Amino acid derivatives for the treatment of neuropathic pain   

Abstract: The invention relates to compounds, to compositions comprising the same and uses thereof for the prevention or treatment of pain, e.g neuropathic pain while having neutral or beneficial effect on metabolic parameters.

This application is a continuation-in-part of PCT international application number PCT/CA2010/000670 filed Apr. 30, 2010, which claims priority to U.S. provisional application No. 61/215,490 filed on May 6, 2009.

FIELD OF THE INVENTION

The invention relates to compounds, to compositions comprising the same and uses thereof for the prevention or treatment of pain, e.g neuropathic pain.

BACKGROUND OF THE INVENTION

Neuropathic pain (or neuralgia) is generally defined as non-nociceptive pain. In fact, neuropathic pain is produced by a change in neurological function or structure as opposed to activation of pain receptor cells in the case of nociceptive pain.

Diabetic neuropathy is a common complication of type II diabetes that can affect virtually every tissue of the body and induce significant morbidity and mortality. Pain affecting the feet and ankles which is often severe, is the most common symptom of the condition. Duration of diabetes and poor glycemic control appears to be responsible to some extent for nerve damage that ultimately is perceived as painful impulses.

Treatment of diabetic neuropathy is challenging and is currently far from optimal. In fact, neuropathic pain is recognized as one of the most difficult pain syndromes to treat. Currently available therapeutics are modestly to moderately effective in relieving symptoms and are limited by side effects and drug-drug interactions. At the present time, only two drugs are officially approved for the symptomatic treatment of diabetic neuropathy: pregabalin (structurally related to gabapentin) and duloxetine. Both have troublesome side effects, including somnolence and dizziness. More particularly, pregabalin, and also gabapentin, are associated with body weight gain which can worsen the metabolic control in patients with type II diabetes.

There is a need for a therapeutic having better or similar analgesic properties as the currently available treatment but with less adverse effects, and more particularly with beneficial or neutral metabolic effect.

SUMMARY

The invention relates to α-amino acid and analogs, to compositions comprising the same and their therapeutic uses. According to one aspect, the compound of the invention is a compound selected from the compounds of any one of Formulae I to VI, including any specific embodiments thereof, a compound selected from Compounds 1 to 30, or a compound of any one of sections a) to e) herein defined, or a pharmaceutically acceptable salt, solvate, prodrug, or ester thereof. In another aspect, the invention relates to a compound of any one of Formulae I to VI, wherein the configuration of the carbon a to the carboxyl is the same as the L-configuration of natural amino acids. Aspects of the invention provide compounds of Formulae II or IV. Another aspect of the invention provides compounds of Formulae II or IV, wherein the configuration of the carbon a to the carboxyl is the same as the L-configuration of natural amino acids. Aspects of the invention provide compounds of Formula II. Another aspect of the invention provides compounds of Formula II, wherein the configuration of the carbon a to the carboxyl is the same as the L-configuration of natural amino acids. The invention also further relates to a compound selected from the group consisting of Compounds 3-5, 11, 13, 15, 17, 19, 23, 24, 26, 27, 29 and the compounds of section d). The invention also further relates to a compound selected from the group consisting of Compounds 6-8, 10, 12, 14, 16, 18, 21, 22, 25, 28, 30, and the compounds of any one of sections a), b), c) or e) herein described. The invention also further relates to a compound selected from the group consisting of Compounds 6 to 8, or Compounds 7 and 8. The invention also further relates to Compound 7. The invention also further relates to Compound 8.

According to another aspect, the invention pertains to pharmaceutical compositions comprising at least one compound of the invention as herein described.

According to other aspects, the invention relates to the use of a compound as herein defined for the treatment of neuropathic pain. The invention also further relates to the use of a compound as herein defined for the treatment of diabetic neuropathy. The invention also further relates to the use of a compound as herein defined for the treatment of diabetic neuropathy while being neutral of beneficial to metabolic symptoms, such as glucose/insulin levels and body weight. The invention also further relates to the use of a compound as herein defined for the treatment of diabetic neuropathy while improving glucose control and/or without body weight gain or reduced body weight. The invention also relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of any of the diseases and conditions herein described.

