WO2012164103A2

WO2012164103A2 - Blockers of the nogo-a s1pr pathway for the treatment of diseases characterized by neuronal damage and lack of subsequent repair

Info

Publication number: WO2012164103A2
Application number: PCT/EP2012/060533
Authority: WO
Inventors: Martin Schwab; Björn Tews; Anissa KEMPF
Original assignee: Universität Zürich
Priority date: 2011-06-03
Filing date: 2012-06-04
Publication date: 2012-12-06
Also published as: WO2012164103A9; WO2012164103A3

Abstract

The present invention provides inhibitors capable of binding to a member of the S1PR receptor group comprised of S1PR2 and S1PR5 with a dissociation constant of 5x10^-7 mol/l or smaller for treating neuronal damage, specifically an antibody, an antibody fragment, an antibody-like molecule, a nucleic acid aptamer or an oligopeptide with 6 to 30 amino acid residues in length. Similarly, an interfering RNA or an antisense modulator of gene expression of G13 or a member of the S1PR receptor group described above are provided for treating of neuronal damage.

Description

Blockers of the Nogo-A S1 PR pathway for the treatment of diseases characterized by neuronal damage and lack of subsequent repair

Description

This invention relates to the treatment of diseases characterized by neuronal damage combined with lack of subsequent repair, using blockers of the Nogo-A Sphingosine 1 - phosphate receptor S1 PR pathway, particularly antibodies to, and small molecule inhibitors of, S1 PR receptors.

Damage to neuronal cells can have severe clinical outcomes depending on which neuronal cells are damaged and where. Damage to or injury of the soma or proximal part of the axon will kill neuronal cells. Damage to the distal part of the axon can only be repaired in cells of the peripheral nervous system, and in some cases even there repair is not possible.

Nogo-A is a protein identified to be an inhibitor of neurite outgrowth and cell spreading. Fragment analysis of the Nogo-A molecule has shown that the molecule has at least two inhibitory domains "Amino-Nogo" (rat aa 1-979), at the N-terminus and Nogo-66. Amino- Nogo-A contains the functionally active Nogo Δ20 fragment (rat aa 544-725). The receptor of Nogo-66, a glycosylphosphatidyl-anchored (GPI-anchored) protein, has been identified and characterized. This receptor is termed NgR1 and signals via the RhoA pathway. Besides NgR1 , other receptors homologs have been characterized, termed NgR2 and NgR3. No receptor for Amino-Nogo has been identified so far.

The objective of the instant invention is to provide safe and efficacious means for treating neuronal damage. This objective is attained by the subject-matter of the independent claims.

The present invention is based on the surprising finding that Nogo-A binds to receptors of the S1 PR family and that inhibition of these receptors suppresses the inhibitory activity of Nogo-A.

According to a first aspect of the invention, an inhibitor capable of binding to a member of the S1 PR receptor group comprised of S1 PR2 (Gene ID: 9294) and S1 PR5 (Gene ID: 53637) with a dissociation constant of 5x10^"7 mol/l or smaller is provided for use in treating neuronal damage. According to an alternative aspect of the invention, an agonist of S1 PR1 (Gene ID: 1901 , S1 PR1 has an antagonistic effect on S1 PR2) is provided for use in treating neuronal damage.

Gene ID numbers in this document refer to entries in the Gene data base of the United States National Center for Biotechnology Information.

According to one embodiment, 1-(2,6-dichloro-4-pyridyl)-3-[(4-isopropyl-1 ,3-dimethyl- pyrazolo[3,4-b]pyridin-6-yl)amino]urea

is provided for use in treating neuronal damage.

Neuronal damage in the sense of the instant invention means injury to or dysfunction of a neuronal cell caused by trauma or neuronal disease resulting in constraint or disruption of the saltatory conduction by the neuronal cell within the nervous system in the absence of repair capacity. Examples of diseases characterized by neuronal damage and subsequent lack of repair include, without being restricted to, paraplegia caused by spinal cord injury, stroke, dementia, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and paralysis and subsequent atrophy of limbs after rupture of a peripheral nerve.

Such an inhibitor according to the first aspect of the invention may be a small molecule pharmaceutical drug, an antibody, an antibody-fragment, an antibody-like molecule, a nucleic acid aptamer or an oligopeptide 6 to 30 amino acid residues in length.

Methods for generating antibodies against the members of the S1 PR receptor group are known in the art. They include, for example, immunization of mice with a S1 PR receptor or soluble parts thereof.

An antibody fragment may be the Fab domain of an antibody (the antigen binding region of an antibody) or a single chain antibody (scFv), a fusion protein consisting of the variable regions of light and heavy chains of an antibody connected by a peptide linker. An antibody-like molecule may be a repeat protein, such as a designed ankyrin repeat protein (Molecular Partners, Zurich). An antibody fragment or an antibody-like molecule may be manufactured by methods such as recombinant protein expression.

Suitable inhibitors according to the first aspect of the invention may also be developed by evolutive methods such as phage display, ribosome display or SELEX, wherein polypeptides or oligonucleotides are selected according to their binding affinity to a target of interest. Additionally, higher affinity inhibitors may be identified by reiterative rounds of evolution and selection of the amino acid sequence or nucleotide sequence.

An oligopeptide according to a first aspect of this invention may be a peptide derived from the part of Nogo-A which is recognized by a member of the S1 PR receptor group. The binding of the peptide results in inhibition of the receptor. Conversely, a peptide may also be derived from the recognition site of member of the S1 PR receptor family that competes with the receptor for Nogo-A. Binding of such an oligopeptide must not activate the signalling pathway downstream of the receptor.

The binding of inhibitors described in the preceding paragraphs results in blocking the S1 PR 2/5 receptor. By hindering the binding of Nogo-A, its biological activity is inhibited and neurite growth is no longer suppressed.

According to another aspect of the invention, a modulator of gene expression of G13 (Gene ID: 10672) or a member of the S1 PR group comprised of S1 PR2 and S1 PR5 is provided for use in treating neuronal damage.

G13 is a G-protein and strongly coupled to S1 PR2.

Such modulator may be single-stranded or double-stranded interfering ribonucleic acid oligomer of precursor thereof, comprising a sequence tract that is complementary to an mRNA molecule encoding G13 or a member of the S1 PR group described in the preceding paragraphs.

The art of silencing or "knocking down" genes, by degradation of mRNA or other effects, is well known. Examples of technologies developed for this purpose include siRNA, miRNA, shRNA, shmiRNA, and dsRNA. A comprehensive overview of this field can be found in Perrimon et al, Cold Spring Harbour Perspectives in Biology, 2010, 2, a003640.

A modulator according to the above aspect may also be an expression vector comprising a sequence encoding an interfering ribonucleic acid oligomer as described in the preceding paragraphs. Optionally, the sequence may be under the control of a promoter operable in mammalian cells. Such expression vectors facilitate production of an interfering RNA within the cell. Methods for making and using such expression vectors are known in the art.

Alternatively, a modulator according to the above aspect of the invention may be a single- stranded or double-stranded antisense ribonucleic or deoxyribonucleic acid, comprising sequences complementary to an operon expressing of a gene encoding a member of the S1 PR group described above or G13. Such operon sequences may include, without being restricted to, intron, exon, operator, ribosome binding site or enhancer sequences. Such antisense molecules may be 12-50 nucleotides in length.

According to one aspect of the invention, a soluble polypeptide for treating neuronal damage is provided, comprising a contiguous amino acid sequence of at least 30 amino acid residues taken from the protein sequence of a member of the S1 PR group. Such a soluble polypeptide can be used to inhibit Nogo-A by specifically binding to it. Specific binding in the sense of the invention means binding with dissociation constant of 5x10^"7 mol/l or smaller. Optionally, the soluble polypeptide is linked to an Fc antibody domain. Such soluble polypeptide may act as a decoy receptor to capture, or to bind to and render inactive, Nogo-A or other S1 PR receptor ligands involved in neuronal damage. An example of a soluble polypeptide may be the extracellular domain of the S1 PR2 or S1 PR5 receptor linked to an Fc antibody domain.

