WO2013050527A1 - Dérivés de quinazoline en tant qu'inhibiteurs de l'enzyme pde10a - Google Patents

Dérivés de quinazoline en tant qu'inhibiteurs de l'enzyme pde10a Download PDF

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Publication number
WO2013050527A1
WO2013050527A1 PCT/EP2012/069718 EP2012069718W WO2013050527A1 WO 2013050527 A1 WO2013050527 A1 WO 2013050527A1 EP 2012069718 W EP2012069718 W EP 2012069718W WO 2013050527 A1 WO2013050527 A1 WO 2013050527A1
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methyl
quinazoline
imidazol
ethyl
thiazol
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PCT/EP2012/069718
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English (en)
Inventor
Jan Kehler
John Paul Kilburn
Jacob Nielsen
Ask Püschl
Morten LANGGÅRD
Mikkel JESSING
Mauro Marigo
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H. Lundbeck A/S
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Publication of WO2013050527A1 publication Critical patent/WO2013050527A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides heteroaromatic compounds that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatric disorders. Especially, the invention provides compounds that are highly selective for PDE10 over other PDE subtypes. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.
  • cyclic-adenosine monophosphate cyclic-adenosine monophosphate
  • cGMP cyclic- guanosine monophosphate
  • Intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases, and are degraded by cyclic nucleotide phosphodiesterases (PDEs) via hydrolysis of the cyclic nucleotides into their respective nucleotide monophosphates.
  • PDEs cyclic nucleotide phosphodiesterases
  • Phosphodieasterase 10A is a dual-specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071 -7076). PDE10A is primarily expressed in the neurons in the striatum, n. accumbens and in the olfactory tubercle (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551 -557 and Seeger, T.F. et al. Brain Research, 2003, 985, 1 13-126).
  • MSN medium spiny neurons
  • D 2 D 2 dopamine receptors
  • the Di class of neurons is part of the 'direct' striatal output pathway, which broadly functions to facilitate behavioral responses.
  • the D 2 class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the 'direct' pathway.
  • Dopamine D 2 receptor antagonism is well established in the treatment of schizophrenia. Since the 1950's, dopamine D 2 receptor antagonism has been the mainstay in psychosis treatment and all effective antipsychotic drugs antagonise D 2 receptors. The effects of D 2 are likely to be mediated primarily through neurons in the striatum, nucleus accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and have the strongest expression of D 2 receptors (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001 , 50, 729-742).
  • PDE10A in this context, has the desired expression profile with high and relatively specific expression in neurons in striatum, nucleus accumbens and olfactory tubercle, PDE10A inhibition is likely to have effects similar to D 2 receptor antagonism and therefore have antipsychotic effects.
  • PDE10A inhibition is expected to mimic D 2 receptor antagonism in part, it might be expected to have a different profile.
  • the D 2 receptor has signaling components besides cAMP (Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), wherefore interference with cAMP through PDE10A inhibition may reduce the risk of the extrapyramidal side effects that are seen with strong D 2 antagonism.
  • PDE10A inhibition may have some effects not seen with D 2 receptor antagonism.
  • PDE10A is also expressed in Di receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985, 1 13-126).
  • Di receptor agonism leads to stimulation of adenylate cyclase and resulting increase in cAMP levels
  • PDE10A inhibition is likely to also have effects that mimic Di receptor agonism.
  • PDE10A inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase.
  • cGMP activates a number of target protein in cells like cAMP and also interacts with the cAMP signaling pathways.
  • PDE10A inhibition is likely to mimic D 2 receptor antagonism in part and therefore has antipsychotic effect, but the profile might differ from that observed with classical D 2 receptor antagonists.
  • the PDE10A inhibitor papaverine is shown to be active in several antipsychotic models. Papaverine potentiated the cataleptic effect of the D 2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499). Papaverine reduced hyperactivity in rats induced by PCP, while reduction of amphetamine induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE10A inhibition has the classic antipsychotic potential that would be expected from the theoretical considerations outlined above. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of associated neurologic and psychiatric disorders.
  • PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats (Rodefer et al. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A inhibition might alleviate cognitive deficits associated with schizophrenia.
  • the tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10A enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, psychosis, obsessive compulsive disorder and addiction, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
  • Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 in WO 05/03129 and WO 05/02579.
  • Piperidinyl-substituted quinazolines and isoquinolines that serve as PDE10 inhibitors are disclosed in WO 05/82883.
  • WO 06/1 1040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10.
  • US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.
  • PDE phosphodiesterase
  • US 20060019975 discloses piperidine derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.
  • US 20060019975 also relates to compounds that are selective inhibitors of PDE10.
  • WO 06/028957 discloses cinnoline derivatives as inhibitors of PDE10 for the treatment of psychiatric and neurological syndromes.
  • WO09/152825 discloses phenylimidazole derivatives as compounds that serve as inhibitors of PDE10.
  • these disclosures do not pertain to the compounds of the invention, which are structurally unrelated to any of the known PDE10 inhibitors (Kehler, J. et al. Expert Opin. Ther. Patents 2007, 17, 147-158), and which have now been found by the inventors to be highly active and selective PDE10A enzyme inhibitors.
  • the present invention provides compounds that are PDE10A enzyme inhibitors and thus useful for treatment for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients. Hence, there remains a need for alternative methods of treatment. Summary of the Invention
  • the objective of the present invention is to provide compounds that are selective PDE10A enzyme inhibitors.
  • a further objective of the present invention is to provide compounds which have such activity, and which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.
  • Another objective of the invention is to provide an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurological and psychiatric disorders. Further objectives of the invention will become apparent upon reading the present specification.
  • Ri is selected from H, Ci-C6 alkyl; C1-C6 alkyl(C3-C8)cycloalkyl; Ci-C hydroxyalkyl, CH 2 CN, CH 2 C(O)NH 2 , Ci-C 6 arylalkyl, and Ci-C 6 alkyl heterocycloalkyl, wherein HET is either a 2-quinazolinyl group of formula Ila or a 4-quinazolinyl group of formula Mb:
  • R2 is selected from the group consisting of aryl, heteroaryl, hydrogen, C1-C6 alkyl; halogen; cyano; amine; halo(Ci-C6)alkyl; alkoxy; C1-C6 hydroxyalkyl; piperazinyl, and morpholinyl, wherein the substituents R3, R4, R5 and R6 are individually selected from hydrogen, C1-C6 alkyl; halogen; cyano, halo(Ci-C6)alkyl; alkoxy and C1-C6 hydroxyalkyl,
  • HET is a moiety of formula Ila
  • R2 is selected from the group consisting of aryl, heteroaryl, hydrogen, Ci-Ce alkyI; halogen; monoalkylannine and dialkylamine; cyano, halo(Ci -C6)alkyl; alkoxy; C1 -C6 hydroxyalkyl; piperazinyl, and morpholinyl.
  • R3, R4, R5 and R6 are individually selected from hydrogen, C1 -C6 alkyl; halogen; cyano, halo(Ci -C6)alkyl; aryl, alkoxy and C1 -C6 hydroxyalkyl.
  • HET is a moiety of formula Mb
  • R2 is selected from the group consisting of hydrogen, C1 -C6 alkyl; halogen; cyano, halo(Ci -C6)alkyl; and alkoxy
  • R3, R4, R5 and R6 are individually selected from hydrogen, Ci-Ce alkyI; halogen; cyano, halo(Ci -C6)alkyl; alkoxy and C1 -C6 hydroxyalkyl.
  • R2 is selected from the group consisting of hydrogen; C1 -4 alkyl, such as methyl, ethyl, propyl, and butyl; dimethylamine; methylamine; triflourethylamine; benzylmethylamine; triflourmethyl; thiophene; thiazole; phenyl; methoxy and ethoxy.
  • R2 is methyl
  • R2 is Ci - C 4 alkyl, in particular methyl or ethyl
  • R3, R4, R5 and R6 are individually selected from the group consisting of methoxy, methyl, fluorine and chlorine.
