US20180344753A1 - Aminophosphinic derivatives for preventing and treating eye pain - Google Patents

Aminophosphinic derivatives for preventing and treating eye pain Download PDF

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US20180344753A1
US20180344753A1 US15/779,220 US201615779220A US2018344753A1 US 20180344753 A1 US20180344753 A1 US 20180344753A1 US 201615779220 A US201615779220 A US 201615779220A US 2018344753 A1 US2018344753 A1 US 2018344753A1
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group
ethyl
phosphinoyl
propionylamino
hydroxy
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Hervé Poras
Michel WURM
Stéphane MELIK PARSADANIANTZ
Annabelle REAUX-LE GOAZIGO
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Pharmaleads SA
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to the prevention and treatment of eye pain.
  • Eye pain is a particular form of pain which appears under many conditions, for instance accidental trauma, surgical procedures, uveitis, dry eye syndrome and diabetic neuropathies.
  • the medicinal products commonly used to treat eye pain are topical or systemic nonsteroidal anti-inflammatories, systemic analgesics, local anaesthetics and, in extreme cases, systemic opiates. These treatments have limited efficacy and systemic local side effects.
  • Local anaesthetics act on pain by directly inhibiting nerve transmission. Their use is limited to brief administration under medical supervision because their mechanism of action induces inhibitory effects at the cellular level in fibroblasts or the surrounding neuronal cells. That is why, even if the pain sensation can be alleviated by local anaesthetics, tissue healing and physiology can be impaired. It is thus important to discover other analgesic agents, without anaesthetic activity, which are effective and well-tolerated when applied topically to the painful eye.
  • Opiates such as morphine sulphate are used systemically to treat severe eye pain, but they have many adverse effects, such as sedation, nausea, constipation and respiratory depression, which substantially limit their use, particularly for chronic eye pain. It has been shown that topical administration of morphine relieves pain associated with corneal lesions in dogs (Stiles et al. (2003) Am. J. Vet. Res., 64, 813-818) and in rats (Wenk et al. (2003) Pain, 105, 455-465) without retarding healing of the corneal wound (Stiles et al. (2003) Am. J. Vet. Res., 64, 813-818).
  • enkephalins Metal-enkephalin and Leu-enkephalin
  • the latter are pentapeptides, endogenous opioids, first discovered in the mammalian brain (Hugues et al. (1975) Nature, 258, 577-580). They bind mainly to two receptor classes, ⁇ - and ⁇ -opioid receptors (Lord et al. (1977) Nature, 267, 495-499), which have different functions and distributions (Waksman et al. (1986) Proc. Natl. Acad. Sci., 83, 1523-1527).
  • Aminophosphinic derivatives “true” mixed inhibitors, i.e., inhibiting both APN and NEP, have been described in previous patents and publications (WO9818803; WO2010010106; Chen et al. (2000) J. Med. Chem., 43, 1398-1408; Chen et al. (2001) J. Med. Chem., 44, 3523-3530; Le Guen et al. (2003) Pain, 104, 139-148; Bonnard et al. (2015) Pharmacol. Res. Persp., 3(2), e00116, doi: 10.1002/prp2.116).
  • One of the objects of this invention is thus to provide novel aminophosphinic-type compounds capable of inhibiting both of the enzymatic activities (neprilysin and aminopeptidase N) responsible for the degradation of enkephalins, the latter which can have action within the context of eye pain.
  • the compounds of the invention can advantageously be used to prevent or relieve eye pain, in particular dry eye syndrome.
  • the compounds of the invention can advantageously be used to prevent or treat corneal neuropathic pain, in particular neuropathic hyperalgesia.
  • FIG. 1 is a graph corresponding to Example 1
  • FIG. 2 is a graph corresponding to Example 2.
  • FIG. 3 is a graph corresponding to Example 3.
  • FIG. 4 is a graph corresponding to Example 4.
  • FIG. 5 is a graph corresponding to Example 5.
  • FIG. 6 is a graph corresponding to Example 5 and 6;
  • FIG. 7 is a graph corresponding to Example 7.
  • FIG. 8 is a graph corresponding to Example 8.
  • Neuropathic pain has peripheral and central causes and can specifically affect the cornea of the eye.
  • Current medicinal products have little efficacy, which makes the discovery and development of novel compounds essential.