According to one aspect of the invention a compound for use in treating neuronal damage is provided, wherein the compound is selected from the group comprised of:

a compound characterized by the general formula I (described in

WO/08154470):

wherein

R1 is a CrC₁₂ alkyl, and

R2, R3 and R4 are each independently hydrogen, halogen, CrC₆ alkyl, Ci-C₆ perhaloalkyl, CrC₄ perhaloalkoxy, amino, mono- or di C C₄ alkylamino, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkoxy, and R3 and R4 are optionally positioned at h, i, or j, but not simultaneously at the same position, wherein h, I or j denotes substitution positions in the pyrimidyl moiety, and

R5 is , halogen, C C₆ alkyl, C C₆ perhaloalkyl, d-C₄ perhaloalkoxy, amino, mono- or di C C₄ alkylamino, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkoxy, and

- n is 0, 1 , 2, 3 or 4;

2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol (Fingolimod):

5-[[3-chloro-4-(2,3-dihydroxypropoxy)phenyl]methyl]-3-(o-tolyl)-2- (propylamino)thiazolidin-4-one (ACT128800):

2-amino-2-[2-[4-(3-benzyloxyphenyl)sulfanyl-2-chloro-phenyl]ethyl]propane- 1 ,3-diol (KRP203):

1-[5-[(3R)-3-amino-4-hydroxy-3-methyl-butyl]-1-methyl-pyrrol-2-yl]-4-(p- tolyl)butan-1-one (CS-0777):

a compound characterized by a general formula III (described

2008/107436):

in free or salt form, wherein

- Q is selected from CH₂, C(O), and C(S), and

Qa and Qb are independently selected from N and CH, and

is selected from C₆-C₁₅-aromatic carbocyclic groups, C₅-C₁₅-carbocyclic group, and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected form the group consisting of oxygen, nitrogen and sulphur, and R¹ is selected from C-i-C₈-alkyl optionally substituted -OH, halogene, -CN, O- d-Ce-alkyl, NR^1cR^1d, carboxy-C C₈-alkyl, and COOH, - C(R^1aR^{1 b})_mC(0)CR^1cR^1dR1 e, -C(R^1aR^{1 b})mC(0)NR^1cR^1d, -C(R^1aR^1b)_tNR^1cR^1d, C(R^1aR^{1 b})mCR^1cR^1dR^1e, and

R¹ , R^1g and R^1h are independently selected from C-|-C₈-alkyl, C-|-C₈-hydroxyl, CrCs-alkylaminoiCrCs-alkyl), d C Cs-alky aminoiC Cs-alkyl), C C₈ cyanalkyl, C₆-C₁₅-aromatic carbocyclic group, C₃-C₁₅-carbocyclic group, CrC₈- haloalkyl and a 4- to 10- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and

each R^1a and R^1b are independently selected from H- OH and CrC₈-alkyl optionally substituted by -OH and halogen, and

R^1c and R^1d are independently selected from H,

C₆-Ci₅-aromatic carbocyclic group, C₇-Ci₅-aralkyl, C₃-Ci₅-carbocyclic group, a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur,

C C₈-alkoxy optionally substituted by -OH, -CN, halogen, NR⁴R⁵, a C₆-C₁₅- aromatic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur,

C₂-C₈-alkenyl optionally substituted by -OH, -CN, halogen, NR⁴R⁵, a C₆-C₁₅- aromatic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur,

C₂-C₈-alkynyl optionally substituted by -OH, -CN, halogen, NR⁴R⁵, a C₆-C₁₅- aromatic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and

C₂-C₈-alkyl optionally substituted by -OH, -CN, halogen, NR⁴R⁵, a C₆-Ci₅- aromatic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and

R^1e is selected from H and CrC₈-alkyl, and R³ is selected from C₆-C₁₅-aromatic carbocyclic group optionally substituted by -C(R^3aR^3b)_nC(0)NR^3cR^3d or -C(R^3aR^3b)_nC(0)OH, a C₇-C₁₅-aralkyl, C C₈-alkyl substituted by a C₃-C₁₅-carbocyclic group, a C₃-C₁₅-carbocyclic group, a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, C-|-C₈- alkylaminocarbonyl, di(C"|-C8-alkyl)aminocarbonyl, C-i-Cs-alkylamino, di(C-|-C₈- alkyl)amino, -C(R^3aR^3b)_nC(0)NR^3cR^3d and -C(R^3aR^3b)_n(C(0)OH; and

R^3a and R^3b are independently selected form H, -OH and CrC₈-alkyl optionally substituted by -OH and halogen; and

R3c and R3d are independently selected from H,

C₆-Ci₅-aromatic carbocyclic group, C₃-Ci₅-carbocyclic group, or R^3c and R3d, together with the N atom that they are attached, form a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur,

a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur,

CrCs-alkyoxy optionally substituted by a C₆-C₁₅-aromatic carbocyclic group, C₃-C₁₅-carbocyclic group and a 4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, a CrCs-alkoxycarbonyl optionally substituted by a C₆- C₁₅-aromatic carbocyclic group, C₃-C₁₅-carbocyclic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and

d-Cs-alkyl optionally substituted by -OH, -CN, halogen, NR⁴R⁵, a C₆-C₁₅- aromatic carbocyclic group, C₃-C₁₅-carbocyclic group and a 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, and

R4 and R5 are independently selected from H and CrC₈-alkyl, and m and n are independently selected from an integer of 0, 1 , 2 and 3, and t is integer from 1 , 2 and 3,

wherein said C₆-Ci₅-aromatic carbocyclic group, C₇-Ci₅-aralkyl, C₃-Ci₅-carbocyclic group and 4- to 15-membered group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, unless otherwise stated, are optionally substituted by C₇-C₁₅-aralkyl, d-C₈-alkyl,CN, d-C₈- alkylsulfonyl, d-C₈-haloalkylsulfonyl, halogen, d-C₈-alkoxy, OH, d-C₈- alkylcarbonyl, -C(0)-C₆-C₁₅-aromatic carbocyclic group, -C(0)-C₃-C₁₅-carbocyclic group, -C(0)-4- to 15-membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur, d-C₈-cyanoalkyl, d-C₈-cyanoalkoxy, d-C₈-halogenalkoxy, d-C₈- alkylaminocarbonyl,

d-d-alkylamino, di(d-C₈- alkyl)amino, COOH, Ci-C₈-alkoxycarbonyl, d-C₈-alkoxycarbonyl, 4- to 15- membered heterocyclic group having one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulphur optionally substituted by d-d₅- aralkyl, Ci-C₈-alkyl,CN, d-C₈-alkylsulfonyl, Ci-C₈-haloalkylsulfonyl, halogen, d- d-alkoxy, OH, Ci-C₈-alkylcarbonyl, d-C₈-cyanoalkyl, Ci-C₈-cyanoalkoxy, Ci-C₈- haloalkyl, Ci-C₈-haloalkoxy, d-C₈-alkylaminocarbonyl, di(Ci-C₈- alkyl)aminocarbonyl, d-d-alkylamino, di(d-d-alkyl)amino, COOH, d-d- alkoxycarbonyl, a C₆-Ci₅-aromatic carbocyclic group optionally substituted by C₇- Ci₅-aralkyl, d-d-alkyl, CN, halogen, d-d-alkoxy, OH, d-d-alkylcarbonyl, d- d-alkylaminocarbonyl, di(d-C₈-alkyl)aminocarbonyl, d-d-alkylamino, COOH, CF3 or d-C₈-alkoxycarbonyl or a C₃-C₁₅-carbocyclic group optionally substituted by d-ds-aralkyl, C C₈-alkyl, CN, halogen, C C₈-alkoxy, OH, C C₈- alkylcarbonyl, d-C₈-alkylaminocarbonyl, diiCrCs-alky aminocarbonyl, C Cs- alkylamino, d d-d-alky amino, COOH, CF₃ or d-C₈-alkoxycarbonyl, a compound characterized by a general formula IV (described in WO

2008/142073 A1 ):

wherein

R-i aynd R₅ have both. In each case, identical meanings and are d-C₆-alkyl, C1-C₆-alkoxy, CI, Br, or CF₃, and R₂ and R₄ have both, in each case, identical meanings are hydrogen, C-|-C₆- alkyl, d-Ce-alkoxy, CI, Br, or CF₃, and

R₃ is hydrogen, C₁-C₄-alkoxy, F, CI, CF₃, or an optionally mono- or

disubstituted C-i-C₈-alkyl group, the optional substitent(s) on the said alkyl group being independently selected from the group consiting of halogen, nitro, cyano, formyl, C₁-C₄-alkylcarbonyl, hydroxy, C₁-C₄-alkoxy, formyloxy, CrC₄- alkoxycarbonyloxy, C₁-C₄-alkoxycarbonyloxy, amino, C1-C4.alkylamino, formylamino, Ci-C₄-alkylcarbonyamino and Ci-C₄-alkoxycarbonylamino, and