Another aspect of the invention also relates to methods of treating neuropathic pain in a subject in need thereof comprising the step of administering a therapeutically effective amount of a compound of the invention. The invention also relates to methods of treating diabetic neuropathy in a subject in need thereof comprising the step of administering a therapeutically effective amount of a compound of the invention. The invention also relates to methods of treating diabetic neuropathy while having a neutral of beneficial effect on metabolic symptoms, such as glucose/insulin levels and body weight of a subject in need of such treatment, the method comprising the step of administering a therapeutically effective amount of a compound of the invention. The invention also relates to methods of treating diabetic neuropathy, improving glucose control and/or reducing body weight of a subject in need of such treatment, the method comprising the step of administering a therapeutically effective amount of a compound of the invention.

Other aspects of the invention include the use of the compounds of the invention in the treatment diseases and conditions treatable by drugs with affinity to an α2δ subunit of voltage-gated N-type calcium ion channels. Examples of such diseases and conditions include, without limitation, neuropathy, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia, epilepsy, and fibromyalgia.

In yet another aspect, the invention includes the use of the compounds of the invention in the control of pain, and more particularly nerve pain. Other aspects of the invention include the use of the compounds of the invention in the treatment of a disease or condition selected from neuropathy, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, migraine headaches, post-operative chronic pain, nerve pain associated with spinal cord injury, multiple sclerosis, and nystagmus.

Additional objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments which are exemplary and should not be interpreted as limiting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows fasted basal glycemia in DIO-mice treated with Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine (4-OH-Ile), and vehicle.

FIG. 1B shows fasted basal insulinemia in DIO-mice treated with Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine (4-OH-Ile) and vehicle.

FIG. 2A shows insulin secretion during OGTT in DIO-mice treated with Compounds 6A and 6B, (2S,3R,4S)-4-hydroxyisoleucine (4-OH-Ile) and vehicle

FIG. 2B shows insulin AUC following administration of Compounds 6A and 6B, 4-OH-Ile and vehicle in DIO-mice.

FIGS. 3B and 3B show pharmacokinetic profile (log scale) in mice following administration of Compound 6B (50 mg/kg) and Compound 18 (50 mg/kg) respectively i.v. and p.o.

FIG. 4 pharmacokinetic profile (log scale) in dogs following administration of Compound 18 (25 mg/kg) p.o. and i.v.

DETAILED DESCRIPTION

All technical and scientific terms used herein have the same meaning as commonly understood by one ordinary skilled in the art to which the invention pertains. For convenience, the meaning of certain terms and phrases used herein are provided below.

To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification control. The section headings used herein are for organizational purposes only, and are not to be construed as limiting the subject matter disclosed.

It should be noted that, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The chemical structures herein are drawn according to the conventional standards known in the art. Thus, where an atom, such as a carbon atom, as drawn appears to have an unsatisfied valency, then that valency is assumed to be satisfied by a hydrogen atom even though that hydrogen atom is not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

The symbol “—” in general represents a bond between two atoms in the chain. Thus CH3—O—CH2—CH(Ri)—CH3 represents a 2-substituted-1-methoxypropane compound. In addition, the symbol “—” also represents the point of attachment of the substituent to a compound. Thus for example aryl(C1-C6)alkyl- indicates an arylalkyl group, such as benzyl, attached to the compound through the alkyl moiety.

Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituent can be the same or different. Thus for example “Rm optionally substituted with 1, 2 or 3 Rq groups” indicates that Rm is substituted with 1, 2, or 3 Rq groups where the Rq groups can be the same or different.

As used herein, the term “Compounds of the present invention” and equivalent expressions refer to compounds mentioned herein as being useful for at least one purpose of the invention, e.g., those encompassed by structural Formulae such as Formulae I to VI and their different aspects and embodiments, and includes specific compounds disclosed herein such as encompassed by those Formulae and to specifically mentioned compounds such as those disclosed in Table 1 or the following sections a) to e), as well as their pharmaceutically acceptable salts and solvates. Embodiments herein may exclude one or more of the compounds of the invention. Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The chemical structures disclosed herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures if applicable. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan, e.g., chiral chromatography (such as chiral HPLC), immunoassay techniques, or the use of covalently (such as Mosher\'s esters) and non-covalently (such as chiral salts) bound chiral reagents to respectively form a diastereomeric mixture which can be separated by conventional methods, such as chromatography, distillation, crystallization or sublimation, the chiral salt or ester is then exchanged or cleaved by conventional means, to recover the desired isomers. The compounds may also exist in several tautomeric forms including the enol form, the keto form, and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The disclosed compounds also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature, for example, without limitation, 2H (D), 3H (T), 11C, 13C, 14C, 15N, 18O, 17O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. Further, when partial structures of the compounds are illustrated, brackets or equivalents indicate the point of attachment of the partial structure to the rest of the molecule.

