KR20070030781A - Novel use of peptide compounds for treating amyotrophic lateral sclerosis - Google Patents

Abstract

The present invention relates to the use of a group of peptide compounds for the treatment of amyotrophic lateral sclerosis (ALS) and other types of motor neuropathic disease and peripheral neuropathy.

Amyotrophic lateral sclerosis, motor neurogenic disease, peripheral neuropathy, peptide compound, SPM 927, (R) -2-acetamide-N-benzyl-3-methoxypropionamide.

Description

Novel use of peptide compounds for treating amyotrophic lateral sclerosis

The present invention relates to the use of a group of peptide compounds for the treatment of amyotrophic lateral sclerosis (ALS) and motoneuron disease and peripheral neuropathies.

Some peptides are known to exhibit central nervous system (CNS) activity and are useful for the treatment of pre-hepatic and other CNS diseases. Such peptides described in US Pat. No. 5,378,729 have the formula (la):

Formula (Ia)

In the formula,

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron withdrawing groups or electron donating groups;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or electron ball Substituted with an excitation or electron withdrawing group; And

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl Lower alkyl, or R ₂ and R ₃ are ZY, which may be unsubstituted or substituted with one or more electron withdrawing groups or electron donor groups;

Z is 0, S, S (O) _a , NR ₄ , PR ₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, Y may be unsubstituted or substituted with an electron donor or electron withdrawing group And Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ or PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ or PR ₄ NR ₅ R ₇ ,

인 조건을 만족하며;

Satisfy the condition of;

R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ and R ₆ are unsubstituted or electron withdrawing groups or May be substituted with an electron donating group; And

R ₇ is R ₆ or COOR ₈ or COR ₈ ;

R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing or electron donor group; And

n is 1-4; And

a is 1-3.

US Pat. No. 5,773,475 also discloses additional compounds useful for the treatment of CNS diseases. These compounds are N-benzyl-2-amino-3-methoxy-propionamides having the formula (IIa):

Formula (IIa)

Wherein Ar is unsubstituted or aryl substituted with halo; R ₃ is lower alkoxy; R ₁ is methyl.

US 5,378,729 and US 5,773,475 are hereby incorporated by reference. However, none of the above applications describes the use of this compound as a specific neuroprotective agent for the treatment of ALS and other motor neuropathic diseases and peripheral neuropathy.

WO 02/074297 relates to peripheral neuropathy of compounds of formula (IIa) wherein aryl is phenyl which may be substituted with one or more halo, R ₃ is lower alkoxy containing 1 to 3 carbon atoms and R ₁ is methyl It relates to the use for the preparation of a pharmaceutical composition useful for the treatment of related allodynia.

WO 02/074784 describes acute and chronic pains of different kinds and symptoms, in particular, non-neuropathic inflammatory pain, for example rheumatoid arthritis pain and / or secondary inflammatory osteo-arthritis pain ( It relates to the use of a compound having formula (Ia) and / or formula (IIa) exhibiting anticiceptive properties for the treatment of secondary inflammatory osteo-arthritic pain.

Amyotrophic lateral sclerosis is characterized by degeneration and loss of motor neurons in the spinal cord and brain stem, and by varying degrees of degeneration of the descending motor pathways in the cortex-spinal passage (Deng et al., 1993; Rothstein et al., 1995). This disease leads to death by progressive muscle hardening, weakness, paralysis and ultimately respiratory failure (Andersen et al., 1995). ALS occurs with familial ALS (FALS) and sporadic ALS (SALS). FALS is an autosomal dominant hereditary, accounting for 5-10% of cases (Gurney et al., 1994; Rosen et al., 1993). About 20% of FALS cases are associated with mutations in SOD1, a gene encoding cytoplasmic Cu, Zn superoxide dismutase (SOD) (Beckman et al., 1993; Rosen et al., 1993). The recent discovery of mutations affecting the SOD gene has prompted the study of the role of oxidative stress in the pathogenesis of FALS.

In order to establish an animal model for familial ALS, several species of transgenic mice carrying the human SOD1 gene have been developed. Mice overproducing wild-type human Cu, Zn SOD are clinically normal and indeed show increased resistance to oxidative stress (Yang et al., 1994). Mice producing mutant Cu, Zn SOD rapidly develop progressive motor neuron disease, very similar to ALS (Gurney et al., 1994; Mohajeri et al., 1998). This phenotype appears in mice expressing G93A mutations and glycine → arginine mutations (Gurney et al., 1994).

The mechanism of motor neuropathic disease is poorly understood. Current treatments use a variety of pharmaceutical, surgical, physical and psychological approaches. However, the evidence for many therapies is still limited.

The use of the compounds of formula (Ib) and / or formula (IIb) for the treatment of motor neurogenic diseases has not been reported. Accordingly, the present invention is directed to motor neuropathic diseases such as ALS, progressive spinal muscular atrophy or progressive soft palsy, and / or Guillain-Barre Syndrome or Charcot-Marie-Tooth disease. And the use of a compound of formula (Ib) and / or formula (IIb) for the preparation of a pharmaceutical composition for the prevention, alleviation and / or treatment of peripheral neuropathy.

Surprisingly, the application of formulas (Ib) and / or (IIb), in particular (R) -2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927), has been found in mice with motor neurogenic disease. Significant efficacy has been shown in prolonging survival and improving motor coordination. Thus, these compounds are useful as agents for motor neuronal disease or peripheral neuropathy.

