WO2015162216A1 - Dérivés de biaryl amide ou d'urée en tant que ligands de trpv1 - Google Patents

Dérivés de biaryl amide ou d'urée en tant que ligands de trpv1 Download PDF

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WO2015162216A1
WO2015162216A1 PCT/EP2015/058830 EP2015058830W WO2015162216A1 WO 2015162216 A1 WO2015162216 A1 WO 2015162216A1 EP 2015058830 W EP2015058830 W EP 2015058830W WO 2015162216 A1 WO2015162216 A1 WO 2015162216A1
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thiophen
butanamide
compound
benzo
methoxybenzyl
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Antonella Brizzi
Francesca AIELLO
Federico Corelli
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Universita' Degli Studi Di Siena
Universita' Della Calabria
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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D333/28—Halogen atoms
    • 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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • 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
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to chemical heterocyclic compounds and synthesis thereof, said compounds having biological activity as Transient Receptor Potential cation channel, subfamily Vanilloid type 1 (TRPV1 ) ligands are potentially useful for use as medicaments, in particular for use in the treatment of pain, inflammation, cancer and vascular disorders.
  • TRPV1 Transient Receptor Potential cation channel, subfamily Vanilloid type 1
  • the Transient Receptor Potential (TRP) channels are a large family of plasma membrane non-selective cation channels, classified into several subfamilies on the basis of their primary structure and involved in the transduction of a remarkable range of stimuli such as temperature, mechanical and osmotic stimuli, electrical charge, light, olfactive and taste stimuli, xenobiotic substances, endogenous lipids, etc.. 1 Among these, the TRPV1 (transient receptor potential cation channel, subfamily Vanilloid type 1 ) has been the first TRP to be cloned by Caterina and coworkers in 1997, 2 and the best characterized founding member of the thermo-TRP subfamily of sensory transducers.
  • TRPV1 transient receptor potential cation channel, subfamily Vanilloid type 1
  • the TRPV1 shows a high Ca 2+ permeability, abundantly expressed in sensory neurons 3 and also in higher brain structures 4 which are involved in pain processing and neurogenic inflammatory response, overlapping only in part with those of endocannabinoid system.
  • TRPV1 is a polymodal nociceptor, up-regulated during chronic pain conditions, and exhibits a dynamic threshold of activation that could be significantly lowered by inflammatory agents such as mild acidification, temperature higher than 43 °C and various, mostly noxious, natural products.
  • the natural pungent principle capsaicin was the first TRPV1 agonist described and its potential analgesic effects were known long before to the identification of its receptor.
  • Capsaicin (irans-8-methyl-/V-vanillyl-6-nonenamide) is a crystalline, lipophilic, colorless and odorless alkaloid found primarily in the Capsicum fruit, 6 responsible of its spicy flavour. Its action is unique in that the initial stimulation of the receptor is followed by a lasting refractory state, traditionally termed desensitization, silencing the whole nerve terminal. 7 However, capsaicin's pungency limits its use in clinical trials, so that the characterization and extraction/synthesis of non-pungent analogues is still in progress.
  • RTX resiniferatoxin
  • SAR early structure-activity relationship
  • TRPV1 agonists and antagonists are being evaluated as potential analgesics.
  • TRPV1 agonists and antagonists are not equivalent therapeutic approaches and their clinical use is not mutually exclusive.
  • Capsaicin-sensitive nerves express a myriad of receptors that are relevant to pain and inflammation of which TRPV1 is just one; moreover, TRPV1 agonists silence the whole nerve terminal, whereas antagonists selectively impair TRPV1 receptors.
  • agonist compounds are expected to be more powerful analgesic drugs than antagonists as they simultaneously block all receptors on capsaicin-sensitive nerves.
  • TRPV1 channels have become a promising pain relief drug target, representing the key mediator in pain processing and neurogenic inflammatory response, and have opened the door to development of new type of analgesics.
  • capsaicin and related compounds called capsaicinoids, provided the basis for developing structurally different TRPV1 modulators, both agonists and antagonists.
  • the aim of the authors was to design and synthesize a novel class of small-molecule TRPV1 ligands, endowed with agonist or antagonist effect, chemically stable, easily prepared through simple synthetic pathways and characterized by a positive biological profile.