The invention pertains to both salt forms and acid/base forms of the compounds of the invention. For example, the invention pertains not only to the particular salt forms of compounds shown herein as salts, but also the invention includes other pharmaceutically acceptable salts, and the acid and/or base form of the compound. The invention also pertains to salt forms of compounds shown herein.

The term “prodrug” and equivalent expressions refer to agents which can be converted in vitro or vivo directly or indirectly to an active form (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), “Design of Prodrugs”. 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), “Prodrugs: Challenges and Rewards, XVIII, 1470 p. Springer). Prodrugs can be used to alter the biodistribution (e.g., to allow agents which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular agent. A wide variety of groups have been used to modify compounds to form prodrugs, for example, esters, ethers, phosphates, etc. When the prodrug is administered to a subject, the group is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, or otherwise to reveal the active form. As used herein, “prodrug” includes pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates as well as crystalline forms of any of the foregoing. Prodrugs can be pharmaceutically active or inactive; and the latter will exert the pharmaceutical activity when it is converted to the parent drug(s).

The term “aliphatic group” includes organic moieties characterized by straight or branched-chains, typically having between 1 and 16 carbon atoms, or having between 1 to 12, 1 to 8, 1 to 5 or 1 to 3 carbon atoms. Aliphatic groups include acyclic alkyl groups, alkenyl groups, and alkynyl groups.

As used herein, the term “acyclic” refers to an organic moiety without ring system.

As used herein, the term “alkyl” refers to saturated hydrocarbons having from one to sixteen carbon atoms, including linear or branched alkyl groups. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, and the like. The term “C1-Cnalkyl” refers to an alkyl group having from 1 to the indicated “n” number of carbon atoms.

As used herein, the term “alkenyl” refers to unsaturated hydrocarbons having from two to sixteen carbon atoms, including linear or branched alkenyl groups, and comprising between one and six carbon-carbon double bonds. Examples of alkenyl groups include, without limitation, vinyl, allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl, 1,3-pentadien-5-yl, and the like. The term alkenyl includes both unsubstituted alkenyl groups and substituted alkenyl groups. The term “C2-Cnalkenyl” refers to an alkenyl group having from 2 to the indicated “n” number of carbon atoms.

As used herein, the term “alkynyl” refers to unsaturated hydrocarbons having from two to twelve carbon atoms, including linear or branched alkynyl groups, and comprising between one to six carbon-carbon triple bond. Examples of alkynyl groups include, without limitation, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-5-yl, 1,3-pentadiyn-5-yl, and the like. The term alkynyl includes both unsubstituted alkynyl groups and substituted alkynyl groups. The term “C2-Cnalkynyl” refers to an alkynyl group having from 2 to the indicated “n” number of carbon atoms.

Unless the number of carbons is otherwise specified, “lower” as in “lower aliphatic,” “lower alkyl,” “lower alkenyl,” and “lower alkylnyl”, as used herein means that the moiety has at least one (two for alkenyl and alkynyl) and equal or less than 6 carbon atoms.

The terms “cycloalkyl”, “alicyclic”, “carbocyclic” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom) or fused (sharing at least one bond) carbocyclic ring systems, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term “C3-Cncycloalkyl” refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, “lower cycloalkyl” groups as herein used, have at least 3 and equal or less than 8 carbon atoms in their ring structure.

The term “heterocycloalkyl” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom) or fused (sharing at least one bond) carbocyclic ring systems, having from three to fifteen ring members, where one or more (up to six) ring members are substituted or unsubstituted heteroatoms (e.g. N, O, S, P) or groups containing such heteroatoms (e.g. NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, and the like). Heterocycloalkyl groups may be C-attached or heteroatom-attached (e.g. via a nitrogen atom) where such is possible. Examples of heterocycloalkyl groups include, without limitation, pyrrolidino, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolizinyl, and sugars, and the like. The term heterocycloalkyl includes both unsubstituted heterocycloalkyl groups and substituted heterocycloalkyl groups. The term “C3-Cnheterocycloalkyl” refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms (carbon or heteroatom or group) in the ring structure, including at least one hetero group or atom as defined above. Unless the number of carbons is otherwise specified, “lower heterocycloalkyl” groups as herein used, have at least 3 and equal or less than 8 ring members in their ring structure.