Compounds according to the invention have the general formula (Ib)

Formula (Ib)

In the formula,

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, respectively Unsubstituted or substituted with one or more electron donating groups and / or one or more electron withdrawing groups; And

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or R ₂ and R _3, is ZY, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

Z is 0, S, S (O) _a , NR ₄ , NR ' ₆ , PR ₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, Y is unsubstituted or one or more electron balls And may be substituted with one or more electron withdrawing groups and Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ or N ⁺ R ₅ R ₆ R ₇ ,

인 조건을 만족하고;

Satisfies the condition of;

R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ and R ₆ are independently unsubstituted or one May be substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And

R ₇ is R ₆ or COOR ₈ or COR ₈ , wherein R ₇ may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And

n is 1-4; And

a is 1-3.

Preferably, the compounds of the present invention have the general formula (IIb)

Formula (IIb)

In the formula,

Ar is aryl, in particular phenyl unsubstituted or substituted with one or more halo; R ₃ is —CH ₂ —Q, wherein Q is lower alkoxy; R ₁ is lower alkyl, in particular methyl.

The invention also relates to a pharmaceutical composition comprising a compound of formula (Ib) or / and (IIb) useful for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy.

When used alone or in combination with other groups, a "lower alkyl" group is lower alkyl comprising 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, and may be straight or branched. have. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl, and the like.

A "lower alkoxy" group is lower alkoxy containing 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, and may be straight or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

"Aryl lower alkyl" groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, And the like.

When used alone or in combination, the term "aryl" means an aromatic group containing from 6 to 18 ring carbon atoms and up to 25 carbon atoms in total and comprising polynuclear aromatics do. These aryl groups are monocyclic, bicyclic, tricyclic or polycyclic and fused rings. As used herein, multinuclear aromatic compounds are intended to include bicyclic or tricyclic fused aromatic ring systems comprising 10-18 ring carbon atoms and up to 25 carbon atoms in total. Aryl groups include phenyl and polynuclear aromatics include, for example, naphthyl, anthracenyl, phenanthrenyl, azulenyl, and the like. Aryl groups also include groups such as ferrocenyl. Aryl groups may be unsubstituted or mono- or multiply substituted with electron withdrawing groups and / or electron donor groups as described below.

"Lower alkenyl" is an alkenyl group containing 2 to 6 carbon atoms and one or more double bonds. These groups may be straight or branched and may be Z or E. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z) -2-pentenyl, (E) -2-pentenyl, (Z)- 4-methyl-2-pentenyl, (E) -4-methyl-2-pentenyl, pentadienyl such as 1,3-, or 2,4-pentadienyl, and the like.

The term "lower alkynyl" is an alkynyl group containing 2 to 6 carbon atoms and may be straight or branched. It is ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl And groups such as 3-hexynyl and the like.

When used alone or in combination, the term "lower cycloalkyl" is a cycloalkyl group comprising from 3 to 18 ring carbon atoms and up to 25 carbon atoms in total. Cycloalkyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. Cycloalkyls can be fully saturated or partially saturated. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, Fenkill, pinenyl, adamantyl and the like. Cycloalkyls include cis or trans forms. Cycloalkyl groups can be unsubstituted or mono-substituted or multiple-substituted with electron withdrawing groups and / or electron donor groups as described below. Substituents may also be in endo or exo positions in a bridged bicyclic system.

The terms "electron-withdrawing and electron donating" refer to the ability of a substituent to attract or donate electrons compared to hydrogen when the hydrogen atoms occupy the same position in the molecule. These terms are fully understood by those skilled in the art and discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, NY, pp. 16-18 (1985), the discussion of which Inc. is incorporated herein by reference. Electron attractors include halo, including bromo, fluoro, chloro, iodo and the like; Nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxamido, aryl, quaternary ammonium, haloalkyl such as trifluoromethyl, aryl lower alkanoyl, carvalcoxyl and the like. Electron donor groups include lower alkoxy including hydroxy, methoxy, ethoxy and the like; Lower alkyl including methyl, ethyl and the like; Amino, lower alkylamino, di (lower alkyl) amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkyl mercapto, disulfide (lower alkyldithio) and the like. Those skilled in the art will appreciate that some of the substituents described above may be considered to donate electrons or attract electrons under different chemical conditions. In addition, the present invention contemplates any combination of substituents selected from the groups described above.

The term "halo" includes fluoro, chloro, bromo, iodo, and the like.

The term "acyl" includes lower alkanoyls containing 1 to 6 carbon atoms and may be straight or branched. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.

As used herein, heterocyclic groups include one or more sulfur, nitrogen, or oxygen ring atoms, but may also include several such atoms in the ring. Heterocyclic groups contemplated in the present invention include heteroaromatic and saturated heterocyclic compounds and partially saturated heterocyclic compounds. This heterocyclic compound is a monocyclic, bicyclic, tricyclic or polycyclic and fused ring. They may preferably comprise up to 18 ring atoms and up to 17 ring carbon atoms and up to 25 carbon atoms in total. Heterocyclic groups are intended to include so-called benzoheterocyclics. Representative heterocyclics are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, py Ferrazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl , Imidazolinyl, imadazolininyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, aze N-oxides of tidinyl, nitrogen-containing heterocycles such as pyridyl, pyrazinyl, and pyrimidinyl. Heterocyclic groups can be unsubstituted or monosubstituted or polysubstituted with electron withdrawing groups and / or electron donors.

