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WO2012150369A1 - Dérivés hétérocycliques inhibiteurs de phosphodiestérase 7 - Google Patents

Dérivés hétérocycliques inhibiteurs de phosphodiestérase 7 Download PDF

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Publication number
WO2012150369A1
WO2012150369A1 PCT/ES2012/070293 ES2012070293W WO2012150369A1 WO 2012150369 A1 WO2012150369 A1 WO 2012150369A1 ES 2012070293 W ES2012070293 W ES 2012070293W WO 2012150369 A1 WO2012150369 A1 WO 2012150369A1
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Prior art keywords
group
trimethoxybenzyl
furoate
substituted
unsubstituted
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Ceased
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English (en)
Spanish (es)
Inventor
Carmen GIL AYUSO-GONTÁN
Ana Martinez Gil
Miriam Redondo Sancho
Nuria Campillo Martin
Daniel Perez Fernandez
María Isabel LOZA GARCIA
María Isabel CADAVID TORRES
José BREA FLORIANI
Ana Perez Castillo
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Universidade de Santiago de Compostela
Consejo Superior de Investigaciones Cientificas CSIC
Universidad Autonoma de Madrid
Original Assignee
Universidade de Santiago de Compostela
Consejo Superior de Investigaciones Cientificas CSIC
Universidad Autonoma de Madrid
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Publication of WO2012150369A1 publication Critical patent/WO2012150369A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C07D307/44—Furfuryl alcohol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to heterocyclic derivatives and their potential for the treatment of neurodegenerative and / or neurological diseases, as well as diseases with a systemic and / or central inflammatory component. Therefore, the invention is framed in the pharmaceutical sector.
  • PDEs phosphodiesterases
  • CAMP and cGMP are generated by the action of adenylate cyclase and guanylate cyclase respectively, acting as second messengers in transduction of intracellular signals.
  • PDEs phosphodiesterases
  • PDE Cyclic nucleotide phosphodiesterase
  • PDEs inhibitors could also be considered as promising drugs for the treatment of psychiatric and neurodegenerative diseases [Brandon, NJ; Rotella, D. P. Potential CNS applications for PDEs inhibitors. Ann. Rep. Med. Chem. 2007, 42, 3-12].
  • cilostazol a selective PDE3 inhibitor
  • Sildenafil a PDE5 inhibitor
  • selective PDE10A inhibitors are potent antipsychotic agents capable of improving the cognitive symptoms of schizophrenia and PDE4 inhibitors represent a good approximation for the treatment of memory disorders.
  • PDE7 is an enzyme specific for cAMP, insensitive to Rolipram (PDE4 inhibitor), which is expressed in different areas of the brain, in addition to lymphocytes [Li, L; Yee, C; Beavo, JA CD3-and CD28-dependent induction of PDE7 required for T cell activation. Science 1999, 283, 848-851; Nakata, A .; Ogawa, K .; Sasaki, T .; Koyama, N .; Wada, K .; Kotera, J .; Kikkawa, H .; Omori, K .; Kaminuma, O.
  • the selective PDE7 inhibitor does not decrease the proliferation of T cells per se, however, it does synergistically increase the effect of the Rolipram PDE4 inhibitor on the elevation of the levels of CAMP.
  • the efficacy of PDE7 inhibitors has recently been demonstrated in Parkinson's animal models [Morales-Garc ⁇ a, J .; Round, M .; Gil, C; Alonso-Gil, S .; Mart ⁇ nez, A .; Santos, A .; Perez-Castillo, A. "Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson's disease ". PLoS ONE.
  • the present invention provides, on the one hand, a new series of compounds belonging to a broad family of heterocyclic derivatives with activity in PDE7 and on the other the use of this broad family of heterocyclic derivatives for the treatment of diseases where PDE7 inhibition is therapeutic. .
  • PDE7 inhibition is therapeutic.