  • Subject-matter of the present invention is a compound of formula (I)
  • n is an integer number varying from 0 to 6;
  • n is an integer number varying from 0 to 2;
  • An is an aromatic ring selected in the group consisting of
  • Ri is H, I, (CH 2 )4-CH 3 , C ⁇ CH-(CH 2 )2-CH 3 , Ph,
  • Rs is H, OH, OMe, O i Pr or CI;
  • R 4 is H or OMe
  • Rs is OMe, COOEt, CN, F, SO2CH3 or CH2OH;
  • X 2 is O, S or NMe.
  • the compounds of general formula (I) according to the invention are chemically stable and were tested for their ability to bind the transient receptor potential vanilloid-type 1 channel, TRPV1 , showing potential activity in illnesses related to pain, inflammatory, cancer, and vascular disorders.
  • Subject-matter of the present invention is therefore also a compound of formula (I) as above described for use as a medicament, in particular for use in the treatment of pain, inflammation, cancer and vascular disorders.
  • the compounds of the invention can also be advantageously used for their ability to bind the endovanilloid receptor channel, TRPV1 , as pharmacological and/or diagnostic tools, in particular as radiotracers for mapping TRPV1 receptors in (patho)physiological conditions.
  • the present invention relates also to a process for preparing a compound of formula (I) according to the invention, said process using a compound of formula (II)
  • X3 is NH2 or OH or N3.
  • FIG.1 - shows the structures of Capsaicin, Resiniferatoxin (RTX) and Capsazepine.
  • FIG.2 - shows critical chemical features of Capsaicin.
  • FIG. 3 - shows the synthetic scheme 1 for some embodiment compounds according to the invention
  • Method A amine, CMC, HOBt, dry DCM, rt, overnight
  • Method B amine hydrochloride and DMAP in dry DCM, CMC, HOBt, rt, overnight
  • Method C amine, HBTU, HOBt, DIPEA, dry DMF
  • Method D i) 4-methoxybenzylamine, CMC, HOBt, dry DCM, rt; ii) dry toluene, BBr 3 , 100 °C.
  • FIG. 4 - shows the synthetic scheme 2 for some embodiment compounds according to the invention.
  • Method E a) dry toluene, DPPA, EtsN, 80 °C, overnight; b) appropriate amine, Et3N, 80 °C 1 h then room temperature overnight.
  • Method F a) dry toluene, DPPA, EtsN, 80 °C, overnight; b) 4-OMe-benzylamine, EtsN, 80 °C 1 h then room temperature overnight; c) dry toluene, BBr3, 100 °C 1 h.
  • FIG. 5 - shows the suitable synthetic scheme 3 for some embodiment compounds according to the invention.
  • FIG. 6 - shows the suitable synthetic scheme 4 for some embodiment compounds according to the invention; a) dry toluene, DPPA, E.3N , 80-90 °C, overnight; b) appropriate alcohol, DMAP, 80-90 °C 4-24 h then room temperature overnight.
  • FIG. 7 - shows a possible synthetic scheme 5 for some embodiment compounds according to the invention.
  • FIG. 8 - shows levels of HNE protein-adducts induced by GO treatment in HaCaT cells, measured by Western blot. Data are representative of three experiments. Cells were pre-treated with MSP-3 for 24 h and then treated with GO for 1 h. Quantifications of HNE protein-adduct bands is shown as ratio of ⁇ / ⁇ -actin (bottom panel). Data are expressed as arbitrary units (average of three different experiments, * vs control, # vs GO).
  • FIG. 9 - shows the cytotoxicity of compound MSP3, MSP18 and MSP20 in HaCaT cell line, concentrations ranging from 0.1 to 10 ⁇ , after 24 and 48 h.
  • n is an integer number varying from 0 to 3;
  • n is an integer number varying from 0 to 2.
  • An is an aromatic ring selected in the group consisting of
  • R 2 is OH, OMe or CI ;
  • R is H.
  • Preferred compounds according to the invention are those wherein Ar is
  • n is an integer number varying from 0 to 3;
  • n is an integer number varying from 0 to 2;
  • An is an aromatic ring selected in the group consisting of
  • R 2 is OH, OMe or CI
  • R 3 is H, OH, OMe or CI
  • R is H.
  • Xi is NH, or S; m is an integer number varying from 0 to 3;
  • n is an integer number varying from 1 to 2;
  • An is an aromatic ring selected in the group consisting of
  • R 2 is OH ;
  • R is H.