Preferred heterocyclic groups are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridylyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl . Preferred heterocyclics are 5 or 6-membered heterocyclic compounds consisting of 5 or 6 atoms. Particularly preferred heterocyclics are furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. Most preferred heterocyclics are furyl and pyridyl.

Preferred compounds are those where n is 1, but di (n = 2), tri (n = 3) and tetra (n = 4) are also contemplated as being within the scope of the present invention.

Preferred values of R are aryl lower alkyl, in particular benzyl, in particular benzyl in which the phenyl ring is unsubstituted or substituted with an electron donor group and / or an electron withdrawing group such as halo (eg F).

Preferred R ₁ is H or lower alkyl. Most preferred R ₁ group is methyl.

Preferred electron donating substituents and / or electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carvalcoxyl, carboxamido, cyano, sulfonyl, sulfoxide, hetero Cyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, mercapto, Mercaptoalkyl, alkylthio, and alkyldithio. The term "sulfide" includes mercapto, mercapto alkyl, and alkylthio, and the term disulfide includes alkyldithio. Particularly preferred electron donor or / and electron withdrawing groups are halo or lower alkoxy, most preferred is fluoro or methoxy. Such preferred substituents are one of the groups in formula (Ib) or in formula (IIb), for example R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R as defined herein. ₆ , R ′ ₆ , R ₇ , R ₈ and / or R ₅₀ .

Representative ZY groups of R ₂ and R ₃ include hydroxy, methoxy, alkoxy such as ethoxy, aryloxy such as phenoxy; Thioalkoxy such as thiomethoxy, thioethoxy; Thioaryloxy such as thiophenoxy; Amino; Alkylamino such as methylamino, ethylamino; Arylamino, such as anilino; Lower dialkylamino such as dimethylamino; Trialkyl ammonium salts, hydrazino; Alkylhydrazinos and arylhydrazinos, such as N-methylhydrazino, N-phenylhydrazino, carvalcoxyl hydrazino, aralkyloxycarbonyl hydrazino, aryloxycarbonyl hydrazino, N-hydroxylamino (-NH Hydroxylamino, such as -OH), lower alkoxy amino [R ₁₈ is lower alkyl (NHOR ₁₈ )], N-lower alkylhydroxy amino [R ₁₈ is lower alkyl (NR ₁₈ ) OH], N-lower alkyl -O-lower alkylhydroxyamino, ie, [R ₁₈ and R ₁₉ are independently lower alkyl N (R ₁₈ ) OR ₁₉ ], and o-hydroxylamino (-0-NH ₂ ); Alkylamido such as acetamido; Trifluoroacetamido; Lower alkoxyaminos (eg, NH (OCH ₃ )) and heterocyclic aminos such as pyrazoylamino;

Preferred heterocyclic groups representing R ₂ and R ₃ are monocyclic 5- or 6-membered heterocyclic moieties consisting of 5 or 6 atoms having the formula:

Or a corresponding partially or fully saturated form thereof, wherein n is 0 or 1;

R ₅₀ is H or an electron withdrawing group or an electron donating group;

A, E, L, J and G are independently CH or heteroatoms selected from the group consisting of N, O, S;

However, when up to two of A, E, L, J and G satisfy heteroatoms, and when n is 0, G is CH or a heteroatom selected from the group consisting of NH, O and S.

When n is 0, the aforementioned heteroaromatic moiety is a ring of 5 atoms, and when n is 1, the heterocyclic moiety is a monocyclic heterocyclic moiety of 6 atoms. Preferred heterocyclic moieties are heterocyclics which are monocyclic as described above.

If the aforementioned ring contains nitrogen ring atoms, it is contemplated that the N-oxide form is also within the scope of the present invention.

If R ₂ or R ₃ is heterocyclic of the above formula, it may be bonded to the main chain by ring carbon atoms. When n is 0, R ₂ or R ₃ may be further bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R ₂ and R ₃ are hydrogen, aryl such as phenyl, aryl alkyl such as benzyl and alkyl.

It will be appreciated that the preferred groups of R ₂ and R ₃ may be unsubstituted or monosubstituted or polysubstituted with an electron donor group and / or an electron withdrawing unit. Lower alkyl, N-hydroxylamino, wherein R ₂ and R ₃ are independently substituted or unsubstituted with an electron withdrawing group and / or an electron donor, such as hydrogen, lower alkoxy (e.g., methoxy, ethoxy, etc.) , N-lower alkylhydroxyamino, N-lower alkyl-O-lower alkyl and alkylhydroxyamino.

One of R ₂ and R ₃ Hydrogen is preferred.

It is preferable that n is 1.

n = 1 and one of R ₂ and R ₃ It is more preferable that it is hydrogen. In this embodiment, R ₂ is hydrogen and R ₃ is lower alkyl or ZY;

인 것이 특히 바람직하다. Z is 0, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ON _R 4R ₇ ,

Is particularly preferred.

In another particularly preferred embodiment, n = 1, R ₂ is hydrogen and R ₃ is lower alkyl, NR ₄ OR ₅ or ONR ₄ R ₇ which may be unsubstituted or substituted with an electron donor or electron withdrawing group.