  • R1 is methyl or ethyl.
  • Q is selected from the group consisting of thiazole, thiophene, and phenyl, optionally the phenyl may be substituted with one, two, three, four or five substituents (R7, R8, R9, R10, R1 1 )
  • R7, R8, R9, R10 and R1 1 substituents
  • one or more of R7, R8, R9, R10 and R1 1 is a halogen, preferably fluorine.
  • the HET is selected from the group consisting of ⁇ 8-fluoroquinazolin-4-yl ⁇ -(2,2,2-trifluoro- ethyl)-amine, ⁇ 8-fluoroquinazolin-4-yl ⁇ -dimethyl-amine, ⁇ 8-fluoroquinazolin-4- yl ⁇ -methyl-amine, 4-(4-methyl-piperazin-1 -yl)-quinazoline, 4,8- dimethylquinazoline, 4-ethoxy-5,8-dimethylquinazoline, 4-methylquinazoline, 4-morpholin-4-yl-quinazoline, 4-phenyl-quinazoline, 4-thiazol-2-yl-quinazoline, 4-thiophen-2-yl-quinazoline, 5,7-difluoro-4-methylquinazoline, 5,8-dimethyl-4- methyl-quinazoline, 5-
  • the compound is selected from the group of compounds listed in Table 2.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a neurodegenerative or psychiatric disorder.
  • the present invention provides a method of treating a subject suffering from a neurodegenerative disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I.
  • the present invention provides a method of treating a subject suffering from a psychiatric disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I.
  • the present invention provides a method of treating a subject suffering from a drug addiction, such as an alcohol, amphetamine, cocaine, or opiate addiction.
  • a drug addiction such as an alcohol, amphetamine, cocaine, or opiate addiction.
  • halo and halogen are used interchangeably and refer to fluorine, chlorine, bromine or iodine.
  • C1-C6 alkyl refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 - butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, and n-hexyl.
  • C1-C6 hydroxyalkyl refers to a C1-C6 alkyl group as defined above which is substituted with one hydroxy group.
  • halo(Ci- C6)alkyl refers to a C1-C6 alkyl group as defined above which is substituted with up to three halogen atoms, such as trifluoromethyl.
  • C1-C6 alkoxy refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.
  • C3-C8 cycloalkyi typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C1-C6 alkyl(C3-C8)cycloalkyl refers to a C3-C8 cycloalkyi as defined above which is substituted with a straight-chain or branched C1-C6 alkyl. Examples of such groups include, but are not limited to, cyclopropylmethyl.
  • heterocycloalkyi refers to a four to eight membered ring containing carbon atoms and up to three N, O or S atoms, provided that the four to eight membered ring does not contain adjacent O or adjacent S atoms.
  • the open valency is on either the heteroatom or carbon atom. Examples of such groups include, but are not limited to, azetidinyl, oxetanyl, piperazinyl, morpholinyl, thiomorpholinyl and [1 ,4]diazepanyl.
  • hydroxyheterocycloalkyl refers to a heterocycloalkyi as defined above which is substituted with one hydroxy group.
  • C1-C6 alkyl-heterocycloalkyl refers to a heterocycloalkyi as defined above which is substituted with a C1-C6 alkyl group.
  • Examples of such groups include, but are not limited to, tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.
  • aryl refers to a phenyl ring, optionally substituted with halogen, Ci- C6 alkyl, C1-C6 alkoxy or halo(Ci-Ce)alkyl as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.
  • Ci-C6 alkyl C1-C6 alkoxy or halo(Ci-Ce)alkyl as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.
  • Ci-C 6 arylalkyl refers to an aryl as defined above which is substituted with a straight-chain or branched C1-C6 alkyl. Examples of such groups include, but are not limited to, benzyl and 4-chlorobenzyl.
  • present invention further provides certain embodiments of the invention as described below.