  • Particularly preferred compounds of the invention are:
  • Such a coupling reaction can be promoted with coupling activating agents well known in the art preferably 1 -cyclohexyl-3-(2-morpholinoethyl)carbodiimide (CMC) and 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ). 13
  • coupling activating agents well known in the art preferably 1 -cyclohexyl-3-(2-morpholinoethyl)carbodiimide (CMC) and 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ). 13
  • 4- (thiophen-2-yl)butanoic acid or similar compounds, such as 3-(benzo[£>]thiophen-2- yl)propanoic acid, 2-(5-hydroxy-1 /-/-indol-3-yl)acetic acid, 1 /-/-indole-2-carboxylic acid, 4-(5-iodothien-2-yl)butanoic acid, 4-(5-phenylthiophen-2-yl)butanoic acid, or 4- [5-(pyridin-3-yl)thiophen-2-yl]butanoic acid can be obtained from commercial sources or by simple organic chemistry reactions.
  • aromatic amides were obtained from different aromatic amines, characterized by polar substituents (i.e. 4- hydroxyaniline, 4-methoxybenzylamine, 3-hydroxytyramine, 3,4- dichlorobenzylamine, 3,4-dimethoxybenzylamine, 3-chloro-4- methoxyphenethylamine, benzo[c
  • polar substituents i.e. 4- hydroxyaniline, 4-methoxybenzylamine, 3-hydroxytyramine, 3,4- dichlorobenzylamine, 3,4-dimethoxybenzylamine, 3-chloro-4- methoxyphenethylamine, benzo[c
  • the present invention is related to a series of urea derivatives of formula (I) (see table 2).
  • 4-(thiophen-2- yl)butanoic acid or similar compounds, such as 3-(benzo[£>]thiophen-2-yl)propanoic acid, 1 /-/-indole-2-carboxylic acid, 4-(5-iodothien-2-yl)butanoic acid, 4-(5- phenylthiophen-2-yl)butanoic acid or 4-[5-(pyridin-3-yl)thiophen-2-yl]butanoic acid, which can be obtained from commercial sources or by simple organic chemistry reactions, were converted in their corresponding isocyanates via the Curtius rearrangement using diphenylphosphoryl azide (DPPA) which reacted further with the appropriate amines (i.e. 3-methoxy-4-hydroxybenzylamine, 4- methoxybenzylamine, 3-hydroxytyramine, 3,4-dichlorobenzylamine) in one pot, as depicted in Scheme 2.
  • DPPA dipheny
  • 4-(thiophen-2-yl)butanoic acid or similar compounds, such as 3- (benzo[£>]thiophen-2-yl)propanoic acid, 1 /-/-indole-2-carboxylic acid, 4-(5-iodothien- 2-yl)butanoic acid, 4-(5-phenylthiophen-2-yl)butanoic acid, or 4-[5-(pyridin-3- yl)thiophen-2-yl]butanoic acid, which can be obtained from commercial sources or by simple organic chemistry reactions, were converted in their corresponding isocyanates via the Curtius rearrangement using diphenylphosphoryl azide (DPPA) which reacted further with the appropriate alcohols (i.e.
  • DPPA diphenylphosphoryl azide
  • a compound of formula (I) according to the invention wherein Y is can be obtained contacting a compound of formula (II) as above described
  • 4-(thiophen-2-yl)butanoic acid or similar compounds, such as 3- (benzo[£>]thiophen-2-yl)propanoic acid, 1 /-/-indole-2-carboxylic acid, 4-(5-iodothien- 2-yl)butanoic acid, 4-(5-phenylthiophen-2-yl)butanoic acid, or 4-[5-(pyridin-3- yl)thiophen-2-yl]butanoic acid, which can be obtained from commercial sources or by simple organic chemistry reactions, were converted to their corresponding aldehydes, 20 which in turn were trasformed without the need to isolate the alkyne intermediates into the 1 ,4-disubstituted 1 ,2,3-triazoles in good yields by a one-pot Cu-catalyzed azide-alkyne click reaction 21 (Scheme 5).
  • one of the aspect of the present invention was the identification of new TRPV1 ligands, chemically characterized by a 4-(thiophen-2-yl)butanoic acid amide moiety and endowed with agonist activity.
  • new TRPV1 ligands chemically characterized by a 4-(thiophen-2-yl)butanoic acid amide moiety and endowed with agonist activity.
  • chemical decoration of the thiophene ring and/or the electronic/steric properties of amide can affect the interaction with the vanilloid receptor and modulate the TRPV1 activity, it is describe here a whole set of derivatives, characterized by modifications both on the acidic moiety and the aromatic amidic head, which are chemically stable and easily prepared through a simple synthetic pathway.
