Amino acid derivatives containing a disulfanyl group in the form of an NEP and APN inhibitor for the prevention and treatment of trigeminal nerve pain

Abstract

The present invention concerns a pharmaceutically acceptable salt of a compound of the following formula (I): H.sub.2N—CH(R.sub.1)—CH.sub.2S—S—CH.sub.2—CH(R.sub.2—CONH—CH(R.sub.3)—COOR.sub.4 (I) and more particularly an acid addition salt thereof, and the compositions comprising the same, for use in the prevention or treatment of trigeminal nerve pain, in particular migraines or trigeminal neuralgia.

Claims

1. A method for preventing or treating a trigeminal-nerve related pain in a subject in need thereof, comprising administering to the subject a pharmaceutically-acceptable salt of a compound of formula (I):
H.sub.2N—CH(R.sub.1)—CH.sub.2—S—S—CH.sub.2—CH(R.sub.2)—CONH—CH(R.sub.3)—COOR.sub.4  (I) wherein: R.sub.1 is: (i) a saturated or unsaturated, linear or branched hydrocarbon chain, containing 1 to 6 carbon atoms, optionally substituted by: an OR, SR or S(O)R radical, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical or a benzyl radical, or a phenyl or benzyl radical, (ii) a phenyl or benzyl radical optionally substituted by: 1 to 5 halogens, or, an OR, SR or S(O)R radical, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, or a methylene radical substituted by a 5 or 6 atom heterocycle, aromatic or saturated, having a nitrogen or sulfur atom as heteroatom, optionally oxidized in the form of N-oxide or S-oxide; R.sub.2 is: (i) a phenyl or benzyl radical optionally substituted by: 1 to 5 halogens, an OR or SR radical, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, an amino group, optionally mono— or disubstituted by a cyclic or linear aliphatic group, of 1 to 6 carbon atoms, a 5 or 6 atom aromatic ring, or an aromatic heterocycle ring with 5 to 6 atoms, the heteroatom being an oxygen, nitrogen or sulfur, or (ii) a methylene group substituted by a 5 or 6 atom heterocycle, aromatic or saturated, being an oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms optionally being oxidized in the form of N-oxide or S-oxide; R.sub.3 is: (i) a hydrogen, (ii) an OH or OR group, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, (iii) a saturated hydrocarbon (alkyl) chain, linear or branched, having 1 to 6 carbon atoms, optionally substituted by an OR or SR radical, R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, (iv) a phenyl radical or a benzyl radical, optionally substituted by 1 to 5 halogens, or (v) an OR or SR group, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, and OR.sub.4 is: (i) a glycolate OCH.sub.2COOR′ or lactate OCH(CH.sub.3)COOR' radical, (ii) an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ group, (iii) an OCH(CH.sub.2OCOR′).sub.2 or OCH.sub.2—CH(OCOR′)—CH.sub.2OCOR′ triglyceride radical, (iv) a glycoside radical, (v) a sulfonate OCH.sub.2CH.sub.2(SO.sub.2)CH.sub.3 radical, or (vi) an OCH(CH.sub.2OH).sub.2 radical, R′ is: a linear or branched C.sub.1-C.sub.6 alkyl optionally substituted by a C1—C.sub.3 alkoxy group, a C.sub.5-C.sub.8, cycloalkyl group, a phenyl group, a benzyl group, a heteroaryl group, or an alkyl heteroaryl group; and —R″ is: a hydrogen atom, a linear or branched C.sub.1-C.sub.6 alkyl chain optionally substituted by a C.sub.1-C.sub.3 alkoxy group, a C.sub.5-C.sub.8, cycloalkyl group, a phenyl group, a benzyl group, a heteroaryl group, or an alkyl heteroaryl group.

2. The method according to claim 1, wherein R.sub.1 is an alkyl radical having 1 to 4 carbon atoms substituted by an SR radical.

3. The method according to claim 1, wherein radical R.sub.2 is a benzyl radical or a methylene radical substituted by a 5 or 6 atom heterocycle, aromatic or saturated, having nitrogen or sulfur as heteroatom, optionally oxidized in the form of N-oxide or S-oxide.

4. The method of claim 1, wherein R.sub.3 is a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms substituted by an OH or SH radical.

5. The method of claim 1, wherein OR.sub.4 is an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ group, radical R′ being a C.sub.1-C.sub.4 alkyl chain, and radical R″ being a methyl, CH(CH.sub.3).sub.2, cyclohexyl or phenyl radical.

6. The method of claim 1, wherein the compound of formula (I) is in the form of a fumarate salt.

7. The method of claim 1, wherein the salt of a compound of formula (I) is a salt of formula (II):
A.sup.−,H.sub.3N.sup.+—CH(R.sub.1)—CH.sub.2—S—S—CH.sub.2—CH(R.sub.2)—CONH—CH(R.sub.3)—COOR.sub.4  (II) wherein: A.sup.− is a phosphate, chloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate or nicotinate anion; R.sub.1 is a saturated or unsaturated hydrocarbon chain, linear or branched, containing 1 to 6 carbon atoms, optionally substituted with an OR, SR or S(O)R group in which R represents a hydrogen, a linear or branched hydrocarbon chain of 1-4 carbons, a phenyl radical or benzyl radical; (i) a phenyl or benzyl group optionally substituted by: 1 to 5 halogen atoms, a thiol, an ether OR, or a thioether SR, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, an aromatic ring or aromatic heterocycle with 5 to 6 atoms, the heteroatom being an oxygen, nitrogen or sulfur, or (ii) a methylene group substituted by a 5 or 6 atom heterocycle, aromatic or saturated, the heteroatom being an oxygen, nitrogen or sulfur, the nitrogen or sulfur atoms optionally being oxidized in the form of N-oxide or S-oxide; R.sub.3 is: (i) a hydrogen, (ii) an OH or OR group, wherein R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, (iii) a linear or branched C.sub.1-C.sub.6 alkyl, optionally substituted by an OH, OR, SH or SR group, R is a hydrogen, a linear or branched hydrocarbon chain 1 to 4 carbon atoms, a phenyl radical, or a benzyl radical, or (iv) a phenyl or benzyl group, optionally substituted by 1 to 5 halogens, notably fluorine or by an OR or SR group, R is a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl radical or a benzyl radical; OR.sub.4 is: (i) a glycolate OCH.sub.2COOR′ or lactate OCH(CH.sub.3)COOR′ radical; (ii) an OCH.sub.2OCOR′ or OCH(CH.sub.3)OCOOR′ group, or (iii) an OCH(CH.sub.2OCOR′).sub.2 or OCH.sub.2—CH(OCOR′)—CH.sub.2OCOR′ triglyceride radical, wherin R′ is a linear or branched C.sub.1-C.sub.4 alkyl.