  • HET is a heteroaromatic group of formula II containing 2 nitrogen atoms. In another embodiment of the invention, HET is a heteroaromatic group of formula II containing 3 nitrogen atoms. In yet another embodiment of the invention, HET is a heteroaromatic group of formula II containing 4 nitrogen atoms. In a further embodiment one or more of the hydrogen atoms of the compound of formula I have been substituted by deuterium.
  • the compound of formula I is selected among the following specific compounds listed in Table 1 and Table2, in the form of the free base, one or more tautomers thereof or a pharmaceutically acceptable salt thereof.
  • Table 1 lists compounds of the invention where HET is a 2-quinazolinyl group of formula I la and the corresponding IC 5 0 values determined as described in the section "PDE10A inhibition assay”.
  • Table 2 lists compounds of the invention where HET is a 4- quinazolinyl group of formula Mb and the corresponding IC 5 0 values determined as described in the section "PDE10A inhibition assay". Each of the compounds constitutes an individual embodiment, of the present invention.
  • the compounds of the present invention have an IC 5 o value of less than 50 nM, such as in the range of 0.1 - 20 nM, particularly in the range of 0.1 - 10 nM, such as in the range of 0.1 - 5 nM or in the range of 0.1 - 1 nM.
  • Pharmaceutically Acceptable Salts such as in the range of 0.1 - 20 nM, particularly in the range of 0.1 - 10 nM, such as in the range of 0.1 - 5 nM or in the range of 0.1 - 1 nM.
  • the present invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-tol
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day.
  • Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day.
  • Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day.
  • Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typical doses are in the order of half the dose employed for oral administration.
  • the present invention also provides a process for making a pharmaceutical composition
  • a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier or diluent.
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section herein.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of formula I in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate
  • the pharmaceutical compositions formed by combining the compounds of formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • compositions of the invention may be prepared by conventional methods in the art.
  • tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • therapeutically effective amount in the present context, means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the invention.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the compounds of formula I are PDE10A enzyme inhibitors and as such are useful to treat associated neurological and psychiatric disorders.
  • the invention thus provides a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, as well as a pharmaceutical composition containing such a compound, for use in the treatment of a neurodegenerative disorder, psychiatric disorder or drug addiction in humans.
  • the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a human.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • the disorder is dyskinesia associated with dopamine agonist therapy.
  • the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
  • schizophrenia for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type
  • schizophreniform disorder for example of the delusional type or the depressive type
  • delusional disorder substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine
  • personality disorder of the paranoid type and personality
  • This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a human, which method comprises administering to said human an amount of a compound of formula I effective in treating addiction, such as drug addiction.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • drug addiction means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
  • NIDDM non-insuline demanding diabetes mellitus
  • ADHD Attention Deficit/Hyperactivity Disorder
  • the compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs (including typical and atypical antpsychotic agent) in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention.
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to other known treatments.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention.
  • the combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
  • neuroleptic agent refers to drugs, which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.
  • neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), sertindole, olan
  • neuroleptic agents for use in the invention are sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • a "neurodegenerative disorder or condition” refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).
  • This reaction is typically carried out in a suitable solvent, such as tetrahydrofuran and performed by mixing the quinazolinyl halide with the heteroaryl alkyne III together with a suitable catalyst e.g. Copper(l) iodide with a phosphine ligand e.g. 1 ,1 '-bis(diphenylphosphino)ferrocene- palladium(ii)dichloride dichloromethane complex and and organic base like triethylamine and then heating the reaction in a sealed vial at 120-130 °C for 15 minutes (MicroWave).
  • a suitable solvent such as tetrahydrofuran
  • Chloroquinazolines of fornnula IVa or IVb are either commercially available or can be prepared by methods as described in the literature, e.g. Sasse, K.; Synthesis, 1978, 379-82, Kanuma, K et. Al. Bioorganic & Medicinal Chemistry Letters 2005, 15:2565-2569, Arienzo, R et. Al. Bioorganic & Medicinal Chemistry Letters 2007, 17:1403-1407, Saari, R et al. Bioorganic & Medicinal Chemistry Letters 2011 , 21 : 939-950, WO 2005123714, WO 20071 17607. Journal of Medicinal Chemistry 2009, 52: 2341 -2351 , WO 2008124826, Beck, H. P. Bioorganic & Medicinal Chemistry Letters 2008, 18:1037-1041 , Abe, Y. et al. Journal of Medicinal Chemistry 1998, 41 : 4062-4079.
