Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms

Definitions

• the present invention relates to novel derivatives of a series of substituted pyrimidines, to pharmaceutical compositions which contain them, to methods for their preparation and to their use in therapy, particularly in the treatment of neurodegenerative or other neurological disorders of the central and peripheral systems including nerve injuries.
• Dementing disorders such as age-related cognitive disorders, e.g., senility or Alzheimer's disease are medical conditions for which there are currently only limited therapies.
• age-related cognitive disorders e.g., senility or Alzheimer's disease are medical conditions for which there are currently only limited therapies.
• studies suggest that multiple neurotransmitter systems are involved in senile dementia, a loss of cholinergic neurons and a severe depletion of choline acetyltransferase appear to show the earliest and strongest correlations with functional cognitive impairment [see P.T. Francis et al., Neurochemical Studies of Early-onset Alzheimer's Disease. N. Engl. J. Med., 313, 7 (1985); R.T. Bartus et al., The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions. Ann. N. Y. Acad.
• Nerve growth factor is the best characterized neurotrophic factor that is capable of inducing cell differentiation of neural cells and promoting neurite sprouting.
• the neurotrophic protein NGF primarily affects cholinergic neurons in the central nervous system and may be necessary for their survival [see F. Hefti and P.A. Lapchak, Pharmacology of Nerve Growth Factor in the Brain. Adv. Pharmacol., 24, 239 (1993)].
• NGF is not systemically bioavailable, but if it is injected or infused directly into brain, it prevents neuronal cell loss and restores cognitive function in aged or lesioned rats or monkeys [see W. Fischer et al., NGF Improves Spatial Memory in Aged Rodents as a Function of Age. J.
• NGF neurotrophic or "nerve growth factor-like”
• AIT-082 (4[[3-(1 ,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid) is reported to enhance NGF action in cultured PC-12 cells and to restore age- induced working memory deficits in mice [see P.J.. Middlemiss et al., AIT- 082, A Unique Purine Derivative, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC-12 cells. Neuroscience Let., 199, 131 (1995)].
• the compound SR57746A is reported to have nerve growth factor potentiating activity and is in clinical trials [see Fournier J, et al.
• R T is NHR4, wherein R4 is C6-10 aryl, C2-10alkyl, (C1-6alkyl)j(C3- 9cycloalkyl)(CH2)q or (C1 -6alkyl)j(C6-10aryl)(CH2)q, wherein j is 0-2 and q is 0-6, or (C1-6alkyl)j(C4-
• heterocycloalkyl (CH2)q wherein j is 0-2, q is 0-6 and the heterocyclic ring contains one or more heteroatoms which may be the same or different and are O, S, N or NR' (wherein R' is hydrogen, C1-6 alkyl, hydroxyC2-6 alkyl, mercaptoC2- ⁇ alkyl, C1 -6alkyloxyC2-6alkyl, C1 -6alkylthioC2-6alkyl, C6-
• Ri is piperazino or homopiperazino wherein the 4-N is substituted with a carbonylR ⁇ or sulfonylR ⁇ , wherein R5 is
• q is 0-6 and the heterocyclic ring contains one or more heteroatoms which may be the same or different and are O,
• R' is hydrogen, C1 -6alkyl, hydroxyC2-
• C1-7alkylsulfonyl or C6-10arylsulfonyl and wherein C atoms of R4 and R5 may optionally be substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, thiol, oxo, thioxo, carboxy, carboxamide,
• R 2 is H or NH2;
• R 3 is H;
• X is a C6-10 aryl ring optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl,
• esters or pharmaceutically acceptable esters, amides, esters, amides, salts or solvates thereof.
• the present invention includes all enantiomeric and diastereomeric forms of the compounds of Formula I either individually or admixed in any proportion.
• the present invention further includes prodrugs and active metabolites of the compounds of Formula I.
• a prodrug includes any compound which, when administered to a mammal, is converted in whole or in part to a compound of Formula I.
• An active metabolite is a physiologically active compound which results from the metabolism of a compound of Formula I, or a prodrug thereof, when such compound or prodrug is administered to a mammal.
• the compounds of Formula I above and their pharmaceutically acceptable esters, amides, salts or solvates are sometimes hereinafter referred to as "the compounds according to the invention".