8. The method of claim 1, wherein the salt is a pharmaceutically-acceptable salt selected from the group consisting of: 1-(2-(1-(2,3-diacetoxypropoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-methanesulfonylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl))-ethylcarbamoyl)-3-thiophen-3-yl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-ethoxycarbonylmethyloxycarbonylethylcarbamoyl)-3-thiophen-3-yl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylméthyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-acetoxy-1-acetoxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-hydroxy-1-hydroxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-yl-propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxy-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-acetoxy-1-acetoxymethyl-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-((1-ethoxycarbonyloxy-ethoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 3-(2-amino-4-methylsulfanyl-butyldisulfanyl)-2-benzyl-N-(5-ethyl-(1,3,4)-thiadiazol-2-yl)-propionamide, 1-(2-((1-ethoxycarbonyloxy-2-methyl-propoxycarbonylméthyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 3-methylsulfanyl-1-(3-phenyl-2-((1-propionyloxy-ethoxycarbonylmethyl)-carbamoyl)-propyldisulfanylmethyl)-propyl-amine, 1-(2-((2-methyl-1-propionyloxy-propoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((cyclohexyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 3-methylsulfanyl-1-(3-phenyl-2-((phenyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-propyldisulfanylmethyl)-propyl-amine.

9. The method of claim 1, wherein the salt is (5S, 10S)-10-benzyl-16-methyl-11,14,18-trioxo-15,17,19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium fumarate.

10. The method of claim 1, comprising administering a therapeutic dose of the salt to the patient in need thereof in one to four administrations.

11. The method of claim 1, comprising administering a therapeutic dose comprising between 200 and 800 mg of the salt to the patient in need thereof.

12. The method of claim 1, comprising administering the salt for preventing migraine attacks.

13. The method of claim 1, comprising administering the salt for preventing or treating migraines or trigeminal neuralgia.

14. The method of claim 1, comprising administering the salt for preventing or treating essential trigeminal neuralgia, symptomatic trigeminal neuralgia, migraines, cephalic cutaneous allodynia, cluster headaches, or peripheral trigeminal pain associated with multiple sclerosis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph showing the comparative tail withdrawal latency time (in seconds) for a control group (with carrier or 20 minutes after IP injection of a dose of 50 mg/kg of compound 1), and the EAE model group (with carrier or after 30 minutes after injection of a dose of 50 mg/kg or 100 mg/kg of compound 1);

(2) FIG. 2 is graph showing the von Frey force necessary to bring about head withdrawal (in g) as a function of time (minutes) after IV injection of a saline solution (carrier, black square), a solution of compound 1 (black circle), or sumatriptan (gray triangle).

(3) FIG. 3 is graph showing the von Frey force necessary to bring about head withdrawal (in g) as a function of time (minutes) after oral administration of a saline solution (carrier, black square), a solution of compound 1 (black circle) or rizatriptan (gray triangle);

(4) FIG. 4 is a graph showing the von Frey force necessary to bring about head withdrawal (in g) as a function of time (minutes) after oral administration of a saline solution (carrier, black circle) or compound 1 (PL37, gray circle, 50 mg/kg);

(5) FIG. 5 is a graph showing the von Frey force necessary to bring about head withdrawal (in g) as measured at t=0 before oral administration of saline solution (carrier, black circle) or compound 1 (gray circle, 50 mg/kg) measured for 5 days;

(6) FIG. 6 is a graph showing the von Frey force necessary to bring about head withdrawal (in g) as a function of time (minutes) after oral administration of a saline solution (carrier, black circle) or compound 1 (gray circle, 50 mg/kg once daily).

DETAILED DESCRIPTION

(7) In the context of the present invention “trigeminal nerve pain” means pain relating to the sensory part of the trigeminal. “Pain relating to the sensory part of the trigeminal”, according to the present invention, covers different types of pain originating from the sensory part of the trigeminal nerve. In particular, it is a question of craniofacial pain, and especially orofacial pain. It can also be pain located in the cornea, meninges or dental pulp, the dermatomas of the face, mucosal tissues, vascular tissues or muscle tissues. It may also be pain located in the cornea, conjunctiva, nose, intranasal mucosa, eyelids, supraorbital skin, forehead, scalp, lips, jaw, tongue, gums or oral mucosa.

(8) In particular, it is a migraine or trigeminal neuralgia, especially essential trigeminal neuralgia and symptomatic trigeminal neuralgia. It may also be headaches, especially acute headaches, in particular recurrent, or their symptoms such as cephalic cutaneous allodynia. It may also be peripheral trigeminal pain associated with multiple sclerosis.

(9) In the context of the present invention, the term “migraine” refers to both acute migraine, which defines an occasional headache lasting 4 to 72 hours occurring less than 15 days a month, and chronic migraine, which is characterized by chronic headaches, with headaches that recur repeatedly either for no apparent reason, or following exposure of the patient to a triggering factor (such as bright light, menstruation, etc.) fifteen days or more a month (Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition, Cephalalgia (2013), 33: 629-808).

(10) In the context of the present invention, the terms “migraine attacks” or “chronic migraine” are interchangeable.

(11) In the sense of the present invention, treatment means the attenuation or resolution of pain. In this case, the compound or composition according to the invention is administered after onset of pain.

(12) In the sense of the present invention, prevention means that the pain has not started and the compound or composition according to the invention is administered before the onset of pain, thereby preventing said onset of pain or attenuating future pain.

(13) In the sense of the present invention, “therapeutic dose” means the daily quantity of active ingredient (for example salt of the compound of formula (I)) administered to the patient having need thereof.

(14) “Repeatedly” means that the therapeutic dose or compositions of the invention, as applicable, are administered by administrations staggered over time for a period ranging from several days to several months, most often with regular time intervals between administrations.

(15) In the sense of the present invention, “amino” group means a group of formula —NR*R**, where R* and R** represent, independently of one another, a hydrogen atom or a saturated or unsaturated, linear, branched or cyclic hydrocarbon group containing 1 to 6, preferably 1 to 4, carbon atoms, or R* and R** form together, with the nitrogen atom which carries them, a 5- or 6-membered heterocycle, saturated or unsaturated, and having no other heteroatom other than the nitrogen which carries both the R* and R** radicals. In particular, the amino group may be an —NH.sub.2, —NHMe, —NHEt, —NHPr, NHiPr, —NHBu, —NHiBu, —NHtBu, piperidinyl or pyrrolidinyl group. Preferably, an amino group is a group of the formula —NR*R**, where R* and R** represent, independently of one another, a hydrogen atom or a linear or branched C.sub.1-C.sub.6 alkyl group (preferably C.sub.1-C.sub.4).

(16) In the context of the present invention, the term “hydrocarbon chain” designates alkanes, alkenes or alkynes. In particular, the expression “saturated hydrocarbon chain” designates alkyl radicals with 1 to 6 carbon atoms (C.sub.1-C.sub.6) or 1 to 4 carbon atoms (C.sub.1-C.sub.4), linear or branched. Examples of alkyl radicals having 1 to 4 carbon atoms include methyl, ethyl, propyl, butyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl and 2-methyl-propyl radicals. Examples of alkyl radicals having 1 to 6 carbon atoms include pentyl, hexyl 1-methyl-butyl, 1-methyl-pentyl 2-methyl-butyl 2-methyl-pentyl, 3-methyl-butyl, 3-methyl-pentyl, 4-methyl-pentyl or 1-ethyl-propyl, 1-ethyl-butyl, 2-ethyl-butyl radicals. The expression “unsaturated hydrocarbon chain” designates alkenyl radicals (at least one double bond), for example vinyl, allyl or the like, or alkynyl radicals (at least one triple bond) containing 2 to 6 carbon atoms, or 2 to 4 carbon atoms, linear or branched.