R₆ is hydrogen, an optionally mono- or disubstituted CrC₈-alkyl, C₂-C₄-alkenyl or C₃-C₇-cycloalkyl group, the optional substituent(s) on the said alkyl, alkenyl or cycloalkyi group being indepentently selected from the group consisting of halogen, nitro, cyano, formyl, CrC₄-alkylcarbonyl, hydroxy, CrC₄-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, CrC₄-alkoxycarbonyloxy, amino, C₁-C4- alkylamino, di-(Ci-C₄-alkyl)amino with two identical or different Ci-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, formylamino, C₁-C4- alkylcarbonylamino and Ci-C₄-alkoxycarbonylamino, an optionally mono- or disubstituted heteroarylgroup, the optional substituent(s) on the said heteroaryl group being independently selected from the group consisting of halogen, nitro, cyano, formyl, C₁-C₄-alkylcarbonyl, hydroxy, C₁-C₄-alkoxy, C C₄-alkyl, hydroxy-C₁-C₄. alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, formyloxy, C₁-C_4- alkylcarbonyloxy, HO-C(=0)-, C₁-C₄-alkoxycarbonyloxy, amino, CrC₄- alkylamino, di-(C₁-C₄-alkyl)amino with two identical or different C₁-C₄-alkyl moieties, pyrrolidyl, piperidiyl, morpholinyl, amino, -C₁-C₄-alkyl, CrC₄- alkylamino-C₁-C₄-alkyl, di-(C₁-C₄-alkyl)-amino-C₁-C4-alkyl with two identical or different C₁-C₄-alkyl moieties in the di-(C₁-C₄-alkyl)-amino moiety, pyrrolidyl- CrC₄-alkyl, piperidyl- CrC₄-alkyl, morpholinyl- CrC₄-alkyl, formylamino, C C₄-alkylcarbonylamino and Ci-C₄-alkoxycarbonylamino, a heteroaryl- C₁-C4- alkyl group which is optionally mono- or disubstituted on the heteroaryl moiety, the optional substituent(s) on the said heteroaryl moiety being independently selected from the group consisting of halogen, nitro, cyano, formyl, C₁-C4- alkoxycarbonyl, hydroxy, CrC₄-alkoxy, CrC₄-alkyl, hydroxy- CrC₄-alkyl, d- C₄-alkoxy-Ci-C₄-alkyl, formyloxy, CrC₄-alkylcarbonyloxy, HO-C(=0)-, C₁-C4- alkoxycarbonyl, amino, Ci-C₄-alkylamino, di-( Ci-C₄-alkyl)amino with two identical or different Ci-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl, di-(C₁-C₄-alkyl)amino-C₁-C₄- alkyl with two identical or different C₁-C₄-alkyl moieties in the di-( C C₄- alkyl)amino moiety, pyrrolidyl- C-|-C₄-alkyl, piperidyl. C-|-C₄-alkyl, morpholinyl- C-|-C₄-alkyl, formylamino, C"|-C₄-alkylcarbonylamino and C C₄- alkoxycarbonylamino, an optionally mono- or disubstituted phenyl group, the optional substituent(s) on the said phenyl group being independently selected form the group consisting of cyano, formyl, C-|-C₄-alkoxycarbonyl, hydroxy, hydroxy-C C₄-alkyl, C C₄-alkoxy, d-C^alkoxy-d-C^alkyl, HO-C(=0)-, C C₄-alkoxycarbonyl, formyloxy, CrC₄-alkylcarbonyloxy, CrC₄- alkoxycarbonyloxy, amino, Ci-C₄-alkylamino, di-(Ci-C₄-alkyl)amino with two identical or different Ci-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- CrC₄-alkyl, Ci-C₄-alkylamino-Ci-C₄-alkyl, di-(Ci-C₄-alkyl)amino-Ci-C₄- alkyl with two identical or different Ci-C₄-alkyl moieties in the di-(CrC₄- alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholinyl- CrC₄-alkyl and Ci-C₄-alkoxycarbonylamino, or an optionally mono- or disubstituted non-aromatic heterocyclyl group, the optional substituent (s) on the said heterocyclyl group being independently selected from the group consisting of C-|-C₄-alkyl, hydroxy-C-|-C₄-alkyl, C"|-C₄-alkoxy-C-|-C₄-alkyl, amino-C"|-C₄-alkyl, Crd-aminoalkyl-C-i-C -alkyl,

R₇ is hydrogen, an optionally mono- or disubstituted C-|-C₈-alkyl, C₂-C₄-alkenyl or C₃-C₇-cycloalkyl group, the optional substituent(s) on the said alkyl, alkenyl or cycloalkyi group being indepentently selected from the group consisting of halogen, nitro, cyano, formyl, Ci-C₄-alkylcarbonyl, hydroxy, C1 -C₄-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, CrC₄-alkoxycarbonyloxy, amino, CrC₄- alkylamino, di-(Ci-C₄-alkyl)amino with two identical or different Ci-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, formylamino, Ci-C₄- alkylcarbonylamino and Ci-C₄-alkoxycarbonylamino, an optionally mono- or disubstituted heteroaryl group, the optional substituent(s) on the said heteroaryl group being independently selected from the group consisting of halogen, nitro, cyano, formyl, CrC₄-alkylcarbonyl, hydroxy, Ci-C₄-alkoxy, C C₄-alkyl, hydroxy-Ci-C₄. alkyl, Ci-C₄-alkoxy-CrC₄-alkyl, CF₃, formyloxy, Ci-C_4- alkylcarbonyloxy, HO-C(=0)-, d-C -alkoxycarbonyl, d-C -alkoxycarbonyloxy, amino, d-d-alkylamino, di-(d-d-alkyl)amino with two identical or different C₁-C₄-alkyl moieties, pyrrolidyl, piperidiyl, morpholinyl, amino-d-d-alkyl, C C₄-alkylamino-C-|-C₄-alkyl, di-(d-d-alkyl)-amino-d-d-alkyl with two identical or different C-|-C₄-alkyl moieties in the di-(C-|-C₄-alkyl)-amino moiety, pyrrolidyl- C-|-C₄-alkyl, piperidyl-d-d-alkyl, morpholinyl-d-d-alkyl, formylamino, C C₄- alkylcarbonylamino and d-d-alkoxycarbonylamino, a heteroaryl-d-d-alkyl group which is optionally mono- or disubstituted on the heteroaryl moiety, the optional substituent(s) on the said heteroaryl moiety being independently selected from the group consisting of halogen, nitro, cyano, formyl, d-d- alkoxycarbonyl, hydroxy, Ci-C₄-alkoxy, Ci-C₄-alkyl, hydroxy-Ci-C₄-alkyl, d- C₄-alkoxy-CrC₄-alkyl, formyloxy, CrC₄-alkylcarbonyloxy, HO-C(=0)-, d-d- alkoxycarbonyl, Ci-C₄-alkoxycarbonyloxy, amino, Ci-C₄-alkylamino, di-( d-d- alkyl)amino with two identical or different Ci-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- CrC₄-alkyl, Ci-C₄-alkylamino-Ci-C₄-alkyl, di-(d- C₄-alkyl)amino-Ci-C₄-alkyl with two identical or different Ci-C₄-alkyl moieties in the di-( Ci-C₄-alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholinyl-Ci-C₄-alkyl, formylamino, Ci-C₄-alkylcarbonylamino and d-d- alkoxycarbonylamino, an optionally mono- or disubstituted phenyl group, the optional substituent(s) on the said phenyl group being independently selected form the group consisting of cyano, formyl, C-|-C₄-alkylcarbonyl, hydroxy, hydroxy-C C₄-alkyl, C C₄-alkoxy, d-d-alkoxy-d-d-alkyl, HO-C(=0)-, C C₄-alkoxycarbonyl, formyloxy, d-d-alkylcarbonyloxy, C C₄- alkoxycarbonyloxy, amino, d-d-alkylamino, di-(d-d-alkyl)amino with two identical or different C-i-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino-C"|-C₄-alkyl, d-d-alkylamino-d-d-alkyl, di-(d-d-alkyl)amino-d-d- alkyl with two identical or different C-i-C₄-alkyl moieties in the di-(d-d- alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholinyl- CrC₄-alkyl and Ci-C₄-alkoxycarbonylamino, or an optionally mono- or disubstituted non-aromatic heterocyclyl group, the optional substituent (s) on the said heterocyclyl group being independently selected from the group consisting of CrC₄-alkyl, hydroxy-CrC₄-alkyl, Ci-C₄-alkoxy-CrC₄-alkyl, amino-Ci-C₄-alkyl, Ci-C₄-aminoalkyl-Ci-C₄-alkyl, di-(Ci-C₄-alkyl)amino-Ci-C₄- alkyl with two identical or different Ci-C₄-alkyl moieties in the di-(d-d- alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholinyl- CrC₄-alkyl, formyl, Ci-C₄-alkylcarbonyl, formyloxy, CrC₄-alkylcarbonyloxy, formylamino and C-|-C₄-alkylcarbonylamino, and

R₈ is hydrogen, d-d-alkyl, d-d-alkoxy, F or CI, a compound characterized by a general formula V (described in WO 2008/129029):

wherein

Ri and R₅ have both, in each case, identical meanings and are CrC₆-alkyl, d- C₆-alkoxy, CI, F, Br or CF₃, and

R₂ and R4 both, in each case, identical meanings and are CrC₆-alkyl, Ci-C₆- alkoxy, CI, F, Br or CF₃, and