In another particularly preferred embodiment, n = 1, R ₂ is hydrogen and R ₃ is lower alkyl, NR ₄ OR ₅ or ONR ₄ R ₇ which is unsubstituted or substituted with hydroxy or lower alkoxy, wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group may be unsubstituted or substituted with an electron withdrawing group and R ₁ is lower alkyl. In this embodiment, aryl is most preferably unsubstituted or phenyl substituted with halo.

It is preferred that R ₂ is hydrogen and R ₃ is hydrogen, unsubstituted or an alkyl group substituted with one or more electron donor groups or electron withdrawing groups or ZY. In this preferred embodiment, R ₃ is hydrogen, an alkyl group such as methyl, unsubstituted or substituted with an electron donor, or NR ₄ OR ₅ , wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl or it is more preferred that ONR ₄ R _7. The electron donating group is preferably lower alkoxy, in particular methoxy or ethoxy.

R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY;

Z is 0, NR ₄ or PR ₄ ;

Y is hydrogen or lower alkyl or

인 것이 바람직하다.ZY is NR ₄ R ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

Is preferably.

In addition, R is preferably aryl lower alkyl. Most preferred aryl for R is phenyl. Most preferred R group is benzyl. In a preferred embodiment, the aryl group can be unsubstituted or substituted with an electron donor group or an electron withdrawing group. When the aryl ring of R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halo, in particular fluoro.

Preferred R ₁ is lower alkyl, in particular methyl.

More preferably, R is aryl lower alkyl and R ₁ is lower alkyl.

Further preferred compounds are n is 1; R ₂ is hydrogen; R ₃ is hydrogen or lower alkyl group, in particular methyl or ZY substituted with an electron donor group or an electron withdrawing group; R is an aryl, a compound of formula (Ib) wherein aryl is unsubstituted or substituted with an electron donor or electron withdrawing group, aryl lower alkyl such as benzyl and R ₁ is lower alkyl. In this embodiment, R ₃ is a lower alkyl group, in particular methyl, NR ₄ OR ₅ as defined above, which may be substituted with an electron donating group such as hydrogen, lower alkoxy (eg methoxy, ethoxy etc.) Or ON ₄ R ₇ is preferred.

Most preferred compounds used are as compounds of formula (IIb):

Formula (IIb)

Wherein Ar is unsubstituted or aryl, in particular phenyl, substituted by one or more electron donating groups or electron withdrawing groups, in particular halo,

R ₁ is lower alkyl, especially lower alkyl comprising 1 to 3 carbon atoms;

R ₃ is as defined herein, but in particular, lower alkyl or ZY substituted with hydrogen, unsubstituted or substituted with one or more electron donor groups or electron substituents. In this embodiment, it is even more preferred that R ₃ is hydrogen, an unsubstituted or substituted alkyl group, NR ₄ OR ₅ or ONR ₄ R ₇ . R ₃ is CH ₂ -Q wherein Q is lower alkoxy, especially lower alkoxy containing 1 to 3 carbon atoms; R ₄ is hydrogen or alkyl containing 1 to 3 carbon atoms, R ₅ is hydrogen or alkyl containing 1 to 3 carbon atoms, and R ₇ is hydrogen or 1 to 3 carbon atoms Most preferably, it is NR ₄ OR ₅ or ONR ₄ R ₇ which is alkyl.

Most preferred R ₁ is CH ₃ . Most preferred R ₃ is CH ₂ -Q, wherein Q is methoxy.

Most preferred aryl is phenyl. Most preferred halo is fluoro.

Most preferred compounds are:

(R) -2-acetamido-N-benzyl-3-methoxy-propionamide;

O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;

O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;

N-acetyl-D-phenylglycine benzylamide;

D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide;

D-1,2- (O-methylhydroxyamino) -2-acetamido acetate benzylamide; and the like.

Various combinations and permutations of the Markush groups of R ₁ , R ₂ , R ₃ , R and n described herein are contemplated as being within the scope of the present invention. The invention also includes compounds and compositions comprising one or more elements of each of the Markush groups of R ₁ , R ₂ , R ₃ , n and R and various combinations thereof. Thus, for example, in the present invention, R ₁ may be one or more substituents described above in the combination having all substituents of R ₂ , R ₃ and R for each n value.

The compounds used in the present invention may comprise one or more asymmetric carbons and may exist in racemic and optically active forms. The arrangement around each asymmetric carbon may be Form D or Form L. It is known in the art that the arrangement around chiral carbons can also be described as R or S in the Cahn-Prelog-Ingold nomenclature system. All various arrangements around each asymmetric carbon are contemplated by the present invention, including racemic mixtures and mixtures comprising various enantiomers and diastereomers and enantiomers, diastereomers or both.

In the main chain, there is asymmetry in the carbon atom to which R ₂ and R ₃ are attached. When n is 1, the compound of the present invention is a compound of formula (III)

(III)

(III)

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ' ₆ , R ₇ , R ₈ , R ₅₀ , Z and Y are as defined above.

As used herein, the term configuration will mean an arrangement around a carbon atom to which R ₂ and R ₃ are bonded, although other chital centers may be present in the molecule. Thus, when referring to specific arrangements such as D or L, it will be understood that R ₂ and R ₃ refer to D or L stereoisomers at the bonded carbon atom. However, if there are other chiral centers in the compound, the arrangement also includes all possible enantiomers and diastereomers at other chiral centers.