(17) In the sense of the present invention, “cycloalkyl” means a saturated hydrocarbon ring containing 5 to 8 carbon atoms, in particular the cyclohexyl, cyclopentyl or cycloheptyl group.

(18) The term “halogen” used here designates a chlorine, a bromine, an iodine and a fluorine. Advantageously, it is a fluorine, bromine or chlorine atom. More advantageously, it is a fluorine or bromine atom, and preferably fluorine.

(19) In the sense of the present invention, “aromatic” means an aromatic group, preferably containing 5 to 10 carbon atoms, unless otherwise stated, and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously it is phenyl.

(20) In the sense of the present invention, “heteroaromatic” group or radical means any aromatic group as defined above in which one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 to 2, such as, for example, sulfur, nitrogen or oxygen atoms, the sulfur and nitrogen atoms possibly being oxidized in the form of S-oxide or N-oxide. Examples of heteroaromatic groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidyl, pyrazolyl, imidazolyl, tetrazolyl or indyl groups. Preferably, it is a thienyl group. In the sense of the present invention, “heteroaromatic ring with 5 or 6 atoms” means a heteroaromatic group such as defined above comprising only a single 5- or 6-atom ring. This is particularly a thienyl, pyrrolyl, pyridinyl, pyrimidyl, pyrazolyl, imidazolyl or tetrazolyl group.

(21) In the sense of the present invention, “heterocycle” means a hydrocarbon ring advantageously with 5 or 6 atoms, of which one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 to 2, such as, for example, sulfur, nitrogen or oxygen atoms, the sulfur and nitrogen atoms possibly being oxidized in the form of S-oxide or N-oxide. Unless otherwise stated, this ring may be saturated or aromatic. Examples of aromatic or saturated 5- or 6-membered heterocyclic rings having a nitrogen or sulfur atom as the heteroatom include, but are not limited to, the following radicals: thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, thiadiazolyl, the nitrogen and sulfur atoms being optionally oxidized in the form of N-oxide or S-oxide. Examples of heterocyclic rings with 5 or 6 atoms, aromatic or saturated, having an oxygen atom as the heteroatom include, but are not limited to, the following radicals: furyl, pyranyl, isoxazolyl, morpholinyl, furazanyl, oxazolyl, oxazolidinyl, oxazolinyl.

(22) Compounds of formula (I) potentially have 2 to 9 asymmetric centers. The radicals R.sub.1, R.sub.2 and R.sub.3 are typically introduced so as to obtain optically pure sequences corresponding to a stereochemistry recognized by enzymatic activities. R.sub.4 radicals may optionally contain an unresolved asymmetric center.

(23) Compounds of the invention are in the form of pharmaceutically-acceptable salts, or a hydrate thereof. In the present invention, “pharmaceutically acceptable” means something usable in the preparation of a pharmaceutical composition that is generally safe, nontoxic and neither biologically or otherwise undesirable and which is acceptable for veterinary use as well as a human pharmaceutical.

(24) “Pharmaceutically-acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined here, and which have the desired pharmacological activity of a parent compound. Such salts include:

(25) (1) pharmaceutically-acceptable acid addition salts formed with acids, and

(26) (2) hydrates and solvates thereof.

(27) Typically, compounds of formula (I) are in the form of addition salts obtained with pharmacologically-acceptable organic or mineral acids such as phosphates, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate and nicotinate.

(28) The solvate is preferably an alcoholate, such as an ethanolate.

(29) Preferably, the compounds of the invention are in the form of fumarate salts, or a hydrate thereof.

(30) Radical R.sub.1 advantageously represents an alkyl radical with 1 to 6 or 1 to 4 carbon atoms, optionally substituted by an OR, SR or S(O)R, radical, in each of these radicals, R has the same meaning as previously, and advantageously represents a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbons, a phenyl or benzyl radical. R.sub.1 still more advantageously represents an alkyl radical having 1 to 4 carbon atoms substituted by an SR radical, R having the same meaning as previously, in particular, R represents a saturated linear or branched hydrocarbon chain of 1 to 4 carbon atoms.

(31) R.sub.2 advantageously represents: a phenyl or benzyl group optionally substituted by: 1 to 5 halogen atoms, notably fluorine, a hydroxyl or a thiol, an ether OR or a thioether SR, R having the same meaning as above, an aromatic ring or aromatic heterocycle with 5 to 6 atoms, the heteroatom being an oxygen, nitrogen or sulfur, a methylene group substituted by a 5 or 6 atom heterocycle, aromatic or saturated, the heteroatom being an oxygen, nitrogen or sulfur, the nitrogen or sulfur atoms optionally being oxidized in the form of N-oxide or S-oxide;

(32) In particular, radical R.sub.2 represents a benzyl or phenyl radical, or a methylene radical substituted by a 5 or 6 atom heterocycle, aromatic or saturated, having nitrogen or sulfur as heteroatom, optionally oxidized in the form of N-oxide or S-oxide; In particular, radical R.sub.2 represents a benzyl or methylene radical substituted by a 5 or 6 atom heterocycle, aromatic or saturated, having nitrogen or sulfur as heteroatom, optionally oxidized in the form of N-oxide or S-oxide, still more advantageously a benzyl radical or a methylene radical substituted by a thiophenyl radical (thienyl).

(33) Advantageously, radical R.sub.3 represents: a hydrogen, an OH or OR group, R having the same meaning as above, a linear or branched C.sub.1-C.sub.6 alkyl, optionally substituted by an OH, OR, SH or SR group, R having the same meaning as above, a phenyl or benzyl group, optionally substituted by 1 to 5 halogens, notably fluorine or by an OR or SR group, R having the same meaning as above.

(34) In particular, radical R.sub.3 represents a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, still more advantageously 1 to 4 carbon atoms, optionally substituted by an OR or SR radical, in each of these radicals, R has the same meaning as previously. Even more advantageously, radical R.sub.3 represents a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, still more advantageously 1 to 4 carbon atoms, substituted by an OH or SH radical.

(35) Radical OR.sub.4 advantageously represents: a glycolate OCH.sub.2COOR′ radical, R′ having the same meaning as previously (in particular R′ represents a C.sub.1-C.sub.4 alkyl group optionally substituted by a methoxy group or a C.sub.5-C.sub.6) cycloalkyl group, an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ radical, R′ and R″ having the same meaning as previously (in particular R □and/or R″ represent a C.sub.1-C.sub.4 alkyl group optionally substituted by a methoxy group or a C.sub.5-C.sub.6 cycloalkyl group where R″ is a hydrogen atom), an OCH(CH.sub.2OCOR′).sub.2 or OCH.sub.2—CH(OCOR′)—CH.sub.2OCOR′ triglyceride radical, in each of these radicals, R′ having the same meaning as previously a glycoside radical such as D-glucose, an OCH.sub.2CH.sub.2(SO.sub.2)CH.sub.3 sulfonate radical; an OCH(CH.sub.2OH).sub.2. radical

(36) Alternatively, radical OR.sub.4 may represent: a glycolate OCH.sub.2COOR′ or lactate OCH(CH.sub.3)COOR′ radical; an OCH.sub.2OCOR′ or OCH(CH.sub.3)OCOOR′ group, or an OCH(CH.sub.2OCOR′).sub.2 or OCH.sub.2—CH(OCOR′)—CH.sub.2OCOR′ triglyceride radical,

(37) R′ representing a linear or branched C.sub.1-C.sub.4 alkyl group.