The terms “aryl” and “aryl ring” refer to aromatic groups having 4n+2 π(pi) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having six to fourteen ring atoms. A polycyclic ring system includes at least one aromatic ring. Aryl may be directly attached, or connected via a C1-C3alkyl group (also referred to as arylalkyl or aralkyl). Examples of aryl groups include, without limitation, phenyl, benzyl, phenetyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl, phenanthernyl, anthracenyl, and the like. The term aryl includes both unsubstituted aryl groups and substituted aryl groups. The term “C6-Cnaryl” refers to an aryl group having from 6 to the indicated “n” number of carbons in the ring structure.

The terms “heteroaryl” and “heteroaryl ring” refer to aromatic groups having 4n+2 π(pi) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having five to fourteen ring members, including one to six substituted or unsubstituted heteroatoms (e.g. N, O, S) or groups containing such heteroatoms (e.g. NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), SO, and the like). A polycyclic ring system includes at least one heteroaromatic ring. Heteroaryls may be directly attached, or connected via a C1-C3alkyl group (also referred to as heteroarylalkyl or heteroaralkyl). Heteroaryl groups may be C-attached or heteroatom-attached (e.g. via a nitrogen atom), where such is possible. Examples of heteroaryl groups include, without limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl, 3H-indolyl, indolinyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolizinyl, quinolonyl, isoquinolonyl, quinoxalinyl, naphthyridinyl, furopyridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, dibenzofurnayl, and the like. The term heteroaryl includes both unsubstituted heteroaryl groups and substituted heteroaryl groups. The term “C5-Cnheteroaryl refers to an heteroaryl group having from 5 to the indicated “n” number of atoms (carbon or heteroatom or group) in the ring structure, including at least one hetero group or atom as defined above.

The terms “heterocycle” or “heterocyclic” or “heterocyclyl” include heterocycloalkyl and heteroaryl groups. Examples of heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4αH-1-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, and the like. The term heterocycle includes both unsubstituted heterocyclic groups and substituted heterocyclic groups.

The term “amine” or “amino,” as used herein, refers to an unsubstituted or substituted moiety of the formula —NRaRb, in which Ra and Rb are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R2 and Rb, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring. The term “amide” or “aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term acylamino refers to an amino group directly attached to an acyl group as defined herein.

The term “nitro” means —NO2; the terms “halo” and “halogen” refer to bromine, chlorine, fluorine or iodine substituents; the term “thiol”, “thio”, or “mercapto” means SH; and the term “hydroxyl” or “hydroxy” means —OH. The term “alkylthio” refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms. The term “alkylcarboxyl” as used herein means an alkyl group having a carboxyl group attached thereto.

The term “alkoxy” or “lower alkoxy” as used herein means an alkyl group having an oxygen atom attached thereto. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy groups and the like. The term alkoxy includes both unsubstituted or substituted alkoxy groups, etc., as well as halogenated alkyloxy groups.

The term “carbonyl” or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term “acyl” refers to a carbonyl group that is attached through its carbon atom to a hydrogen (i.e., formyl), an aliphatic group (C1-Cnalkyl, C1-Cnalkenyl, C1-Cnalkynyl, wherein n is an integer from 2 to 10; e.g. acetyl, a cycloalkyl group (e.g. C3-C8cycloalkyl), a heterocyclic group (e.g. C3-C8heterocycloalkyl and C5-C6heteroaryl), an aromatic group (e.g. C6aryl, e.g., benzoyl), and the like. Acyl groups may be unsubstituted or substituted acyl groups (e.g. salicyloyl).

The term “amino acid” generally refers to an organic compound comprising both a carboxylic acid group and an amine group. The term “amino acid” includes both “natural” and “unnatural” or “non-natural” amino acids. Additionally, the term amino acid includes O-alkylated or N-alkylated amino acids, as well as amino acids having nitrogen or oxygen-containing side chains (such as Lys, Orn, or Ser) in which the nitrogen or oxygen atom has been acylated or alkylated. Amino acids may be pure L or D isomers or mixtures of L and D isomers, including racemic mixtures. Amino acid may be α-, or β-, or γ-, or δ-, or ω-amino acid.

