeutic window.
1. Closed Head Injury (CHI)- Experimental traumatic brain injury produces a series of events contributing to neurological and neurometabolic cascades, which are related to the degree and extent of behavioral deficits. CHI is induced under anesthesia, while a weight is allowed to free-fall from a prefixed height (Chen et al, J. Neurotrauma 13, 557, 1996) over the exposed skull covering the left hemisphere in the midcoronal plane.
2. Transient middle cerebral artery occlusion (MCAO). A 90 to 120 minutes transient focal ischemia may be performed in adult, male Sprague Dawley rats, 300-370 g. The intraluminal suture MCAO method described by Longa et al.(Stroke, 30, 84, 1989) and Dogan et al. (J. Neurochem. 72, 765, 1999) may be employed. Generally, under halothane anesthesia, a 3-0-nylon suture material coated with Poly-L-Lysine is inserted into the right internal- carotid artery (ICA) through a hole in the external carotid artery. The nylon thread is pushed into the ICA to the right MCA origin (20-23 mm), 90-120 minutes later the thread is pulled off, and the animal is closed and allowed to recover.
3. Permanent middle cerebral artery occlusion (MCAO). In this model the occlusion is permanent and is unilaterally-induced by electrocoagulation of MCA. Both MCAO methods lead to focal brain ischemia of the ipsilateral side of the brain cortex leaving the contralateral side intact (control). Example 4 - Mouse Experimental Allergic Encephalomyelitis (EAE) Model
An experimental chronic EAE animal model may be used to test pyridazine compounds for efficacy in treating multiple sclerosis. This model is a well accepted experimental model for MS. EAE can be induced in female C57BL/6 mice using the protocol described by Mendel et al. (Eur. J. Immunol. 25:1951-59, 1995). Briefly, disease is induced by immunizing mice with a MOG35-55 peptide derived from rat myelin oligodendrocyte glycoprotein (Mendel et al., 1995). To induce EAE, groups of age and weight-matched mice are given a dose of 100 μg of rat MOG35-55 injected subcutaneously at three sites distributed over the shaved flank (Experiment 1). To induce EAE with accelerated onset, mice in a second experiment (Experiment 2) are given an intravenous injection of 500 ng pertussis toxin administered 48 hours after they receive the dose of MOG35-55. The mice in Experiment 1 receive no pertussis toxin; therefore disease onset in Experiment 2 is accelerated as compared with Experiment 1
Administration of a pyridazine compound or placebo may be initiated on the day after the MOG35-55 is administered (day 1) and it may be continued through day 11. Each mouse is injected intraperitoneally every other day with pyrogen-free phosphate-buffered saline (PBS) or 0.2 ml PBS containing a suitable dose of a pyridazine compound. Mice are monitored daily for 35 days (Experiment 1) or 30 days (Experiment 2) for. weight loss, disease onset and severity of clinical signs of EAE by an independent observer blinded to the treatment groups. The severity of EAE is assessed using a standard EAE index system in which "0" is used to indicate an asymptomatic mouse and clinical scores ranging from 0.5 to 4 are used to indicate varying degrees of ascending paralysis.
A particular study will focus on the efficacy of MWO 1-2-15 ISRM or MW01-5-188WH in the SJL EAE model of the relapsing-remitting disease process in MS. The .autoimmune ' relapsing-remitting model approximates the disease course that most MS patients experience: relapsing-remitting or secondary progressive. In the relapsing-remitting model there is a requirement for the upregulation of cytokines in the CNS for the progression of disease. . ■ 1. In the first paradigm: SJL mice will be treated with 5.0 mg/kg MWOl -2-151 SRM or MW01-5-188WH per day, beginning two days prior to induction of EAE by active immunization with PLP139-151 peptide in CFA, for a total of 14 days and they will be compared to an equal number of control-treated animals. The mice will be observed for presentation of clinical signs of disease; immunologic parameters (peripheral and CNS cytokine expression patterns), CNS histology, and CNS flow cytometric analysis of inflammatory cell populations will be analyzed. The time points that will be examined will correspond to peak clinical disease, remission, and first relapse.