  • Compound MSP3 our first identified TRPV1 ligand, has about the 80% of efficacy compared to ionomycin (4 ⁇ ) and an ECso value of 0.87 ⁇ . Comparable behaviour is exhibited by compound MSP25 with about 67% of efficacy and an ECso of 0.56 ⁇ , compound MSP27 with about 78% of efficacy and an ECso of 0.53 ⁇ , compound MSP30 with about 66% of efficacy and an ECso of 0.1 1 ⁇ , and MSP52 with about 48% of efficacy and an ECso of 0.15 ⁇ .
  • Compounds MSP18, MSP20, and MSP44 are the most potent derivatives with efficacy of approximately 80%, for the first two compounds, and 70% for the third, and ECso of 7.45, 46 and 1 .6 nM, respectively.
  • ECso (for activation) and ICso (for desensitization) values are of the same order of magnitude and thus activation and desensitization potencies are comparable (see Table 1 ).
  • the 4-(thien-2-yl)butanoic acid fragment seems to well mimic the unsaturated acyl portion present in the capsaicin structure (compound MSP3); further introduction on the thiophene ring of a iodine atom (MSP18) or its condensation with an additional aromatic ring (MSP20 and MSP34) or the replacement of the iodine atom with a phenyl ring (MSP44 and MSP52) gave the most potent compounds, suggesting a significant role for liphophilicity or the need of a more extensive ⁇ - ⁇ hydrophobic interaction.
  • indole scaffold furnished an active derivative (MSP25) while the introduction in the aromatic moiety of a polar substituent (MSP24) seems to be detrimental for TRPV1 binding.
  • MSP25 active derivative
  • MSP24 polar substituent
  • capsaicinoid antioxidant properties also contributes to their beneficial effects, 23 especially on cardiovascular system, and capsaicin possesses some structural requirements for free radical-scavenging activity, 24 the antioxidant properties of MSP3 and the biological profile, i.e. cytotoxicity and viability behaviour, of compounds MSP3, MSP18 and MSP20 have been investigated.
  • the 4- methoxy-3-hydroxy moiety in the aromatic ring of the amide is one of the structural arrangements imparting high antioxidant activity.
  • HaCaT cells 25 were treated with glucose oxidase (GO) to generate hydrogen peroxide (H2O2).
  • GO glucose oxidase
  • H2O2 hydrogen peroxide
  • the level of lipid peroxidation was measured based on the presence of the alpha-beta unsaturated aldehyde protein adducts.
  • HNE 4-hydroxy-2- nonenale
  • the formation of HNE protein-adducts in keratinocytes pre-treated with or without compound MSP3 was evaluated. 26 As shown in figure 7, the GO treatment induced a significant increase of HNE protein-adduct levels, effect prevented in a dose-dependent fashion by pre-treatment with compound MSP3.
  • This strategy could be exploited to develop new potential pharmacological tools and/or anti-inflammatory/analgesic agents, characterized by a positive biological profile.
  • the chemical structure of the compounds according to the invention provides the opportunity of introducing a radiolabeled atom (i.e. iodine-125 in compound MSP18, and analogous derivatives, or carbon-1 1 in the methoxy substituent of all the vanillamides), to develop new radiotracers for Positron Emission Tomography (PET) imaging.
  • PET Positron Emission Tomography
  • LC-MS chromatography-mass spectrometry
  • Nitrogen (purity 99.995%) was used as nebulizer and drying gas. UV detection was monitored at 254 nm. Mass spectra were acquired in positive or negative mode scanning over the mass range m/z of 150-1500. IR spectra were recorded on a Perkin-Elmer FT-IR Spectrum TWO (Nujol dispersion or CHC solution). The structures of final compounds were unambiguously assessed by 1 H NMR, 13 C NMR, MS and/or IR. All compounds were checked for purity by TLC on Merck 60 F254 silica plates. For column chromatography, Merck 60 silica gel, 230-400 mesh, was used.
  • Method A A solution of the appropriate acid (1 .0 eq.), the appropriate amine (1 .5 eq.) and /V-hydroxybenzotriazole (HOBt) (1 .2 eq.) in dry DCM (2.5 ml_) was cooled at 0 °C and stirred under N2 atmosphere for 15'. Thereafter a solution of 1 - cyclohexyl-3-(2-morpholinoethyl)carbodiimide (CMC) (1 .5 eq.) in dry DCM (3.5 ml_) was added dropwise. The mixture was stirred at rt for 24 hours.
