Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/62—Benzothiazoles
  • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D277/82—Nitrogen atoms

Definitions

• Neurologic disorders are becoming increasingly common in North America. For example, Parkinson's disease is the second most common neurologic disorder, affecting nearly 1 million people in North America. Thus, developing an effective treatment for neurologic disorders has become a high priority in the drug industry.
• Neurologic disorders can generally be divided into two groups based on their physiological and pathological characteristics. Parkinson's disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) are all progressive disorders (i.e., their symptoms are not apparent until months or more commonly years after the disease has begun) , caused by an initial reduction of neuronal function, followed by a complete loss of function upon neuronal death. In addition, these progressive neurologic disorders are characterized by the presence of protein aggregates that are believed to hamper cellular functions (e.g., neurotransmission) , and may ultimately result in cell death (Sasaki et al . , Am. J. Pathol . , 153:1149-1155 [1998]).
• Multiple sclerosis is a disorder of the central nervous system, which is slowly progressive and is characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations. The cause is unknown but an immunologic abnormality is suspected (THE MERCK MANUAL, 17th EDITION, 1999 MERCK & CO.). Several different drug therapies are currently being investigated.
• brain stroke is the third leading cause of death in the developed countries. Survivors often suffer from neurological and motor disabilities.
• CNS central nervous system
• R(+) -N-propargyl-1-aminoindan has been shown to be an effective treatment for stroke and traumatic brain injury (U.S. Patent No. 5,744,500).
• a series of propargylamines including Selegiline and Rasagiline, have been shown to prevent apoptosis in dopamine neurons in Parkinson's models (Naoi, M. et al . J. Neural Transmission (2002) 109: 607-721).
• N-Propargyl-1-Aminoindan has recently been suggested as being useful for treating Parkinson's disease, dementia and depression (U.S. Patent No. 5,453,446).
• the neuroprotective activity of these molecules is attributed by some to the presence of the propargyl moiety. The mechanism by which the propargyl moiety may confer neuroprotection is not fully understood.
• WO 01/95907 suggests the use of Riluzole for treatment or prevention of the onset of symptoms of multiple sclerosis .
• PCT International Publication No. WO 00/74676 suggests the use of Riluzole for treatment of multiple sclerosis either alone or in combination with other drugs.
• 6-trifluoromethoxy-2-amino-benzothiazole, PK 26124, RP 54274, Riluzole was synthesized for the first time by a Russian group (J " . Gen . Chem. USSR, 1963, 33, 2240-2246, U. S. Pat. 2,822,359; Ch.A . , 52, 8570d 1958) as a part of their investigation on the influence of electronegative substituents at the 6 position of the benzothiazole nucleus on the color of diazastyryl bases .
• 2-Aminobenzothiazoles exist in tautomeric forms (where the proton is shifted between the 2-amino group and the ring nitrogen) .
• this process is blocked by complete alkylation of the 2-amino group or by alkylation of the ring nitrogen to give for instance 2-imino-3-methylbenzothiazoline, the depressant effect of the 2-aminobenzothiazole is changed to stimulation of the CNS.
• U.S. Patent No. 4,535,088 discloses propynylaminothiazole derivatives having anti-fungal and/or anti-microbial activity.
• the present invention provides novel derivatives of propargyl- trifluoromethoxy-amino-benzothiazole which are effective at treating neurologic disorders, including Parkinson's disease, and multiple sclerosis.
• the subj ect invention provides compounds having the structure ;
• R 2 is H or C 1 -C 4 alkyl
• R 3 is H or C 1 -C 4 alkyl
• R 4 is present or absent, and when present is H, Ci-C ⁇ alkyl, C ⁇ -C 6 alkynyl, - (CH 2 ) y S (CH 2 ) X CH 3 , C ⁇ -C 6 aminoalkyl, C ⁇ -C 6 hydroxyalkyl or
• n is an integer from 1-6; wherein x is 0 or an integer from 1-5 and y is an integer from 1-5, such that x+y ⁇ 6; at least one of Ri or R 4 is present; the dashed line represents a bond between one of the nitrogen atoms and the intervening carbon atom; and any compound is charged when both Ri and R 4 are present, or any specific enantiomer thereof or any pharmaceutically acceptable salt thereof .
• the subject invention also provides a method for treating a subject afflicted with a neurologic disorder comprising administering to the subject a therapeutically effective amount of any of the compounds of the invention or pharmaceutically acceptable salts thereof so as to thereby treat the neurologic disorder in the subject.