The term “natural amino acid” and equivalent expressions refer to amino acids commonly found in naturally occurring proteins. Examples of natural amino acids include, without limitation, alanine (Ala), cystein (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asp), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA).

The term “unnatural amino acid” refers loosely to any compound which bears at least one amino group and at least one carboxylic group in the same molecule; and the compound is not a natural product or has not been found in nature at the time being but rather a synthetic chemical entity. Examples of unnatural amino acids include derivatives of natural amino acids including D forms, and α- and β-amino acid derivatives. The terms “unnatural amino acid” and “non-natural amino acid” are used interchangeably herein and are meant to include the same moieties. It is noted that certain amino acids, e.g., hydroxyproline, that are classified as a non-natural amino acid herein, may be found in nature within a certain organism or a particular protein. Amino acids with many different protecting groups appropriate for immediate use in the solid phase synthesis of peptides are commercially available. In addition to the twenty most common naturally occurring amino acids, the following examples of non-natural amino acids and amino acid derivatives may be used according to the invention (common abbreviations in parentheses): 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta), aminooxyacetic acid (Aoa), 2-aminotetraline-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), para-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), para-bromophenylalanine (4-Br-Phe), ortho-chlorophenylalanine (2-Cl-Phe), meta-chlorophenylalanine (3-Cl-Phe), para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine (3-Cl-Tyr), para-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-C12-Phe), 3,4-difluororphenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), ortho-fluorophenylalanine (2-F-Phe), meta-fluorophenylalanine (3-F-Phe), para-fluorophenylalanine (4-F-Phe), meta-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), allo-hydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), para-iodophenylalanine (4-I-Phe), 3-iodotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), isodesmosine (Ide), allo-isoleucine (a-Ile), isonipecotic acid (Inp), N-methylisoleucine (MeIle), N-methyllysine (MeLys), meta-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-NaI), 2-naphthylalanine (2-NaI), para-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), norleucine (Nie), norvaline (Nva), ornithine (Orn), ortho-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine, and thiazolidine-4-carboxylic acid (thioproline, Th).

It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is meant to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more. The term “substituted”, when in association with any of the foregoing groups refers to a group substituted at one or more position with substituents such as acyl, amino (including simple amino, mono and dialkylamino, mono and diarylamino, and alkylarylamino), acylamino (including carbamoyl, and ureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonato, phosphinato, oxo, guanidine, imino, formyl and the like. Any of the above substituents can be further substituted if permissible, e.g. if the group contains an alkyl group, an aryl group, or other.

The term “solvate” refers to a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, hemiethanolates, and the like, preferably hydrates.

A “pharmaceutically acceptable salt” of a compound means a salt of a compound that is pharmaceutically acceptable. Desirable are salts of a compound that retain or improve the biological effectiveness and properties of the free acids and bases of the parent compound as defined herein or that takes advantage of an intrinsically basic, acidic or charged functionality on the molecule and that is not biologically or otherwise undesirable. Example of pharmaceutically acceptable salts are also described, for example, in Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977). Such salts include:

(1) acid addition salts, formed on a basic or positively charged functionality, by the addition of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonate forming agents, and the like; or formed with organic acids such as acetic acid, propionic acid, lactic acid, oxalic, glycolic acid, pivalic acid, t-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylaminosulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenyl propionic acid, lauryl sulphonic acid, lauryl sulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, embonic (pamoic) acid, palmoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynapthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, and the like;

(2) base addition salts, formed when an acidic proton present in the parent compound either is replaced by a metal ion, including, an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron and the like; or coordinates with an organic base such as ammonia, ethylamine, diethylamine, ethylenediamine, N,N′-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocain, procain, choline, lysine and the like.

Pharmaceutically acceptable salts may be synthesized from the parent agent that contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Salts may be prepared in situ, during the final isolation or purification of the agent or by separately reacting a purified compound of the invention in its free acid or base form with the desired corresponding base or acid, and isolating the salt thus formed. The term “pharmaceutically acceptable salts” also include zwitterionic compounds containing a cationic group covalently bonded to an anionic group, as they are “internal salts”.

All acid, salt, base, and other ionic and non-ionic forms of the compounds described are included as compounds of the invention. For example, if a compound is shown as an acid herein, the salt forms of the compound are also included. Likewise, if a compound is shown as a salt, the acid and/or basic forms are also included.