  • CMC 1 - cyclohexyl-3-(2-morpholinoethyl)carbodiimide
  • Method B The amine hydrochloride (1 .5 eq.) was suspended in dry DCM (5.0 ml_), DMAP added and the mixture allowed to stir at room temperature for 30' under nitrogen atmosphere. Afterward, a solution of the appropriate acid (1 .0 eq.) in dry DCM (2.0 ml_), HOBt (1 .2 eq.) solid and a solution of CMC (1 .5 eq.) in dry DCM (3.0 ml_) were added respectively. The mixture was stirred at rt for 24 hours. After this time, the solvent was distilled off under vacuum and the residue was washed twice with a 5% NaHCO3 solution and extracted with chloroform.
  • reaction mixture was diluted with saturated NH 4 CI solution and extracted with ethyl acetate (4 times).
  • the collected organic layers were washed twice with brine, dried over anhydrous Na2S0 4 , filtered and evaporated to dryness.
  • the crude residue was purified by flash chromatography on silica gel with the appropriate eluent mixtures.
  • Method D A solution of the appropriate acid (1 .0 eq.), the appropriate amine (1 .5 eq., 4-methoxybenzylamine) and /V-hydroxybenzotriazole (HOBt) (1 .2 eq.) in dry DCM (2.5 ml_) was cooled at 0 °C and stirred under N2 atmosphere for 15'. Thereafter, a solution of 1 -cyclohexyl-3-(2-morpholiinoethyl)carbodiimide (CMC) (1 .5 eq.) in dry DCM (3.5 ml_) was added dropwise.
  • CMC 1 -cyclohexyl-3-(2-morpholiinoethyl)carbodiimide
  • reaction mixture was allowed to reach room temperature, recooled to 0 °C and cautiously treated dropwise with H2O.
  • the organic layer was separated and washed with NaCI saturated solution and 2 N NaOH (3-4 times).
  • the alkaline aqueous phase was treated with concentrated HCI to pH 2 and extracted with E.2O.
  • the dried and filtered organic layer afforded the pure compound after evaporation of solvent.
  • Method E The appropriate carboxylic acid (1 .0 eq.) was dissolved in dry toluene (15 ml_), and diphenylphosphoryl azide (1 .17 eq.) was added. Triethylamine (1 .2 eq.) was added dropwise and the reaction mixture was stirred first at room temperature for 30'and then heated to 80 °C overnight. A solution of the desired amine (0.9 eq.) in dry toluene together with triethylamine (1 .2 eq.) was added and the heating continued for 1 h at 80 °C. After this time, the reaction mixture was allowed to reach room temperature and stirred overnight.
  • Method F The appropriate carboxylic acid (1 .0 eq.) was dissolved in dry toluene (15 ml_), and diphenylphosphoryl azide (1 .17 eq.) was added. Triethylamine (1 .2 eq.) was added dropwise and the reaction mixture was stirred first at room temperature for 30'and then heated to 80 °C overnight. A solution of the 4-methoxybenzylamine (0.9 eq.) in dry toluene together with triethylamine (1 .2 eq.) was added and the heating continued for 1 h at 80 °C. After this time, the reaction mixture was allowed to reach room temperature and stirred overnight.
  • reaction mixture was allowed to reach room temperature, recooled to 0 °C and cautiously treated dropwise with H2O.
  • the organic layer was separated and washed with NaCI saturated solution and 2 N NaOH (3-4 times).
  • the alkaline aqueous phase was treated with concentrated HCI to pH 2 and extracted with Et20.
  • the dried and filtered organic layer afforded the pure compound after evaporation of solvent.
  • the collected methyl 4-(5- iodothiophen-2-yl)butanoate was dissolved in a mixture of methanol and sodium hydroxide solution (2:1 ) and refluxed for about 2 h, until starting ester could not be detected by TLC.
  • the aqueous phase was acidified first with concentrated HCI and then with 2 N HCI and extracted more times (3-4) with chloroform.
  • the collected organic layer were dried on anhydrous Na2S0 4 , filtered and concentrated to dryness under reduced pressure.
  • the crude 4-(5-iodothiophen-2-yl)butanoic acid was was purified by flash chromatograpy on silica gel, eluent chloroform.
  • MSP2 /V-(4-Hydroxyphenyl)-4-(thiophen-2-yl)butanamide
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 4-hydroxy-3- methoxybenzylamine hydrochloride, following Method B.