(38) In particular, radical OR.sub.4 represents an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ group, radical R′ representing a C.sub.1-C.sub.4 alkyl chain (in particular the ethyl radical) and radical R″ representing a methyl, CH(CH.sub.3).sub.2, cyclohexyl or phenyl radical.

(39) According to one particular embodiment, the salt of the invention is a salt of formula (II):
A−,H.sub.3N.sup.+—CH(R.sub.1)—CH.sub.2—S—S—CH.sub.2—CH(R.sub.2)—CONH—CH(R.sub.3)—COOR.sub.4  (II)

(40) wherein: A− represents a phosphate, chloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemi-tartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate or nicotinate anion; R.sub.1 represents a saturated or unsaturated, linear or branched hydrocarbon chain, containing 1 to 6 carbon atoms, optionally substituted by an OR, SR or S(O)R group in which R represents a hydrogen, a linear or branched hydrocarbon chain of 1-4 carbons, a phenyl or benzyl radical; R.sub.2 represents: a phenyl or benzyl group optionally substituted by: 1 to 5 halogen atoms, notably fluorine, a hydroxyl or a thiol, an ether OR or a thioether SR, R having the same meaning as above, an aromatic ring or aromatic heterocycle with 5 to 6 atoms, the heteroatom being an oxygen, nitrogen or sulfur, a methylene group substituted by a 5 or 6 atom heterocycle, aromatic or saturated, the heteroatom being an oxygen, nitrogen or sulfur, the nitrogen or sulfur atoms optionally being oxidized in the form of N-oxide or S-oxide; R.sub.3 represents: a hydrogen, an OH or OR group, R having the same meaning as above, a linear or branched C.sub.1-C.sub.6 alkyl, optionally substituted by an OH, OR, SH or SR group, R having the same meaning as above, a phenyl or benzyl group, optionally substituted by 1 to 5 halogens, notably fluorine or by an OR or SR group, R having the same meaning as above; OR.sub.4 represents: a glycolate OCH.sub.2COOR′ or lactate OCH(CH.sub.3)COOR′ radical; an OCH.sub.2OCOR′ or OCH(CH.sub.3)OCOOR′ group, or an OCH(CH.sub.2OCOR′).sub.2 or OCH.sub.2—CH(OCOR′)—CH.sub.2OCOR′ triglyceride radical,

(41) R′ representing a linear or branched C.sub.1-C.sub.4 alkyl.

(42) Preferably, in formula (II), A.sup.− represents a fumarate anion.

(43) All the combinations of particular, advantageous and preferred embodiments of substituents R.sub.1, R.sub.2, R.sub.3 and R.sub.4 in formulas I and II are envisaged in the present invention.

(44) In particular, the invention concerns the acid addition salts of the following compounds, in particular fumarate salts thereof: 1-(2-(1-(2,3-diacetoxypropoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-methanesulfonylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl))-ethylcarbamoyl)-3-thiophen-3-yl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-ethoxycarbonylmethyloxycarbonylethylcarbamoyl)-3-thiophen-3-yl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-acetoxy-1-acetoxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-yl propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-hydroxy-1-hydroxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-yl propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-yl-propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(1-ethoxycarbonyloxy-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenyl propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-(1-(2-acetoxy-1-acetoxymethyl-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine, 1-(2-((1-ethoxycarbonyloxy-ethoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyl disulfanylmethyl)-3-methylsulfanylpropyl-amine, 3-(2-amino-4-methylsulfanyl-butyldisulfanyl)-2-benzyl-N-(5-ethyl-(1,3,4)-thiadiazol-2-yl)-propionamide, 1-(2-((1-ethoxycarbonyloxy-2-methyl-propoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 3-methylsulfanyl-1-(3-phenyl-2-((1-propionyloxy-ethoxycarbonylmethyl)-carbamoyl)-propyldisulfanylmethyl)-propyl-amine, 1-(2-((2-methyl-1-propionyloxy-propoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 1-(2-((cyclohexyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine, 3-methylsulfanyl-1-(3-phenyl-2-((phenyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-propyl disulfanylmethyl)-propyl-amine.

(45) Preferably, the compound of the invention is (5S, 10S)-10-benzyl-16-methyl-11,14,18-trioxo-15,17,19-trioxa-2,7,8-trithia-12-azahenicosan-5-aminium fumarate (or (E)-3-carboxyacrylate) (hereinafter compound 1):

(46) ##STR00001##

(47) Salts of compounds of formula (I) may be synthesized, for example, by methods described in WO 2007/048787. More particularly, compound 1 may be synthesized as described in WO 2017/064250.

(48) Compounds of formula (I) are formulated in accordance with the methods described by the person skilled in the art for the desired administration route.

(49) The invention also relates to pharmaceutical compositions containing as active ingredient at least one pharmaceutically acceptable salt of a compound of general formula (I) or hydrates of these salts in combination with one or more inert carriers or other pharmaceutically-acceptable carriers, for use in preventing or relieving trigeminal nerve pains, particularly migraines or trigeminal neuralgia.

(50) Pharmaceutical compounds according to the invention may be, for example, compositions that can be administered orally, nasally (aerosol administration), sublingually (administration by perlingual diffusion), rectally, parenterally, intravenously and percutaneously. Examples of compounds that can be administered orally include tablets, capsules, granules, microspheres, powders and oral solutions or suspensions. In particular, they are soluble in alcohol/polysorbate/water solvents, in particular ethanol/Tween®/water and mannitol/water or by means of cyclodextrins suitable for administration in humans, which are frequently used for intravenous administration. Compositions according to the invention may therefore be administered intravenously. They may also be administered orally or nasally, in particular via an aerosol or by perlingual diffusion or in an appropriate galenic preparation (microemulsions).

(51) Compositions according to the invention may be administered either in the aerosol (microemulsion) form orally or nasally or administered intravenously. These administration routes also permit the composition according to the invention to be administered by a non-digestive route. This is particularly interesting when the composition comprises additional compounds, which may have adverse effects on the digestive system (in particular the intestine), such as, for example, cannabinoid derivatives. This also permits increasing the bioavailability (especially cerebral) of compounds or associations

(52) Preferably, compositions of the invention are appropriate for oral administration or intravenous administration.

(53) In one particular embodiment, a formulation of the present invention comprises a cyclodextrin, such as hydroxypropyl beta-cyclodextrin or sulfobutyl ether beta-cyclodextrin, or sodium polystyrene sulfonate.

