WO2021048431A1 - Compounds for treating ataxia - Google Patents
Compounds for treating ataxia Download PDFInfo
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- WO2021048431A1 WO2021048431A1 PCT/EP2020/075582 EP2020075582W WO2021048431A1 WO 2021048431 A1 WO2021048431 A1 WO 2021048431A1 EP 2020075582 W EP2020075582 W EP 2020075582W WO 2021048431 A1 WO2021048431 A1 WO 2021048431A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Abstract
The present invention relates to a compound of the following formula (I): or a pharmaceutically acceptable salt or hydrate thereof, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
Description
COMPOUNDS FOR TREATING ATAXIA
Field of the invention
The present invention relates to compounds, compositions and methods for treating ataxia, in particular Friedreich ataxia.
Background of the invention
Ataxia is a neurodegenerafive disorder affecting parts of the nervous system which coordinate movement, such as the cerebellum. Ataxia symptoms vary by person and type of ataxia. Flowever common symptoms associated with ataxia include depression, diziness, vertigo, fatigue, imbalance, incoordination, muscle cramps or spasms, neuropathy, stiffness, spasticity, rigidity, dystonia tremor or res† tremor. Complications from the disease are serious, oftentimes debilitating and can lead †o an early death.
The two main types of ataxias are (i) hereditary ataxias, which are genetic and include autosomal dominant ataxias and autosomal recessive ataxias, and (ii) acquired ataxias, which develop in people with no known family history of the disease, because of an external cause, such as vitamin deficiencies, autoimmune conditions, infections, exposures †o toxic substances or drugs and cancers.
Friedreich ataxia is associated with a reduction in the expression of, and/or a mutation in, the Frataxin (FXN) gene. Friedreich ataxia is one of the most common genetic autosomal recessive ataxia. Friedreich ataxia typically begins in childhood and young adults and leads †o a disability and premature death. Neurological signs are associated with degeneration of sensory neurons and affect the flow of sensory information through the peripheral nerves and the spinal cord. There is also some impairment of muscle-controlling signals from the cerebellum and spinal cord. These problems lead †o the progressive loss of balance, coordination and muscle strength. As the disease progresses, dysarthria, dysphagia, and lower extremity weakness become more apparent, and complete loss of ambulation occurs 9 to 15 years after symptom onset.
Friedreich ataxia treatment involves a combination of medication †o treat symptoms and therapy †o improve quality of life. By way of example, speech and language therapy, occupational therapy, and physical therapy are common treatment options. A† this time, current therapeutic approach under evaluation are no† able †o stop disease progression. By way of example, administration of
nicotinamide provides an increase in the rate of frataxin, however without demonstrated effects on the disease (Libri e† al. (2014) Lance†, 384: 504-13).
Accordingly, there is a need for alternative treatments of ataxia, in particular Friedreich ataxia, notably by altering the pathologival mechanism of this condition, in addition †o treating the symptoms.
Summary of the invention
The present invention arises from the recognition, by the present inventors, of the potential of queuine as a neuroprofecfive agent in the prevention, in particular of symptoms, or treatment of ataxia, in particular Friedreich ataxia.
Thus, the present invention relates †o queuine, a precursor of queuine, a derivative of queuine or a stereoisomer of queuine, an analogue of queuine, or a pharmaceutically acceptable sal† or hydrate thereof, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
The present invention relates †o a compound of the following formula (I):
wherein:
Ri represents -FI or a ribosyl group of the following formula:
wherein:
• R0 represents -FI; -O-R9 or -O-CO-R9 wherein R9 is FI, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms;
• R7 represents -H; -O-R10 or-O-CO-Rio wherein Rio is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms; a deoxyribonucleic acid group; or a ribonucleic acid group;
• Re represents -H; -O-Rn or-O-CO-Rn wherein Rn is H, an alkyl group having from 1 †o 20 carbon atoms or an aryl group having from 3 to 20 carbon atoms; a phosphate group; a diphosphate group; a triphosphate group; a deoxyribonucleic acid group; or a ribonucleic acid group;
R 12 represents a saturated or unsafurafed alkyl, cycloalkyl, heferocycloalkyl or ether group having from 1 †o 20 carbon atoms, optionally substituted by a† leas† one group selected from the group consisting of:
• an alkyl group having from 1 †o 20 carbon atoms,
• an aryl or heteroaryl group having from 3 to 20 carbon atoms,
• a cycloalkyl or heferocycloalkyl group having from 3 to 20 carbon atoms,
• a hydroxyl group,
• a carbonyl or carboxyl group having from 1 †o 20 carbon atoms,
• an epoxy group,
• an -O-R4 group wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group,
• an -O-CO-R5 group wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms or a glycosyl group; or a pharmaceutically acceptable sal† or hydrate thereof, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
The present invention also relates †o a compound of formula (I), having the following formula (II):
wherein: a represents a double bond or an epoxy group, and - Ri represents -H or a ribosyl group of the following formula:
wherein:
• R0 represents -H; -O-R9 or -O-CO-R9 wherein R9 is H, an alkyl group having from 1 to 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms;
• R7 represents -H; -O-Rio or-O-CO-Rio wherein Rio is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms; a deoxyribonucleic acid group; or a ribonucleic acid group;
• Re represents -H; -O-Rn or-O-CO-Rn wherein Rn is H, an alkyl group having from 1 †o 20 carbon atoms or an aryl group having from 3 to 20 carbon atoms; a phosphate group; a diphosphate group; a triphosphate group; a deoxyribonucleic acid group; or a ribonucleic acid group;
R2 and R3, which are identical or different, represent -O-R4 wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group; or -O-CO-R5
wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 †o 12 carbon atoms or a glycosyl group; or a pharmaceutically acceptable salt or hydrate thereof, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
In an embodiment of the invention the compound of formula (I), in particular the compound of formula (II), or the pharmaceutically acceptable salt or hydrate thereof, for use as defined above, is in combination with at least one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich.