  • the pure compound was isolated as brown oil (yield 20%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3- hydroxytyramine hydrochloride, following Method B. Pure compound was isolated as dark yellow oil (yield 30%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and pyridin-4- yimethanamine, following Method A. Pure compound was isolated as white solid (yield 82%, eluent: CHCIs/MeOH 50/2).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and benzo[c
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3,4- dimethoxybenzylamine, following Method A. The pure compound was isolated as pale yellow solid (yield 80%, eluent: CHCIs/MeOH 50/1 ).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and thiophen-2- ylmethanamine, following Method A. The pure compound was isolated as cream solid (yield 84%, eluent: CHCIs).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3,4- dichlorobenzylamine following Method A. Pure compound was isolated as yellow solid (yield 25%, eluent: CHCIs/MeOH 48/2).
  • MSP16 /V-(4-Methoxybenzyl)-4-(thiophen-2-yl)butanamide
  • This compound was prepared from 4-(thiophen-2-yl)butanoic and 4- methoxybenzylamine following Method D. Pure compound was isolated as brown solid (yield 7%).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic acid and 4- hydroxy-3-methoxybenzylamine hydrochloride, following Method B.
  • the pure compound was isolated as yellow oil (yield 70%, eluent: CHCh/MeOH 50/2).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic and 3- hydroxytyramine hydrochloride, following Method B. Pure compound was isolated as pasty yellow solid (yield 60%, eluent: CHCIs/MeOH 47/3).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 3,4-dichlorobenzylamine, following Method A. Pure compound was isolated as white solid (yield 76%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 4- methoxybenzylamine, following Method A. Pure compound was isolated as yellow solid (yield 95%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 2-(5-hydroxy-1 /-/-indol-3-yl)acetic acid and 4- hydroxy-3-methoxybenzylamine hydrochloride, following Method B. Pure compound was isolated as pale pink solid (yield 35%, eluent: CHCIs/MeOH 47/3). Mp 143-145 °C (K).
  • This compound was prepared from 1 /-/-indole-2-carboxylic acid and 4-hydroxy-3- methoxybenzylamine hydrochloride, following Method B. Pure compound was isolated as pink solid (yield 89%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 1 /-/-indole-2-carboxylic acid and 3,4- dichlorobenzylamine, following Method A. Pure compound was isolated as violet solid (yield 61 %, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 1 /-/-indole-2-carboxylic acid and 3- hydroxytyramine hydrochloride, following Method B. Pure compound was isolated as light brown solid (yield 10 %, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3-chloro-4- methoxyphenethylamine, following Method A. Pure compound was isolated as white solid (yield 70.0 %, eluent: CHCIs/MeOH 50/1 ).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic acid and 3- chloro-4-methoxyphenethylamine, following Method A. Pure compound was isolated as transparent oil (yield 68.0 %, eluent: CHCI3).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 3- chloro-4-methoxyphenethylamine, following Method A. Pure compound was isolated as white solid (yield 75.0 %, eluent: CHCIs/MeOH 50/1 ).
  • This compound was prepared from 1 /-/-indole-2-carboxylic acid and 3,4- dichlorobenzylamine, following Method E. Pure compound was isolated as orange solid (yield 27 %, eluent: n.Hex/EtOAc 2/1 .).
  • CDCIs 160.0, 139.1 , 135.7, 135.7, 133.2, 132.54, 131 .3, 131 .2, 131 .1 , 130.7,
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 4- hydroxy-3-methoxybenzylamine hydrochloride, following Method E. Pure compound was isolated as pasty light brown oil (yield 46,0 %, eluent: CH2Cl2/n.Hex 3/1 ).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 4- methoxybenzylamine, following Method F. Pure compound was isolated as brown oil (yield 31.0%).
  • This compound was prepared from 1 /-/-indole-2-carboxylic acid and 4-hydroxy-3- methoxybenzylamine hydrochloride, following Method E. Pure compound was isolated as yellow solid (yield 8.0%, recrystallized from CHCIs/petroleum ether).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3,4- dichlorobenzylamine, following Method E. Pure compound was isolated as white needles (yield 62.0 %, eluent: CHC /MeOH 48/2, recrystallization from n.Hexane). Mp 86-88 °C (K).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 4-hydroxy-3- methoxybenzylamine hydrochloride, following Method E. Pure compound was isolated as white solid (yield 58.0 %, eluent: CHCIs/MeOH 47/3).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 3,4-dichlorobenzylamine, following Method E. Pure compound was isolated as white solid (yield 60.0%, eluent: CHCIs/MeOH 50/0.5).