The compounds of the invention relate to all optical isomers, ie the compounds of the invention are L-stereoisomers or D-stereoisomers (at the carbon atoms to which R ₂ and R ₃ are bonded). These stereoisomers can be found as mixtures of L stereoisomers and D stereoisomers, for example racemic mixtures. D stereoisomers are preferred.

More preferably substituent R is benzyl unsubstituted or substituted with one or more halo groups, R ₃ is CH ₂ -Q wherein Q is lower alkoxy containing 1 to 3 carbon atoms, and R ₁ is methyl It is a compound of formula (III) in the R configuration, and is preferably substantially pure enantiopure. Preferably R is benzyl substituted with one or more halo groups which are unsubstituted benzyl or fluoro groups.

Depending on the substituents, the compounds of the present invention may also form addition salts. All such forms, including mixtures of stereoisomers, are contemplated as being within the scope of this invention.

The preparation of the compounds used is described in US Pat. No. 5,378,729 and US Pat. No. 5,773.475, incorporated herein by reference.

The compounds used in the present invention as described by formula (Ib) or / and (IIb) may be useful on their own or in the form of salts in view of the basicity due to the presence of free amino groups. Thus, the compounds of formula (Ib) or / and (IIb) form salts with a wide range of inorganic and organic acids, including pharmaceutically acceptable acids. Salts with pharmaceutically acceptable acids are of course useful in the preparation of formulations in which increased water solubility is most advantageous.

This pharmaceutically acceptable salt also has therapeutic efficacy. Salts of inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, perchloric acid, glycolic acid, gluconic acid, succinic acid, aryl sulfonic acid (e.g. Salts of organic acids such as p-toluene sulfonic acid, benzenesulfonic acid), phosphoric acid, malonic acid and the like.

The invention also provides a method of preventing, alleviating or / and treating a disease or condition as described above in a mammal, including a human, comprising administering at least one compound of formula (Ib) or / and (IIb). It is about.

The compound used in the present invention is preferably used in a therapeutically effective amount.

The physician will determine the most suitable dosage of the therapeutic agent of the invention, which will depend on the particular compound and dosage form chosen, and also on the patient being treated, the age of the patient, the type of disease being treated. The physician will generally want to start treatment at a dose substantially lower than the optimal dose of the compound and increase the dose in small amounts until the optimum effect is reached. When the composition is administered orally, higher amounts of active agent will be required to produce the same effect as the less parentally administered amount. The compounds are useful in the same manner as similar therapeutic agents and the dosage level is as generally applied to such other therapeutic agents.

In a preferred embodiment, the compound of the present invention is administered in an amount of about 1 mg to about 100 mg / 1 kg / day, more preferably in an amount of about 1 mg to about 10 mg / 1 kg / day body weight. This dosage regimen can be adjusted by the physician to provide the optimum therapeutic response. Patients in need of administration are treated with a dose of a compound of the invention of at least 50 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day and most preferably at least 400 mg / day. In general, patients in need of administration can be treated at a dose of up to 6 g / day, more preferably at a dose of up to 1 g / day, and most preferably at a dose of up to 600 mg / day. In some cases, however, higher or lower dosages may be required.

In another preferred embodiment, the daily dose is increased until a predetermined daily dose is reached that will be maintained for further treatment.

In another preferred embodiment, several divided doses may be administered daily. For example, three doses per day, preferably twice a day, may be administered. More preferably, once daily administration.

In another preferred embodiment, the compounds of the present invention result in plasma concentrations of 0.1-15 μg / ml (lowest) and 5-18.5 μg / ml (highest), calculated as averages for the plurality of treated subjects. Amounts may be administered.

The compound of formula (Ib) or / and (IIb) may be administered in a convenient manner such as oral, intravenous (if water soluble), intramuscular, intrathecal or subcutaneous route of administration. Oral or / and intravenous administration is preferred.

The pharmaceutical composition of the present invention may be treated with a treatment regimen as described above, in particular with a duration of administration and / or route of administration as specified in embodiments of the invention as described above at the above-mentioned dosages. It may be prepared for a method of treatment for obtaining a plasma concentration as such.

In another preferred embodiment, the method as described above for treating a mammal, including a human in need thereof, is administered with an additional active agent for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy. Administering a compound of the invention in combination with the. The compounds of the present invention and the additional active agents can be administered together, ie in a single dose form, or separately, ie in separate dosage forms. Accordingly, the pharmaceutical compositions of the present invention for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy comprise a compound of the present invention as defined above and may further comprise additional active agents. . The pharmaceutical composition may comprise a separate dosage form comprising a single dosage form or comprising a first composition comprising a compound of the invention as defined above and a second composition comprising an additional active agent.

Additional active agents for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy can be any suitable agent known to those skilled in the art to which this invention pertains.

The compounds of the present invention can be used for the preparation of pharmaceutical compositions as described above.

The compound of formula (Ib) and / or (IIb) may be administered orally, for example, with an inert diluent or with an absorbable edible carrier, or in a hard or soft gelatin capsule. It may be enclosed, compressed into tablets, or directly included in the diet. For oral therapeutic administration, the active compound of formula (Ib) and / or (IIb) may be combined with excipients for ingestible tablets, buccal tablets, troches, capsules, elixirs (elixir), suspensions, syrups, wafers and the like. Such compositions and preparations should comprise at least 1% of the active compounds of formula (Ib) or / and (IIb). The percentage of compositions and formulations may of course vary and may conveniently be between about 5% and about 80% of the unit weight. The amount of active compound of formula (Ib) and / or formula (IIb) in such therapeutically useful compositions is determined such that a suitable dosage can be obtained. Preferred compositions or preparations according to the invention comprise about 10 mg to 6 g of the active compound of formula (Ib) and / or formula (IIb).