• the subject invention also provides a method for- treating a subject afflicted with multiple sclerosis comprising administering to the subject a therapeutically effective amount of any of the compounds of the invention or pharmaceutically acceptable salts thereof so as to thereby treat multiple sclerosis in the subject.
• Figure 1-A shows the daily EAE GMS for compound 3 (10 mg/kg twice daily) .
• - ⁇ - indicates the control group (PBS) ;
• Figure 1-B shows the daily EAE GMS for Glatiramer
• - ⁇ - indicates the control group (PBS) ;
• Figure 1-C shows the daily EAE GMS for Glatiramer
• - ⁇ - indicates the control group (PBS) ; - ⁇ - indicates the group under study.
• FIG. 1 shows dose response of EAE MMS (averages from several experiments) for Compound 3
• the subject invention provides compounds having the structure (Formula I) :
• Ri is present or absent, and when present is H,
• R 2 is H or C 1 -C 4 alkyl
• R 3 is H or C 1 -C 4 alkyl
• At least one of Ri and R 4 is - (CH 2 ) y S (CH 2 ) X CH 3 .
• the subject invention provides compounds having the structure (Formula ID :
• Ri is present or absent, and when present is H or C 1 -C 4 alkyl
• R 2 is H or C1-C4 alkyl
• R 3 is H or C 1 -C 4 alkyl ; . _ - - . R 4 .is present or absent , and when present is
• the compounds have the structure:
• At least one of Ri, R 2 and R 3 is Ci- C 4 alkyl .
• Ri is H or methyl; R 2 is H or methyl; and R 3 is H or methyl, or a pharmaceutically acceptable salt thereof.
• Ri is absent and R 4 is present.
• Ri is absent and R 4 is methyl .
• the chiral carbon is in the R configuration .
• the chiral carbon is in the S configuration .
• the subject invention provides the pharmaceutically acceptable salt of any of the aforementioned compounds, wherein the salt is the chloride, mesylate, maleate, fumarate, tartarate, hydrochloride, hydrobromide, —esylate, p-toluenesulfonate, benzoate, acetate, phosphate., or sulfate salt.
• the compound has the structure:
• the compound has the structure:
• the compound has the structure:
• the compound has the structure:
• the compound has the structure:
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure:
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure :
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure:
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure:
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure:
• the subject invention provides the hydrochloride salt of the above compound.
• the compound has the structure:
• the compound has the structure.:
• the subject -invention also- provides a method for treating_a_ subject afflicted with a neurologic disorder comprising administering to the subject a therapeutically effective amount of any of the aforementioned compounds represented by Formula I or a pharmaceutically acceptable salt thereof, so as to thereby treat the neurologic disorder in the subject.
• the disorder is Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, stroke, a neuromuscular disorder, schizophrenia, cerebral infarction, head trauma, glaucoma, facialis or Huntington's Disease.
• the therapeutically effective amount is from about 1 to about 1000 mg/day.
• the subject invention also provides a method for treating a subject afflicted with multiple sclerosis comprising administering to the subject a therapeutically effective amount of any of the aforementioned compounds represented by Formula I or a pharmaceutically acceptable salt thereof so as to thereby treat multiple sclerosis in the subject.
• the above method further comprises administering to the subject a therapeutically effective amount of levodopa, glatiramer acetate, interferon beta-lb, interferon beta-la, steroids or Mitoxantrone (Novantrone) .
• the therapeutically effective amount is from about 1 to about 1000 mg/day.
• the therapeutically effective amount of the compound is administered by injection, systemically, orally or nasally.
• the subject invention also provides the use of any of the aforementioned compounds for manufacturing a medicament useful for treating a neurologic disorder in a subject.
• the neurologic disorder is Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, stroke, a neuromuscular disorder, schizophrenia, cerebral infarction, head trauma, glaucoma, facialis or Huntington's Disease.
• the subject invention also provides the use of any of the aforementioned compounds for manufacturing a medicament useful for treating multiple sclerosis in a subject.
• the medicament further comprises levodopa, glatiramer acetate, interferon beta-lb, interferon beta-la, steroids or Mitoxantrone (Novantrone) .
• the compounds of this invention may be used therapeutically in addition to currently available treatments for neurologic disorders.
• the compounds of the invention may be used in addition to levodopa therapy for Parkinson's disease or in addition to glatiramer acetate (the drug substance of Copaxone) , interferon beta-lb, interferon beta-la, steroids or Mitoxantrone (Novantrone) .
• the subject invention also provides the use of any of the aforementioned compounds for manufacturing a medicament in a package having instructions for administration of the medicament to treat a neurologic disorder in a subject.