  • This compound was prepared from 3-(benzo[£>]thiophen-2-yl)propanoic acid and 3,4-dihydroxyphenethylamine, following Method E. Pure compound was isolated as pale pink solid (yield 20.0%, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic acid and 4- hydroxy-3-methoxybenzylamine, following Method E. Pure compound was isolated as white solid (yield 25.0 %, eluent: CHCIs/MeOH 50/2).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic acid and 3,4- dichlorobenzylamine, following Method E. Pure compound was isolated as white solid (yield 45.0 %, eluent: CHCIs/MeOH 50/0.5).
  • This compound was prepared from 4-(5-iodothiophen-2-yl)butanoic acid and 3,4- dihydroxyphenethylamine, following Method E. Pure compound was isolated as brown oil (yield 20.0 %, eluent: CHCIs/MeOH 48/2).
  • This compound was prepared from 4-(thiophen-2-yl)butanoic acid and 3,4- dihydroxyphenethylamine, following Method E. Pure compound was isolated as brown oil (yield 25.0 %, eluent: CHCIs/MeOH 50/2).
  • This compound was prepared from 4-(5-phenylthiophen-2-yl)butanoic acid and 3,4- dichlorobenzylamine, following Method A. Pure compound was isolated as pasty white solid (yield 40.0 %, eluent: CHCIs/MeOH 50/1 ).
  • This compound was prepared from 4-[5-(pyridine-3-yl)thiophen-2-yl]butanoic acid and 4-hydroxy-3-methoxybenzylamine, following Method C. Pure compound was isolated as pasty yellow solid (yield 75.0 %, eluent: CHCIs/MeOH 50/2).
  • This compound was prepared from 4-[5-(pyridine-3-yl)thiophen-2-yl]butanoic acid and 4-hydroxyaniline, following Method C. Pure compound was isolated as white solid (yield 45.0 %, eluent: CHCIs/MeOH 50/2).
  • HEK293 human embryonic kidney cells stably over-expressing recombinant human TRPV1 were grown on 100 mm diameter Petri dishes as mono-layers in minimum essential medium (EMEM) supplemented with nonessential amino acids, 10% foetal bovine serum, and 2 mM glutamine, and maintained at 5% CO2 at 37 °C. Stable expression of channels was checked by quantitative PCR (data not shown). The effect of the substances on intracellular Ca 2+ concentration ([Ca 2+] i) was determined by using Fluo-4, a selective intracellular fluorescent probe for Ca 2+ .
  • EMEM minimum essential medium
  • CHO cells Chinese hamster ovary cells (CHO) stably transfected with cDNA encoding human cannabinoid CBi receptors were maintained at 37 °C and 5% CO2 Dulbecco's modified Eagle's medium nutrient mixture F-12 HAM supplemented with 1 mM L-glutamine, 10% foetal bovine serum and 0.6% penicillin-streptomycin together with G418 (600 ⁇ mL 1 ). These cells were passaged twice a week using non-enzymatic cell dissociation solution.
  • Fatty acid amide hydrolase assay The effect of increasing concentrations of the test compounds on the enzymatic hydrolysis of [ 14 C] anandamide was studied as described previously, by using membranes prepared from rat brain (which express high amounts of FAAH).
  • the whole rat brain was homogenized at 4 °C in 50 mM Tris-HCI buffer, pH 7.0, by using an ultraturrax and adic homogenizer. Homogenates were first centrifuged at 800 g for 15 min to get rid of the debris and the supernatant was centrifuged at 10 000 g for 30 min. The pellet from this latter centrifugation was used for the assay.
  • Membranes (100 ⁇ 9) were incubated in 50 mM Tris-HCI, pH 9, for 30 min at 37 °C with increasing concentrations (up to 25 ⁇ ) of the test compounds and with synthetic N-arachidonoyl-[ 14 C]-ethanolamine (55 mCi/mmol, ARC St. Louis, MO, USA) properly diluted with AEA (Tocris Bioscience, Avonmouth, Bristol, UK) to the final concentration of 4 ⁇ . After incubation, the amount of [ 14 C]-ethanolamine produced was measured by scintillation counting of the aqueous phase after extraction of the incubation mixture with 2 volumes of CHCI3/CH3OH 1 /1 (by vol.). Water-soluble [ 14 C]-ethanolamine produced from [ 14 C]- anandamide was used as a measure of anandamide hydrolysis.