Tablets, troches, pills, capsules and the like may also include the following: binders such as tragacan gum, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And sweetening agents such as sucrose, lactose or saccharin can be added or flavorings such as peppermint, methyl salicylate (oil of wintergreen), or cherry flavor can be added. When the dosage unit form is a capsule, it may comprise a liquid carrier, in addition to the substances of the aforementioned kind.

Various other materials may be present in the coating or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. Syrups or elixirs may include active compounds, sucrose as a sweetening agent, methylparabens and propylparabens as preservatives, dyes and flavoring agents such as cherry or orange flavors. Of course, the materials used to prepare any dosage unit formulations must be pharmaceutically pure and non-toxic in practically the amount used. The active compounds can also be mixed into sustained release formulations and compositions. For example, sustained release dosage forms are contemplated in which the active ingredient is bound to an ion exchange resin that can be optionally coated with a diffusion barrier coating to modify the release characteristics of the resin.

The active compound may be administered parenterally or intraperitoneally. Disperisons can be prepared in glycerol, liquids, polyethylene glycols, and mixtures and oils thereof. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical formulations suitable for injection use include sterile aqueous solutions (if water soluble) or dispersants and sterile powders for the instant preparation of sterile injectable solutions or dispersants. In all cases, the formulation must be sterile and fluid to the extent that easy syringability in the syringe is possible. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium comprising water, ethanol, polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycols, etc.), suitable mixtures thereof, and vegetable oils. Suitable fluidity should be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the desired particle size in the case of dispersants and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be more desirable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable composition can be achieved by the use of agents that delay absorption in the composition, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by mixing the desired amount of active compound with a suitable solvent containing the various ingredients described above as needed and subject to filtered sterilization. Generally, dispersants are prepared by mixing the various sterilized active ingredients into a sterile vehicle that contains the desired ingredients from the basic dispersion medium and those described above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying, lyophilization of additional desired components from the previous sterile-filtered solution.

As used herein, "pharmaceutically acceptable carrier" isotonicity for all solvents, dispersion media, coatings, antibacterial and antifungal agents, pharmaceutically active substances known in the art to which this invention pertains. Agonists and absorption retardants. Except insofar as conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients can also be mixed into the compositions.

It is particularly advantageous to prepare parenteral compositions in dosage unit dosage forms or in dosage forms and in dosages that are uniform. Dosage unit dosage form as used herein refers to physically discrete units suited as unitary dosages for the mammal to be treated; Each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with the desired pharmaceutical carrier. Details of the novel dosage unit formulations of the present invention are directed to (a) the unique properties of the active substance for the particular therapeutic effect to be achieved, and (b) a disease state in which physical health is impaired as described in detail herein. It is determined and directly depends on the limitations inherent in the art of preparing such active substances for the treatment of diseases in living subjects.

The main active ingredients are formulated in dosage unit formulations as described above with pharmaceutically acceptable carriers suitable for convenient and effective administration in effective amounts. Unit dosage formulations may comprise a major active compound, eg, in an amount from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in about 1 to about 750 mg of the formulation per ml of carrier. In the case of compositions comprising supplementary active ingredients, the dosage is determined with reference to the usual dosages and modes of administration of the above ingredients.

The term "patient" or "subject" as used herein includes warm blooded animals, preferably cats, dogs, horses, cattle, pigs, mice, mice, and humans, for example. Means mammals such as primates. Preferred patients are humans.

The term "treat" means alleviating pain associated with a disease or condition, or treating or alleviating a disease or condition of a patient, or prolonging survival.

The compounds of the present invention are administered in an effective amount to a patient suffering from a disease of the aforementioned kind. These amounts correspond to the therapeutically effective amounts described above.

The examples and figures below show the properties of SPM 927 to improve motor coordination and prolong survival of SOD mutant mice.

The material used is SPM 927, a synonym for Harkosride. The standard chemical name is (R) -2-acetamide-N-benzyl-3-methoxypropionamide. The international non-proprietary name of SPM 927 is lacosamide.

1 shows that SPM 927 extends the lifespan of SOD mutant mice in a dose dependent manner.

2 shows that SPM 927 (30 mg / kg) attenuates motor impairment (grid performance) in SOD mutant mice.

3 shows that SPM 927 (10 mg / kg) attenuates motor impairment (latent potential of complex muscle action potential) in SOD mutant mice.

Effect of SPM 927 in SOD Mutant Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

This study shows that long-term treatment with SPM 927 attenuates motor symptoms and prolongs survival in mouse models of ALS (SOD mutant mice). SPM 927 treatment has been shown to attenuate motor symptoms, including myocardial record (EMG) abnormalities, and prolong survival after developing symptoms in mouse models.

This study examined the effect of SPM 927 on protecting or reducing the damage observed in this ALS model. For this purpose, behavioral measurements and EMG were performed in SOD-G93A mice overexpressing mutant human Cu, Zn SOD.

Materials and methods

The transgenic mouse species used in this study was G1H (Gurney et al., 1994). The animals showed signs of posterior limb weakening at about 3 months of age and died at 4 months of age.