  • Corneal neuropathic hyperalgesia involves a dysfunctional corneal pain perception and control system. It is associated with significant discomfort and persistent heightened corneal sensitivity (peripheral sensitization) in the absence of overt trauma or harmful stimuli (reviewed in Belmonte et al. (2004) Exp. Eye Res., 78(3), 513-525; Rosenthal & Borsook (2012) Ocul. Surf., 10(1), 2-14; Rosenthal et al. (2009) Ocul. Surf., 7(1), 28-40).
  • Corneal hypersensitivity, neuroinflammation, pain and photophobia are reported among patients after eye surgery or chemical or toxic exposure, including repeated use of benzalkonium chloride, the usual preservative in eye drops.
  • Corneal neuropathic pain is also a consequence of eye conditions generally referred to as dry eye syndrome. That includes non-infectious immunological causes such as Goujerot-Sjögren syndrome or systemic lupus as well as ophthalmic zoster due to Herpesvirus zoster (reviewed in Rosenthal & Borsook (2012) Ocul.
  • dry eye syndrome is refractory to treatment and there is no real correlation between the symptoms and associated signs.
  • corneal hyperalgesia due to desiccation of the ocular surface (dry eye evaporation)
  • corneal neuropathic hyperalgesia is the most common form of corneal neuropathic hyperalgesia
  • many patients presenting with symptoms of ocular dryness do not have objective signs of dry eye (reduced lachrymal volume) or of superficial corneal erosion.
  • neuropathy can sometimes precede deterioration of the lachrymal film (Rosenthal & Borsook (2012) Ocul. Surf., 10(1), 2-14; Rosenthal et al. (2009), Ocul. Surf., 7(1), 28-40).
  • the compounds prescribed for corneal neuropathic pain include a wide variety of different compounds such as opiates, nonsteroidal anti-inflammatories, sodium channel blockers (local anaesthetics), antiepileptics, tricyclic antidepressants and GABA analogues.
  • This arsenal remains inadequate, however, and the complex nature of neuropathic corneal pain is shown by the fact that there is no known single treatment effective against the various symptoms. Furthermore, the side effects of many currently prescribed agents limit the therapeutic window. Corneal inflammatory neuropathic pain thus represents an unmet therapeutic need (Rosenthal & Borsook (2012) Ocul. Surf., 10(1), 2-14; Rosenthal et al. (2009) Ocul. Surf., 7(1), 28-40).
  • the term “pharmaceutically acceptable” refers to that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for both veterinary and human pharmaceutical use.
  • salts of a compound, as used in the present invention, refers to salts which are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound. Within the context of the present invention, they are addition salts obtained with an inorganic or organic base. Thus, the salt formed corresponds:
  • Acceptable organic bases include amines such as ammonia, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, triethylamine, tromethamine and the like.
  • Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, lithium hydroxide (lithine), potassium hydroxide (potash), sodium carbonate and sodium hydroxide (soda).
  • the pharmaceutically acceptable salts of the compounds of the invention will be addition salts obtained with a pharmaceutically acceptable inorganic or organic base, such as lithine, soda, potash, ammonia, a tertiary amine of formula NR a R b R c , where R a , R b and R c are each independently an alkyl group as defined below, such as triethylamine, or a basic amino acid such as lysin or arginine and derivatives thereof.
  • a pharmaceutically acceptable inorganic or organic base such as lithine, soda, potash, ammonia, a tertiary amine of formula NR a R b R c , where R a , R b and R c are each independently an alkyl group as defined below, such as triethylamine, or a basic amino acid such as lysin or arginine and derivatives thereof.
  • unsaturated means that the hydrocarbon chain includes one or more unsaturation(s).
  • unsaturation refers to a double or triple bond.
  • halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
  • it is a fluorine, chlorine or bromine atom. More advantageously, it is a fluorine or bromine atom, preferably fluorine.
  • amino group refers to a group having the formula —NR*R**, where R* and R** are each independently a hydrogen atom or a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having from 1 to 6, preferably from 1 to 4, carbon atoms, or R* and R** form, together with the nitrogen atom to which they are attached, a 5- or 6-member heterocycle which is optionally saturated and which does not contain a heteroatom other than the nitrogen to which the two radicals R* and R** are attached.
  • the amino group can be an —NH 2 , —NHMe, —NHEt, —NHPr, —NHiPr, —NHBu, —NHiBu, —NHtBu, piperidinyl or pyrrolidinyl group.