The present invention also relates to a pharmaceutical composition comprising as active substance a compound of formula (I), in particular a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof as defined above, optionally in association with at least one pharmaceutically acceptable excipient or vehicle, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
In an embodiment of the present invention the above defined pharmaceutical composition further comprises at least one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia.
The present invention also relates to a pharmaceutical composition comprising as active substance a compound of formula (I), in particular a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, as defined above, further comprising at least one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia, optionally in association with at least one pharmaceutically acceptable excipient or vehicle.
The present invention also relates to products comprising:
- a compound of formula (I), in particular a compound of formula (II), or a pharmaceutically acceptable salt or hydrate thereof, as defined above,
- at least one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia. as a combined preparation for simultaneous, separated or sequential use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
The present invention also relates to a dietary supplement comprising a compound of formula (I), in particular a compound of formula (II), or a
pharmaceutically acceptable salt or hydrate thereof, as defined above, for use for reducing the risk of ataxia, in particular Friedreich ataxia, in an individual.
In an embodiment of the present invention, the dietary supplement as defined above, optionally comprises additional compounds, preferably selected from the group consisting of vitamins, minerals, taffy acids, amino acids and antioxidants.
The present invention also relates †o a method for the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual, comprising administering †o the individual an effective amount of a compound of formula (I), in particular of a compound of formula (II), or of a pharmaceutically acceptable sal† or hydrate thereof, as defined above.
In an embodiment of the present invention, the method as defined above further comprises the administration of a† leas† one compound useful for the prevention or treatment of ataxia, in particular Freidreich ataxia.
The present invention also relates †o the use of a compound of formula (I), in particular a compound of formula (II), as defined above for the manufacture of a medicament intended for the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
In an embodiment of the present invention, the medicament as defined above further comprises a† leas† one compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia.
Compound of formula ( I )
Compounds of formula (I) as defined above can be readily chemically synthesized by one of skilled in the ar†, as is in particular described in Borne†† & Grubb (2000), Tetrahedron 56: 9221-9225, Oxenford et al. (2004) Tetrahedron Letters 45:9053- 9055, Brooks et al. (2010) Tetrahedron Letters 51: 4163-4165, Gerber et al. (2012) Org. Blomol. Chem. 10: 8660-8668, the thesis by Allen Brook entitled “Synthesis of Tritium Labeled Queuine, PreQi and Related Azide Probes Toward Examining the Prevalence of Queuine’’ (2012, University of Michigan), Akimoto et al. (1986) J. Med. Chem., 29: 1749-1753, Kelly et al. (2016) Nucleic Acids Research, 1-1 1 , and international application WO2016/050806, all of which are incorporated herein by reference.
Briefly, by way of example, queuine can be synthesised according †o the following reaction scheme:
In additions, compounds of formula (I) as defined above may be extracted and optionally purified from natural sources such as microorganisms, in particular bacteria, or from plants, in particular from plants nodulated with alpha- Proteobacteria such as bacteria of the Rhizobium, Mesorhizobium, and Sinorhizobium genii. By way of example, queuosine can be obtained from tRNAs, in particular
†RNAAsn, †RNAASP, †RNAHis and tRNATvr, prepared as follows:
Preparation of total RNA under acidic conditions
B. subtilis strains (or other relevant bacteria) are grown in ED liquid medium with appropriate supplements at 37°C with constant aeration. Fresh overnight cultures are inoculated in 15 ml of ED medium to an optical density at 600 nm (OD600) of 0.1. Cells are grown at 37°C to OD600 of 1 and chilled in equal volume of 60% methanol in 70 mM Hepes pH 7.5 at - 80°C. All subsequent steps are carried out in the cold and the solution for
prepared crude RNA are treated with diethyl pyrocarbonate and sterilized. Cells are pelleted at 4°C, washed in water and re-suspended in 0.5 ml of 10% glucose, 11 mM Tris, 10 mM EDTA. The suspensions are transferred †o tubes containing 0.1 g glass beads acid-washed (sigma- Aldrich, G4649). Tubes are disposed info The CoolPrep Adapter of Fas†Prep®-24 Instrument (MP Biomedicals) containing 50 g of dry ice. Cells are broken after three cycles using following parameters: 6 meters per second during 45 s. After each cycle, suspensions are kept 1 min on ice. After centrifugation 2 min a† 10,000 rpm, the supernatants are transferred †o a fresh Eppendorf tube. 0.3 M sodium acetate pH 5.2 is added and total RNA is isolated under acidic conditions. One volume of acid phenol: chloroform with Isoamyl alcohol (125:24:1) pH 4.5 (Amresco, AM9720) is added. The sample are mixed by vorfexing 10s and incubated for 3 min in a 65°C wa†er-ba†h. The phases are separated by spinning 5 min a† 14,000 rpm, then the aqueous phase is re-ex†rac†ed once with the same ho† acid phenol procedure. The aqueous phase is transferred †o a new tube and supplemented by one volume of cold acid phenol. After centrifugation 5 min a† 14,000 rpm, RNA are precipitated with 2.5 volumes of absolute ethanol 1 h a† -80°C. The RNA is pelleted a† 14,000 rpm for 15 min a† 4°C and washed with 70% ethanol. The RNA pellet is dissolved in 10 mM Tris, 1 mM EDTA pH 7.5.
