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1. WO2021038241 - DÉRIVÉS TRIAZINE POUR LE TRAITEMENT DE MALADIES ASSOCIÉES À DES NEUROTROPHINES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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Claims

1. A compound of formula I,


wherein represents the point of attachment to the nitrogen atom;

R3 represents hydrogen, methyl or methoxymethyl; and

R4 represents hydrogen, methoxy or methoxymethyl;

R2 represents methyl, ethyl, methoxymethyl, methylsulfanyl or -A-R5; wherein

A represents Ci_2 alkylene, -Ci-2alkyleneO-, -OCi-2alkylene-, which three groups are optionally substituted by one or more groups selected from halo, Ci_2 alkyl and =0; and

R5 represents oxetanyl or a 4-7-membered nitrogen-containing heterocyclyl group, each of which groups are optionally substituted by one or more groups selected from halo, Ci_2 alkyl and =0;

or a pharmaceutically-acceptable salt thereof,

with the proviso that the compound of formula I does not represent


2. A compound as claimed in Claim 1 , wherein R1 represents
, wherein ~ , R3 and R4 are as defined in Claim 1 .

3. A compound as claimed in Claim 1 or Claim 2, wherein at least one of R3 and R4 represents hydrogen.

4. A compound as claimed in any one of Claims 1 to 3, wherein R3 represents methyl or methoxymethyl and R4 represents hydrogen.

5. A compound as claimed in any one of Claims 1 to 3, wherein R3 represents hydrogen and R4 represents methoxy.

6. A compound as claimed in any one of Claims 1 to 3, wherein R3 and R4 each represent hydrogen.

7. A compound as claimed in any one of Claims 1 to 6, wherein R2 represents methyl, ethyl or methoxymethyl.

8. A compound as claimed in any one of Claims 1 to 7, wherein R2 represents ethyl or methoxymethyl.

9. A compound as claimed in any one Claims 1 to 6, wherein R2 represents -A-R5, wherein A and R5 are as defined in Claim 1.

10. A compound as claimed in Claim 9, wherein R5 represents a 4-7-membered nitrogen-containing heterocyclyl group, which heterocyclyl group is optionally substituted by one or more groups selected from halo, Ci_2 alkyl and =0;

11. A compound as claimed in any one of Claims 1 to 6 or 9 to 10, wherein A represents -CH2- or -0CH2C(0)-.

12. A compound as claimed in any one of Claims 1 to 6 or 9 to 11, wherein R5 represents a 4-6-membered nitrogen-containing heterocyclyl group, which heterocyclyl group is optionally substituted by one or more groups selected from halo, Ci_2 alkyl and

=o.

13. A compound as claimed in Claim 12, wherein R5 represents a 4-6-membered nitrogen-containing heterocyclyl group selected from:


wherein -~ represents the point of attachment to A,

each of which heterocyclyl groups is optionally substituted by a =0 group.

14. A compound as claimed in Claim 1 , wherein the compound is selected from the group consisting of:


or a pharmaceutically-acceptable salt thereof.

15. A pharmaceutical composition comprising a compound as defined in any one of

Claims 1 to 14, including pharmaceutically-acceptable salts thereof, in combination with one or more pharmaceutically-acceptable excipient.

16. A compound as defined in any one of Claims 1 to 14, including pharmaceutically-acceptable salts thereof, or a pharmaceutical composition as defined in Claim 15, for use in medicine.

17. A compound as defined in any one of Claims 1 to 14, including pharmaceutically-acceptable salts thereof, or a pharmaceutical composition as defined in Claim 15, for use in the treatment and/or prevention of a disease characterised by impaired signalling of neurotrophins and/or other trophic factors.

18. A method of treating and/or preventing a disease characterised by impaired signalling of neurotrophins and/or other trophic factors, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of Claims 1 to 14, including pharmaceutically-acceptable salts thereof, or a pharmaceutical composition as defined in Claim 15.

19. The use of a compound as defined in any one of Claims 1 to 14, including pharmaceutically-acceptable salts thereof, or a pharmaceutical composition as defined in Claim 15, for the manufacture of a medicament for the treatment or prevention of a disease characterised by impaired signalling of neurotrophins and/or other trophic factors.

20. The compound for use, method or use as defined in any one of Claims 17 to 19, wherein the disease characterised by impaired signalling of neurotrophins and/or other trophic factors is selected from Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, cognitive dysfunction, mild cognitive impairment, other dementia disorders, Parkinson’s, disease, other Parkinsonian disorders and/or othertauopathies, Huntington’s disease, brain injuries, stroke, motor neurone diseases, multiple sclerosis, spinal cord injury, hypoxia, ischemia, hypoxic ischemia injury, coronary artery disease, obesity, diabetes, metabolic syndrome, diabetic neuropathy, Charcot-Marie-Tooth disease and its variants, nerve injury, genetic or acquired or traumatic hearing loss, blindness, posterior eye diseases, anterior eye diseases, dry eye syndrome, neurotrophic keratitis, glaucoma, high intraocular pressure, retinitis pigmentosa, post-traumatic stress disorders, WAGR syndrome, Prader-Willi syndrome, olfactory decline, olfactory dysfunction, fragile X syndrome, congenital hypoventilation syndrome, obsessive-compulsive disorder, anxiety, generalised anxiety disorder, schizophrenia, depression, eating disorders, bipolar disorder, chronic fatigue syndrome, neuromyelitis optica, Rett syndrome, epilepsy, Friedreich’s ataxia, obstructive sleep apnea-hypopnea syndrome, pain and constipation.

21 . The compound for use, method or use as claimed in Claim 20, wherein the disease characterised by impaired signalling of neurotrophins and/or other trophic factors is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, other Parkinsonian diseases, other tauopathies, Lewy body dementia, motor neurone disease, Pick’s disease, obesity, metabolic syndrome, diabetes, diabetic neuropathy, glaucoma, dry eye syndrome, neurotrophic keratitis, genetic, acquired or traumatic hearing loss and Rett Syndrome.

22. The compound for use, method or use as claimed in Claim 21 , wherein the disease characterised by impaired signalling of neurotrophins and/or other trophic factors is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, cognitive dysfunction, depression, diabetic neuropathy, glaucoma, dry eye syndrome, genetic, acquired or traumatic hearing loss and Rett syndrome.

23. The compound for use, method or use as claimed in Claim 22, wherein the disease characterised by impaired signalling of neurotrophins and/or other trophic factors is Alzheimer’s disease.

24. A combination product comprising:

(I) a compound as defined in any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof; and

(II) one or more other therapeutic agent that is useful in the treatment or prevention of a disease characterised by impaired signalling of neurotrophins and/or other trophic factors,

wherein each of components (I) and (II) is formulated in admixture, optionally with a pharmaceutically-acceptable excipient, such as a pharmaceutically-acceptable adjuvant diluent or carrier.

25. A kit-of-parts comprising:

(a) a pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, formulated in admixture with a pharmaceutically-acceptable excipient; and

(b) a pharmaceutical composition comprising one or more other therapeutic agent that is useful in the treatment or prevention of a disease characterised by impaired signalling of neurotrophins and/or other trophic factors, formulated in admixture with a pharmaceutically-acceptable excipient,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

26. A process for the preparation of a compound as defined in any one of Claims 1 to 14, including a pharmaceutically-acceptable salt thereof, comprising the step of reacting a compound of formula II,


wherein R1 and R2 are as defined in any one of Claims 1 to 14, with ethoxycarbonyl isocyanate.