  • aromatic group refers to an aromatic group having preferably from 5 to 10 carbon atoms, unless specified otherwise, and having one or more fused rings, such as for example a phenyl or naphthyl group.
  • it is phenyl.
  • heteroaromatic group refers to any aromatic group as defined above in which one or more carbon atom(s) has(have) been replaced by one or more heteroatom(s), advantageously 1 to 4, even more advantageously 1 to 2, such as for example sulphur, nitrogen or oxygen atoms, wherein the nitrogen and sulphur atoms can be optionally oxidized in S-oxide or N-oxide form.
  • heteroaromatic groups include furyl, thienyl, pyrrolyl, pyridinyl, pyrimidyl, pyrazolyl, imidazolyl, tetrazolyl and indyl groups.
  • heteroaromatic ring having 5 or 6 atoms refers to a heteroaromatic group as defined above having only one 5- or 6-atom ring. It is in particular a thienyl, pyrrolyl, pyridinyl, pyrimidyl, pyrazolyl, imidazolyl or tetrazolyl group.
  • heterocycle refers to a hydrocarbon ring, advantageously having 5 or 6 atoms, of which one or more carbon atom(s) has(have) been replaced by one or more heteroatom(s), advantageously 1 to 4, even more advantageously 1 to 2, such as for example sulphur, nitrogen or oxygen atoms, wherein the sulphur and nitrogen atoms can be optionally oxidized in N-oxide or S-oxide form. Unless specified otherwise, this ring may be saturated or aromatic.
  • the heterocycle may be in particular one of the following groups: piperidinyl, pyrrolidinyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, piperazinyl, thiadiazolyl, tetrahydrothienyl or thiazolyl.
  • alkyl refers to a saturated, linear or branched hydrocarbon chain having from 1 to 4 carbon atoms, unless specified otherwise. It is in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups.
  • cycloalkyl refers to a saturated hydrocarbon ring having from 5 to 8 carbon atoms, in particular a cyclohexyl, cyclopentyl or cycloheptyl group.
  • alkylheteroaromatic refers to a heteroaromatic group as defined above attached to the molecule via an alkyl group as defined above. It is in particular a thenylmethyl or furylmethyl group.
  • R 1 is an (acyloxy)alkyl carbamate group —C( ⁇ O)—O—C(R)(R′)—OC( ⁇ O)—R′′.
  • R 1 is a —C( ⁇ O)—O—CHMe-OC( ⁇ O)—CHMe 2 group.
  • R 1 is a hydrogen atom.
  • radical R 2 is a saturated, linear or branched hydrocarbon chain having from 1 to 4 carbon atoms.
  • radical R 2 is a methyl group.
  • R 3 is a hydrogen atom and R 4 is as previously defined.
  • R 3 is a hydrogen atom and R 4 is a benzyl group optionally substituted by 1 to 5 halogen atom(s) such as fluorine or bromine, a phenyl or a 5- or 6-member heteroaromatic group.
  • R 3 is a hydrogen atom and R 4 is a benzyl group substituted in the para position by a halogen atom, such as a bromine atom, or by a phenyl.
  • radical R 5 is a hydrogen atom.
  • radical R 6 is an alkyl group such as a methyl group.
  • radical R 7 is a hydrogen atom or a benzyl.
  • radicals are defined as follows:
  • the compound of the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compounds of formula (I) have been described as dual inhibitors of APN and NEP and exhibit analgesic activities in numerous models of central or peripheral pain after intravenous or oral administration (Chen et al. (2000) J. Med. Chem., 43, 1398-1408; Bonnard et al. (2015) Pharmacol. Res. Persp., 3(2), e00116, doi: 10.1002/prp2.116).
  • the compounds of formula (I) can be synthesized, for example, by methods described in: FR 2 755 135 and FR 2 934 267.
  • Compound 1, for example can be synthesized as described in Chen et al. (2000) J. Med. Chem., 43, 1398-1408 and compound 2, for example, can be synthesized as described in Bonnard et al. (2015) Pharmacol. Res. Persp., 3(2), e00116, doi: 10.1002/prp2.116.
  • the compounds of formula (I) are formulated according to the methods described by the person skilled in the art, in particular for the desired route of administration.
  • the compounds are formulated as an ophthalmic composition, in particular as eye drops, ophthalmic ointments, ophthalmic gels, or ophthalmic inserts.