Enrichment of tRNA
The total RNA preparation is then mixed with one volume of lithium chloride 8 M pH 4.5 and sodium acetate pH 5.2 a† 0.01 mM final concentration. This RNA solution is incubated 2 h a† -80°C. After centrifugation a† 14,000 rpm for 15 min a† 4°C, the †RNA remained in supernatant. To remove sal† contamination, †RNA is precipitated Ih a† - 80°C by addition of 0.3 M sodium acetate pH 5.2 and 2.5 volumes of absolute ethanol. Then, †RNA is pelleted by centrifugation a† 14,000 rpm for 15 min a† 4°C and washed with 70% ethanol. The †RNA pellet is dissolved in 10 mMTris, 1 mM EDTA pH 7.5.
The stereoisomer of queuine according †o the invention can be of any type.
Preferably, the stereoisomer of queuine is en†-queuine.
The pharmaceutical acceptable salt or hydrate according to the invention can be of any type. However, if is preferred that the pharmaceutical acceptable sal† according †o the invention is a hydrochloride sal†.
Preferably, the glycosyl group according †o the invention is selected from the group consisting of a mannosyl group, a galactosyl group or a glutamyl group.
Preferably, the aminoacyl group is selected from alanine (ala, A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gin, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (me†, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y) and valine (val, V).
In an embodiment of the invention, the substituents of formula (I), in particular of formula (II), according †o the invention may be linked together.
In a preferred embodiment of the compound of formula (I) as defined above:
- Ri is H, and
- R 12 represents a saturated or unsa†ura†ed alkyl, cycloalkyl, heterocycloalkyl or ether group having from 1 †o 20 carbon atoms, optionally substituted by a† leas† one group selected from the group consisting of:
• an alkyl group having from 1 †o 20 carbon atoms,
• an aryl or heteroaryl group having from 3 to 20 carbon atoms,
• a cycloalkyl or heterocycloalkyl group having from 3 to 20 carbon atoms,
• a hydroxyl group,
• a carbonyl or carboxyl group having from 1 †o 20 carbon atoms,
• an epoxy group,
• an -O-R4 group wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group,
• an -O-CO-R5 group wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms or a glycosyl group.
In another preferred embodiment of the compound of formula (I) as defined above:
- R 12 represent a group of the following formula:
wherein:
• a represents a double bond or an epoxy group, and
• l¾ and R3, which are identical or different, represent -O-R4 wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group; or -O-CO-R5 wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms or a glycosyl group.
In another preferred embodiment of the compound of formula (I), as defined above:
- Ri is H, and
- R 12 represents a saturated or unsafurafed alkyl group having from 1 †o 20 carbon atoms, optionally substituted by a† leas† one of a hydroxyl group.
In another preferred embodiment of the compound of formula (I), in particular of the compound of formula (II), as defined above:
- R2 and R3, which are identical or different, represent -OH, a -O-mannosyl group, a - O-galactosyl group or a -O-glutamyl group;
- R0 represents -OH;
- R7 and Rs, which are identical or different, represent -OH or a ribonucleic acid group.
Preferably, when Rz and Rs both represent a ribonucleic acid group, the compound of formula (I) according †o the invention is included in a transfer RNA (†RNA) as a ribonucleoside of the †RNA. More preferably, the compound of formula (I) according †o the invention is a ribonucleoside of the anticodon of the †RNA, most preferably the firs† nucleoside of the anticodon, i.e. the 5’ nucleoside of the anticodon or the nucleoside in the wobble position of the anticodon. Preferred †RNAs according †o the invention are selected from the list consisting of †RNAAsn, †RNAASP, †RNAHis and †RNATyr.