  • heterocyclic compounds are described, as well as their method of obtaining them, being able to have a great application as drugs or drug candidates. Therefore, a first aspect of the present invention relates to a compound of formula (I) or a tautomer, salt, solvate or prodrug thereof.
  • Q is selected from -O-, -S-, or -NR 9 , where Rg is selected from hydrogen or a substituted or unsubstituted C1-C3 alkyl group,
  • n and m are the same or different and independently select from an integer selected from 1, 2, 3, 4 and 5 with the proviso that the following compounds:
  • each Ri is the same or different and is independently selected from hydrogen or a -OR3 group wherein R3 is selected from hydrogen or a substituted or unsubstituted C1-C4 alkyl group.
  • n is 3.
  • each R2 is the same or different and is independently selected from hydrogen, a nitro group, a substituted or unsubstituted C1-C2 alkyl group, a C1-C4 haloalkyl , chlorine, fluorine, bromine or a group - OR3 in where R3 is selected from hydrogen or a substituted or unsubstituted C1-C4 alkyl group.
  • m is an integer selected from 1 to 2.
  • Another preferred embodiment comprises the compound of general formula (I), which is selected from the following list: -3, 5- (4-Nitrophenyl) -2-furylmethyl 4,5-triethoxybenzoate (MR 1 .44)
  • the compound of general formula (I) is selected from the following list -3,4,5-5- (4-nitrophenyl) -2-furylmethyl triethoxybenzoate (MR 1 .44)
  • the compound of the general formula (I) is selected from the following list -3,4,5-5-phenyl-2-furylmethyl triethoxybenzoate (MR 1 .62):
  • a second aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I) or a tautomer, salt, solvate or prodrug thereof.
  • Q is selected from -O-, -S-, or -NR 9 , where Rg is selected from hydrogen or a substituted or unsubstituted C1-C3 alkyl group,
  • n and m are the same or different and independently select from an integer selected from 1, 2, 3, 4 and 5 and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle.
  • each R1 is the same or different and is independently selected from hydrogen or a -OR3 group wherein R3 is selected from hydrogen or a substituted or unsubstituted C1-C4 alkyl group.
  • each R2 is the same or different and is independently selected from hydrogen, a nitro group, a substituted or unsubstituted C1-C2 alkyl group, a C1-C4 haloalkyl group , chlorine, fluorine, bromine or a -OR3 group wherein R 3 is selected from hydrogen, or a substituted or unsubstituted C4 alkyl group.
  • m is an integer selected from 1 to 2.
  • composition which in turn comprises the compound of general formula (I), which is selected from the following list: -3, 5- (4-Nitrophenyl) -2-furylmethyl 4,5-triethoxybenzoate (MR 1 .44)
  • a third aspect of the present invention relates to the use of a compound of general formula (I), or a tautomer, salt, solvate or prodrug thereof, as defined above in the second aspect of the present invention, for the preparation of a medicine
  • a fourth aspect of the present invention relates to the use of the compound of general formula (I), or a tautomer, salt, solvate or prodrug thereof, as defined above in the second aspect of the present invention, for the preparation of a medication for the treatment and / or prophylaxis of:
  • inflammatory and / or autoimmune pathologies selected from the following list: inflammatory bowel disease, inflammatory joint pathologies, atopic dermatitis and other inflammatory dermatological pathologies, neuritis, encephalitis, encephalomyelitis and inflammatory pathologies that affect the central nervous system such as multiple sclerosis, or peripheral , myositis, vasculitis, systemic lupus erythematosus, asthma, chronic obstructive pulmonary disease, infectious diseases that occur with inflammation, host rejection reactions against grafting, inflammation associated with spinal cord injury, conjunctivitis and inflammatory oculopathies, otitis and mucositis.
  • neurodegenerative and / or neurological pathologies selected from the following list: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, post-encephalitic parkinsonisms, dystonia, Tourette's syndrome, periodic limbic movement pathologies, restless legs syndrome and attention deficit hyperactivity disorders.