• alkyl is meant straight or branched chain alkyl.
• the alkyl groups may be optionally substituted with hydroxy, amino or halogen.
• aryl is meant an aromatic ring such as phenyl or naphthyl.
• the aryl groups may be optionally substituted with hydroxy, amino or halogen.
• heteroaryl is meant a ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S.
• halogen is meant F, Cl, Br or I.
• Preferred compounds of Formula I are those wherein X is substituted phenyl; and pharmaceutically acceptable esters, amides, salts or solvates thereof.
• Ri is C1- 10alkylcarbonylpiperizino, hydroxyC3-9cycloalkylamino, or hydroxyC6- 10arylamino
• X is substituted phenyl, and pharmaceutically acceptable esters, amides, salts or solvates thereof.
• R-i is 4- acetylpiperazino, 4-oxocyclohexylamino, trans-4-hydroxycyclohexylamino, 4-hydroxyanilino, or 4-(2-hydroxyethylamino);
• X is phenyl optionally substituted with 4-chloro, 2,4 dichloro, 4- bromo, 2-fluoro-4-chloro, 2- chloro-4-fluoro, 2-methyl-4-chloro, 4-methyl, or 4-ethyl; and R 2 is NH2; and pharmaceutically acceptable esters, amides, salts or solvates thereof.
• Specifically preferred compounds of Formula I are:
• esters, amides, salts or solvates thereof are included in the composition.
• amides, salts or solvates thereof are included in the composition.
• the compounds according to the invention for use in medical therapy, particularly for the treatment of neurodegenerative or neurological disorders of the central or peripheral nervous systems.
• nervous system disorders which may be treated in accordance with the invention include dementing disorders such as age- related senility, senile dementia or Age Related Mental Impairment (ARMI), cerebral ataxia, Parkinson's disease, Alzheimer's disease, peripheral neuropathy, cognitive disorders secondary to stroke or trauma and attention-deficit hyperactivity disorder.
• ARMI Age Related Mental Impairment
• cerebral ataxia Parkinson's disease
• Alzheimer's disease peripheral neuropathy
• cognitive disorders secondary to stroke or trauma attention-deficit hyperactivity disorder
• nerve injuries for example, spinal cord injuries, that require neuroregeneration may also be treated in accordance with the invention.
• spinal cord injuries that require neuroregeneration may also be treated in accordance with the invention.
• a method for the treatment of neurodegenerative or neurological disorders of the central or peripheral nervous systems which comprises treating the subject e.g., a mammal, such as a human, with a therapeutically effective amount of a compound according to the invention.
• Examples of pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts.
• salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compounds of the invention.
• Preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethansulfonic, p-toluenesulfonic, benzenesulfonic and isethionic acids.
• the compounds according to the invention and pharmaceutically acceptable esters, amides, salts or solvates thereof may be employed in combination with other therapeutic agents for the treatment of the above disorders.
• further therapeutic agents include Cognex, Ahcept and other agents (e.g., acetylcholine esterase inhibitors, muscarinic or nicotinic receptor agonists, MAO inhibitors) that are effective for the treatment of neurodegenerative or neurological disorders of the central or peripheral nervous systems.
• the component compounds of such combination therapy may be administered simultaneously in either separate or combined formulations, or at different times, e.g., sequentially such that a combined effect is achieved. While it is possible for compounds according to the invention to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation.
• the formulations of the present invention comprise a compound of Formula I, as above defined, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic ingredients.
• the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the formulations include those suitable for oral, parenteral (including subcutaneous, transdermal, intradermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well know in the art of pharmacy. All methods include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable salt thereof (active ingredient) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non- aqueous liquid; or as an oil-in-water liquid emulsion, or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, 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 may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
• Formulations for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophillised) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1 % to 35%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis, as generally described in Pharmaceutical. Res., 3(6), 318 (1986). Formulations for rectal administration may be presented as suppository with the usual carriers such as cocoa butter or polyethylene glycol.
• Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
• Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
• formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• Tablets or other forms of presentation in discrete units may conveniently contain an amount of compound of the Formula I which is effective for each of the above-mentioned indications at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually between 10 mg to 250 mg.
• the compounds of the Formula I are preferably administered orally or by injection (intraparenteral or subcutaneous).