2. In the second paradigm: the treatment of SJL mice will start at the time of remission from initial clinical disease induced by active immunization with PLP139-151 peptide and the same endpoints as above will be used. The time points examined will correspond to peak clinical disease in the first relapse, remission of the first relapse, and progression to a second relapse. Example 4
Effect of MWO 1-2-15 ISRM (also referred to herein as Minozac) in an Animal Model of Traumatic Brain Injury
In studies over the past several years, a number of investigators have discovered that inflammation in the brain which is seen in a variety of disorders, such as AD, TBI and stroke, involves the activation of microglia and astrocytes. In order to extend the observations described above with activated microglia cells in vitro and animal models of AD, to other therapeutic indications, studies were carried out in an animal model of TBI. The studies were designed to examine the ability of Minozac to reduce brain inflammation and loss of cognitive function., In these studies, adult mice were subjected to a pneumatic impactor, closed-head TBI or sham conditions. At 3h and 9h after injury, Minozac (5mg/kg) or saline vehicle were injected IP. Mice were sacrificed at 12 h, and proinflammatory cytokine levels in hippocampus and cortex determined. Daily Y-maze testing was done until sacrifice of mice at 28d, and values averaged. The rationale for treating with Minozac several hours after the onset of injury was to more closely mimic the clinical situation in which human patients with severe head injuries suffered in accidents such as automobile crashes arrive in hospital trauma centers hours after sustaining their injury. Minozac treatment under these conditions readily suppressed the injury-associated release of neurotoxic cytokines over a 12-hour period both in the hippocampus and the cortex of mice subjected to TBI. Moreover, Minozac dosing also prevented the loss of cognitive function over a 4-week recovery period, as measured in a Y- maze behavioral test that assesses memory retention and learning.This indicates that Minozac also suppresses cognitive dysfunction characteristic of TBI.
The present invention is not to be limited in scope by the specific embodiments described herein, since such embodiments are intended as but single illustrations of one aspect of the invention and any functionally equivalent embodiments are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.
All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. All publications, patents and patent applications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the methods etc. which are reported therein which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
Table 1
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Table 2
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Table 3 Compounds of the Formula π -(4-(6-phenylpyridazin-3-yl)piperazine-l-yl) pyrimidine and Derivatives
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Table 4
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Table 5
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001

Claims

WHAT IS CLAIMED IS:
A pharmaceutical composition comprising a pyridazine compound in a therapeutically effective amount for treating a Demyelinating Disease, a Demyelinating Condition,
Neuropathic Pain or Chemokine-Induced Pain, or for Stroke Rehabilitation, and a pharmaceutically acceptable carrier, excipient, or vehicle.
A pharmaceutical composition according to claim 1 wherein the pyridazine compound comprises a pyridazinyl radical pendant with an aryl or substituted aryl, a heteroaryl or substituted heteroaryl. 3. A pharmaceutical composition according to claim 2 wherein the heteroaryl is piperazinyl substituted with pyrimidinyl, or pyridinyl.
4. A pharmaceutical composition according to claim 1 wherein the pyridazine compound has the Formula Ia or Ib
Figure imgf000182_0001
wherein R1, R2, and R3 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; R7 is 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide or R7 may be absent and there is a double bond between N at position 1 and C at position 6; R4, R5, and R6 are independently hydrogen, alkyl, alkoxy, halo, or nitro; or R1 and R2, R1 and R7, or R2 and R3 may form a heteroaryl or heterocyclic ring; or an isomer or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition according to claim 1 wherein the pyridazine compound has the Formula II:
Figure imgf000183_0001
wherein R10 and R11 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulflnyl, sulfenyl, sulfoxide, sulfate, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, phosphonate, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition according to claim 1 wherein the pyridazine compound has the Formula III:
Figure imgf000184_0001
wherein R15 and R16 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof. A pharmaceutical composition according to claim 1 wherein the pyridazine compound has the Formula IV:
Figure imgf000184_0002
wherein R70 is 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, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, carboxyl, phosphonate,. carbonyl, carbamoyl, or carboxamide, especially heterocyclic, heteroaryl, amino, and substituted amino and R71 is aryl or substituted aryl; or an isomer or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition according to claim 1 wherein the pyridazine compound has the Formula V:
Figure imgf000185_0001
wherein R , R51, and R 2 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfmyl, sulfenyl, sulfoxide, sulfate, sulfonate amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, =0, =S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition according to claim 1 wherein the pyridazine compound does not include the compounds depicted in Table 1.
10. A method for treating and/or preventing Multiple Sclerosis, Spinal Cord Injury, Traumatic Brain Injury and Stroke in a subject comprising administering a therapeutically effective amount of a composition according to any preceding claim.
11. A method for treating a subject in need of Stroke Rehabilitation comprising administering a therapeutically effective amount of a composition according to .any preceding claim.
12. A method for treating nerve injury in a subject comprising administering a therapeutically effective amount of a composition according to any preceding claim.
13. A method for treating and/or preventing neuropathic pain in a subject comprising administering a therapeutically effective amount of a composition according to any preceding claim.
14. Use of a pyridazine compound for the preparation of a medicament for treating a Demyelinating Disease, a Demyelinating Condition, Neuropathic Pain or Chemokine-
Induced Pain, or for Stroke Rehabilitation
15. A kit comprising a pyridazine compound or a composition as claimed in any preceding claim for preventing and/or treating a Demyelinating Disease, a Demyelinating Condition, Neuropathic Pain or Chemokine-Induced Pain, or for Stroke Rehabilitation, a container, and instructions for its use.
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