  • a fifth aspect of the present invention relates to a compound of general formula (II)) or a tautomer, salt, solvate or prodrug thereof:
  • each Ri is the same or different and is independently selected from hydrogen, a substituted or unsubstituted C1-C4 alkyl group, a halogen group, a substituted or unsubstituted C1-C4 haloalkyl group, a nitro group, an OR3 group wherein R3 is selected from hydrogen or an alkyl group C1-C4 substituted or unsubstituted or -NR4R 5 group - wherein R4 and R5 are identical or different and is independently selected from H or Ci- C 5 alkyl;
  • Q is selected from -O-, -S-, or -NR 9 , where Rg is selected from hydrogen or a substituted or unsubstituted C1-C3 alkyl group.
  • K is selected from a substituted or unsubstituted C1-C4 alkyl group, hydrogen or a halogen. If the alkyl group is substituted, it will be at least one hydroxyl group.
  • n is an integer selected from 1, 2, 3, 4 and 5
  • each Ri is the same or different and is independently selected from hydrogen or a -OR3 group wherein R3 is selected from hydrogen or a substituted or unsubstituted C1-C4 alkyl group.
  • n 3.
  • K is a halogen
  • K is a substituted alkyl group.
  • the compound of general formula (II) or a tautomer, salt, solvate or prodrug thereof is selected from the following list:
  • the compound of general formula (II) or a tautomer, salt, solvate or prodrug thereof is selected from the following list:
  • the compound of general formula (II) or a tautomer, salt, solvate or prodrug thereof is 5- (2,4-dichlorophenyl) -2-furyl methanol (MR 1 .32).
  • the compounds of general formula (II) are used as reaction intermediates in order to synthesize the compounds of general formula (I) described in the present invention. Further in the present invention, some of the compounds of the general formula (II) have the same activity as the compounds of the general formula (I).
  • a sixth aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of general formula (II) or a tautomer, salt, solvate or prodrug thereof, according to any one of claims 24 to 32 and at least one carrier, adjuvant and / or pharmaceutically acceptable vehicle.
  • a seventh aspect of the present invention relates to the use of the compound of formula (II) or a tautomer, salt, solvate or prodrug thereof, as defined above, which is selected from the following list:
  • An eighth aspect of the present invention relates to the use of the compound of general formula (II), or a tautomer, salt, solvate or prodrug thereof, as defined above, which is selected from the following list:
  • inflammatory, autoimmune, neurodegenerative, neurological and / or movement disorders inflammatory and / or autoimmune selected from the following list: inflammatory bowel disease, inflammatory joint pathologies, atopic dermatitis and other inflammatory dermatological pathologies, neuritis, encephalitis, Encephalomyelitis and inflammatory pathologies that affect the central nervous system such as multiple or peripheral sclerosis, myositis, vasculitis, systemic lupus erythematosus, asthma, chronic obstructive pulmonary disease, infectious diseases that occur with inflammation, host rejection reactions against grafting, associated inflammation to spinal cord injury, conjunctivitis and inflammatory oculopathies, otitis and mucositis.
  • neurodegenerative and / or neurological selected from the following list: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, post-encephalitic parkinsonisms, dystonia, Tourette's syndrome, periodic limbic movement pathologies, restless legs syndrome and disorders of attention deficit hyperactivity disorder. - they are involved with movement disorders.
  • alkyl preferably comprises branched and unbranched alkyls such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, and their corresponding isomers
  • alkenyl preferably comprises branched and unbranched alkenyls, for example vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but- 2-en-1-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, or 2- methyl-prop-1 -en-1-yl and its corresponding isomers.
  • C1-C4 is used in relation to the text for example in the context of the definition "C 1 -C 4 alkyl", as the group of alkyls having a finite number of carbon atoms from 1 to 4, that is 1, 2, 3 or 4 carbon atoms.