• the subject invention also provides a method for destroying or inhibiting the proliferation of microbes or fungus which comprises contacting the microbes or fungus with a composition comprising any of the aforementioned compounds and an acceptable carrier.
• the subject invention also provides a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable carrier.
• the pharmaceutical composition further comprises a therapeutically effective amount of levodopa, glatiramer acetate, interferon beta-lb, interferon beta-la, steroids or Mitoxantrone (Novantrone) .
• the pharmaceutical composition further comprises a therapeutically • effective amount of glatiramer acetate.
• the subject invention also provides a process for the manufacture of the above pharmaceutical composition comprising admixing any of the aforementioned compounds with a pharmaceutically acceptable carrier.
• the subject invention also provides a packaged pharmaceutical composition for treating a neurologic disorder in a subject comprising: (a) any of the aforementioned pharmaceutical compositions; and (b) instructions for using the composition for treating the neurologic disorder in the subject.
• the subject invention also provides a process of manufacturing compound of Structure II, comprising the steps of:
• Ri is present or absent, and when present is H or C1-C 4 alkyl
• R 2 is H or C 1 -C 4 alkyl ;
• R 3 is H or C 1 -C 4 alkyl ;
• step (d) optionally alkylating the product of step (c) , wherein Ri is H, to provide the compound.
• the above process further comprises reacting the product of step (c) , wherein Ri, R 2 and R 3 are each H, with 2-bromo-4 ' -methylacetophenone in a polar solvent in the presence of a base to produce a compound having the structure:
• the polar solvent is acetonitrile and the base is potassium carbonate.
• the process further comprises reacting the product of step (c) , wherein Ri, R 2 and R 3 are each H, with propargyl bromide in a polar solvent in the presence of a base to produce- a compound having-.the..structure:
• the polar solvent is acetonitrile and the base is potassium carbonate.
• the process further comprises reacting the product of step (c) , wherein Ri, R 2 and R 3 are each H, with 2-chloroethyl methylsulfide in a polar . solvent in the presence of a base, to produce a compound having the structure:
• the polar solvent is acetonitrile and the base is potassium carbonate.
• the amine exchanging agent is a mixture of aqueous NH 2 NH 2 and hydrazinium sulfate in ethylene glycol .
• the chlorinating agent is S0C1 2 .
• Ri is C ⁇ -C 4 alkyl and R 2 and R 3 are H.
• the alkylating agent in step (d) is methyliodide or dimethyl sulfate.
• the subject invention also provides a process of manufacturing a compound having the structure:
• Ri is C1-C4 alkyl
• R 2 is H or C 1 -C 4 alkyl ;
• R 3 is H or C 1 -C 4 alkyl , comprising reacting a compound having the structure :
• RiX in a polar solvent in the presence of a base, wherein X is a halogen atom, to produce the compound.
• the polar solvent is acetonitrile and the base is potassium carbonate.
• the subject invention also provides a process of manufacturing a compound having the structure:
• R 2 is H or C 1 -C 4 alkyl
• R 3 is H or C 1 -C 4 alkyl
• step b) reacting the product of step a) with
• step (b) is further alkylated with an alkylating agent to provide a compound having the structure:
• the methylating agent in step (a) is methyliodide or dimethyl sulfate. In a further embodiment of the above process , the methylating agent is methyliodide.
• the subject invention further provides a process of manufacturing compound 14 comprising reacting a compound having the structure:
• the subject invention further provides a process of manufacturing compound 15 comprising reacting a compound having the structure:
• the subject invention further provides a process of manufacturing compound 9 comprising reacting a compound having the structure: with
• the polar solvent is acetonitrile .
• the subject invention further provides any of the aforementioned compounds for use as antimicrobial and/or antifungal agents.
• the invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention (see, e. g. , R.B. Silverman, 1992, "The Organic Chemistry of Drug Design...and. Drug . Action”-,...Academic .Press, Chapter 8, the entire contents of which are hereby incorporated by reference) .
• prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics of the therapeutic compound.
• certain embodiments of the present compounds can contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids .
• pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in si tu during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al . (1977) "Pharmaceutical Salts", J. Pharm. Sci . 66:1-19).
• pharmaceutically acceptable salts as used herein also includes a quaternary ammonium salt.
• the structure of some of the compounds of this invention includes asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers . All such- some-ri-c--fo-rms—- ⁇ -f---these compounds are expressly—included in this invention.
• Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis .
• the compounds of the present invention are administered as pharmaceuticals, to humans and mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier .
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound (s) of the present invention within or to the subject such that it can performs its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydrox toluene (BHT) , lecithin, propyl gallate, alpha- tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydrox toluene
• Formulations of the present invention include those suitable for oral administration.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
• formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the invention suitable for oral administration may be in the form of capsules, pills, tablets, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato, or _ apioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and gly
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycol ⁇ and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) , surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well -known in the pharmaceutical- formulating art . They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions- -to -provide -the desired release profile,, other polymer matrices, liposomes and/or microspheres .
• compositions may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient (s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients .
• Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert dilutents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents .
• Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents .
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents .
• adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents .
• Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
• prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial , intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient .
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above .
• the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
• the compounds of the invention can prevent neuronal death and improve the outcome in various models resembling human degenerative disorders.
• neurodegenerative disorder refers to a disorder whose adverse affects are localized in the nervous system.
• neurotraumatic injury refers to damage to the central or peripheral nervous system caused by a traumatic event, such as head trauma, spinal trauma, neurotoxic injury, stroke, ischemia, hypoxia, or anoxia.
• stroke or "ischemic stroke” as used herein means a brain infarct manifested by neurologic deficits .
• Stroke may refer to a “stroke in evolution” in which the infarction is still enlarging or a “completed stroke” in which the infarction size is no longer growing. (THE MERCK MANUAL, 17th EDITION, 1999 MERCK & CO.)
• treatment of stroke is meant to include the treatment of the brain infarction per se or the treatment of the symptoms caused by the brain infarction.
• symptoms may include neurological deficits, cognitive disturbances, brain edema, decreased cerebral blood flow, catecholamine fluctuations, or neurological or motor disabilities .
• Benzothiazoles la and lb were prepared by converting 6- trifluoromethoxy 2-amino benzothiazole to the corresponding 2- hydrazino analogue by direct exchange amination (C. J. Barnett and J. C. Smirz, Organic. Prep . Proc. Int . 6(4), 1974, 179- 182) using a mixture of aqueous hydrazine and hydrazinium sulfate in ethylene glycol, followed by substituting the 2- hydrazino group with a chlorine atom by reacting 1 with S0C1 2 , to give 2 (Barry A. Dreikorn and Paul Unger, J. Heterocyclic Chem.
• Example 1 (6-Trifluoromethoxy-benzothiazol-2-yl) -hydrazine 1
• Example 3a Methyl-prop-2-ynyl- (6-trifluoromethoxy- benzothiazol-2-yl) -amine.HC1 salt 3a Free base 3 was dissolved in HCl/EtOH solution, stirred for 0.5 h and the product was precipitated by addition of Et 2 0, filtered, washed with Et 2 0 and dried to give 1.15 g (65%) of 3a.
• This compound can be prepared by the same synthetic procedure described for methyl-prop-2-ynyl- (6-trifluoromethoxy- benzothiazol-2-yl) -amine 3, starting from 4-
• Example 5a But-2-ynyl- (6-trifluoromethoxy-benzothiazol-2-yl) - amine.HCl salt 5a 0.255 g of 5 were converted to the HCl salt using HCl/EtOH as described for 3a.
• Example 9 2- [Prop-2-ynyl- (6-trif luoromethoxy- benzothiazole-2-yl) -amino] -1-p-tolyl-ethanone 9
• the title compound was prepared by the procedure described in Ex. 7: prop-2-ynyl- ( 6-trif luoromethoxy-benzothiazol-2-yl) - amine (the compound of Ex. 4, 5.0 g, 18.3 mmol) was reacted with 2-bromo-4' -methylacetophenone (3.9 g, 18.3 mmol) to give 9 as a white solid (3 g, 40%) .
• Prop-2-ynyl- (6-trifluoromethoxy-benzothaizol-2-yl) -amine (the compound of example 4, 0.3 g, 1.1 mmole) was dissolved in methyl ethyl ketone, (3 ml) and excess Mel (2 ml) was added. The reaction mixture was refluxed for 4.5 h and then an additional amount of Mel (1-2 ml) was added and the reaction mixture was refluxed over night. The mixture was concentrated, toluene was added and the white precipitate obtained, filtered, washed extensively with toluene and dried in vacuum to give 0.285 g (63%) of 11 as a white solid.
• Example 12 (3-Methyl-4-trifluoromethoxy-3H-benzothiazol-2- ylidene) -prop-2-ynyl-amine 12
• the title compound may be prepared from 2-imino-3-methy1- 4-trifluoromethoxybenzothiazoline (prepared from 4- ( trifluoromethoxy) -2-benzothiazolamine) by reacting it in toluene with propargylamine in the presence of p-TsOH at 125°C overnight .