  • compositions of the present invention will be formulated as solutions, suspensions or other dosage forms for topical administration, in particular ocular administration. Consequently, such compositions are formulated so as to be well-tolerated (in particular acceptable pH) and to have physiological osmolarity. It is also preferable that the compositions are sterile and formulated so as to avoid bacterial contamination during use. Ophthalmic solutions are advantageously clear, characterized by an absence of particles. Suspensions are advantageously characterized by a particle size of less than 25 ⁇ m.
  • pharmaceutical formulations for ocular administration include:
  • Aqueous solutions will preferably be used because they are easier to formulate, and it is also easier for a patient to administer such a composition by instilling 1 or 2 drops of the solution in the affected eye. All the same, the composition may also be a suspension, a viscous or semi-viscous gel, or other types of solid or semi-solid compositions.
  • the vehicle preferably used for the ophthalmic formulations of the present invention is Milli-Q water, and preferentially physiological saline solution.
  • the pH of such a solution will preferably be kept between 5.5 and 8, and preferentially between 6.5 and 7.2, with suitable buffer such as acetate, citrate, phosphate or borates buffers.
  • suitable buffer such as acetate, citrate, phosphate or borates buffers.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and/or penetration enhancers.
  • the ophthalmic composition is advantageously an aqueous solution, advantageously having a pH in the range from 5.5 to 8.
  • compositions administered in accordance with the methods described in the present invention contain an active amount for ophthalmic use of a compound of formula (I). That means a sufficient amount to prevent or relieve eye pain.
  • the compositions described in the present invention will contain from 0.01% to 3% (weight/volume) of a compound of formula (I).
  • the compositions of the present invention will contain from 0.1% to 1% (weight/volume) of a compound of formula (I).
  • the ophthalmic composition advantageously comprises from 0.01% to 3% (weight/volume) of said compound of formula (I), more advantageously from 0.1% to 1% (weight/volume).
  • the administered composition may also contain other various ingredients which include, but are not limited to, surfactants, osmolarity agents, buffers, preservatives, co-solvents, or viscosity enhancers.
  • osmolarity adjusters can be used to adjust the osmolarity of a solution in order to make the composition more like natural tears.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol can be used in order to approach physiological osmolarity (generally, about 150-450 mOsm and preferentially 250-350 mOsm).
  • the preservatives which can be used in the ophthalmic formulations of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Such preservatives are generally used in an amount from 0.001% to 1.0% weight/volume.
  • the viscosity agents which can be used in the ophthalmic formulations of the present invention include, but are not limited to, monomeric polyols, povidone, hydroxypropylmethyl cellulose, poloxamers, carboxymethyl cellulose, carbomers or hydroxyethylcellulose, dextrans such as dextran 70, water-soluble proteins such as gelatin, etc.
  • the penetration agents which can be used include organic solvents such as dimethylsulphoxide or other sulphoxides, dimethylacetamide and pyrrolidones; certain amide of heterocyclic amine compounds, glycols (e.g., propyleneglycol); propylene carbonates; oleic acid; alkylated amines and other ammonium salt derivatives; various anionic, cationic or non-ionic surfactants, etc.
  • a formulation of the present invention comprises a cyclodextrin, such as hydroxypropyl beta-cyclodextrin or sulphobutyl ether beta-cyclodextrin, or sodium polystyrene sulphonate.
  • the ophthalmic composition advantageously further comprises cyclodextrin, such as hydroxypropyl beta-cyclodextrin or sulphobutyl ether beta-cyclodextrin, or sodium polystyrene sulphonate.
  • FIG. 1 representing the degree of palpebral opening, in mm, at the time of the pre-test, just before pain induction and then at 5, 10, 15, 20, 25 and 30 min after pain induction.
  • FIG. 2 representing the degree of palpebral opening, in mm, at the time of the pre-test, just before pain induction and then at 5, 10, 15, 20, 25 and 30 min after pain induction.
  • corneal pain by observing conjunctival hyperaeria after pain induction (a single instillation of 1% capsaicin (33 mM) in the right eye) in albino rabbits. Pre-treatment with the compound to be tested, 15 min before capsaicin instillation.
  • FIG. 3 representing conjunctival hyperaemia (scale: 0-3) at the time of the pre-test, just before pain induction and then at 1, 5, 10, 15, 20, 25, 30, 40, 50 and 60 min after pain induction.
  • Black histograms the administered solution contains 5 mM capsazepine (reference control product).