  • the term "Ci-C 4 " is interpreted as any sub-interval between Ci-C 4 , C2-C3, C1-C2, C1-C3, C2-C 4 , C3-C 4 .
  • C1-C3 is used in relation to the text for example in the context of the definition "C1-C3 alkyl", as the group of alkyls having a finite number of carbon atoms from 1 to 3, that is 1, 2 or 3 carbon atoms.
  • C1-C3 is interpreted as any sub-interval between C1-C3, CrC 2 , C 2 -C 3 .
  • Ci-C 2 is used in reference to the text for example in the context of the definition "CrC 2 alkyl", as the group of alkyls having a finite number of carbon atoms from 1 to 2, that is 1 or 2 carbon atoms.
  • C 2 -C4 is used in relation to the text for example in the context of the definitions "C 2 -C 4 alkenyl”, they are understood as alkenyl groups with a finite number of atoms of 2 to 4 carbon, that is 2, 3 or 4 carbon atoms. It is understood that the term “C 2 - C 4 " implies any sub-interval between. C 2 -C 4 , C 2 -C3, C3-C 4
  • haloalkyl preferably comprises branched and unbranched alkyls such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, and their corresponding isomers , which at least have a substitution by a halogen.
  • halogen is meant in the present invention a bromine, chlorine, iodine or fluorine atom.
  • the present invention also comprises the isomers, constitutional isomers and stereoisomers of the compounds of formula (I).
  • isomers is understood as chemical compounds with the same number and type of atoms as another chemical species. There are two large classes of isomers, constitutional isomers and stereoisomers.
  • constitutional isomers is understood as having a chemical meaning where chemical compounds have the same number and type of atoms but are connected by different sequences. These are functional isomers, structural isomers, tautomers or valence isomers.
  • Stereoisomers are those that have their atoms connected sequentially in the same way, so the two condensed formulas of the isomers are identical. Isomers differ in the way atoms are oriented in space. There are two large subclasses of stereoisomers; conformational, which can be interconverted by rotation of simple and configurational links, which cannot be interconverted.
  • the term "pharmaceutical composition” refers to a set of components that is formed at least by the compound of formula (I) of the invention, which has at least one application in the improvement of physical or physiological or psychological well-being. of a subject, which implies an improvement of the general state of his health, for example a cosmetic application, although it may not imply a physiological effect on the organism but an improvement in the well-being of the subject related to his psychology. Therefore, said pharmaceutical composition may be the basis for the preparation of a medicament.
  • the term “medicament” has a more limited meaning than the meaning of "pharmaceutical composition", as defined in the present invention, since the medicament necessarily implies a therapeutic effect, that is, a physiological effect on the subject's metabolism.
  • the medicament referred to in the present invention can be for human or veterinary use.
  • the "medicine for human use” is any substance or combination of substances that is presented as having properties for the treatment and / or prophylaxis of diseases in humans or that can be used in humans or administered to humans in order to restore , correct or modify physiological functions by exercising a pharmacological, immunological or metabolic action, or establishing a medical diagnosis.
  • the "veterinary medicinal product” is any substance or combination of substances that is presented as having curative and / or preventive properties with respect to animal diseases or that can be administered to the animal in order to restore, correct or modify its physiological functions exercising a pharmacological, immunological or metabolic action, or establishing a veterinary diagnosis. "Premixes for medicated feedingstuffs" - prepared to be incorporated into a feed will also be considered "veterinary drugs”.
  • excipient refers to a substance that helps the absorption of the extract of the invention, stabilizes said extract or aids in the preparation of the medicine in the sense of giving it consistency or providing flavors that make it more pleasant.
  • the excipients could have the function of keeping the ingredients together such as starches, sugars or cellulose, sweetening function, dye function, drug protection function such as to isolate it from air and / or moisture, function filling a tablet, capsule or any other form of presentation such as dibasic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
  • composition of the invention may further comprise a pharmacologically acceptable carrier.
  • vehicle must be pharmaceutically acceptable.