(54) Compositions administered in accordance with the methods described in the present invention contain an active quantity for use, of a salt of a compound of formula (I) or a salt of formula (II), in particular of compound 1. This means a sufficient quantity to prevent or relieve (treat) trigeminal nerve pains, in particular migraines, trigeminal neuralgia, cluster headaches or peripheral trigeminal pains related to multiple sclerosis.

(55) The therapeutic dose of a compound of the invention varies depending on numerous parameters such as, for example, the administration route chosen, weight, age, sex, advanced state of the disease to be treated and the sensitivity of the individual to be treated. Consequently, the optimum dosage will be determined, depending on the parameters deemed relevant, by the specialist in the case.

(56) According to the examples of the present invention, the administration of a daily dose of 4000 mg for 5 consecutive days did not cause the appearance of adverse side effects. The treatment may therefore be administered for several days without risk of toxicity.

(57) Advantageously, the compositions according to the invention, for their use to prevent or treat trigeminal nerve pains, in particular migraines and trigeminal neuralgia, may include a second active ingredient already known for pain prevention and treatment.

(58) Another object of the invention is a kit comprising: i) A first composition comprising at least one compound of formula (I) such as defined previously, and ii) A second composition comprising at least a second active ingredient useful to prevent or treat trigeminal nerve pains as a combination product for simultaneous, separate or staggered use.

(59) According to one embodiment, the pharmaceutically-acceptable salt of a compound of formula (I) or a salt of formula (II) according to the invention, in particular compound 1, is used for the prevention of migraine attacks.

(60) The prevention of chronic migraines by the pharmaceutically-acceptable salt of a compound of formula (I) or of a salt of formula (II) according to the invention, in particular of compound 1, is particularly suitable for patients sensitive to migraines, whose headaches recur periodically or are caused by a specific factor such as fatigue, stress, menstruation, bright or artificial light (during long exposure to screens for example), noise, some odors, certain foods (alcohol). The pharmaceutically acceptable salt of a compound of formula (I) may also be used preventively during the appearance of warning signs of a migraine attack such as an aura, a visual disorder which may manifest itself in the form of a dark spot surrounded by a glittering halo, geometric lines, bright spots in half the field of vision, visual field loss, double vision or the temporary loss of vision of one or both eyes. The patient will have identified the risks factors that are highly likely to induce migraines for them from experience.

(61) According to one embodiment, the pharmaceutical compositions according to the invention are used for preventing migraine attacks, in particular migraine attacks triggered by a specific risk factor such as described above.

(62) Thus, preferably, the pharmaceutical compositions used to prevent migraine attacks are administered orally. Advantageously, these compositions are administered repeatedly.

(63) Advantageously, a therapeutic dose of a salt of a compound of formula (I) or a salt of formula (II), in particular compound 1 such as described above is administered to a patient in order to prevent migraine attacks. Preferably, said dose is administered for preventing migraine attacks in patients sensitive to migraine attacks as described above. Thus, for preventing migraine attacks, the therapeutic dose is administered before the onset of pain and/or before exposure to a specific migraine trigger factor. For example, a women who regularly has migraines during her menstrual period could take the therapeutic dose one to several days before the start of her period.

(64) Preferably, in order to prevent migraine attacks, the therapeutic dose administered to the patient in need thereof is administered repeatedly. Advantageously, the therapeutic dose is administered for preventing migraine attacks orally or parenterally, advantageously orally, in particular in galenic form.

(65) The compositions of the invention may advantageously comprise a second active ingredient useful for preventing migraine attacks, in particular beta blockers, antidepressants, anticonvulsants, calcium channel blockers, and/or CGRP inhibitors.

(66) Thus, in order to prevent migraine attacks, the composition also comprises a beta blocker, such as atenolol, metoprolol, nadolol, propranolol and/or timolol. Antidepressants may be selected from amitriptyline, doxepin, nortriptyline, protriptyline and/or venlafaxine. Anticonvulsants may be selected from carbamazepine, gabapentin, topiramate and/or valproate/divalproex. Calcium channel blockers may be selected from verapamil, dihydropyridines and/or flunarizine. CGRP (calcitonin gene-related peptide) inhibitors are described in Tso A R et al., Curr Treat Options Neurol (2017), 19: 27 DOI 10.1007/s11940-017-0463-4 “Anti-CGRP monoclonal antibodies: the next era of migraine prevention?” whose content is incorporated here for reference.

(67) According to one particular embodiment, the composition of the invention used to prevent migraine attacks, also comprises a second active ingredient selected from beta blockers, antidepressants, calcium channel blockers and/or CGRP inhibitors; advantageously the second active ingredient is selected from propranolol, topiramate or amitriptyline.

(68) Another object of the invention is a kit comprising: i) a first composition comprising at least one compound of formula (I) such as defined previously, and ii) a second composition comprising at least one second active ingredient useful for preventing migraine attacks, notably selected from beta blockers, antidepressants, anticonvulsants, calcium channel blockers and/or CGRP inhibitors, advantageously the second active ingredient is selected from propranolol, topiramate or amitriptyline, as combination products for simultaneous, separate or staggered use.

(69) This kit may be used as a drug, notably in the prevention of migraine attacks.

(70) According to another embodiment, the pharmaceutically-acceptable salt of a compound of formula (I) or a salt of formula (II) according to the invention, in particular compound 1, is used for the treatment of trigeminal nerve pains, especially migraines or trigeminal neuralgia.

(71) Advantageously, according to the preceding embodiment, the pharmaceutically-acceptable salt of a compound of formula (I) or a salt of formula (II) according to the invention, in particular compound 1, is used for the treatment of acute migraines.

(72) According to one embodiment, the pharmaceutical compositions according to the invention are used for the treatment of trigeminal nerve pains, notably migraines or trigeminal neuralgia, in particular acute migraines. According to one embodiment, a therapeutic dose of a salt of a compound of formula (I) or a salt of formula (II), in particular compound 1 such as described above is administered to a patient in order to treat trigeminal nerve pains. In particular, this dose is administered to a patient in order to treat migraines, for example acute migraines.

(73) According to the preceding embodiment, the therapeutic dose to treat trigeminal nerve pains, especially migraines or trigeminal neuralgia, in particular acute migraines, is administered to the patient when the pain occurs. In the case of acute pain, this dose is generally effective, i.e. a single therapeutic dose is sufficient to attenuate or resolve the pain.

(74) Advantageously, in order to treat trigeminal nerve pain, in particular migraines or trigeminal neuralgia, the therapeutic dose of a salt of a compound of formula (I) or a salt of formula (II), in particular compound 1, administered to the patient in need thereof is comprised between 200 and 800 mg.

(75) Preferably, in order to treat trigeminal nerve pains, particularly migraines, the therapeutic dose such as described above is administered in one to four administrations. This therapeutic dose may advantageously be administered parenterally or orally.