Preferably, the compound of formula (I), in particular the compound of formula (II), as defined above is represented by the following formulae (III), (IV) or (V):
Preferably, when a compound of formula (I), in particular a compound of formulae (III) - (V) according †o the invention is included in a †RNAASP, then R3 is OH and R2 is O-mannose.
Preferably also, when a compound of formula (I), in particular a compound of formulae (III) - (V) according †o the invention is included in a †RNATvr, then R3 is OH and R2 is O-galacfose.
Preferably, the compound of formula (I), in particular the compound of formula (II) according †o the invention is represented by the following formula (VI):
As should be clear †o one of skilled in the art, all the stereochemical configurations of the compounds according †o the invention are intended †o be covered by the formulae shown herein. In particular, as is intended herein, when the sfereoconfigurafion of a bond is no† specified, the bond may represent any of an upward bond, a downward bond, and a mixture of the two, in particular a 1 /1 mixture of the two.
Thus, the compound of formula (I) according †o the invention also relates †o the optically active forms of the compound of formula (V), such as the enantiomers represented by the following formulae (Va) and (Vb):
or their mixtures, in particular a racemic mixture thereof.
The compound of formula (Via) is queuine. Queuine, is also known as 7- (3,4- †rans-4,5-c/s-dihydroxy-l-cyclopen†en-3-ylaminome†hyl)-7-deazaguanine. The compound of formula (Vlb) is enf-queuine.
Preferably, the compound of formula (I), notably the compound of formula (II) according †o the invention is represented by the following formulae (VII), (Vila), (VI lb), (VIII), (Vila), (Vlllb), (IX), (IXa) (IXb), (X)
(VI lb) (VIII)
(XII) (Xlla)
(XVI) (XVII)
The compound of formula (Vila) is epoxyqueuine, also known as 7-(5-[3,4- epoxy-2,5-dihydroxycyclopen†-l-yl)amino]me†hyl)-7-deazaguanine.
The compound of formula (Villa) is queuosine also known as 2-amino-5- ({[(lS,4S,5R)-4,5-dihydroxycyclopen†-2-en-l-yl]amino}me†hyl)-7-(P-D-ribofuranosyl)- l,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one.
The compound of formula (IXa) is epoxyqueuosine also known as 7-(5-[(3,4- epoxy-2,5-dihydroxycyclopen†-l-yl)amino]me†hyl)-7-deazagua nosine.
Preferably, the compound of formula (II) according †o the invention is selected from the group consisting of mannosyl-queuine, galacfosyl-queuine, glufamyl-queuine, galacfosyl-queuosine, mannosyl-queuosine, glufamyl-queuosine, queuine-†RNA, and epoxyqueuine-†RNA.
The compound of formula (XIII) is N-((2-amino-4-oxo-4,7-dihydro-3Hpyrrolo[2,3- d]pyrimidin-5-yl)me†hyl)-3-phenylpropan-l -amine. The compound (XIV) is N-((2-amino-4-oxo-4,7-dihydro-3Hpyrrolo[2,3- d]pyrimidin-5-yl)me†hyl)-propan-l -amine.
The compound (XVII) is N-((2-amino-4-oxo-4,7-dihydro-3Hpyrrolo[2,3- d]pyrimidin-5-yl)me†hyl)-bu†an-l -amine.
The compound (XVIII) is N-((2-amino-4-oxo-4,7-dihydro-3Hpyrrolo[2,3- d]pyrimidin-5-yl)me†hyl)-hexan-l-amine.
Preferably also the compound of formula (I), in particular the compound of formula (II), according †o the invention is selected from the group consisting of queuine-†RNAAsP, queuine-†RNATyr, epoxyqueuine-† RNAASP, epoxyqueuine-† RNATyr, queuine-†RNAAsn, queuine-†RNAHis, epoxyqueuine-†RNAAsn, epoxyqueuine-†RNAHis,
mannosyl-queuine-†RNAAsP, galac†osyl-queuine-†RNATyr, mannosyl-epoxyqueuine- †RNAASP, and galac†osyl-epoxyqueuine-†RNATyr.
Most preferably also the compound of formula (I), in particular the compound of formula (II), according †o the invention (e.g., in the subject prophylactic methods, therapeutic methods, pharmaceutical compositions, products, and dietary supplements) is selected form the group consisting of queuine, en†-queuine, queuosine, epoxyqueuine, epoxyqueuosine, mannosyl-queuine, galactosyl-queuine, glutamyl-queuine, galactosyl-queuosine, mannosyl-queuosine, glutamyl-queuosine, queuine-†RNA and epoxyqueuine-Trna, a compound of formula (XII), (Xlla) and (XI I b) .
Ataxia
As used herein, “treating” a subject afflicted with a disorder shall include, without limitation, (i) slowing, stopping or reversing the progression of the disorder’s symptoms, and/or (ii) reducing the likelihood that the disorder’s symptoms will recur. In the preferred embodiment, treating a subject afflicted with a disorder means reversing the progression of the disorder’s symptoms, ideally †o the point of eliminating the symptoms.
As used herein, “preventing” a disorder in a subject includes, without limitation, reducing the likelihood of onset of the disorder’s symptoms.