• Example 13 2- (2-Prop-2-ynylimino-6-trifluoromethoxy- benzothiazole-3-yl) -1-p-tolyl-ethanone 13
• Example 17 Effect of 3a on MPP+ treated PC-12 cells.
• Pheochromocytoma PC-12 cells (at a density of 200,000 cells/well) were cultured for 10 days with 50 ng/ml NGF on 6- well culture dishes ' coated with 200 ug/ml rat tail type I collagen (BD Biosciences, Bedford, MA, USA). On the day of the experiment the morphological differentiation of the cells was very advanced (typical network formation) .
• cells were treated with 1000 ⁇ M of l-methyl-4-phenylpyrdinium XMPP+ -iodide . salt from RBI chemicals (Natick, MA, USA) for 48 hours in the absence or presence of tested compounds, added to the culture 30 min.
• MPP+ has been shown to inhibit mitochondrial electron transport (complex I) in neurons and to induce a syndrome resembling Parkinson disease in mice and monkeys.
• complex I mitochondrial electron transport
• neuronal cell death is induced by several mechanisms including pathological concentrations of intracellular calcium and free oxygen radicals. Therefore the positive control in -this experiment was nimodipine at the concentration of lO ⁇ M (RBI chemicals, Natick, MA, USA) (a potent L-type calcium channel blocker) .
• lO ⁇ M a potent L-type calcium channel blocker
• Lactate dehydrogenase activity in the medium was performed using a Sigma Diagnostics LD-L reagent.
• LDH activity was spectrophotometrically monitored at 340 nm by following the rate of conversion of oxidized nicotinamide adenine dinucleotide (NAD + ) to the reduced form of (NADH) .
• Total LDH of each culture (extracellular + intracellular) was obtained by measuring LDH in the medium after freezing and thawing of the cultures .
• Basal LDH release was measured in untreated cultures (no MPP+) .
• Each compound was tested in sixplicate.
• MPP+ is a neuro-toxin and its injection into the brain causes depletion of striatal dopamine .
• CMC Carboxymethyl cellulose
• ICV intracerebroventricular
• 3a/CMC or CMC alone were orally administered 30 minutes before and 2 hours after ICV injection.
• the injection was done according to Haley T.J and McCormick W.G (Brit.J. Pharmacol., 1957, 12, 12) using ether anesthesia.
• Saline or MPP+/saline were injected during 1 second using a syringe that delivered the liquid at a rate of 0.6 ml/min.
• Two ICV injections were carried out with a 24 hour interval between them. Mice were killed six days after the last injection and striata taken for dopamine and DOPAC determinations.
• Each striatum was weighed, homogenized in 0.1M Perchloric acid (0.6ml) containing 2mM sodium metabisulfite and 0.3mM EDTA. After centrifugation at 13000g for 7 minutes, the supernatant was taken for catecholamine determination. Aliquotes of 20 ⁇ l were injected into the solvent stream of an HPLC apparatus equipped with a Microsorb column (packing 3 ⁇ m, 4.6 mm diameter, 12.5 cm long).
• the mobile phase was composed of NaHP ⁇ 4 100 mM, octan-1- sulphonic acid 1.5 mM, disodium ethylenediaminetetracetic acid 250 ⁇ M, methanol 2.3%, acetonitrile 4% in grade deionized water, at a flow rate of 1.0 ml min "1 .
• Dopamine and DOPAC were detected with an ESA Coulochem model 5014 detector (Bedford, MA, USA) .
• Column eluates were initially oxidized by an ESA guard cell (model 5020) at +300 mV, then reduced at +60 mV at detector 1 and measured at detector 2 at -250 mV.
• Results are-presented in the table below as concentrations " of" dopamine or DOPAC in pmol per mg striatal tissue.
• MPP+ caused a depletion of about 30% in striatal concentrations of dopamine and DOPAC (Group C) and 3a reduced this depletion (Group D) .
• EAE is an accepted animal model of autoimmune disorder (Tisch et al. Proc . Natl . Acad. Sci . USA (1994) 91:437-438). EAE was induced by injecting the encephalitogenic agent consisting of MSCH and commercial CFA containing Mycobacterium tuberculosis H37Ra to the foot-pads of the animals and pertussis toxin intravenously;— . . . . . . .
• GA-DS in MSCH emulsion was injected in the four footpads.
• the other compounds were administered to the respective groups by oral gavage twice daily for 30 consecutive days starting from the day of induction until the termination of the study.
• the ' GA was weighed and diluted in sterilized phosphate buffered saline (PBS) and test compounds in 0.5% methyl- cellulose.
• PBS sterilized phosphate buffered saline

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