  • corneal pain by observing conjunctival hyperaemia after pain induction (a single instillation of 1% capsaicin (33 mM) in the right eye) in albino rabbits. Pre-treatment with the compound to be tested, 15 min before capsaicin instillation.
  • FIG. 4 representing conjunctival hyperaemia (scale: 0-3) at the time of the pre-test, just before pain induction and then at 1, 5, 10, 15, 20, 25, 30, 40, 50 and 60 min after pain induction.
  • Black histograms the administered solution contains 5 mM capsazepine (reference control product).
  • the compounds of formula I of the present invention were also tested, in 8-week-old male C57BL/6 mice (JANVIER LABS), using a capsaicin test (100 ⁇ M) after twice-daily treatment for 5 days of the compound of formula I on cornea injured beforehand (with a 1.5 mm diameter trephine).
  • Analgesic effect of compound 2 in the model of capsaicin-induced ocular pain 100 ⁇ M.
  • a corneal epithelial injury was made on the right cornea of male C57BL/6 mice (JANVIER LABS) using a 1.5 mm diameter trephine.
  • a twice-daily topical treatment for 4 days, is carried out with 1 ⁇ PBS (5 animals per group) or with 10 mM compound 2 (5 animals per group).
  • 1 ⁇ PBS 5 animals per group
  • 10 mM compound 2 5 animals per group
  • 15 minutes after the last instillation 100 ⁇ M capsaicin is instilled and the behavioural analysis is performed.
  • the results obtained corresponding to the trephine injury alone before capsaicin are shown in FIG. 5 (y-axis: palpebral closure time in seconds).
  • de-epithelialization of the corneal epithelium of the left eye of the mouse is carried out using a 1.5 mm diameter trephine. This surgery is carried out under a surgical microscope. This procedure lasts at most 3 minutes per animal. The depth and surface area of corneal de-epithelialization are standardized and then evaluated by a slit-lamp examination. The advantage of this surgical tool is standardization of the injury.
  • the 8-week-old male C57BL/6 mice thus treated receive a twice-daily treatment for 5 days of the compound of formula I or PBS before the application of capsaicin.
  • the histogram on the left (black) represents the response of mice treated with PBS, the histogram in the middle represents the response of mice treated with compound 1 and the histogram on the right represents the response of mice treated with compound 2.
  • Twice-daily topical treatment for 5 days with compound 1 or compound 2, on a cornea injured beforehand (1.5 mm diameter trephine), induced a significant decrease, when measured with Von Frey filaments, in mechanical sensitivity (expressed as a higher tolerable filament weight) in comparison with the results obtained in control mice treated with 1 ⁇ PBS (n 5 mice per group).
  • FIG. 7 shows that mechanical allodynia induced by 0.2% BAC is significantly reduced (higher sensitivity threshold) in the presence of compound 2 (10 mM).
  • LPS Bacterial lipopolysaccharide

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FR1561598 2015-11-30
FR1561598A FR3044227B1 (fr) 2015-11-30 2015-11-30 Derives aminophosphiniques pour la prevention et le traitement des douleurs oculaires
PCT/EP2016/079285 WO2017093322A1 (fr) 2015-11-30 2016-11-30 Dérivés aminophosphiniques pour la prévention et le traitement des douleurs oculaires

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EP3383403B1 (fr) 2019-12-25
ES2773148T3 (es) 2020-07-09
MX2018006580A (es) 2018-08-01
TWI729039B (zh) 2021-06-01
KR20180095555A (ko) 2018-08-27
CN108289901B (zh) 2021-05-04
FR3044227A1 (fr) 2017-06-02
TW201726146A (zh) 2017-08-01
IL259562B (en) 2020-08-31
CN108289901A (zh) 2018-07-17
DK3383403T3 (da) 2020-03-16
JP6889176B2 (ja) 2021-06-18
CA3006365A1 (fr) 2017-06-08
ZA201804037B (en) 2020-07-29
WO2017093322A1 (fr) 2017-06-08
US10688113B2 (en) 2020-06-23
FR3044227B1 (fr) 2017-11-24
KR102657652B1 (ko) 2024-04-15
US20190167701A1 (en) 2019-06-06
IL259562A (en) 2018-07-31
HK1259181A1 (zh) 2019-11-29
JP2018536714A (ja) 2018-12-13
CN112121008A (zh) 2020-12-25
BR112018010007A2 (pt) 2018-11-21

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