  • 2-ethynyl imidazole of formula III can be prepared by methods described in the literature e.g. Li, J. Bioorganic & Medicinal Chemistry Letters 2009, 19:6293-6297, WO 2007023242, Laroche, C. et al. Tetrahedron Letters 2009, 50: 5194-5197,
  • This reaction is typically carried out in a suitable solvent, such as dimethylformaide and performed by mixing the alkyne of formula V together with a hydrogen source like e.g. tosylhydrazide and an organic base like e.g. triethylamine and then heating the reaction.
  • a hydrogen source like e.g. tosylhydrazide and an organic base like e.g. triethylamine and then heating the reaction.
  • the reduction can be carried out by hydrogenation using a transition metal catalyst, such as palladium metal, together with a hydrogen source, such as hydrogen gas, ammonium hydrogen carbonate, or cyclohexadiene.
  • the alkynes of formula V can be prepared as described in scheme 1.
  • This reaction is typically carried out in a suitable solvent, such as methanol and performed by mixing a solution of 2-acyl-phenyl-3-(1 H-imidazol-2-yl)- acrylamides of formula VI in 7M NH3/MeOH solution and heating at 50°C for 6-24h.
  • a suitable solvent such as methanol
  • the 2-acyl-phenyl-3-(1 H-imidazol-2-yl)-acrylamides of formula VI can be prepared from commercially available substituted anthranilic acids VII by standard organic synthesis methods known in the art as shown in scheme 4.
  • This reaction is typically carried out by conversion of the 3H-quinazolin-4-one of formula XI by using phosphoryl chloride as a suitable solvent and heating in a sealed vial for at 140°C for 45 minutes, followed by standard workup of the intermediate 4-chloro-quinazoline, which is dissolved without further purification in a suitable solvent such as tetrahydrofuran and a alkyl magnesium chloride or aryl magnesium chloride is added at room temperature together with a palladium (II) salt and the mixture stirred for 24 hours before standard workup.
  • the 3H-quinazolin-4-one of formula XI is can be prepared from commercially available substituted anthranilic acids XII by standard organic synthesis methods known in the art as shown in scheme 6.
  • LC-MS were run on a Sciex API150EX equipped with APPI-source operating in positive ion mode.
  • the HPLC consisted of Shimadzu LC10-ADvp LC pumps. SPD-M20A PDA detector (operating at 254 nM) and SCL-10A system controller. Autosampler was Gilson 215. Colomn oven was a Jones Chromatography 7990R and ELS detector was a Sedere Sedex 85.
  • LC-conditions The column was a Waters Symmetry C-18. 4.6 x 30 mm. 3.5 ⁇ operating at 60 °C with 2.5 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and methanol + 0.05 % TFA.
  • LC-MS were run on a Sciex API300 equipped with APPI source operating in positive ion mode.
  • the UPLC consisted of Waters Aquity including column mager. binary solvent manager, sample organizer. PDA detector (operating at 254 nM) and ELS detector.
  • LC-conditions The column was a Waters Aquity UPLC BEH C-18. 2.1 x 50 mm. 1 .7 ⁇ operating at 60 °C with 1 .2 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and 95 % acetonitrile containing 5 % water + 0.03 % TFA.
  • LC-MS were run on an Agilent 1 100 LCMS system with ELS Detector, Pump G131 1A, Degasser G1379A,Well-plate Autosampler, G1367A, Column Oven G1316A, DAD G1315B,MSD G1946C or G1956A,Alltech ELSD 800,Column YMC ODS-AQ,Particle size 5 micrometer, Pore size 12 nm, Dimension 50 * 2.0 mm ID, Injection volume 2 microliter, Column temperature 50°C, Flow 0.8 ml/min.