  • a “pharmaceutically acceptable carrier” refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes, but are not limited to, solids, liquids, solvents or surfactants.
  • the vehicle can be an inert substance or action analogous to any of the sequences of the present invention.
  • the function of the vehicle is to facilitate the incorporation of the extract of the invention as well as other compounds, allow a better dosage and administration or give consistency and form to the pharmaceutical composition.
  • the presentation form is liquid, the vehicle is the diluent.
  • the pharmacologically acceptable carrier could be, but not limited to, a nanoparticle, a liposome, a micelle or a microemulsion.
  • (ii) convert a salt of the compound of the invention into another, by reaction with an appropriate acid or by a suitable ion exchange column.
  • the two reactions are typically carried out in solution.
  • the salt can precipitate in solution and can be collected by filtration or solutions of the compound of the invention and the desired acid or base can be recovered, as appropriate.
  • the salt can be precipitated from a solution and collected by filtration or can be recovered by evaporation of the solvent.
  • the degree of ionization in the salt can vary between completely ionized to almost non-ionized.
  • Pharmaceutically acceptable salt by the addition of acids refers to those salts that retain the biological effectiveness and properties of free bases, which are not undesirable neither biologically nor otherwise, and which are formed with inorganic acids such as, but not limited to , hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenosulfonic acid, benzoic acid, 4-acetamidobenzoic acid, canphonic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 acid, 2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid
  • Pharmaceutically acceptable salt by addition of bases refers to those salts that retain the biological effectiveness and properties of free acids, which are not undesirable either biologically or otherwise. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines; substituted amines that include natural substituted amines, cyclic amines, substituted guanidines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-methylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procalna, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucamine, ethylamine, glucamine, ethylamine, glucamine, ethylamine, glucamine theobromine, triethanolamine, tromethamine, pur
  • Figure 1A represents the production of nitrites in microglia stimulated with LPS and using different compounds of the invention at 5 and 10 ⁇ M (Production of nitrites in microglia stimulated with LPS).
  • Figure 1 B represents the viability of the microglia in the presence of the different compounds at 5 and 10 ⁇ (Cytotoxicity study of the microglia compounds).
  • Figure 2A represents the production of nitrites in astrocytes stimulated with LPS and using different compounds of the invention at 5 and 10 ⁇ M (Production of nitrites in astrocytes stimulated with LPS).
  • Figure 2B) represents the viability of astrocytes in the presence of the different compounds at 5 and 10 ⁇ (Cytotoxicity study of compounds in astrocytes).
  • Figure 3 represents the linear correlation between described and experimental permeability of 10 commercial compounds using the PAMPA-Blood-brain Barrier methodology.
  • DCC ⁇ /, ⁇ / '- dicyclohexylcarbodiimide
  • DME 1,2-dimethoxyethane
  • Pd (0) tetrakis Palladium (0) -tetrakis (triphenylphosphine)
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
  • ASD triethylamine.
  • a - (3,4,5-trimethoxybenzyl) -5-bromo-2-thiophenecarboxamide (MR 2.43): On a solution of 5-bromo-2-thiophenecarboxylic acid (300 mg, 1.40 mmol) in 10 ml of dichloromethane PyBOP coupling agent (730 mg, 1.40 mmol) is added and stirred at room temperature for one hour. Then, 3,4,5-trimethoxybenzylamine (198 ⁇ , 1.16 mmol) and TEA (332 ⁇ , 2.40 mmol) are added as a base and stirred at room temperature for 12 hours. After this time, the solvent is removed by evaporating under reduced pressure.
  • % inhibition ((cpm control - cpm sample) x 100) / (cpm control - white cpm)
  • IC 5 0 inhibitory potency
  • the data was adjusted with the Prism v 2.1 software (GraphPad Software) using a non-linear adjustment.