• the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
• the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration is likely to vary depending on the condition and its severity.
• the compounds of the Formula I may be administered orally.
• the dose range for adult humans is generally from about 10 to 4000 mg/day and preferably from about 100 to 1000 mg/day. It may be advantageous to administer an initial dose of 200 to 2000 mg the first day then a lower dose of 100 to 1000 mg on subsequent days.
• the compounds according to the invention may be administered by injection at a dose of from about 1 to 2000 mg/day, and preferably from about 5 to 1000 mg/day.
• the present invention further includes processes for the preparation of compounds of Formula I and esters, amides, salts or solvates thereof.
• the compounds of Formula (I) and their esters, amides, salts and solvates may be prepared in accordance with the present invention by those methods hereinafter described, or in any manner known in the art for the preparation of compounds of analogous structure.
• the compounds, esters, amides, salts and solvates of Formula (I) may be prepared by a process which comprises:
• R 2 , R 3 and X are as hereinbefore defined and U is a leaving group, with an amine NH2R4 wherein R4 is as hereinbefore defined, or with a monosubstituted piperazine.
• Suitable leaving groups include halogens such as chloride.
• the reaction is carried out in an organic solvent (e.g., ethanol, propanol) at a temperature of approximately 20 C to approximately
• the compound of Formula (II) may be isolated and purified prior to reaction with the amine or may be used in situ.
• Formula III wherein R 2 , R 3 and X are as hereinbefore defined, by reaction with a halogenating agent (e.g., phosphorous oxychloride, phosphorous pentachloride, or a Vilsmeier reagent created using oxalyl chloride and N,N-diisopropylformamide) in a suitable organic solvent (e.g., dichloromethane, 1 ,2-dichloroethane, toluene, N,N-dimethlyformamide) at a temperature of approximately 40 C to approximately 100 C.
• a halogenating agent e.g., phosphorous oxychloride, phosphorous pentachloride, or a Vilsmeier reagent created using oxalyl chloride and N,N-diisopropylformamide
• a suitable organic solvent e.g., dichloromethane, 1 ,2-dichloroethane, toluene, N
• R 2 and R 3 are as hereinbefore defined and W is a halogen atom such as bromo or chloro, by reaction with a suitable benzenethiol (e.g., 4- chlorobenzenethiol, 4-ethylbenzenethiol, 2,4-dichlorobenzenethiol) and a suitable base (e.g., potassium carbonate) in a suitable organic solvent (e.g., N,N-dimethylformamide, ethylene glycol, dimethylsulfoxide) at a temperature of 80°C to 140 °C.
• a suitable benzenethiol e.g., 4- chlorobenzenethiol, 4-ethylbenzenethiol, 2,4-dichlorobenzenethiol
• a suitable base e.g., potassium carbonate
• a suitable organic solvent e.g., N,N-dimethylformamide, ethylene glycol, dimethylsulfoxide
• Compounds of Formula (IV) can be prepared by various methods known in the art or are available from commercial sources.
• Formula V wherein R 3 and X are as hereinbefore defined by reaction of an alkaline earth salt of Formula (V) with formamidine or guanidine in a suitable organic solvent (e.g., ethanol, methanol, 2-propanol, tert-butanol, tetrahydrofuran) at a temperature of approximately 60 C to the reflux temperature.
• a suitable organic solvent e.g., ethanol, methanol, 2-propanol, tert-butanol, tetrahydrofuran
• Formula VI wherein X is as hereinbefore defined by reaction with an ester (e.g., ethyl formate) and a strong base (e.g., sodium hydride, potassium hydride, potassium tert-butoxide, sodium metal, lithium diisopropylamide) in a suitable organic solvent (e.g., tetrahydrofuran, ether, toluene) at a temperature of approximately 0 C to approximately 40 C.
• ester e.g., ethyl formate
• a strong base e.g., sodium hydride, potassium hydride, potassium tert-butoxide, sodium metal, lithium diisopropylamide
• a suitable organic solvent e.g., tetrahydrofuran, ether, toluene
• esters and amides of compounds of Formula I can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4- dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol, pyridine,
• a carbonylating agent e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride
• a suitable base e.g., 4- dimethylaminopyridine
• N,N-dimethylformamide at a temperature of 0°C to 60° C.