  • Aldehydes of the formula XV are prepared as described in the patent literature e.g. WO-201 1072694 A1 , US-20100016303 and WO- 2009152825 A1 . 8-Fluoro-2-[2-(1-methyl-4-thiazol-2-yl-1 H-imidazol-2-yl)-ethyl]-3H- quinazolin-4-one
  • Ammonium formate (8.17 g, 1 .30E2 mmol) was added. The mixture was flushed with nitrogen and 10% Palladium on Charcoal (10:90, Palladium:carbon black, 0.550 g) was added. After that the mixture was refluxed for 5 hours. The mixture was cooled, filtered and rotovaped. The residue was stirred with 150 ml hot tetrahydrofuran for 10 minutes. 200 ml ethylacetate was added. The mixture was dried with magnesiumsulfate, filtered and rotovaped. The residue was dissolved in 125 ml hot tetrahydrofuran and 10 ml methanol.The mixture was filtered to remove a minor amount of white solid.
  • N-methyl imidazole (65.6 g, 0.8 mol) in CHCl3 (1 .5 L), N-bromosuccinimide (NBS; 476 g,2.4 mol) was added in portion and then the mixture was stirred at room temperature for 1 .5 hour, filtered and concentrated, the residue was purified by column chromatography over silica gel (eluent: EA/PE 1/10) to afford 2,4,5-Tribromo-1 -methyl-1 H-imidazole (63.76 g, 0.2 mol), which was dissolved in in dry THF (2L) and EtMgBr (220 ml_, 0.22 mol) was added slowly under N 2 atmosphere at ambient temperature during 3 hour and stirred for another 2 hour.
  • N-bromosuccinimide (NBS; 476 g,2.4 mol) was added in portion and then the mixture was stirred at room temperature for 1 .5 hour, filtered and concentrated, the residue was purified by column chromatography over silica gel (elu
  • Example 1 General procedure for preparing 4-methyl-2-(1 -methyl-4-thiazol-2-yl-1 H- imidazol-2-ylethynyl)-quinazolines (take 7-Methoxy-4-methyl-2-(1 -methyl- 4-thiazol-2-yl-1 H-imidazol-2- lethynyl)-quinazoline as example):
  • 6-Fluoro-4,8-dimethyl-2-[(E)-2-(1 -methyl-4-thiazol-2-yl-1 H-imidazol-2-yl)-vinyl]- quinazoline (94 mg, 0.20 mmol) was dissolved in N,N-Dimethylformamide (5 ml_, 60 mmol) and p-Toluenesulfonylhydrazide (1 10 mg, 0.62 mmol) was added and the reaction was stirred at 130 °C for 2 hours. The reaction mixture was poured into sat.
  • Active PDE10A enzyme is prepared in a number of ways for use in PDE assays (Loughney, K. et al. Gene 1999, 234, 109-1 17; Fujishige, K. et al. Eur J Biochem. 1999, 266, 1 1 18-1 127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071 -7076).
  • PDE10A can be expressed as full-length proteins or as truncated proteins, as long as they express the catalytic domain.
  • PDE10A can be prepared in different cell types, for example insect cells or E. coli.
  • catalytically active PDE10A is as follows: The catalytic domain of human PDE10A (amino acids 440-779 from the sequence with accession number NP 006652) is amplified from total human brain total RNA by standard RT-PCR and is cloned into the BamH1 and Xho1 sites of the pET28a vector (Novagen). Expression in coli is performed according to standard protocols. Briefly, the expression plasmids are transformed into the BL21 (DE3) E. coli strain, and 50 mL cultures inoculated with the cells allowed to grow to an OD600 of 0.4-0.6 before protein expression is induced with 0.5mM IPTG.
  • a PDE1 OA assay may for example, be performed as follows: The assay is performed in 60 uL samples containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI 2 ; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of 3 H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors.
  • Reactions are initiated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature before being terminated through mixing with 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC 5 o values can be calculated using the Xlfit extension to EXCEL.