(76) According to another embodiment, the compositions of the invention may advantageously comprise a second active ingredient useful to treat trigeminal nerve pains, in particular migraine, especially acute migraine, chosen from among analgesics, nonsteroidal antiinflammatories (NSAIDs), opioids, triptans, GABA modulators, Nav1.7 sodium channel blockers, CGRP inhibitors and/or cannabinoids, without this being limiting.

(77) Thus, according to one embodiment, the composition to treat trigeminal nerve pains, in particular migraines, especially acute migraines, also comprises an analgesic, especially NSAIDs, aspirin and acetaminophen.

(78) According to another embodiment, the composition to treat trigeminal nerve pains, in particular migraines, especially acute migraines, also comprises an NSAID, such as ibuprofen, diclofenac, piroxicam, ketoprofen, indomethacin, acetylsalicylic acid, celecoxib, naproxen.

(79) According to another embodiment, the composition to treat trigeminal nerve pain, in particular migraines, especially acute migraines, also comprises an opioid, especially alfentanil, anileridine, buprenorphine, butorphanol, carfentanil, codeine, dextropropoxyphene, fentanyl, hydrocodone, hydromorphone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, meperidine, propoxyphene, remifentanil, sufentanil, and tramadol. Advantageously, it is morphine or one of its derivatives, especially morphine. Indeed, morphine is also able to potentiate the analgesic effect induced by the compounds according to the invention.

(80) According to another embodiment, the composition to treat trigeminal nerve pains, in particular migraines, especially acute migraines, also comprises a triptan, especially sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, and/or rizatriptan.

(81) GABA modulators are particularly carbamazepine, oxcarbazepine, baclofen, clonazepam, lamotrigine, gabapentin or pregabalin. Advantageously, it is carbamazepine, gabapentin or pregabalin.

(82) In particular, Nav 1.7 sodium channel inhibitors are described in Zakrzewska J M et al., Lancet Neurol (2017), 16: 291-300 “Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial” whose contents are incorporated here for reference.

(83) Compositions of the invention to treat trigeminal nerve pains, in particular migraines, especially acute migraines, can also comprise at least one cannabinoid derivative, in particular Δ.sup.9 THC, or a protector of its metabolism (Piomelli et al. review, TIPS (2000), 21: 218-224). It has actually been observed that the coadministration (simultaneous or staggered in time) of small doses of cannabinoids (in particular, Δ.sup.9 THC) potentiates the analgesic effects of the salts according to the invention (salts of the compound of formula (I) or salts of formula (II)) without significantly inducing the detrimental effects of cannabinoids, which appear intravenously (IV) at 4-5 mg/kg (sedation). In the sense of the present invention, “very low cannabinoid content” means cannabinoid contents less than those inducing said adverse side effects. In the sense of the present invention, “cannabinoids” means Δ.sup.9 THC, synthetic CB1 receptor agonists or inhibitors of anandamide degradation. The cannabinoids introduced into the composition according to the invention are preferably Δ.sup.9 THC.

(84) According to a particular embodiment, the composition of the invention to treat trigeminal nerve pains, in particular migraines, especially acute migraines, also comprises a second active ingredient chosen from among morphine, Δ.sup.9 THC, carbamazepine, oxcarbazepine, baclofen, clonazepam, lamotrigine, gabapentin or pregabalin, Nav1.7 sodium channel blockers, CGRP inhibitors, advantageously the second active ingredient is selected from morphine, Δ.sup.9 THC, gabapentin or Ia pregabalin.

(85) Another object of the invention is a kit comprising: 1) a first composition comprising at least one compound of formula (I) such as defined previously, and ii) a second composition comprising at least one second active ingredient useful to treat trigeminal nerve pain, in particular migraines, for example acute migraines, especially selected from analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, triptans, GABA modulators and/or cannabinoids (advantageously chosen from morphine, Δ.sup.9 THC, oxcarbamazepine, baclofen, clonazepam, lamotrigine, gabapentin or pregabalin, Nav1.7 sodium channel blockers and CGRP inhibitors, preferably morphine, Δ.sup.9 THC, gabapentin or pregabalin), as combination products for simultaneous, separate, or staggered use.

(86) This kit can be used as a drug, especially in the treatment of trigeminal nerve pains, such as migraine, trigeminal neuralgia or neuropathic pain associated with multiple sclerosis. Preferably, this kit is used to treat acute migraines.

(87) The present invention also concerns a composition comprising a quantity comprised between 50 mg and 800 mg, of a salt of a compound of formula (I) or a salt of formula (II), in particular of compound 1.

(88) According to a first variant, the present invention also concerns a composition comprising a quantity comprised between 200 mg and 800 mg, of a salt of a compound of formula (I) or a salt of formula (II), in particular of compound 1.

(89) According to a second variant, the present invention also concerns a composition comprising a quantity comprised between 100 mg and 400 mg, of a salt of a compound of formula (I) or a salt of formula (II), in particular of compound 1.

(90) According to a third variant, the present invention also concerns a composition comprising a quantity comprised between 50 mg and 200 mg, of a salt of a compound of formula (I) or a salt of formula (II), in particular of compound 1.

(91) According to one embodiment, the compositions such as described above are used for the treatment of trigeminal nerve pains. Preferably, these compositions are used for the treatment of migraines, for example acute migraines.

(92) Advantageously, these compositions may be administered to the patient suffering from trigeminal nerve pains, in particular migraines, by following the dosage regimen described above.

DESCRIPTION OF FIGURES

(93) FIG. 1: Tail withdrawal latency time (in seconds), for the control group (with the carrier or 20 minutes after IP injection of a dose of 50 mg/kg of compound 1), and for the EAE model group (with the carrier or 20 minutes after injection of a dose of 50 mg/kg or 100 mg/kg of compound 1). Nociceptive thresholds are measured on D21, D28 and D35. Representation is done on D28. *: p<0.05 versus carrier control group or EAE (ANOVA+Newman-Keuls).

(94) TABLE-US-00001 Nociceptive threshold (in seconds, Dn = threshold measurement day, 20 min after administration of compound 1 (PL37)) Before Compound 1, Compound 1, Day Injection 50 mg/kg 100 mg/kg Control D 21 2.69 5.12 (4) D 28 3.0/2.69 4.14 (5) 5.98 (5) 4.85 (7) D 35 2.69 5.46 (5) 4.85 (7)

(95) FIG. 2: Headache/chronic migraine (chronic administration of ISDN): Von Frey force necessary to bring about head withdrawal (in g) as a function of time, measured in minutes, after IV injection of a saline solution (carrier, black square), a solution of compound 1 (black circle) or sumatriptan (gray triangle).

(96) FIG. 3: Acute headache (1 administration of ISDN): Von Frey force necessary to bring about head withdrawal (in g) as a function of time, measured in minutes, after oral administration of a saline solution (carrier, black square), a solution of compound 1 (black circle) or rizatriptan (gray triangle).