Ataxia is well known †o one of skilled in the art. The term ataxia according †o the invention notably emcompasses hereditary ataxia including autosomal dominant ataxia and autosomal recessive ataxia, and acquired ataxia due †o external causes such as vitamin deficiencies, autoimmune conditions, infections, exposures †o toxic substances or drugs (especially alcohol) and cancers.
Friedreich ataxia is an autosomal recessive ataxia. If is notably defined by class 8A03.10 of the 1 1 th revision of the International Classification of Diseases (ICD- 1 1 ) set by the World Health Organization. As should be clear †o one of skill in the art, the expressions “Friedreich ataxia” and Friedreich’s ataxia” are considered synonyms herein.
Preferably, the prevention or treatment of ataxia, in particular Friedreich ataxia, according †o the invention relates †o the prevention or treatment of a† leas† one, more preferably several, most preferably all, disorders due or associated †o ataxia, in particular Friedreich ataxia, in particular selected from the group consisting
of cognitive or neurocognifive disorders, such as difficulties †o coordinate movements, dysarthria, loss of reflexes, decrease of deep sensation, pes cavus and scoliosis; cardiomyopathy; and diabetes mellifus.
The invention also relates †o the prevention or treatment of symptoms of ataxia, in particular Friedreich ataxia.
Individual
The individual according †o the invention is preferably a human.
The individual according †o the invention is preferably a child. In one embodiment, the child is from 2 years old †o 5 years old, from 5 years old †o 10 years old, or from 10 years old to 15 years old. In another embodiment, the human is from 15 years old †o 20 years old, from 20 years old †o 30 years old, from 30 years old to 40 years old, or from 40 years old to 50 years old.
Preferably, the individual according to the invention presents one or more symptoms of ataxia, in particular Friedreich ataxia.
Additional compound
The additional compound useful for the prevention or treatment of ataxia according †o the invention can be of any type known of one of skilled in the art. Preferably, the additional compound according †o the invention is selected from the group consisting of 5-hydroxy†ryp†ophan (5-HTP), idebenone, amantadine, physosfigmine, L-carni†ine or derivatives, frimefhoprim/sulfamefhoxazole, vigabafrin, phosphatidylcholine, acefazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
Preferably, the additional compound in the dietary supplement is selected from the group consisting of vitamins, minerals, taffy acids, amino acids, antioxidants and derivatives or precursors thereof.
Preferably vitamins are selected from the group consisting of pyridoxine, pyridoxal phosphate (Vitamin EV), riboflavin, thiamine, vitamin E, vitamin K3, vitamin C, niacin, CoQl O and b-carofene (befa-carofene).
Preferably, minerals are selected from the group consisting of calcium, magnesium, selenium and phosphorus.
Administration
As intended herein, “combined” or “in combination” means that the compound of formula (I), in particular the compound of formula (II) as defined above, is administered at the same time than another compound or product, either together, i.e. a† the same administration site, or separately, or a† different times, provided that the time period during which the compound of formula (I) as defined above exerts its effects on the individual and the time period during which the additional agent or product exerts its pharmacological effects on the individual, a† leas† partially intersect.
Preferably also, the compound of formula (I), in particular the compound of formula (II), according †o the invention or the pharmaceutically acceptable sal† or hydrate thereof is for an administration or is administered a† a dosage regimen of from 0.01 to 40 mg/kg/d, more preferably of from 0.01 to 10 mg/kg/d, even more preferably of from 0.01 to 1 mg/kg/d, and most preferably of from 0.01 to 0.1 mg/kg/d. In an additional embodiment, the compound of formula (I), in particular the compound of formula (II), and most preferably queuine, according †o the invention or the pharmaceutically acceptable sal† or hydrate thereof is for an administration or is administered a† a dosage regimen of (i) 0.01 mg/kg/d, 0.02 mg/kg/d, 0.03 mg/kg/d, 0.04 mg/kg/d, 0.05 mg/kg/d, 0.06 mg/kg/d, 0.07 mg/kg/d, 0.08 mg/kg/d, 0.09 mg/kg/d, or 0.1 mg/kg/d; or (ii) from 0.01 to 0.02 mg/kg/d, from 0.02 †o 0.03 mg/kg/d, from 0.03 to 0.04 mg/kg/d, from 0.04 †o 0.05 mg/kg/d, from 0.05 to 0.06 mg/kg/d, from 0.06 to 0.07 mg/kg/d, from 0.07 to 0.08 mg/kg/d, from 0.08 to 0.09 mg/kg/d, or from 0.09 to 0.1 mg/kg/d. For the subject therapeutic methods, the amounts exemplified in this paragraph are “therapeutically effective amounts.” For the subject prophylactic methods, the amounts exemplified in this paragraph are “prophylactically effective amounts.”