  • Primary microglia cultures are used [Luna-Medina, R .; Cortes-Canteli, M .; Alonso, M .; Santos, A .; Mart ⁇ nez, A .; Perez-Castillo, A., Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. J. Biol. Chem. 2005, 280, 21453-21462]. Primary microglia cultures are obtained from the cortex and hippocampus of rats 2 days old post-natal.
  • the cells are broken down by mechanical crushing and incubation with 0.25% trypsin / EDTA at 37 ° C for 45 minutes.
  • DMEM with 10% fetal serum is added to stop digestion with trypsin and the tissue is crushed mechanically. It is centrifuged at 800xg / 5 min and the precipitate is washed 3 times in EBSS; finally the cells are resuspended in DMEM plus 10% fetal serum and seeded at a density of 0.5x105 cells / cm 2 . They are incubated for 10-12 days after which a monolayer of astrocytes is observed on which the microglia cells slightly adhere.
  • the culture flasks are incubated on a rotary shaker at 37 ° C for 4 hours at 250 rpm and the medium containing the microglia is centrifuged at 1500xg / 5 min.
  • Microglia cells are resuspended in DMEM / 10% FBS and seeded at a density of 2-4x10 5 cells / cm 2 . After 1 hour of incubation, to allow them to adhere to the plate, they are washed with TD and incubated in DMEM / 10% FBS for 24 hours after which they are used for the various experiments.
  • the degree of purity of these cultures is determined by immunocytochemical studies with antibodies specific for neurons ( ⁇ -tubulin and MAP2), astrocytes (GFAP), oligodendrocytes (CNPase) and microglia (0X42).
  • Microglia cell cultures are treated with LPS (10 ⁇ g / mi) in the absence and presence of the different compounds.
  • the compounds are added 1 h before the inflammatory stimulus.
  • the corresponding measures of the effect of the compounds on the production of NO (nitric oxide) by the NOS (inducible nitric oxide synthase) are performed as an indicator of neural damage due to inflammatory processes [Kroncke KD; Fehsel K .; Kolb- Bachofen V., Nitric oxide: cytotoxicity versus cytoprotection-how, why, when, and where? Nitric Oxide 1997, 7, 107-120].
  • the amount of nitrites is determined.
  • the method based on the Griess reaction is used]: 100 ⁇ of culture supernatant is mixed with 100 ⁇ of Griess reagent in a 96-well plate incubating for 15 min at room temperature. Next, the absorbance at 540 nm is measured in a microplate reader. The amount of nitrite produced is determined using a standard curve of sodium nitrite ( Figure 1). Measurement of the neuroprotective effect of furan derivatives by nitrite production in primary astroglia cultures
  • DMEM with 10% fetal serum is added to stop digestion and the tissue is crushed mechanically. It is centrifuged at 800xg / 5 min and the precipitate is washed 3 times in EBSS; finally, the cells are resuspended in DMEM plus 10% fetal serum and seeded at a density of 0.5x10 5 cells / cm2 in FLASK boats of 75cm 2 . They are now incubated at 37 ° C and 5% CO 2 for 10-12 days, period after which the astroglial cells are isolated. For this, the cultures are shaken for 16-18h at 250 rpm and the supernatant is removed. The plates are washed several times with 1X PBS to eliminate possible debris.
  • the astrogly which is forming a monolayer at the base of the culture pot, is obtained by incubation with 0.25% trypsin / EDTA for 5 minutes at 37 ° C. After lifting the cells, the medium is centrifuged at 1500xg / 10min. The astroglia cells are resuspended in DMEM / 10% FBS and seeded at a density of 2-4x10 5 cells / cm2 for 24 hours, from which they are used for the various experiments.
  • the degree of purity of the cultures is determined by an immunocytochemical analysis with specific antibodies for different cell types: neurons ( ⁇ -tubulin and MAP2), astrocytes (GFAP), oligodendrocytes (CNPase) and microglia (0X42).
  • Astroglia cell cultures are treated with LPS (10 ⁇ g / mi) in the absence and presence of the different compounds. The compounds are added 1 h before the inflammatory stimulus.