R₃ is hydrogen, CrC₄-alkoxy, F, CI, CF₃, or an mono- or disubstituted CrC₈- alkyl, C₂-C₄-alkenyl or C₃-C₇-cycloalkyl group, the optional substituent(s) on the said alkyl, alkenyl or cycloalkyl being independently selected from the group consisting of halogen, nitro, cyano, formyl C₁-C₄-alkylcarbonyl, hydroxy, C-|-C₄- alkoxym formyloxy, C₁-C₄-alkylcarbonyloxy, C₁-C₄-alkoxycarbonyloxy, amino, C₁-C₄-alkylamino, di-(C₁-C₄-alkyl)amino, with two identical or different C₁-C₄- alkyl moieties, pyrrolidyl, piperidly, morpholinyl, formylamino, C-|-C₄- alkycarbonylamino and C₁-C₄-alkyloxycarbonylamino, an optionally mono- or disubstituted heteroaryl group, the optional substituent(s) on the said heteroaryl being independently selected from the group consisting of halogen, nitro, cyano, formyl, CrC₄-alkylcarbonyl, hydroxy, C1-C₄-alkoxy, CrC₄-alkyl, hydroxy-CrC₄- alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, formyloxy, CrC4-alkylcarbonyloxy, HO-C(=0)-, CrC₄-alkoxycarbonyl, CrC₄-alkoxycarbonyloxy, amino, Ci-C₄-alkylamino, di- (Ci-C₄-alkyl)amino with two identical or different CrC₄-alkyl moieties, pyrrolidyl, piperidiyl, morpholinyl, amino, -CrC₄-alkyl, di-(Ci-C₄-alkyl)-amino-Ci-C₄-alkyl with two identical or different CrC₄-alkyl moieties in the di-(Ci-C₄-alkyl)-amino moiety, pyrrolidyl- CrC₄-alkyl, piperidyl- CrC₄-alkyl, morpholinyl- CrC₄-alkyl, formylamino, Ci-C₄-alkylcarbonylamino and Ci-C₄-alkoxycarbonylamino, a heteroaryl- CrC₄-alkyl group which is optionally mono- or disubstituted on the heteroaryl moiety, the optional substituent(s) on the said heteroaryl moiety being independently selected from the group consisting of halogen, nitro, cyano, formyl, C₁-C₄-alkoxycarbonyl, hydroxy, C-|-C₄-alkoxy, C-|-C₄-alkyl, hydroxy- C C₄-alkyl, C"|-C₄-alkoxy-C-|-C₄-alkyl, formyloxy, C-|-C₄-alkylcarbonyloxy, HO- C(=0)-, CrC^alkoxycarbonyl, d-C -alkoxycarbonyloxy, amino, C C₄- alkylamino, di-( d-d-alkyl)amino with two identical or different C-|-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- C-|-C₄-alkyl, d-d-alkylamino- CrC₄-alkyl, di-(Ci-C₄-alkyl)amino-Ci-C₄-alkyl with two identical or different d- C₄-alkyl moieties in the di-( Ci-C₄-alkyl)amino moiety, pyrrolidyl- CrC₄-alkyl, piperidyl. CrC₄-alkyl, morpholinyl- Ci-C₄-alkyl, formylamino, d-d- alkylcarbonylamino and Ci-C₄-alkoxycarbonylamino, an optionally mono- or disubstituted phenyl group, the optional substituent(s) on the said phenyl group being independently selected form the group consisting of cyano, formyl, d-d- alkoxycarbonyl, hydroxy, hydroxy-CrC₄-alkyl, Ci-C₄-alkoxy, d-d-alkoxy-d- C₄-alkyl, HO-C(=0)-, Ci-C₄-alkoxycarbonyl, formyloxy, CrC₄-alkylcarbonyloxy, CrC₄-alkoxycarbonyloxy, amino, Ci-C₄-alkylamino, di-(Ci-C₄-alkyl)amino with two identical or different C-i-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- C-|-C₄-alkyl, d-d-alkylamino-d-d-alkyl, di-(d-d-alkyl)amino-d-d- alkyl with two identical or different C-i-C₄-alkyl moieties in the di-(d-d- alkyl)amino moiety, pyrrolidyl-C-|-C₄-alkyl, piperidyl-d-d-alkyl, morpholinyl-d- C₄-alkyl and C-i-C₄-alkoxycarbonylamino, or an optionally mono- or disubstituted non-aromatic heterocyclyl group, the optional substituent (s) on the said heterocyclyl group being independently selected from the group consisting of C-|-C₄-alkyl, hydroxy-C-|-C₄-alkyl, C"|-C₄-alkoxy-C-|-C₄-alkyl, armino-C-|-C₄-alkyl, d-d-aminoalkyl-d-d-alkyl, di-(d-d-alkyl)amino-d-d-alkyl with two identical or different Ci-C₄-alkyl moieties in the di-(Ci-C₄-alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholinyl-Ci-C₄-alkyl, formyl, d- C₄-alkylcarbonyl, formyloxy, CrC₄-alkylcarbonyloxy, formylamino and d-d- alkylcarbonylamino, and

R₇ is hydrogen, an optionally mono- or disubstituted CrC₈-alkyl, C₂-C₄-alkenyl or C₃-C₇-cycloalkyl group, the optional substituent(s) on the said alkyl, alkenyl or cycloalkyi group being indepentently selected from the group consisting of halogen, nitro, cyano, formyl, Ci-C₄-alkylcarbonyl, hydroxy, C1 -C₄-alkoxy, formyloxy, Ci-C4-alkylcarbonyloxy, CrC₄-alkoxycarbonyloxy, amino, d-d- alkylamino, di-(C-|-C₄-alkyl)amino with two identical or different C-|-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, formylamino, d-d- alkylcarbonylamino and C₁-C₄-alkoxycarbonylamino, an optionally mono- or disubstituted heteroarylgroup, the optional substituent(s) on the said heteroaryl group being independently selected from the group consisting of halogen, nitro, cyano, formyl, C₁-C₄-alkylcarbonyl, hydroxy, C₁-C₄-alkoxy, C₁-C₄-alkyl, hydroxy- C₁-C₄.alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, formyloxy, C₁-C_4-alkylcarbonyloxy, HO- C(=0)-, C₁-C₄-alkoxycarbonyloxy, amino, C₁-C₄-alkylamino, di-(C C4- alkyl)amino with two identical or different C₁-C₄-alkyl moieties, pyrrolidyl, piperidiyl, morpholinyl, amino, -CrC₄-alkyl, Ci-C₄-alkylamino-Ci-C₄-alkyl, di-(Ci- C₄-alkyl)-amino-Ci-C4-alkyl with two identical or different d-C₄-alkyl moieties in the di-(Ci-C₄-alkyl)-amino moiety, pyrrolidyl- CrC₄-alkyl, piperidyl- CrC₄-alkyl, morpholinyl- CrC₄-alkyl, formylamino, Ci-C₄-alkylcarbonylamino and C1-C4- alkoxycarbonylamino, a heteroaryl- CrC₄-alkyl group which is optionally mono- or disubstituted on the heteroaryl moiety, the optional substituent(s) on the said heteroaryl moiety being independently selected from the group consisting of halogen, nitro, cyano, formyl, CrC₄-alkoxycarbonyl, hydroxy, CrC₄-alkoxy, C C₄-alkyl, hydroxy- CrC₄-alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, formyloxy, C1-C4- alkylcarbonyloxy, HO-C(=0)-, C₁-C₄-alkoxycarbonyl, C₁-C₄-alkoxycarbonyloxy, amino, C₁-C₄-alkylamino, di-( C₁-C₄-alkyl)amino with two identical or different C₁-C₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- C₁-C₄-alkyl, CrC₄- alkylamino-C₁-C₄-alkyl, di-(C₁-C₄-alkyl)amino-C₁-C₄-alkyl with two identical or different C₁-C₄-alkyl moieties in the di-( C₁-C₄-alkyl)amino moiety, pyrrolidyl- C C₄-alkyl, piperidyl. C₁-C₄-alkyl, morpholinyl- C₁-C₄-alkyl, formylamino, C-|-C₄- alkylcarbonylamino and C₁-C₄-alkoxycarbonylamino, an optionally mono- or disubstituted phenyl group, the optional substituent(s) on the said phenyl group being independently selected form the group consisting of cyano, formyl, C-|-C₄- alkoxycarbonyl, hydroxy, hydroxy-CrC₄-alkyl, CrC₄-alkoxy, Ci-C₄-alkoxy-Cr C₄-alkyl, HO-C(=0)-, CrC₄-alkoxycarbonyl, formyloxy, CrC₄-alkylcarbonyloxy, CrC₄-alkoxycarbonyloxy, amino, Ci-C₄-alkylamino, di-(Ci-C₄-alkyl)amino with two identical or different CrC₄-alkyl moieties, pyrrolidyl, piperidyl, morpholinyl, amino- CrC₄-alkyl, Ci-C₄-alkylamino-Ci-C₄-alkyl, di-(Ci-C₄-alkyl)amino-Ci-C₄- alkyl with two identical or different Ci-C₄-alkyl moieties in the di-(CrC₄- alkyl)amino moiety, pyrrolidyl-Ci-C₄-alkyl, piperidyl-CrC₄-alkyl, morpholidyl-d- C₄-alkyl and Ci-C₄-alkoxycarbonylamino, or an optionally mono- or disubstituted non-aromatic heterocyclyl group, the optional substituent (s) on the said heterocyclyl group being independently selected from the group consisting of C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, C₁-C₄-aminoalkyl-C₁-C₄-alkyl,

with two identical or different C-i-C₄-alkyl moieties in the di-(C"i-C₄-alkyl)amino moiety, pyrrolidyl-CrC -alkyl, piperidyl-CrC -alkyl, morpholinyl-d-C -alkyl, formyl, C C₄-alkylcarbonyl, formyloxy, C-|-C₄-alkylcarbonyloxy, formylamino and C C₄- alkylcarbonylamino, and