Forty mice were used in this study and they were divided into four groups of 10 animals.

. SOD vehicle group

. SOD treatment group (SPM 927 3 mg / kg)

. SOD treatment group (SPM 927 10 mg / kg)

. SOD treatment group (SPM 927 30 mg / kg)

The animals were weighed every day. The overall condition of the mice was checked daily, and in particular, the presence of tremor, skin condition and muscle wasting. EMG testing was performed once a week starting from 70 days of age (D70) until death. Survival and interval between onset of symptoms and death were recorded.

Exercise coordination measurement

Rotarod test: This test evaluates the ability of an animal to stay on a rotating dowel, allowing for the assessment of motor coordination and proprioceptive sensitivity. The device is a 3 cm diameter automated rod rotating 12 times per minute (Bioseb, Paris, France). The rotarod test measures how long the mouse can hold itself on the axis without falling off. The test was stopped after a randomly set time limit of 120 seconds. If the animal fell 120 seconds ago, the performance was recorded and two additional tests performed. The average of three trials was calculated. Lack of exercise was manifested by a decrease in walking time.

Grid test: During the test, mice are placed on a grid (length: 37 cm, width: 10.5 cm, net size: 1 * 1 cm) placed on a flat support. The number of times mice drop their feet into the net is measured and used as an indicator of motor coordination.

Hanging test: This test evaluates the ability of an animal to hang on a wire. The device is a wire stretched horizontally at a height of 40 cm from the table. The animal is attached to the wire with its paws. Record the time it takes for the animal to line up with its hind paws for three consecutive attempts (up to 60 seconds).

Electrophysiological measurement

EMG recordings were performed using a Neuromatic 2000M EMG device. During EMG, mice were anesthetized (60 mg kg-1, Imalgene®). The measured parameters were the amplitude and latency of the complex muscle action potential (CMAP). CMAP was measured in gastrocnemius muscle after sciatic nerve stimulation. A reference electrode was inserted around the Achilles tendon and an active needle was placed at the base of the tail. A ground needle was inserted at the waist of the mouse. The sciatic nerve was stimulated with a single 0.2 ms pulse at ultramaximum intensity (12.9 mA). The amplitude (mV) and latency (ms) of the response were measured. The amplitude represents the number of active motor units, and the distal latency reflects the motor nerve conduction velocity.

drug injection

Animals were treated with treatment from 60 days of age (before the onset of clinical signs) to death. The therapeutic agent was administered intraperitoneally twice a day.

Data analysis

Global analysis of the data was carried out using one-way ANOVA or repeated ANOVA measurements. The Fisher test or Student-Newman-Keuls t test was used for multiple comparisons between the test and individual controls or for multiple comparisons between paired groups. Intra-group analysis was performed to evaluate the variation in performance within each group.

result

SPM 927 is:

. Prolong survival after onset of symptoms (FIG. 1)

. Relieves motor symptoms in the rodda rod, lattice (FIG. 2) and suspension tests

. Weakened EMG abnormalities (FIG. 3);

conclusion

These results show that SPM 927 and related compounds are useful for the treatment of amyotrophic lateral sclerosis and other motor neuronogenic diseases including, but not limited to, progressive spinal cord muscle atrophy and progressive soft palsy. In addition, the results indicate that SPM 927 and related compounds are active in the treatment of peripheral neuropathy, including but not limited to, Guillain-Barre Syndrome or Charcot-Marie-Tooth disease. Shows that it has

references

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BECKMAN JS, CARSON M, SMITH CD, KOPPENOL WH (1993) ALS, SOD and peroxynitrite. Nature 364: 584

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DENG HX, HENTATI A, TAINER JA, IQBAL Z, CAYABYAB A, HUNG WY, GETZOFF ED, HU P, HERZFELDT B, ROOS RP et al. (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261: 1047-1051.

GURNEY ME, PU H, CHIU AY, DAL CANTO MC, POLCHOW CY, ALEXANDER DD, CALIENDO J, HENTATI A, KWON YW, DENG HX et al. (1994) Motor neuron degeneration in mice that express a humanCu, Zn superoxide dismutase mutation . Science 264: 1772-1775.

GURNEY M, CUTTING FB, ZHAI P, DOBLE A, TAYLOR C, ANDRUS PK, HALL ED (1996) Benefit of vitamin E riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39: 147-157.

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Claims (35)

 As a compound having the following formula (Ib):

Formula (Ib) In the above, R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, respectively Unsubstituted or substituted with one or more electron donating groups and / or one or more electron withdrawing groups; And R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or R ₂ and R _3, is ZY, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; Heterocyclic in R ₂ and R ₃ is furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl , Pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, Indolinyl, pyrazolindinyl, imidazolinyl, imadazolininyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino , Oxetanyl, azetidinyl or, if N is present in the heterocyclic, its N-oxide Z is 0, S, S (O) _a , NR ₄ , NR ' ₆ , PR ₄ or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, Y is unsubstituted or one or more electron balls And may be substituted with one or more electron withdrawing groups, wherein the heterocyclic has the same meaning as in R ₂ or R ₃ , If Y is halo, Z is a chemical bond, or ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ or N ⁺ R ₅ R ₆ R ₇ ,