  • mice Male mice (NMRI, Charles River) weighing 20-25g are used. Eight mice are used in each group receiving the test compound (5 mg/kg) plus PCP (2.3 mg/kg) including the parallel control groups receiving the vehicle of the test compound plus PCP or vehicle injections only. The injection volumen is 10 ml/kg. The experiment is made in normal light conditions in an undisturbed room. The test substance is injected per oss 60 min before injection of PCP, which is administered subcutaneous. Immediately after injection of PCP the mice are placed individually in special designed test cage (20 cm x 32 cm). The activity is measured by 5X8 infrared light sources and photocells spaced by 4 cm. The light beams cross the cage 1 .8 cm above the bottom of the cage. Recording of a motility count requires interruption of adjacent light beams, thus avoiding counts induced by stationary movements of the mice.
  • Motility is recorded in 5 min intervals for a period of 1 hour.
  • the drug effect is calculated on the total counts during the 1 hour behavioral test period in the following manner:
  • the mean motility induced by vehicle treatment in the absence of PCP is used as baseline.
  • the 100 per cent effect of PCP is accordingly calculated to be total motility counts minus baseline.
  • the response in groups receiving test compound is thus determined by the total motility counts minus baseline, expressed in per cent of the similar result recorded in the parallel PCP control group.
  • the per cent responses are converted to per cent inhibition.

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Abstract

L'invention concerne des composés qui sont des inhibiteurs de l'enzyme PDE10A. L'invention concerne une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé selon l'invention et un véhicule pharmaceutiquement acceptable. La présente invention concerne également des procédés de préparation des composés de formule I. La présente invention concerne également un procédé de traitement d'un sujet souffrant d'un trouble neurodégénératif comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule I. La présente invention concerne également un procédé de traitement d'un sujet souffrant d'une accoutumance à un médicament comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule I. La présente invention concerne également un procédé de traitement d'un sujet souffrant d'un trouble psychiatrique comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé de formule I.
PCT/EP2012/069718 2011-10-05 2012-10-05 Dérivés de quinazoline en tant qu'inhibiteurs de l'enzyme pde10a WO2013050527A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN104628646A (zh) * 2015-02-16 2015-05-20 中国科学院上海有机化学研究所 N-吡唑基甲酰苯胺类化合物、中间体、组合物、制备方法及应用
CN105712969A (zh) * 2016-01-27 2016-06-29 杭州科巢生物科技有限公司 维帕他韦中间体的合成方法
CN109384683A (zh) * 2018-11-12 2019-02-26 杭州科耀医药科技有限公司 一种2-氨基-5-氟苯乙酮的制备方法
WO2023007185A1 (fr) * 2021-07-30 2023-02-02 Benevolentai Cambridge Limited Composés organiques imidazoles et leur utilisation contre la maladie intestinale inflammatoire
CN117550981A (zh) * 2024-01-12 2024-02-13 成都工业学院 一种2-氨基-5-氟苯乙酮的制备方法

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CN104628646A (zh) * 2015-02-16 2015-05-20 中国科学院上海有机化学研究所 N-吡唑基甲酰苯胺类化合物、中间体、组合物、制备方法及应用
CN105712969A (zh) * 2016-01-27 2016-06-29 杭州科巢生物科技有限公司 维帕他韦中间体的合成方法
CN109384683A (zh) * 2018-11-12 2019-02-26 杭州科耀医药科技有限公司 一种2-氨基-5-氟苯乙酮的制备方法
CN109384683B (zh) * 2018-11-12 2021-09-03 杭州科耀医药科技有限公司 一种2-氨基-5-氟苯乙酮的制备方法
WO2023007185A1 (fr) * 2021-07-30 2023-02-02 Benevolentai Cambridge Limited Composés organiques imidazoles et leur utilisation contre la maladie intestinale inflammatoire
CN117550981A (zh) * 2024-01-12 2024-02-13 成都工业学院 一种2-氨基-5-氟苯乙酮的制备方法
CN117550981B (zh) * 2024-01-12 2024-03-15 成都工业学院 一种2-氨基-5-氟苯乙酮的制备方法

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