“Bioavailability” refers to the rate and amount of a drug that reaches the systemic circulation of a patient following administration of the drug or prodrug thereof to the subject and can be determined by evaluating, for example, the plasma or blood concentration-versus-time profile for the drug. Parameters useful in characterizing a plasma or blood concentration-versus-time curve include the area under the curve (AUC), the time to peak concentration (Tmax), and the maximum drug concentration (Cmax). Bioavailability is often expressed as F(%) referring to the ratio in percentage of the AUC of the compound for a specific mode of administration (e.g. orally) over AUC of the compound after an IV administration.

The term “reduction of side effects” of a compound (e.g. a compound of the invention) refers to decreasing the amount of or severity of one or more side effects of the compound by, e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9%, or even 100%, which decrease is with respect to the side effects observed when a patient is treated with gabapentin or pregabalin.

More generally, the terms “lessening” etc., “increasing” etc., refer in context herein to the percentage changes, e.g., by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 125%, etc., or even more, e.g., 2, or 4 fold, or even more.

“Pharmaceutically acceptable” refers to drugs, medicaments, inert ingredients etc., which the term describes, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. It preferably refers to a compound or composition that is approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.

“Pharmaceutically acceptable vehicle” or “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or carrier with which a compound is administered.

“Pharmaceutical composition” refers to at least one compound and at least one pharmaceutically acceptable vehicle or carrier, with which the compound is administered to a patient.

Reference will now be made in detail to certain embodiments of compounds and methods. The disclosed embodiments are not intended to be limiting of the invention.

One aspect of the invention relates to new compounds, α-amino acid derivatives, to compositions comprising the same and uses thereof for the prevention or treatment of pain, e.g. neuropathic pain.

Thus, in one aspect, the invention relates to a compound of Formula I defined as follows:

wherein,

R1 is hydrogen, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6heterocycloalkyl, C6aryl, or C5-9heteroaryl;

R2 is hydrogen, or an N-protecting group;

X is O, NH, or S;

R3 is hydrogen, C1-12alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6heterocycloalkyl, NH2, NHR6, NR6R7, OR6, halide, or R3 and R5 taken together with their adjacent carbon atoms form a C3-12cycloalkyl, C3-12heterocycloalkyl, C6-10aryl, or C5-10heteroaryl; and

R4, R5, R6 and R7 are each independently hydrogen, C1-12alkyl, or C6-10aryl, or R4 and R5 are taken together with their adjacent atoms to form a heterocycloalkyl or heteroaryl group;

wherein when R1, R2, R3, R4, R5, R6 or R7 is a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be unsubstituted or substituted with a group selected from the group consisting of acyl, unsubstituted amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, carbamoyl, ureido, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonato, phosphinato, oxo, guanidine, imino, and formyl; or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In one embodiment, the compound is a compound of Formula I and X is O. In an embodiment, the compound is a compound of Formula I, provided that the compound is not a naturally occurring amino acid. In a subclass of any of the above embodiments, the compound is a compound of Formula I, provided that when R1, R2 and R4 are all hydrogen atoms, R3 is hydrogen or a C1-10alkyl, then R5 is not a C1-8alkyl. In another embodiment, R2 is a protecting group selected from the group selected from the group consisting of acyl, and amino-substituted acyl, such as an amino acid residue (e.g. valyl, leucyl and isoleucyl). In yet another embodiment, R2 is hydrogen and all other groups are as previously defined.

In another aspect, the invention relates to a compound of Formula II defined as follows:

wherein,

X is O, NH, or S;

R3 is hydrogen, C1-12alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6heterocycloalkyl, NH2, NHR6, NR6R7, OR6, or halide;

R8 and R9 are each independently hydrogen, C1-12alkyl, C6-10aryl, NH2, NHR6, NR6R7, OR6, halide, cycloalkyl, alkylenyl, arylalkyl, or R8 and R9 are taken together with their adjacent atoms to form a spiro or fused heterocycloalkyl or heteroaryl group, or R8 and R9 are attached to the same carbon atom and together with the adjacent carbon atom form a carbonyl;

n is an integer selected from 0 to 3; and

R1, R2, R6, R7 and X are as previously defined;

wherein when R1, R2, R3, R4, R5, R6, R7, R8 or R9 is a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be unsubstituted or substituted with a group selected from the group consisting of acyl, unsubstituted amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, carbamoyl, ureido, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxy, carboxylate, aminocarbonyl, mono and dialkylaminocarbonyl, cyano, azido, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonato, phosphinato, oxo, guanidine, imino, and formyl;