(97) FIG. 4: Headache/chronic migraine (chronic administration of ISDN): Von Frey force necessary to bring about head withdrawal (in g) as a function of time, measured in minutes, after oral administration of a saline solution (carrier, black circle) or compound 1 (PL37) (gray circle, 50 mg/kg)

(98) FIG. 5: Headache/chronic migraine (chronic administration of ISDN and compound 1 (PL37))—Cutaneous sensitivity before administration of compound 1: Von Frey force necessary to bring about head withdrawal (in g) as a measured at t=0, before oral administration of a saline solution (carrier, black circle) or compound (gray circle, 50 mg/kg) measured for 5 days

(99) FIG. 6: Headache/chronic migraine (chronic administration of ISDN and compound 1 (PL37)): Von Frey force necessary to bring about head withdrawal (in g) as a function of time, measured in minutes, after oral administration of a saline solution (carrier, black circle) or compound 1 (gray circle, 50 mg/kg) once daily

EXAMPLES

(100) The invention will be further illustrated, without being limited, by the examples below.

Example 1: Multiple Sclerosis Model (Experimental Autoimmune Encephalitis, EAE)

(101) The multiple sclerosis model can be induced in SJL mice, female albino white mice, by the administration of an emulsion made up of a myeline fragment and complete Freund adjuvant (Aicher et al., Pain (2004), 110: 560-570). Central nervous system inflammation appears at the end of around ten days=experimental autoimmune encephalomyelitis, or EAE.

(102) Female SJL mice, purchased from Charles River Laboratories, arrive at the age of 5 weeks and are immunized at the age of 6 weeks. Each mouse receives, under mask anesthesia (2% isoflurane), an emulsion of a volume of 200 μL in the left flank, containing 150 μg of PLP.sub.139-151 (Proteolipid Protein Myelin, fragment 139-151) in 100 μL of sterile 0.9% NaCl as well as 100 μL of incomplete Freund adjuvant (Sigma) completed by inactivated Mycobacterium tuberculosis (Difco, USA) at 4 mg/mL=complete adjuvant.

(103) The symptoms of the disease are reported between D10 and D15, which is reflected by an acute phase, during which scores are high and the animals present a loss of pain sensitivity. This phase precedes a chronic phase which starts around D18 and is characterized by stabilization of the animals general condition and the onset of a significant lowering in the pain perception threshold (hyperalgic state) (Aicher et al., Pain (2004), 110: 560-570).

(104) Nociceptive thresholds were determined from D12 by the tail immersion test.

(105) Compound 1 is administered IP (intraperitoneally) at 50 mg/kg and 100 mg/kg in a EtOH/Tween 80/Water carrier (10/10/80) (100 μL per 10 g of mice). The measurement of time of tail withdrawal from a 48° C. bath is done at 20 min after injection (cut-off=10 sec).

(106) The administration of compound 1 (PL37) at 50 and 100 mg/kg IP permits reducing hyperalgesia in mice in a multiple sclerosis experimental autoimmune encephalomyelitis (EAE) model (see FIG. 1).

Example 2: Migraine Attack Model

(107) Migraine is a neurovascular disorder characterized by recurrent headache attacks accompanied by variable neurological problems, including cephalic cutaneous allodynia. This symptom is most common in migraine patients. It affects 60 to 80% of chronic migraine patients (Guy et al., Cephalalgia (2010), 30: 881-886; Lovatti, Expert Rev Neurother (2009), 9: 395-408; Louter et al., Brain (2013), 136: 3489-3496). Moreover, the onset of allodynia is considered to be a risk factor for chronic migraine (Louter et al., Brain (2013), 136: 3489-3496) and is also indicative of a state of central sensitization (Boyer et al., Pain (2014), 155: 1196-1205).

(108) a) Persistent Allodynia Model Induced by Recurrent Systemic Administration of Isosorbide Dinitrate (Migraine/Chronic Headache)

(109) The effects of systemic administration of compound 1 on mechanical cephalic allodynia were tested in rats in a migraine model induced by repeated systemic injection of an NO donor, isosorbide dinitrate (ISDN). Indeed, the powerful vasodilating action of “NO donors” explains their particular propensity to trigger headache in healthy subjects and migraine attacks in migraine patients (Hansen & Olesen, Cephalalgia (2017), 37: 11-19).

(110) Animals

(111) The experiments were conducted on male Sprague-Dawley CD rats (200-250 g, Charles River Laboratories). A minimum delay of 7 days was respected before any experimentation.

(112) Assessment of Cephalic Cutaneous Sensitivity

(113) The animals were first subjected to habituation sessions designed to reproduce the animal environmental conditions and handling by the experimenter during the final test.

(114) The mechanical sensitivity of the periorbital region was measured by the von Frey test, which consists of applying a range of von Frey filaments in this region, calibrated to exert a constant force (expressed in grams) to determine the force (threshold) that leads to a head withdrawal reaction. The rats were habituated to these tests for 5 days preceding the experiment for one hour, so that repeated measurements give reproducible results. At the end of the habituation period, the mechanical pain sensitivity thresholds were 8 g on average (Boyer et al., Pain (2014), 155: 1196-1205; Dallel et al., Cephalalgia (2017), January 1:333102417714032. doi: 10.1177/0333102417714032). These values are not very painful since they consist of measuring a threshold with the possibility of escape and do not lead to reactions other than head withdrawal. The rats then received successive intraperitoneal injections of ISDN (10 mg/kg) and cutaneous sensitivity was assessed by means of the von Frey test. Mechanical allodynia developed progressively, reflected by a reduction in the values of the force necessary (thresholds) to induce head withdrawal. On the day of the experiment, the forces exerted by the von Frey filaments that led to head withdrawal were measured in each rat under controlled conditions every 30 minutes for 4 hours.

(115) Assessment of Antimigraine Activity

(116) On the day of experimentation, the rats received a first injection (intravenous) of physiological saline, sumatriptan or compound 1 followed, 5 minutes later, by a second intraperitoneal injection of ISDN (10 mg/kg). The rat was then replaced in the observation box. The forces inducing head withdrawal were measured every 30 minutes for 4 hours, to follow the kinetics of the effect.

(117) 3 groups were made up: 1 control group: intravenous injection of physiological saline (n=10) 1 test group: intravenous injection of compound 1 (20 mg/kg; n=10) 1 reference group: intravenous injection of sumatriptan (300 μg/kg; n=10)

(118) Data Analysis

(119) A two-way analysis of variance (effect of time and treatment) was done by repeated measurements and was followed by a post-hoc test. The results are presented in FIG. 2.

(120) It is observed that compound 1—administered intravenously at the dose of 20 mg/kg—considerably reduces cephalic cutaneous sensitivity, which is significant for a reduction in associated migraine activity, in chronic conditions.

(121) b) Mechanical Allodynia Model Induced by Single Administration of Isosorbide Dinitrate (Acute Migraine/Headache)

(122) The effects of systemic administration of compound 1 on mechanical cephalic allodynia were tested in rats in a migraine model induced by single systemic injection of an NO donor, isosorbide dinitrate (ISDN). Indeed, the powerful vasodilating action of “NO donors” explains their particular propensity to trigger headache in healthy subjects and migraine attacks in migraine patients (Hansen & Olesen, Cephalalgia (2017), 37: 11-19).

(123) Animals

(124) The experiments were conducted on male Sprague-Dawley CD rats (200-250 g, Charles River Laboratories). A minimum delay of 7 days was respected before any experimentation.