- R8 is hydrogen, Ci-C₄-alkyl, CrC₄-alkoxy, F or CI, and

- X is CH or N,

In free form or salt,

2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-quinazolin-3- yl]acetic acid (WO 2008/107436):

N-(5-chloro-2,4-dimethoxy-phenyl)-2-[2,4-dioxo-3-[2-oxo-2-[2-(3- pyridyl)ethylamino]ethyl]quinazolin-1-yl]acetamide acetamide (WO

2008/107436):

2-[4-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-quinazolin- yl]phenyl]-N-phenethyl-acetamide (WO 2008/107436):

4-[6-chloro-1-[2-(3-chloro-4-ethoxy-phenyl)-2-oxo-ethyl]-2,4-dioxo-quinazolin yl]-N-cyclopentyl-butanamide (WO 2008/107436):

N-(5-chloro-2,4-dimethoxy-phenyl)-2-[2,4-dioxo-3-[2-oxo-2-

(phenethylamino)ethyl]quinazolin-1-yl]acetamide (WO 2008/107436):

- tert-butyl 2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo- quinazolin-3-yl]acetate (WO 2008/107436):

- tert-butyl N-[2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo- quinazolin-3-yl]ethyl]carbamate (WO 2008/107436):

2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-pyrido[3,2- d]pyrimidin-3-yl]acetic acid (WO 2008/107436):

2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2-oxo-4H-quinazolin yl]acetic acid (WO 2008/107436):

N-(5-chloro-2,4-dimethoxy-phenyl)-2-[3-(3-methoxybenzoyl)-7-methyl-4- 4a_!8a-dihydro-1 ,8-naphthyridin-1 -yl]acetamide (WO 2008/107436):

- 2-[1-[2-[(2,6-dichloro-4-pyridyl)amino]-2-oxo-ethyl]-5-methyl-2,4-dioxo- quinazolin-3-yl]acetic acid (WO 2008/107436):

- 4-methyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1 -one (WO 2008/129029):

- 4-methyl-8-(2_!4_!6-trimethylanilino)-2H-isoquinolin-1 -one (WO 2008/129029):

- 8-(2,6-dimethylanilino)-2H-isoquinolin-1 -one (WO 2008/129029):

- 8-(4-fluoro-2,6-dimethyl-anilino)-4-methyl-2H-phthalazin-1 -one (WO

2008/129029):

- 4-ethyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1 -one (WO 2008/129029):

- 4-isopropyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1-one (WO 2008/129029):

- 4-(2-hydroxyethyl)-8-(2_!4,6-trimethylanilino)-2H-phthalazin-1-one (WO

2008/129029):

- 8-(2,6-diethyl-4-fluoro-anilino)-4-methyl-2H-phthalazin-1 -one (WO 2008/129029):

- 8-(4-chloro-2_!6-dimethyl-anilino)-4-methyl-2H-phthalazin-1-one (WO 2008/129029):

- 4-ethyl-8-(4-fluoro-2,6-dimethyl-anilino)-2H-phthalazin-1 -one (WO 2008/129029):

5-(2-propylpyrazol-3-yl)-2-(2,4,6-trimethylanilino)benzamide (WO

2008/142073):

- 5-methoxy-2-(2_!4,6-trimethylanilino)benzamide (WO 2008/142073):

- 5-chloro-2-(2_!4,6-trimethylanilino)benzamide (WO 2008/142073):

According to one aspect of the invention, a pharmaceutical composition for treating neuronal damage is provided, comprising an inhibitor, modulator, soluble polypeptide or compound according to the above aspects of the invention. Pharmaceutical compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as subcutaneous, intravenous, intrahepatic or intramuscular administration, are preferred. The pharmaceutical compositions comprise from approximately 1 % to approximately 95% active ingredient, preferably from approximately 20% to approximately 90% active ingredient.

Similarly, a dosage form for treating neuronal damage is provided, comprising an inhibitor, modulator, soluble polypeptide or compound according to the above aspects of the invention. Optionally, a pharmaceutical carrier or excipient may be present.

For parenteral administration preference is given to the use of solutions of active agents like an inhibitor, modulator, soluble polypeptide or compound according to the above aspects of the invention, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example, can be prepared shortly before use. Pharmaceutical compositions may be sterilized and/or comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, viscosity-increasing agents, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.

For oral pharmaceutical preparations suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates. Binders, such as starches, cellulose derivatives and/or polyvinylpyrrolidone may also be employed, Disintegrators, flow conditioners and lubricants, for example stearic acid or salts thereof and/or polyethylene glycol may be added in addition or instead. Tablet cores can be provided with suitable, optionally enteric, coatings. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes to indicate different types or doses of active ingredient. Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules may contain the active ingredient in the form of granules, or dissolved or suspended in suitable liquid excipients, such as in oils.

Transdermal/intraperitoneal and intravenous applications are also considered, for example using a transdermal patch, which allows administration over an extended period of time, e.g. from one to twenty days. Intravenous or subcutaneous applications are particularly preferred as well as intrathecal applications.

According to one aspect of the invention, a method for treating neuronal damage is provided, comprising the administration of an inhibitor, modulator, soluble polypeptide or compound according to the above aspect of the invention to a patient in need thereof.

The treatment may be for prophylactic or therapeutic purposes. For administration, an active agent as described in the preceding paragraphs is preferably provided in the form of a pharmaceutical preparation comprising the active agent in chemically pure form and optionally a pharmaceutically acceptable carrier and optionally adjuvants. The active agent is used in an amount effective against the diseases characterized by neuronal damage and lack of subsequent repair. The dosage of the active agent depends upon the species, the patient age, weight, and individual condition, the individual pharmacokinetic data, mode of administration, and whether the administration is for prophylactic or therapeutic purposes. For individual having a body weight of about 70 kg, the daily dose administered ranges from approximately 0.1 mg/kg to approximately 1000 mg/kg, preferably from approximately 0.5 mg to approximately 100 mg/kg, of an active agent.

According to one aspect of the invention, a method of manufacturing a medicament for treating neuronal damage is provided comprising the use of an inhibitor, modulator, soluble polypeptide or compound according to the above aspects of the invention. Medicaments according to the invention are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.

An active agent as described in the preceding paragraphs can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations of a blocker of the Nogo-A S1 PR pathway and one or more other therapeutic agents known in treating neuronal damage. Administration can be staggered or combined agents can be given independently of one another, or in the form of a fixed combination.

ATI355, a human monoclonal antibody neutralizing Nogo-A (Novartis AG, Basel) is a possible combination partner.

Description of the figures:

Fig 1 shows binding of Nogo-A-A20 to S1 PR receptors and TSPAN3.

Fig 2 shows that Nogo-A-A20 inhibits cell spreading and neurite outgrowth via S1 PR2 and S1 PR5. Fig 3 shows that Nogo-A-A20 signals via S1 PR2 and the G protein G13 in a S1 P- independent manner.

Fig 4 shows /^'n-v/Vo-treatment of damaged neurons with JTE013 and genetic depletion of S1 PR2.

Fig 5: S1 PR2 inhibition resembles the LTP phenotype of anti-Nogo-A treatment in hippocampal slice cultures.

The Nogo-A S1 PR pathway can be blocked by administration of blockers of S1 PR2 or S1 PR5, such as antibodies or antibody fragments directed against S1 PR2 or S1 PR5, small molecules that interfere with the binding of either Nogo-A to S1 PR2 or S1 PR5 or proteins downstream in the signal transduction pathway which are triggered either by the receptor or, soluble S1 PR2 or S1 PR5 or fragments thereof, agonists of S1 PR2 or S1 PR5 which lead to a down regulation of the receptor.

Preferred blockers according to the invention are blockers of S1 PR2 or S1 PR5, such as antibodies or antibody fragments directed against S1 PR2, small molecules that interfere with the binding of Nogo-A to S1 PR2 or S1 PR5 or proteins downstream in the signal transduction pathway and triggered by the receptor and, soluble S1 PR2 or S1 PR5 or fragments thereof, agonists of S1 PR2 or S1 PR5 which lead to a down regulation of the receptor. Examples of blockers of the Nogo-A S1 PR pathway according to the invention are disclosed below.