  • the method based on the Griess reaction is used]: 100 ⁇ of culture supernatant is mixed with 100 ⁇ of Griess reagent in a 96-well plate incubated for 15 min at room temperature. Next, the absorbance at 540 nm is measured in a microplate reader. The amount of nitrite produced is determined using a standard curve of sodium nitrite ( Figure 2).
  • the prediction of the permeability of the various compounds on the central nervous system (CNS), passing the hemtoencephalic barrier was determined using the methodology of parallel artificial membranes (PAMPA) [Di, L .; kerns, EH; Fan, K .; McConnell, OJ; Crankcase, GT "High throughput artificial membrane permeability assay for blood-brain barrier” Eur. J. Med. Chem., 2003, 38 (3), 223-232].
  • PAMPA parallel artificial membranes
  • Ethanol and dodecane were obtained from Sigma, Acros organics, Merck, Aldrich and Fluka commercial houses, respectively.
  • the porcine brain lipid was purchased from Avanti Polar Lipids.
  • Both the 96-well donor plate (Multiscreen® IP Sterile P ⁇ ate membrane PDVF, pore size 0.45 ⁇ , catalog reference MAIPS4510) as the 96-well acceptor plate (Multiscreen®, reference catalog MAMCS9610) were purchased at Millipore.
  • PDVF membrane filters (30 mm in diameter, pore size 0.45 ⁇ ) from the Symta commercial house were used.
  • the equipment used to perform ultraviolet absorbance measurements on 96-well plates was a Thermoscientific Multiskan spectrum.
  • Desipramine 12 1 1 .7 + 0.1

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Abstract

La présente invention concerne, d'une part, une nouvelle série de composés de formule générale (I) et (II) faisant partie d'une grande famille de dérivés hétérocycliques présentant une certaine activité pour le traitement de maladies pour lesquelles l'inhibition de PDE7 est thérapeutique. De préférence pour des maladies inflammatoires, auto-immunes et neurodégénératives. D'autre part, l'invention concerne des composés hétérocycliques, ainsi que le procédé permettant de les obtenir, lesquels composés peuvent largement être utilisés comme médicaments ou comme candidats à des médicaments.
PCT/ES2012/070293 2011-05-04 2012-04-27 Dérivés hétérocycliques inhibiteurs de phosphodiestérase 7 Ceased WO2012150369A1 (fr)

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ES201130712A ES2391732B1 (es) 2011-05-04 2011-05-04 Derivados heterocíclicos inhibidores de fosfodiesterasa 7.
ESP201130712 2011-05-04

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038089A1 (fr) 2022-08-18 2024-02-22 Mitodicure Gmbh Utilisation d'un agent thérapeutique ayant une activité inhibitrice de phosphodiestérase-7 pour le traitement et la prévention de maladies associées à la fatigue, à l'épuisement et/ou à l'intolérance à l'effort chroniques

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KR101621444B1 (ko) * 2008-07-02 2016-05-19 (주)아모레퍼시픽 바닐로이드 수용체 길항제로 작용하는 신규 화합물, 이의 이성질체 또는 이의 약제학적으로 허용 가능한 염, 및 이를 포함하는 약학 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C GIL ET AL.: "Phosphodiesterase 7 (PDE7) inhibitors as new drugs for neurological and inflammatory disorders", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 18, no. 10, October 2008 (2008-10-01), pages 1127 - 1139 *
J MORALES-GARCIA ET AL.: "Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease", PLOS ONE, vol. 6, 24 February 2011 (2011-02-24), pages E17240 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038089A1 (fr) 2022-08-18 2024-02-22 Mitodicure Gmbh Utilisation d'un agent thérapeutique ayant une activité inhibitrice de phosphodiestérase-7 pour le traitement et la prévention de maladies associées à la fatigue, à l'épuisement et/ou à l'intolérance à l'effort chroniques

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