(125) Assessment of Cephalic Cutaneous Sensitivity

(126) The animals were first subjected to habituation sessions designed to reproduce the animal environmental conditions and handling by the experimenter during the final test.

(127) The mechanical sensitivity of the periorbital region was measured by the von Frey test, which consists of applying a range of von Frey filaments in this region, calibrated to exert a constant force (expressed in grams) to determine the force (threshold) that leads to a head withdrawal reaction. The rats were habituated to these tests for 5 days preceding the experiment for one hour, so that repeated measurements give reproducible results. At the end of the habituation period, the mechanical pain sensitivity thresholds were 8 g on average (Boyer et al., Pain (2014), 155: 1196-1205; Dallel et al., Cephalalgia (2017), January 1:333102417714032. doi: 10.1177/0333102417714032). These values are not very painful since they consist of measuring a threshold with the possibility of escape and do not lead to reactions other than head withdrawal. The rats then received an intraperitoneal injection of ISDN (10 mg/kg) and cutaneous sensitivity was assessed by means of the von Frey test. Mechanical allodynia developed progressively, reflected by a reduction in the values of the force necessary (thresholds) to induce head withdrawal. On the day of the experiment, the forces exerted by the von Frey filaments that led to head withdrawal were measured in each rat under controlled conditions every 30 minutes for 4 hours.

(128) Assessment of Antimigraine Activity

(129) On the day of experimentation, the rats received a first injection (oral) of physiological saline, rizatriptan (10 μg/kg) or compound 1 (50 mg/kg) followed, 5 minutes later, by an intraperitoneal injection of ISDN (10 mg/kg). The rat was then replaced in the observation box. The forces inducing head withdrawal were measured every 30 minutes for 4 hours, to follow the kinetics of the effect.

(130) 3 groups were made up: 1 control group: oral administration of physiological saline (n=10) 1 test group: oral administration of compound 1 (50 mg/kg; n=10) 1 reference group: oral administration of rizatriptan (10 μg/kg; n=10)

(131) Data Analysis

(132) A two-way analysis of variance (effect of time and treatment) was done by repeated measurements and was followed by a post-hoc test. The results are presented in FIG. 3.

(133) It is observed that compound 1—administered orally at the dose of 50 mg/kg—considerably reduces cephalic cutaneous sensitivity, which is significant for a reduction in the intensity of the acute migraine attack.

Example 3: Model for Prevention of Migraine Attacks by Oral Administration

(134) The effects of oral administration of compound 1 on mechanical cephalic allodynia were tested in rats in a chronic migraine model induced by repeated systemic injection of an NO donor, isosorbide dinitrate (ISDN). Indeed, the powerful vasodilating action of “NO donors” explains their particular propensity to trigger headache in healthy subjects and migraine attacks in migraine patients (Hansen & Olesen, Cephalalgia (2017), 37: 11-19).

(135) Animals

(136) The experiments were conducted on male rats (10 rats per group of the Sprague-Dawley CD strain (200-250 g, Charles River Laboratories), randomly assigned into each group before experimentation. A minimum delay of 7 days was respected before any experimentation. The experiments were conducted with the experimenter blinded.

(137) Assessment of Cephalic Cutaneous Sensitivity

(138) The animals were first subjected to habituation sessions designed to reproduce the animals environmental conditions and handling by the experimenter during the final test.

(139) The mechanical sensitivity of the periorbital region was measured by the von Frey test, which consists of applying a range of von Frey filaments in this region, calibrated to exert a constant force (expressed in grams) to determine the force (threshold) that leads to a head withdrawal reaction. The rats were habituated to these tests for 5 days preceding the experiment for one hour, so that repeated measurements give reproducible results. At the end of the habituation period, the mechanical pain sensitivity thresholds were 8 g on average (Boyer et al., Pain (2014), 155: 1196-1205; Dallel et al., Cephalalgia (2017), January 1:333102417714032. doi: 10.1177/0333102417714032). These values are not very painful since they consist of measuring a threshold with the possibility of escape and do not lead to reactions other than head withdrawal. The rats then received successive intraperitoneal injections of ISDN (10 mg/kg) and cutaneous sensitivity was assessed by means of the von Frey test. Mechanical allodynia developed progressively, reflected by a reduction in the values of the force necessary (thresholds) to induce head withdrawal.

(140) Cutaneous mechanical sensitivity was measured before and on the test day (FIG. 4, single administration of compound 1 or FIG. 6, repeated administration of compound 1) or before and on the test day (Days 1, 2, 3, 4 and 5) (FIG. 5, repeated administration of compound 1) before injection and at 30 min intervals for 4 h in the different groups of rats receiving intraperitoneal ISDN (10 mg/kg, volume of 10 mL/kg).

(141) Assessment of Antimigraine Activity

(142) On the day of experimentation, the rats received a first oral administration of carrier (10% EtOH in 0.9% NaCl physiological saline) or compound 1 (50 mg/kg in the carrier) followed, 5 minutes later, by a second intraperitoneal injection of ISDN (10 mg/kg). The rat was then replaced in the observation box. The forces inducing head withdrawal were measured every 30 minutes for 4 hours, to follow the kinetics of the effect.

(143) Data Analysis

(144) A two-way analysis of variance (effect of time and treatment) was done by repeated measurements and was followed by a post-hoc test.

(145) Compound 1—administered orally at the dose of 50 mg/kg once on the experiment day (FIG. 4) had no effect on cutaneous cephalic sensitivity. Compound 1, administered repeatedly over several days (5 days) significantly reduces cutaneous cephalic sensitivity compared to the carrier one day compared to the previous one, before administration of ISDN (FIG. 5) or as a function of time, after administration of ISDN (FIG. 6), which is significant for prevention and reduction of associated migraine activity, in chronic condition.

Example 4: Dosage Regimen for Compound 1—Study of Adverse Effects Observed During Phase 1b of the Clinical Study for Compound 1 (PL37)

(146) Details on the Experimental Conditions

(147) Forty healthy volunteers aged 18 to 65 randomly divided into five groups of 8 subjects (6 groups receiving four daily doses of compound 1 (PL37), and two groups receiving four daily doses of placebo)

(148) The doses indicated in the following table were administered 4 times a day for 5 days, the daily dose varying from 800 to 4000 mg, the total quantity over five days being comprised between 4000 and 20,000 mg.

(149) TABLE-US-00002 Compound 1 (PL37) 200 mg 400 mg 600 mg 800 mg 1000 mg Placebo Total Subjects N = 6 N = 6 N = 6 N = 6 N = 6 N = 10 N = 40 with: n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E n (%) E TEAEs 1(16.7)3 5(83.3)12 4(66.7)7 6(100.0)10 4(66.7)15 5(50.0)10 25(62.5)57 LAE 0 0 0 0 0 0 0 SAE 0 0 0 0 0 0 0 Death 0 0 0 0 0 0 0 E = number of adverse reactions n = number of subjects who had adverse reactions N = number of subjects per treatment group LAE = limiting adverse event TEAEs = treatment-emergent adverse event SAE = serious adverse event