Preferred blockers of the Nogo-A S1 PR pathway according to the invention are:

- soluble S1 PR2 or S1 PR5 or fragments thereof;

- antibodies that bind to S1 PR2 or S1 PR5, antigen binding fragments of an antibody (e.g. Fab fragments) or antibody-like molecules (e.g. repeat proteins) which by binding to S1 PR2 or S1 PR5, block the binding between S1 PR2 or S1 PR5 and Nogo-A. Such antibodies preferably bind to S1 PR2 or S1 PR5, in the region where Nogo-A would normally bind, but do not induce signaling;

- Virus-like particles loaded with immunogenic sequences of S1 PR2 or S1 PR5, and therefore capable of inducing an antibody response directed against these molecules with the effect of blocking their biological activity;

- antisense molecules for down regulation of S1 PR2 or S1 PR5. These antisense molecules are 12-50 nucleotides in length and complementary to exons or introns of genes coding for S1 PR. Moreover, antisense molecules containing sequences complementary to promoter regions of these genes may be used. Finally, antisense molecules binding in the 3' UTR -non translated regions of S1 PR genes are contemplated;

- small molecules that inhibit binding of Nogo-A to S1 PR2 or S1 PR5, or small molecules which are S1 PR1 agonists and lead to down regulation of S1 PR2 or S1 PR5. Small molecules contemplated are synthetic compounds of molecular weights up to 1000, which have suitable physiological activity and pharmacological properties to make them useful for application as medicaments. Such small synthetic molecules are, for example, found by the screening method of the present invention described below. Alternatively, such small molecules are designed by molecular modelling, taking into account possible binding sites of S1 PR2 or S1 PR5;

- proteins and protein analogs which by binding to S1 PR2 or S1 PR5, prevent binding of Nogo-A to S1 PR2 or S1 PR5, for example, synthetic proteins or protein analogs which mimic the variable region scFv of binding and/or neutralizing antibodies, or antibodies that mimic a binding pocket for S1 PR2 or S1 PR5.

The most preferred blockers are:

- JTE-013 (Cayman Chemical Company, Ann Arbor, Ml, USA), a S1 PR2 blocker;

- S1 P2 Receptor Antagonists as described in WO 08/154470;

- Gilenia (Novartis AG, Basel, Switzerland), a sphingosine 1 -phosphate receptor agonist, acting on the four Sphingosine 1-Phosphate Receptors S1 P1 , S1 P3, S1 P4 and S1 P5 and leading to a down regulation of S1 PR, chemical formula 2-amino-2-[2-(4- octylphenyl)ethyl]propane-1 ,3-diol hydrochloride;

- ACT128800 ((2Z,5Z)-5-[[3-chloro-4-(2,3-dihydroxypropoxy)phenyl]methylene]-3-(o-tolyl)- 2-propylimino-thiazolidin-4-one, Actelion AG, Basel, Switzerland), a sphingosine 1 - phosphate receptor agonist;

- BAF312 (Novartis AG, Basel, Switzerland), a sphingosine 1 -phosphate receptor modulator;

- ON04641 (Ono Pharmaceutical Co., Ltd., Merck-Serono SA), a sphingosine 1 - phosphate receptor agonist;

- EXEL-9953 (Exelexis Inc.) a sphingosine-1-phosphate type 1 receptor (S1 P1 ) agonist;

- S1 P receptor agonist APD334 (Arena Pharmaceuticals Inc., San Diego);

- S1 P Receptor modulator CS0777 (Daiichi Sankyo Company); - GSK2018682 (Glaxo Smith Kline), an agonist of the S1 P1 receptor;

- S1 P Receptor Agonist BIOGEN (Biogen Idee Inc., Boston);

- KRP203 (Kyorin Co. Ltd. and Novartis AG, Basel), a sphingosine 1 -phosphate receptor agonist, chemical formula 2-amino-2-(2-(4-(3-benzyloxyphenylthio)-2- chlorophenyl)ethyl)-1 ,3-propanediol hydrochloride;

- RPC1063 (Receptos, Inc.), a S1 P1 agonist;

- Bicyclic organic compounds as described in WO 2008/107436 (Novartis AG);

- Phtalazine and isoquinoline derivatives as described in WO 2008/129029 (Novartis AG);

- Benzamides as described in WO 2008/142073 (Allergan, Inc.).

Concepts and Evidence behind the Invention

This invention is based on the finding that Nogo-A is a high affinity agonist of S1 PR2/5. Its effect can be reversed by the S1 PR2 specific blocker JTE-013 (Cayman Chemical Company, Ann Arbor, Ml).

Examples:

Example 1 : Noqo-A-A20 binds to S1 PR2, S1 PR5 and TSPAN3.

Nogo-A-A20 is immunoprecipitated with S1 PR2 and S1 PR5 from membrane preparations of cells overexpressing the corresponding receptor isoforms, and with TSPAN3 from total protein brain extracts. Figure 1A shows the co-immunoprecipitation of Nogo-A-A20 and S1 PR2 (upper panel), S1 PR5 (middle panel) and TSPAN3 (lower blot) from total rat brain protein extracts. Additionally, data demonstrate that Tetraspanin-3 (TSPAN3) acts as a co-receptor of Nogo-A-A20 (Figure 1A).

Figure 1 B shows the Label-free interaction measurements (OctedRed) to determine affinity range and constant for S1 PR1 , S1 PR2 and S1 PR5 using a recombinant Strep- tagged fusion protein of the extracellular N-terminal part of Nogo-A (rat aa 1-979) containing the Nogo-A-A20 region. Recombinant S1 PR1 , S1 PR2, S1 PR5 and parental (control) membrane preparations were immobilized on amine-reactive biosensors (25 g/ml). Nogo-A-ext was serially diluted and allowed to bind the saturated biosensor tips for 15 min at 1000 rpm. Nogo-A-ext bound stronger to S1 PR2 (-142 nM) and S1 PR5 (-109 nM) than to S1 PR1 (-382 nM). Nogo-A-ext binding to parental membrane preparations and blank surfaces was minimal and subtracted from all values. Data shown are mean ± SEM (n = 5). Using BioLayer interferometry technology, it was demonstrated for the first time that Amino-Nogo binds to S1 PR1 , S1 PR2 and S1 PR5. The Biolayer interferometry technology is a label-free technology for measuring biomolecule interactions and described in detail by Witte et al. (Comb. Chem. High Throughput Screen, 12(8), 791 -800, 2009). Binding affinities are strong and vary between the different isoforms (Figure 1 B). They can be ordered as follows: S1 PR5 > S1 PR2 > S1 PR1 .

Example 2: Nogo-A-A20 inhibition of cell spreading and neurite outgrowth can be blocked by S1 PR2 or S1 PR5 inhibition.

JTE-013 was screened for its ability to reverse Nogo-A-A20-induced inhibition of cell spreading of 3T3 fibroblasts. 3T3 fibroblasts were plated on different concentrations of a Nogo-A-A20 substrate (20, 40 or 80 pmol/cm²) in the presence of increasing concentrations of JTE-013 (Fig. 2A, first column DMSO, second column 0.1 μΜ, third column 1 μΜ, fourth column 10 μΜ and fifth column 20 μΜ, respectively). DMSO was used as a vehicle control. The endogenous expression level of S1 PR2 on 3T3 fibroblasts was confirmed by Fluorescence Activated Cell Sorting. At 1 μΜ, JTE-013 prevented the inhibitory effects of Nogo-A-A20 on cell spreading (Figure 2A). The effect of JTE-013 was dose-dependent and almost completely reversed the spreading inhibition of 20 pmol / cm² Nogo-A-A20 at the highest concentration used in the assay (20 μΜ) (Figure 2A, fifth column, respectively). JTE-013 significantly rescued Nogo-A-A20-mediated cell spreading inhibition at a concentration of 1 μΜ (Figure 2A, third column, respectively). Figure 2B (first vertical column DMSO, second column JTE-013, first horizontal line: control, second line Nogo-A- Δ20, third line myelin) and Figure 2C (first column DMSO, second column JTE-013, respectively) show a rescue of Nogo-A-A20- and myelin-mediated inhibition of cell spreading after treatment of 3T3 cells with JTE-013 (1 μΜ). Figure 2D (first vertical column sh-control, second column shS1 PR2, first horizontal line control, second line Nogo-A- Δ20, third line myelin), Figure 2E (first column sh-control, second column S1 PR2 sh-RNS, respectively) and Figure 2F (first column WT, second column S1 PR2^"'^", first line control, second line Nogo-A- Δ20, third line myelin), Figure 2G (first column WT, second column S1 PR2^"'^", respectively) show the same rescue effects of Nogo-A-A20- and myelin- mediated inhibition of cell spreading after knockdown of S1 PR2 using an shRNA or a DNA for lentiviral expression (data not shown) against S1 PR2 in 3T3 cells or transgenic depletion of S1 PR2 in mouse embryonic fibroblasts. The following constructs targeting S1 PR2 mRNA transcript were used: ACCAAGGAGACGCTGGACATG (SEQ ID 01 ) and ACCAAGGAGACGCUGGACAUG (SEQ ID 02).