Preferably, the compound of formula (I), in particular the compound of formula (II) according †o the invention or the pharmaceutically acceptable sal† or hydrate thereof is in a form suitable for an administration or is administered by the oral route, the intradermal route, the intravenous route, the intramuscular route or the subcutaneous route. Preferably, the compound of formula (I), in particular the compound of formula (II), according †o the invention, or the pharmaceutical composition, medicament, products or dietary supplement comprising i† is in a form suitable for an administration or is administered by a hypodermic implant.
Preferably, the compound of formula (I) according †o the invention, or the pharmaceutical composition, medicament, products or dietary supplement comprising it is in the form of a powder, sachets, tablets, gelatine, capsules, or a liquid or gel solution.
Preferably also, the pharmaceutical composition, medicament, products or dietary supplement according to the invention, comprises the compound of formula (I) according to the invention, in particular queuine, ent-queuine, queuosine, the compound of formula (XII), (Xlla), or (Xllb) at a unit dose of at least 0.15 mg, at least 1 mg, at least 10 mg, at least 50 mg, at least 100 mg, at least 500 mg or at least 1000 mg.
Preferably also, the pharmaceutical composition, medicament, products or dietary supplement according to the invention, comprises an extract, in particular a purified extract, from microorganism and/or plant, which comprises the compound of formula (I) according to the invention, in particular queuine, ent-queuine, queuosine, the compound of formula (XII), (Xlla), or (Xllb) in particular at a unit dose of (i) at least 0.15 mg, at least 1 mg, at least 10 mg, at least 50 mg, at least 100 mg, at least 200 mg, at least 500 mg or at least 1000 mg, or (ii) from 0.2 mg to 0.5 mg, from 0.5 mg to 1 mg, from 1 mg to 10 mg, from 10 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, from 200 mg to 500 mg, or from 500 mg to 1000 mg.
Additional Embodiments
The present invention further provides a method for causing a glioprotective effect in an individual having ataxia (e.g., Friedreich’s ataxia) comprising administering to the individual queuine or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, the queuine or pharmaceutically acceptable salt or hydrate thereof is administered in a dosage regimen of from 0.01 mg/kg/d to 40 mg/kg/d; from 0.01 mg/kg/d to 10 mg/kg/d; from 0.01 mg/kg/d to 1 mg/kg/d; or from 0.01 mg/kg/d to 0.1 mg/kg/d. In another embodiment, the queuine or pharmaceutically acceptable salt or hydrate thereof is administered orally, intradermally, intravenously, intramuscularly, or subcutaneously.
In a further embodiment, the queuine or pharmaceutically acceptable salt or hydrate thereof is administered in combination with a compound selected from the group consisting of 5-hydroxy†ryp†ophan (5-HTP), idebenone, amantadine, physostigmine, L-carni†ine or derivatives, trimethoprim/sulfamethoxazole, vigabatrin,
phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
In a further embodiment, the queuine or pharmaceutically acceptable sal† or hydrate thereof is administered in the form of a pharmaceutical composition comprising a† leas† one pharmaceutically acceptable excipient or vehicle and queuine. The pharmaceutical composition optionally comprises a compound selected from the group consisting of 5-hydroxy†ryp†ophan (5-HTP), idebenone, amantadine, physostigmine, L-carni†ine or derivatives, trimethoprim/ sulfamethoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
In a further embodiment, the queuine or pharmaceutically acceptable sal† or hydrate thereof is formulated as a dietary supplement. This dietary supplement optionally comprises additional compounds selected from the group consisting of vitamins, minerals, fa††y acids, amino acids, and antioxidants.
The invention will be explained in more detail in the following non-limiting Example.
Description of the figure
Figure 1
Figure 1 represents the viability (arbitrary units (a.u.), vertical axis) of fibroblasts from healthy controls and from Friedreich ataxia (FA) patients treated with queuine a† 10 nM and challenged for 4h or 8h with gliofoxin (* p < 0.05)
Examples
Example 1
Investigation of the effects of queuine in murine immortalized fibroblasts expressing mutated FXN
Efficacy of queuine in the treatment of Friedreich ataxia is tested on the murine model described Calmels et al. (2009) PLoS One, 4: e6379 according to the following protocol. A. Material and methods
1 . Fibroblast cell lines
4 differents cell lines are used:
- NC6 SV40 L3/L- => WT mFXN
- 1 D12 SV40 L-/L- => WT hFXN - 1 D3 (1154F) L-/L- => hFXNllMF
- 1 D4 (R26G) L-/L- => hFXNR26G
Medium used: medium 1 g/L glucose + 10% FCS serum + Gentamicin antibiotic Thawed fibroblasts are seed in 75 cm2 culture flask:
For Mitosox and D H R 123 experiment: cells are plated in 6-well plates For western blot and enzymatic activities: cells are plated in 75 cm2 flask
2. Treatment The fibroblasts are mixed with Queuine according to the following table:
B. Measurements and analysis
1 . Indirect evaluation of Fe-S proteins by western blot The protocol used is the classical Western blot protocol.
An increase in the quantity of Fe-S proteins in in the treated fibroblasts vs. the untreated fiborblasfs is indicative of a therapeutic effect of queuine in Friedreich ataxia.