or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In one embodiment, X is oxygen and all other groups are as previously defined. In another embodiment, X is oxygen, n is 1, R3 is a hydrogen and all other groups are as previously defined. In another embodiment, X is oxygen, n is 1, R3 is a hydrogen, the chiral center C* is in the S configuration and all other groups are as previously defined. In another embodiment, X is O, n is 1, R2 is a protecting group selected from the group selected from the group consisting of acyl, and amino-substituted acyl, such as an amino acid residue (e.g. valyl, leucyl and isoleucyl) and all other groups are as previously defined. In yet another embodiment, X is O, n is 1, R2 is hydrogen and all other groups are as previously defined. In another embodiment, X is oxygen, n is 0, and all other groups are as previously defined. In another embodiment, X is oxygen, n is 2 and all other groups are as previously defined. In another embodiment, X is oxygen, n is 3 and all other groups are as previously defined. In a further embodiment, the compound is a compound of Formula II, wherein X is oxygen, n is 1 and R3 is hydrogen. I another embodiment, the compound is a compound of Formula II, wherein X is oxygen, n is 1 and R3 is C1-6alkyl, or a C1-4alkyl, or a methyl, ethyl, propyl, or i-propyl group. In yet another embodiment, X is NH and all other groups are as previously defined. In further embodiment, X is sulfur and all other groups are as previously defined.

In another aspect, the invention relates to a compound of Formula III defined as follows:

wherein,

m is an integer from 1 to 3, wherein R8 is the same or different in each instance;

R1, R2, R3, R8 and X are as previously defined;

or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In an embodiment, R3 is a hydrogen, n is 1 or 2 and all other groups are as previously defined. In one embodiment, X is oxygen and all other groups are as previously defined. In yet another embodiment, X is NH and all other groups are as previously defined. In further embodiment, X is sulfur and all other groups are as previously defined.

In yet another aspect, the invention relates to a compound of Formula IV defined as follows:

wherein,

p is an integer from 1 to 2; and

R1, R2, R4, R8, R9, and X are as previously defined;

or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In one embodiment, X is oxygen and all other groups are as previously defined. In another embodiment, X is oxygen, p is 1 and all other groups are as previously defined. In another embodiment, X is oxygen, p is 2 and all other groups are as previously defined. In another embodiment, X is oxygen, p is 1, R4 is a hydrogen, the chiral center C* is in the S configuration and all other groups are as previously defined. In another embodiment, X is O, p is 1, R2 is a protecting group selected from the group selected from the group consisting of acyl, and amino-substituted acyl, such as an amino acid residue (e.g. valyl, leucyl and isoleucyl) and all other groups are as previously defined. In yet another embodiment, X is O, p is 1, R2 is hydrogen and all other groups are as previously defined. In another embodiment, R2 is a protecting group selected from the group selected from the group consisting of acyl, and amino-substituted acyl, such as an amino acid residue (e.g. valyl, leucyl and isoleucyl). In yet another embodiment, R2 is hydrogen and all other groups are as previously defined. In yet another embodiment, X is NH and all other groups are as previously defined. In a further embodiment, X is sulfur and all other groups are as previously defined.

In yet another aspect, the invention relates to a compound of Formula V defined as follows:

wherein,

R1, R2, R8, R9, X and p are as previously defined;

or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In one embodiment, p is 1 and all other groups are as previously defined. In another embodiment, p is 2 and all other groups are as previously defined.

In yet another aspect, the invention relates to a compound of Formula VI defined as follows:

wherein,

R1, R2, R4, R8, R9, and X are as previously defined;

or a pharmaceutically acceptable salt, prodrug, metabolite, or solvate thereof.

In one embodiment, the invention relates to a compound of any one of Formulae I to VI, wherein the compound is a mixture of compounds where the chiral center C* is in the S or the R configuration and all other groups are as previously defined, or substantially pure S configuration, or substantially pure R configuration, preferably in the S configuration. In another embodiment, the invention relates to a compound of any one of Formulae I to VI, wherein the compound is a mixture of compounds where the chiral center C* is has the same configuration as D and L amino acid and all other groups are as previously defined, or substantially pure L configuration, or substantially pure D configuration, preferably in the L configuration.

Exemplary compounds include, but are not limited to, the compounds of Table 1:

TABLE 1 ID Structure 1 2 3 4 5 6

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