Postnatal day (P) 8 rat cerebellar granule neurons (CGNs) are frequently used as a model to study neurite outgrowth mechanisms in vitro. S1 PR2 is expressed on the cell surface of CGNs. There was a potent inhibition of neurite outgrowth of CGNs plated on a Nogo-A- Δ20 substrate (20 pmol / cm²; Figure 2H, I). In the presence of JTE-013, neurite outgrowth was significantly increased, suggesting that S1 PR2 plays a major role in Nogo-A- A20- mediated outgrowth inhibition (Figure 2H, first column control, second column JTE-013, third column a-S1 PR5, respectively). Using CGNs from S1 PR2 KO mice in this assay resulted in a similar phenotype of increased neurite outgrowth (Figure 2I, first column WT, second column S1 PR5 KO, respectively). Furthermore, inhibition of S1 PR5 by using a function-blocking antibody resulted in increased neurite outgrowth as well, indicating, that S1 PR5 may also contribute to in Nogo-A- A20-mediated outgrowth inhibition (Figure 2H). Data shown are mean ± SEM (n > 3). ^* p < 0.05, ^** p < 0.01 , ^*** p < 0.001 ; unpaired Student's t-test.

Example 3: Nogo-A-A20 inhibits cell spreading and neurite outgrowth via G13, LARG and RhoA.

It has been shown recently that surface bound Nogo-A-A20 is internalised into neuronal and non-neuronal cells. This results in the formation of Nogo-A-A20-containing signalling endosomes which then activate RhoA. It was investigated whether S1 PR2 is also internalised upon treatment with Nogo-A-A20. Plasma membranes were prepared from 3T3 cells 15, 30 and 60 min after Nogo-A-A20 addition and were then analysed for S1 PR2 expression by western blot analysis. Cell membrane S1 PR2 levels were almost completely depleted 15 min after Nogo-A-A20 treatment; they remained low at 30 min and recovered to control levels after 60 min (Figure 3A, upper panel). The lower panel of Figure 3A shows the relative quantification of S1 PR2 signal intensities at 15, 30 and 60 min post Nogo-A-A20 incubation versus control. Western blot analysis of ubiquitin- conjugates and non-ubiquitinated protein fractions of 3T3 cells transiently transfected with S1 PR2 shows that S1 PR2 is not ubiquitinated post Nogo-A-A20 stimulation versus control (Figure 3B). Nogo-A-A20-induced activation of RhoA was significantly reversed by 1 μΜ JTE-013 (Figure 3C, first lane DMSO, second lane JTE-013, third lane DMSO, fourth lane JTE-013). A representative RhoA western blot analysis of RhoA-GTP and total RhoA 20 min after treatment with 1 μΜ Nogo-A-A20 is shown. Figure 3C (first column DMSO, second column JTE-013, respectively) shows the corresponding quantification. Similar results were obtained when interfering with S1 PR2-signalling by shRNA against S1 PR2 shown by Figure 3D (first lane control, second lane D20, third lane control, fourth lane D20) and Figure 3D' (first column sh-control, second column sh-S1 PR2, respectively). 3T3 fibroblasts were transfected with control (ctrl), G_q, Gi₂, Gi₃ and LARG siRNA, respectively. Knockdown of Gi₃ and LARG abolished Nogo-A-A20-mediated cell spreading inhibition (Figure 3E, first column control siRNA, second column G_q siRNA, third column G₁₂ siRNA, fourth column G₁₃ siRNA, fifth column G₁₂ siRNA + JTE-013, sixth column LARG siRNA, seventh column control, eighth column PTX). Combined treatment with siRNA against G₁₃ and JTE-013 did not result in more cell spreading than siRNA treatment against G₁₃ alone. Furthermore, arresting the Gi subunit with Pertussis toxin (PTX) in its GDP-bound, inactive state did not influence cell spreading behaviour on Nogo-A-A20 substrate (Figure 3E). Competitive ELISA quantification of S1 P levels in cells and corresponding media. S1 P levels did not significantly change in CGNs and 3T3 cells treated with Nogo-A-A20 versus control (Figure 3F, circles Nogo- Α- Δ20; S1 P medium, triangles Nogo- Α- Δ20; cellular S1 P, dashed line control). Data shown are mean ± SEM (n > 3). ^* p < 0.05, ^** p < 0.01 ; unpaired Student's t-test.

Example 4: Micro-crush lesion of the optic nerve.

S1 PR2 is expressed in retinal ganglion cells. The optic nerve micro-crush model was used to evaluate the effect of S1 PR2 receptor blockade or genetic depletion on axonal outgrowth in vivo (Figure 4). Gelfoam-containing JTE-013 or vehicle was applied onto the optic nerve at the time of the crush lesion and at 7 days post-injury. To visualise optic axons, alexa-594-coupled cholera-toxin beta subunit (CTb) was intraocularly injected the day preceding the perfusion. Axons growing across the lesion site were examined on longitudinal sections of optic nerves 2 weeks after injury. The number of axons growing past the lesion site was significantly higher after JTE-013 treatment or S1 PR2 genetic depletion compared to control optic nerves (Fig. 4 C and D). White stars indicate the lesion site. Higher magnification shows that the density of axons extending in the distal optic nerves appeared bigger in the JTE-013 and S1 PR2 genetic depletion group than in control mice. Data shown in Figure D (first column vehicle [n=5], second column JTE-013 [n=7], third column S1 PR2 KO [n=6], respectively) are mean ± SEM. ^* p < 0.05; ^** p < 0.01 ; unpaired Student's t-test. Scale bar: C: 100 μηι.

Local in vivo application of JTE-013 is crucial to achieve the maximal pharmacologic efficacy because this compound is highly lipophilic and can be sequestered by myelin (data not shown). To study the effects of S1 PR2 blockade on axonal outgrowth in vivo, we applied JTE-013-soaked gelfoam onto the crushed optic nerve of adult mice (Figure 4B). Immunohistochemistry results reveal that retinal ganglion cells (RGCs) express S1 PR2 (Figure 4A). Two weeks after injury, JTE-013 treatment or genetic depletion induced significantly more axonal growth past the lesion site than the vehicle control (Figure 4 C and D). More axons extended in the distal segment of optic nerves treated with JTE-013 than in those receiving the vehicle (Figure 4 C and D). Sprouting axons contained the growth-associated protein 43 (GAP-43), a marker indicating the active growth state of neurons. This growth induction by JTE-013 was comparable to the blockade of the Chondroitin sulfate proteoglycan receptor Protein tyrosine phosphatase sigma and higher than in PirB-deficient mice.

Example 5: JTE013 treatment in LTP experiments in WT and Nogo-A KO acute slices.

Fig. 5A shows the expression pattern of S1 PR2 in the dentate gyrus (DG) and in the CA1 - CA3 regions of the hippocampus in adult BL/6 mice. Hippocampal WT slices were treated with JTE-013 (open circles) or DMSO as vehicle control (black circles) (Fig. 5B). LTP was induced by application of theta-burst stimulation (TBS, arrow): 10 trains of 4 pulses at 100 Hz, interburst interval of 200 ms, repeated 3x (arrow). 60 min after TBS, a significant difference between JTE-013 and DMSO treatment could be observed (average level 60 min after TBS: JTE-013: 184 ± 8%; DMSO: 151 ± 8.5%; p = 0.018). Hippocampal Nogo-A KO slices were treated with JTE-013 (open circles) or DMSO (black circles) (Fig. 5C. LTP induced by TBS (arrow revealed no significant differences in Nogo-A KO mice treated with JTE-013 (average level 60 min after TBS: JTE-013: 180 ± 12%) and DMSO (181 ± 13%). Inserts show original traces from representative individual experiments; letters correspond to the time point at which the traces were taken. ^* p < 0.05; unpaired Student's t-test. Scale bar: A: 300 μηι (left), 30 μηι (right).

It was recently demonstrated that long-term potentiation (LTP) of CA3-CA1 synapses in mouse hippocampus was significantly increased by acute, antibody-mediated neutralisation of neuronal Nogo-A or NgR1 . LTP was analysed in the presence of the S1 PR2 specific blocker JTE-013 in WT and Nogo-A KO mice. Long-term potentiation (LTP) was significantly increased by JTE-013 treatment in WT (Figure 5B), but not Nogo- A KO mice (Figure 5C). These results suggest a functional Nogo-A-S1 PR2 interaction which restricts hippocampal synaptic plasticity independently of S1 P. Baseline synaptic transmission was not affected by the treatment with JTE-013.

Claims

Claims:

1. 1-(2,6-dichloro-4-pyridyl)-3-[(4-isopropyl-1 ,3-dimethyl-pyrazolo[3,4-b]pyridin-6- yl)amino]urea for use in prevention or therapy neuronal damage.

2. An inhibitor capable of binding to a member of the S1 PR receptor group comprised of S1 PR2 and S1 PR5 with a dissociation constant of 5x10^"7 mol/l or smaller, comprising an antibody, an antibody fragment, an antibody-like molecule, a nucleic acid aptamer or an oligopeptide with 6 to 30 amino acid residues in length, for use in treating neuronal damage.