  • Monoacylglycerol lipase assay The hydrolysis of 2-AG was measured by incubating the 10,000 g cytosolic fraction (100 ⁇ g/sample) of COS-7 cells (which express high amounts of MAGL), homogenized as described above for rat brain (but without using the ultraturrax in this case), in Tris-HCI 50 mM, at pH 7 at 37 °C for 20 min, with synthetic 2-arachidonoyl-[ 3 H]-glycerol (40 Ci/mmol, ARC St. Louis, MO, USA) properly diluted with 2-AG (Cayman Chemicals, Ann Arbor, Ml, USA) to the final concentration of 20 ⁇ .
  • Colour change of the redox indicator resazurin was measured at 585 nm (excitation) and 590 nm (emission) wavelengths to evaluate oxidized versus reduced forms of the reagent respectively.
  • Western blot analysis Total cell lysates were extracted in solubilization buffer containing 50 mM Tris (pH 7.5), 1 50 mM NaCI, 1 0% glycerol, 1 % Nonidet P-40, 1 mM EGTA, 0.1 % SDS, 5 mM N-ethylmaleamide (Sigma-Aldrich Corp.), protease and phosphatase inhibitor cocktails (Sigma-Aldrich Corp.) as previously described.
  • Membranes were incubated overnight at 4 °C with the primary antibody, goat anti-HNE (Millipore Corporation, Billerica, MA, USA). The membranes were then incubated with horseradish peroxidase-conjugated secondary antibody (anti-goat) for 1 h, and the bound antibodies were detected using chemiluminescence (BioRad, Milan, Italy). Images of the bands were digitized and the densitometry of the bands were performed using Image-J software.
  • HaCaT cells 5 x 10 4 cell/mL were incubated with 20 ⁇ DCFH-DA in the loading medium in 95% air/5% CO2 at 37 °C for 30 minutes. After this time, cells were treated with GO for different times (15, 30, 45 and 60 minutes) and the fluorescence of the cells from each well was measured at 485 nm (excitation filter) and 530 nm (emission filter) by using a plate reader (TECAN-infinite M200). Preliminary study on the antinociceptive activity of compound MSP18 in rats
  • MSP18 the latter (or the vehicle) was i.p. injected (1 mg/Kg) 15 min before formalin injection.
  • the rats were then placed in the Open Field apparatus (a square transparent Plexiglas cage, 50 x 50 x 30 cm) and its behaviour was recorded for 60 min.
  • Open Field apparatus a square transparent Plexiglas cage, 50 x 50 x 30 cm
  • licking duration time spent licking the injected foot
  • flexing duration time spent with the leg held off the floor, flexed close to the body
  • paw-jerk frequency number of phasic flexions of the leg
  • MSP18 treated rats have shown to decrease significantly the licking, the flexing and the paw jerk duration as compared to control rats. Moreover MSP18 treated rats did not modified the rearing and spontaneous behaviour (locomotion, grooming, crouching) as compared to control rats (figure 9).
  • c As percent of the effect of ionomycin (4 ⁇ ).
  • Analgesic Agents Structure-Activity Studies. 4. Potent, Orally Active Analgesics. /. Med.

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Abstract

La présente invention concerne des composés à haute affinité, aptes à se lier au canal cationique à potentiel de récepteur transitoire, sous-famille vanilloïde, de type 1 ou TRPV1. Ce récepteur étant impliqué dans le traitement de la douleur et les réponses inflammatoires neurogènes et étant régulé positivement dans les états de douleurs chroniques, les composés selon l'invention s'appliquent en particulier à tous les états pathologiques impliquant lesdits récepteurs, notamment en tant qu'agents pour une thérapie de la douleur et/ou comme anti-inflammatoires et/ou pour une thérapie de la céphalée vasculaire de Horton et/ou comme anti-oxydants et/ou pour une thérapie anticancéreuse. De plus, la structure chimique de ces composés offre l'opportunité de mettre au point de nouveaux traceurs radioactifs pour l'imagerie par Tomographie par Émission de Positrons (PET). Ces traceurs radioactifs sont d'une grande pertinence pour la cartographie des récepteurs TRPV1 dans des états (patho)physiologiques.
PCT/EP2015/058830 2014-04-24 2015-04-23 Dérivés de biaryl amide ou d'urée en tant que ligands de trpv1 WO2015162216A1 (fr)

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CN114478359A (zh) * 2022-03-17 2022-05-13 河南大学 氨基甲酸酯类trpv1拮抗/faah抑制双靶点药物及其制备方法和应用
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