Satisfies the condition of being; R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ and R ₆ are independently unsubstituted or one May be substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And R ₇ is R ₆ or COOR ₈ or COR ₈ , wherein R ₇ may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And n is 1-4; And a is a use of a compound of formula (Ib) wherein 1-3 is a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition useful for the prevention, alleviation and / or treatment of motor neuropathic disease and / or peripheral neuropathy. The use of claim 1, wherein the disease is amyotrophic lateral sclerosis (ALS). The use according to claim 1 or 2, wherein one of R ₂ and R ₃ is hydrogen. 4. Use according to any one of claims 1 to 3, wherein n is one. 5. The use according to claim 1, wherein one of R ₂ and R ₃ is hydrogen and n is 1. 6. 6. The use according to claim 1, wherein R is aryl lower alkyl and R ₁ is lower alkyl. 7. The method according to any one of claims 1 to 6, R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY; Z is 0, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

Use that is. 8. The compound of claim 7, wherein R ₂ is hydrogen and R ₃ is lower alkyl or ZY; Z is 0, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

Use that is. The lower alkyl, NR ₄ of claim 1, wherein R ₂ is hydrogen and R ₃ is unsubstituted or substituted with one or more electron donor groups and / or one or more electron withdrawing groups. 0R ₅ , or ONR ₄ R ₇ . Claim 1 to according to any one of claim 9, wherein R ₃ is unsubstituted or or a hydroxy or lower alkyl which may be substituted by lower alkoxy, NR ₄ 0R _5, or ONR ₄ R _7, wherein R ₄ R ₅ and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group is unsubstituted or can be substituted with one or more electron withdrawing groups and R ₁ is lower alkyl . The use according to any one of claims 1 to 10, wherein the aryl is phenyl and unsubstituted or substituted with halo. The compound of claim 1, wherein the compound is (R) -2-acetamido-N-benzyl-3-methoxy-propionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide; D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide; or D-1,2- (O-methylhydroxyamino) -2-acetamido acetate benzylamide. The compound according to any one of claims 1 to 12, wherein the compound has the formula (IIb)

Formula (IIb) In the above, Ar is unsubstituted or phenyl substituted with one or more halo; R ₃ is CH ₂ -Q wherein Q is lower alkoxy containing 1 to 3 carbon atoms, and R ₁ is lower alkyl containing 1 to 3 carbon atoms, or a compound thereof Use is a pharmaceutically acceptable salt. The use according to claim 13, wherein Ar is unsubstituted phenyl. Use according to claim 13 or 14, wherein said halo is fluoro. Use according to any one of claims 13 to 15, wherein R ₃ is CH ₂ -Q, wherein Q is lower alkoxy comprising 1 to 3 carbon atoms and Ar is unsubstituted phenyl. The compound of any one of claims 1 to 16, wherein the compound is of R type

R Has, In the above, R is unsubstituted or benzyl substituted with one or more halo; R ₃ is CH ₂ -Q, wherein Q is lower alkoxy containing 1 to 3 carbon atoms and R ₁ is methyl; or a pharmaceutically acceptable salt thereof. 18. The use of claim 17, which is a substantially pure mirror image. Use according to claim 17 or 18, wherein R is unsubstituted benzyl. 20. The use according to any one of claims 17 to 19, wherein said halo is fluoro. 21. The use according to any one of claims 17 to 20, wherein R ₃ is CH ₂ -Q, wherein Q is alkoxy containing 1 to 3 carbon atoms, and R is unsubstituted benzyl. Use according to claim 1 or 2, wherein the compound of formula (Ib) is (R) -2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof. The use of claim 22, wherein the compound is a substantially pure mirror image. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is at least 100 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day, most preferably 400 mg For use by a dosage of said compound per day or more. The method of claim 1, wherein the pharmaceutical composition is administered at a dose of up to 6 g / day, more preferably at most 1 g / day and most preferably at most 600 mg / day. Use prepared for treatment. The method of claim 1, wherein the pharmaceutical composition is prepared for treatment with a dose that is increased until a predetermined daily dose is reached and maintained for subsequent treatment. Use that is. 27. The method according to any one of claims 1 to 26, wherein the pharmaceutical composition is for treatment by three doses per day, preferably twice a day, more preferably a single daily dose. To be prepared. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is 0.1-15 μg / ml (lowest) and 5-18.5 μg / ml (highest) calculated as an average for the plurality of treated subjects. And is prepared for administration resulting in a plasma concentration of. The use according to any one of claims 1 to 28, wherein said pharmaceutical composition is prepared for oral or intravenous administration. 30. The use according to any one of claims 1 to 29, wherein the pharmaceutical composition comprises an active agent for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy. 31. The composition of claim 30, wherein said pharmaceutical composition comprises a single dosage form or comprises a first composition comprising said compound as defined by any one of claims 1 and 3 to 23 and said additional active agent. Use comprising a second composition comprising. 32. The use according to any one of claims 1 to 31, wherein said pharmaceutical composition is prepared for administration in a mammal. The use of claim 33, wherein the pharmaceutical composition is prepared for administration in humans. (a) a compound as defined in any one of claims 1 and 3 to 23, and (b) A pharmaceutical composition comprising additional active agents for the prevention, alleviation or / and treatment of motor neuropathic disease and / or peripheral neuropathy. 35. The method of claim 34, wherein the first composition comprises a compound as defined in any one of claims 1 and 3 to 23 and a separate composition comprising a second composition comprising said additional active agent (b), respectively. A pharmaceutical composition comprising a single dosage form comprising a dosage form.

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