2. Enzyme activity : succinate dehydrogenase (SDH) and aconitase (ACO)
The activities of SDH and ACO are evaluated according †o the protocol described in Calmels et al. (2009) PLoS One, 4: e6379 and Rusfin et al. (1994) Clin Chim Acta. 228: 35-51.
An increase of the SDH and ACO activity in the treated fibroblasts vs. the untreated fiborblasfs is indicative of a therapeutic effect of queuine in Friedreich ataxia.
3. Mitochondrial Superoxide Indicator (MitoSOX) or Dihvdrorhodamine 123 (DHR123) 1D3 (I154F) L-/L- fibroblasts show an increased production of ROS in response †o an incubation with FI202 (hydrogen peroxide). The level of ROS in the fibroblasts incubated in the presence or absence of FI202 with varying concentrations of Queuine is determined using the MifoSOX and DH R 123 fluorescent probes.
The protocol is described below:
• Star† from 6-well plates a† -80% confluence;
• Remove medium and wash once with PBS 1 X;
• Add 500mI of PBS+ Mitosox (Cf= 1 mM) or PBS + DH R 123 (Cf= 30 mM) in all the wells except one (= negative control);
• Incubate a† 37°C during 15 min;
• Remove PBS+Mi†osox or PBS+DH R 123;
• Wash twice with PBS 1 X (with 2 mL then 1 mL);
• Add 500mI of PBS with or without PI202 (Of: 10 mM or 10 mM);
• Incubate a† 37°C during 30 min;
• Remove PBS with or without PI202;
• Add 500mI of trypsin and incubate for 5 min a† 37°C;
• Add 1 mL of medium;
• Centrifuge 3 min a† 1 000 rpm;
• Wash the pellet once with PBS IX;
• Centrifuge 3 min a† 1 000 rpm;
• Resuspend the pellet in 500 mI PBS IX;
• Go †o FACS (Mitosox emission: 580 nm, D H R 123 emission: 530 nm).
A reduced level of ROS production by 1 D3 (I154F) L-/L- fibroblasts incubated with H202 treating by queuine vs. untreated 1 D3 (I 154F) L-/L- fibroblasts is indicative of a therapeutic effect of queuine in Friedreich ataxia. Example 2
Differential protective activity of queuine against gliotoxin toxicity
Efficacy of queuine in the treatment of Friedreich ataxia was evaluated using gliotoxin, a mycotoxin which is also a specific chelator of zinc.
Briefly, primary cultures of fibroblasts taken from two patients suffering from Friedreich ataxia were established, as well as primary cultures of fibroblasts taken from three healthy donnors (control). On Day 0, queuine was added to the culture medium of the fibroblasts at the concentration of 10 nM. On Day 1 , gliotoxin was further added to the culture medium at the concentration of 1 mM. The cultures were then continued for 4h or 8h before fixation and cell viability was assessed using sulforhodamine B. Statistical analysis was done with the unpaired t-test, significance threshold was p < 0.05, using the Graphpad software. The results are presented in Figure 1. The viability of fibroblasts from patients with Friedreich ataxia exposed to gliotoxin for 4h or 8h is significantly increased with respect to controls. This indicates that queuine exerts a positive effect in patients with Friedreich ataxia.
Claims
1. A compound of the following formula (I):
wherein:
Ri represents -H or a ribosyl group of the following formula:
wherein:
• R0 represents -H; -O-R9 or -O-CO-R9 wherein R9 is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 †o 12 carbon atoms;
• R7 represents -H; -O-R10 or-O-CO-Rio wherein Rio is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 †o 12 carbon atoms; a deoxyribonucleic acid group; or a ribonucleic acid group;
• Re represents -H; -O-Rn or-O-CO-Rn wherein Rn is H, an alkyl group having from 1 †o 20 carbon atoms or an aryl group having from 3 †o 20 carbon atoms; a phosphate group; a diphosphate group; a triphosphate group; a deoxyribonucleic acid group; or a ribonucleic acid group;
R 12 represents a saturated or unsaturated alkyl, cycloalkyl, heterocycloalkyl or ether group having from 1 †o 20 carbon atoms, optionally substituted by a† leas† one group selected from the group consisting of:
• an alkyl group having from 1 †o 20 carbon atoms,
• an aryl or heteroaryl group having from 3 to 20 carbon atoms,
• a cycloalkyl or heterocycloalkyl group having from 3 to 20 carbon atoms,
• a hydroxyl group,
• a carbonyl or carboxyl group having from 1 †o 20 carbon atoms,
• an epoxy group,
• an -O-R4 group wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group,
• an -O-CO-R5 group wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms or a glycosyl group; or a pharmaceutically acceptable sal† or hydrate thereof, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
2. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o claim 1 , wherein the compound of formula (I) is of the following formula
(II)
wherein:
a represents a double bond or an epoxy group, and Ri represents -H or a ribosyl group of the following formula:
wherein:
• R0 represents -H; -O-R9 or -O-CO-R9 wherein R9 is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms;
• R7 represents -H; -O-Rio or-O-CO-Rio wherein Rio is H, an alkyl group having from 1 †o 6 carbon atoms or an aryl group having from 3 to 12 carbon atoms; a deoxyribonucleic acid group; or a ribonucleic acid group;
• Re represents -H; -O-Rn or-O-CO-Rn wherein Rn is H, an alkyl group having from 1 †o 20 carbon atoms or an aryl group having from 3 to 20 carbon atoms; a phosphate group; a diphosphate group; a triphosphate group; a deoxyribonucleic acid group; or a ribonucleic acid group;
R2 and R3, which are identical or different, represent -O-R4 wherein R4 is H, an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms, a glycosyl group or an aminoacyl group; or -O-CO-R5 wherein Rs is an alkyl group having from 1 †o 6 carbon atoms, an aryl group having from 3 to 12 carbon atoms or a glycosyl group;
3. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o claim 1 or 2, wherein:
- R2 and R3, which are identical or different, represent -OH, a -O-mannosyl group, a -
O-galactosyl group or a -O-glutamyl group;
- R0 represents -OH;
- R7 and Rs, which are identical or different, represent -OH or a ribonucleic acid group.