• Salts of the compounds of Formula I can be made from the free base form by reaction with the appropriate acid.
• N,N-diisopropylformamide (31.0 g, 0.24 mole) and methylene chloride (550 mL) were combined in a 2 L 3-neck round bottom flask equipped with an air stirrer, dropping funnel, and reflux condenser.
• the apparatus was flushed with argon, and oxalyl chloride (33.4 g, 0.26 mole) was placed in the dropping funnel.
• the oxalyl chloride was added portionwise over approximately 1.5 hours to the rapidly stirred solution. Stirring was continued for about 15 minutes after completion of the addition and then 5- (4-chlorophenylthio)isocytosine (21.6g, 0.085 mole)was added through a powder funnel.
• the pH was adjusted to 7 with 3N NaOH. A large precipitate formed in the organic phase.
• the aqueous phase was removed and the solids in the organic phase were collected by filtration and washed with dichloromethane.
• the crude product (1.35g) was suspended in 80 ml of ethanol, then heated to boiling, and filtered while hot. As the filtrate cooled, a cotton-like precipitate formed.
• the solids were collected by filtration, washed with ethanol, and dried in vacuo at 110 C for 15 hours. 1.05g (42% yield) of a white solid was obtained, mp. 200 C.
• the organic phase was washed twice with 450 ml of water then with 200 ml of brine and dried over Na 2 S0 4 . After filtration, the dried organic phase was applied to a Silica Gel (230-400 mesh) column (4 x 6 cm). The product was eluted with ethyl acetate and spin evaporated at 60 C in vacuo. The resulting material was redissolved in 5 ml of hot ethyl acetate. Upon the addition of hexanes, a solid formed. The solvents were removed by decanting and the solids were suspended in 40 ml of diethyl ether and boiled with stirring. The solids were collected by filtration, washed with hexanes, and dried in vacuo at 105° C. 300 mg (10% yield) of white powder was obtained, mp 140-141 C.
• Example A Tablet Composition m ⁇ /tablet
• composition is prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
• a capsule composition is prepared by admixing the ingredients and filling into a two-part hard gelatin capsule. m ⁇ /capsule
• Example C Injectable Composition
• the active ingredient is dissolved in most of the water (35 - 40 C) and the pH is adjusted to between 4.0 and 7.0.
• the batch is then made up to volume with sterile water and filtered through a sterile micropore filter into a sterile amber glass vial (type 1) and sealed with sterile closures and overseals.
• the compounds of the invention were assayed for neurotrophic activity as follows:
• PC12 cells rat adrenal pheochromocytoma from ATCC have receptors for NGF. Responses include promotion of neurite outgrowth and elevation of choline acetyltransferase(ChAT) (L.A. Greene and A.S. Tischler, Cell Neurobiol., 3, 373 (1982)).
• ChAT choline acetyltransferase
• PC12 cells were cultured at 37° C in RPMI supplemented with HEPES buffer, pH7.5 (to 10 mM), fetal bovine serum, horse serum, glutamine, penicillin, streptomycin and non- essential amino acids. Cultures were split 1 :3 every 3 to 4 days. Exponentially dividing cells were plated into fresh medium on collagen-
• the medium was replaced with low serum medium, with or without test compounds with each condition in triplicate.
• the medium may contain up to 0.2 % ethanol, which was used as a solvent for most compounds tested.
• Cells were examined for morphological changes using an Olympus IMT-2 inverted research microscope. After 3 days incubation with test compounds, medium was removed and replaced with 0.2 ml of lysis and
• ChAT assay mixture The plates were incubated at 37° C for 2 hours and then placed into a freezer at -20 C.
• Compounds are judged NGF-like in this primary screen if they (1) increase the activity of ChAT, (2) enhance NGF-stimulated neurite outgrowth or (3) potentiate or appear additive with the action of NGF itself.
• the assay mixture contained 100 mM phosphate, pH7.4, 0.1% NP-40, 150 mM NaCI, 1.5 mM choline, 10 mM EDTA, 0.1 mM eserine, 0.1 mM acetyl- coenzyme A and about 0.5 uCi (40-70 Ci/mol) [14C]acetyl-coenzyme A in each ml of mixture.

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