3. A modulator of gene expression of G13 or a member of the S1 PR receptor group comprised of S1 PR2 and S1 PR5 comprising

- a single-stranded or double-stranded interfering ribonucleic acid oligomer or precursor thereof, comprising a sequence tract complementary to an mRNA molecule encoding any member of said S1 PR group or G13; or

- an expression vector, comprising a sequence encoding said interfering

ribonucleic acid oligomer or precursor thereof, or

a single-stranded or double-stranded antisense ribonucleic or deoxyribonucleic acid, comprising sequences complementary to a regulatory region of a gene encoding a member of said S1 PR group or G13.

for use in treating neuronal damage.

4. A soluble polypeptide comprising a contiguous amino acid sequence of at least 30 amino acids comprised within the protein sequence of a member of the S1 PR receptor group comprised of S1 PR2 and S1 PR5 for use in treating neuronal injury.

5. A compound for use in treating neuronal damage selected from the group

comprised of a compound characterized by the general formula I:

- R1 is a C1-C12 alkyl, and

R2, R3 and R4 are each independently hydrogen, halogen, C1 -C6 alkyl, C1-C6 perhaloalkyi, C1 -C4 perhaloalkoxy, amino, mono- or di C1-C4 alkylamino, C3-C7 cycloalkyl or C3-C7 cycloalkoxy, and

R3 and R4 are optionally positioned at h, i, or j, but not simultaneously at the same position, and

- R5 is , halogen, C1 -C6 alkyl, C1 -C6 perhaloalkyi, C1-C4 perhaloalkoxy, amino, mono- or di C1-C4 alkylamino, C3-C7 cycloalkyl or C3-C7 cycloalkoxy, and

- n is 0, 1 , 2, 3 or 4;

2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol:

5-[[3-chloro-4-(2,3-dihydroxypropoxy)phenyl]methyl]-3-(o-tolyl)-2- (propylamino)thiazolidin-4-one:

2-amino-2-[2-[4-(3-benzyloxyphenyl)sulfanyl-2-chloro-phenyl]ethyl]propane- 1 ,3-diol:

1-[5-[(3R)-3-amino-4-hydroxy-3-methyl-butyl]-1-methyl-pyrrol-2-yl]-4-(p- tolyl)butan-1-one:

[3-amino-4-(3-octylanilino)-4-oxo-butyl]phosphonic acid:

5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)^

oxadiazole:

a compound characterized by a general formula II:

wherein,

- X is NR^aR^b, SR^b, F, CI, Br or I, and

- R1 is H or R^b

- R2 is H, F, CI, Br, I, or R^b

- R^a is H or R^b, and

R^b is branched or linear alkyl having 1 to 12 carbon atoms, wherein one or more, preferably 1 to 7 hydrogen atoms may be replaced by F, CI, Br, I, OR^a, COOR³, CN, N(R^a)₂ and wherein one or more, preferably 1 to 7 non- adjacent CH2-group may be replaced by O, NR^a, S or S0₂, and/or by -CH=CH- groups, or is cycloalkyl or cycloalkylalkylene having 3 to 7 ring carbon atoms, and

- W is C=0, C=S, S02 or SO, and

- Q is NR3, -O- or -S-, and

R is hydrogen, Rb, Ar or Het, and Ar is a monocyclic or bicyclic, saturated, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted, mono-, di-, or tri- substituted by F, CI, Br, I, R^b, OR3, -[C(R³)₂]n-OR³, N(R³)₂, -[C(R³)2]n-N(R³)₂, N0₂, CN, COOR³, CF₃, OCF₃, CON(R³), NR³COA, NR³CON(R³)₂, -[C(R³)₂]n-Het, -[C(R³)₂]n-Ar, -[C(R³)₂]n- cycloalkyl, -[C(R³)₂]n-CON(R³)₂, -[(R³)₂]n-COOR³, -[C(R³)₂]n-NR³- [C(R³)₂]n-C0₂R³; -[C(R³)₂]n-NR³-[C(R³)₂]n-OR³, -S0₂-[C(R³)2]n-C0₂R³, - S0₂-N(R³)₂]n-[C0₂R³, -[C(R³)₂]N-S0₂-[C(R³)]n-C0₂R3, -S02[C(R³)₂]n- OR³, -S0₂N(R³)₂-[C(R³)₂]n-OR³, -[C(R³)₂]N-S0₂-[C(R³)₂]n-OR³,

NR³CON(R³)₂, NR³S0₂R^b, COR³, S0₂N(R³)₂, S02N(R3)Rb, SORb, SONR³R^b, S0₂R^b, and/or -0[C(R³)₂]n-COOR³ and

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S which may be unsubstituted, mono-, di-, or trisubstituted by F, CI, Br, I, R^b, OR3, -[C(R³)₂]n-OR³, N(R³)₂, -[C(R³)2]n-N(R³)₂, N0₂, CN, COOR³, CF₃, OCF₃, CON(R³), NR³COA, NR³CON(R³)₂, -[C(R³)₂]n-Het, -[C(R³)₂]n-Ar, -[C(R³)₂]n- cycloalkyl, -[C(R³)₂]n-CON(R³)₂, -[(R³)₂]n-COOR³, -[C(R³)₂]n-NR³- [C(R³)₂]n-C0₂R³; -[C(R³)₂]n-NR³-[C(R³)₂]n-OR³, -S0₂-[C(R³)2]n-C0₂R³, - S0₂-N(R³)₂]n-[C0₂R³, -[C(R³)₂]N-S0₂-[C(R³)]n-C0₂R3, -S02[C(R³)₂]n- OR³, -S0₂N(R³)₂-[C(R³)₂]n-OR³, -[C(R³)₂]N-S0₂-[C(R³)₂]n-OR³,

NR³CON(R³)₂, NR³S0₂R^b, COR³, S0₂N(R³)₂, S02N(R3)Rb, SORb, SONR³R^b, S0₂R^b, and/or -0[C(R³)₂]n-COOR³, and

- R¹ is H or Rb, and

- R² is H, F, CI, Br, I, or Rb, and

- R³ is is H or Rb, and

- n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8;

2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-quinazolin-3- yl]acetic acid:

- N-(5-chloro-2,4-dimethoxy-phenyl)-2-[2,4-dioxo-3-[2-oxo-2-[2-(3- p ridyl)ethylamino]ethyl]quinazolin-1-yl]:

2-[4-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-quinazolin-3- yl]phenyl]-N-phenethyl-acetamide:

H

4-[6-chloro-1-[2-(3-chloro-4-ethoxy-phenyl)-2-oxo-ethyl]-2,4-dioxo-quinazolin-3- yl]-N-cyclopentyl-butanamide:

N-(5-chloro-2,4-dimethoxy-phenyl)-2-[2,4-dioxo-3-[2- (phenethylamino)ethyl]quinazolin-1-yl]acetamide:

- tert-butyl 2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo- quinazolin-3-yl]acetate:

- tert-butyl N-[2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo- quinazolin-3-yl]ethyl]carbamate:

- 2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2,4-dioxo-pyrido[3,2- d]pyrimidin-3-yl]acetic acid:

- 2-[1-[2-(5-chloro-2,4-dimethoxy-anilino)-2-oxo-ethyl]-2-oxo-4H-quinazolin-3- yl acetic acid:

N-(5-chloro-2,4-dimethoxy-phenyl)-2-[3-(3-methoxybenzoyl)-7-methyl-4- 4a,8a-dihydro-1 ,8-naphthyridin-1 -yl]acetamide:

2-[1-[2-[(2,6-dichloro-4-pyridyl)amino]-2-oxo-ethyl]-5-methyl-2,4-dioxo- quinazolin-3- l]acetic acid:

4-methyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1 -one:

4-methyl-8-(2,4,6-trimethylanilino)-2H-isoquinolin-1 -one:

8-(2,6-dimethylanilino)-2H-isoquinolin-1 -one:

8-(4-fluoro-2,6-dimethyl-anilino)-4-methyl-2H-phthalazin-1 -one:

- 4-ethyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1 -one:

4-isopropyl-8-(2,4,6-trimethylanilino)-2H-phthalazin-1-one:

- 4-(2-hydroxyethyl)-8-(2,4,6-trimethylanilino)-2H-phthalazin-1-one:

8-(4-chloro-2,6-dimethyl-anilino)-4-methyl-2H-phthalazin-1-one:

5-chloro-2-(2,4,6-trimethylanilino)benzamide:

6. A pharmaceutical composition for treating neuronal damage, comprising an

inhibitor, a modulator, a soluble polypeptide or a compound according to any of the above claims 1 to 5.

7. A dosage form for treating neuronal damage, comprising an inhibitor, a modulator, a soluble polypeptide or a compound according to any of the above claims 1 to 5, and optionally a pharmaceutically acceptable carrier and/or excipient.

8. A method for treating neuronal damage, comprising the administration of an

inhibitor, a modulator, a soluble polypeptide or a compound according to any of the above claims 1 to 5 to a patient in need thereof.

9. A method for the manufacture of a medicament for treating neuronal damage, comprising the use of an inhibitor, a modulator, a soluble polypeptide or a compound according to any of the above claims 1 to 5.