4. The compound or pharmaceutically acceptable salt or hydrate thereof for use according †o any one of claims 1 †o 3, wherein the compound is selected form the group consisting of queuine, enf-queuine, queuosine, epoxyqueuine, epoxyqueuosine, mannosyl-queuine, galacfosyl-queuine, glufamyl-queuine, galacfosyl-queuosine, mannosyl-queuosine, glufamyl-queuosine, queuine-†RNA and epoxyqueuine-†RNA.
5. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o any one of claims 1 †o 4, wherein the compound is selected from the group consisting of the compounds of the following formulae:
6. The compound or pharmaceutically acceptable salt or hydrate thereof for use according †o any one of claims 1 †o 5, administered a† a uni† dose of from 5 to 1500 mg/kg.
7. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o any one of claims 1 †o 6, for an administration with a dosage regimen of from 0.01 to 40 mg/kg/d.
8. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o any one of claims 1 †o 7, in a form suitable for an administration by the oral route, the intradermal route, the intravenous route, the intramuscular route or the subcutaneous route.
9. The compound or pharmaceutically acceptable sal† or hydrate thereof for use according †o any one of claims 1 †o 8, in combination with a† leas† one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia.
10. The compound or pharmaceutically acceptable salt or hydrate thereof for use according †o any one of claims 1 †o 9, in combination with a† leas† one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia, selected from the group consisting of 5-hydroxy†ryp†ophan (5-HTP), idebenone, amantadine, physostigmine, L-carni†ine or derivatives, †rime†hoprim/sulfame†hoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4- aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
11. A pharmaceutical composition comprising as active substance a compound of formula (I) or a pharmaceutically acceptable sal† or hydrate thereof as defined in any one of claims 1 †o 5, optionally in association with a† leas† one pharmaceutically acceptable excipient or vehicle, for use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
12. A pharmaceutical composition comprising as active substance a compound of formula (I) or a pharmaceutically acceptable sal† or hydrate thereof as defined in any one of claims 1 †o 5, further comprising a† leas† one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia, optionally in association with a† leas† one pharmaceutically acceptable excipient or vehicle.
13. A pharmaceutical composition comprising as active substance a compound of formula (I) or a pharmaceutically acceptable sal† or hydrate thereof as defined in any one of claims 1 †o 5, optionally in association with a† leas† one pharmaceutically acceptable excipient or vehicle, comprising a† leas† one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia, selected from the group consisting of 5-hydroxy†ryp†ophan (5-HTP), idebenone, amantadine, physostigmine, L-carni†ine or derivatives,
†rime†hoprim/sulfame†hoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4- aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.
14. Products comprising:
- a compound of formula (I) as defined in any one of claims 1 †o 5,
- a† leas† one additional compound useful for the prevention or treatment of ataxia, in particular Friedreich ataxia, as a combined preparation for simultaneous, separated or sequential use in the prevention or treatment of ataxia, in particular Friedreich ataxia, in an individual.
15. A dietary supplement comprising a compound of formula (I) as defined in any one claims 1 †o 5, for use for reducing the risk of a†axa, in particular Friedreich ataxia, in an individual.
16. The dietary supplement for use according †o claim 15, comprising additional compounds selected from the group consisting of vitamins, minerals, fa††y acids, amino acids and antioxidants.
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| WO2016050806A1 (en) | 2014-09-29 | 2016-04-07 | The Provost, Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin | Treatments for autoimmune disease |
| EP3290039A1 (en) * | 2016-08-30 | 2018-03-07 | Amabiotics | Compounds for treating diseases associated with a mitochondrial dysfonction |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016050806A1 (en) | 2014-09-29 | 2016-04-07 | The Provost, Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin | Treatments for autoimmune disease |
| EP3290039A1 (en) * | 2016-08-30 | 2018-03-07 | Amabiotics | Compounds for treating diseases associated with a mitochondrial dysfonction |
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