RU2006139931A - NEUROLOGICALLY ACTIVE COMPOSITIONS - Google Patents

Claims (37)

1. The compound of formula I

wherein R ² is H or CH ₂ NR ¹ R ⁴ , where R ¹ and R ^{4 are} independently selected from H, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 picloalkyl; R ³ represents H; substituted or unsubstituted C _1-4 alkyl; substituted or unsubstituted C _2-4 alkenyl; substituted or unsubstituted C _3-6 cycloalkyl; substituted or unsubstituted 6-membered aryl, condensed or not condensed with substituted or unsubstituted 6-membered aryl or heteroaryl; substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle, condensed or not condensed with substituted or unsubstituted 6-membered aryl or heteroaryl; (CH ₂ ) _n R ⁶ , where n is an integer from 1 to 6, and R ⁶ is substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted saturated or unsaturated 5- or A 6-membered N-containing heterocycle or substituted or unsubstituted 6-membered aryl; NR ⁸ R ⁹ , where R ⁸ and R ^{9 are} independently selected from H, substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle and substituted or unsubstituted 6-membered aryl; NHCOR ¹⁰ , where R ¹⁰ is substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle, or substituted or unsubstituted 6-membered aryl ; CH ₂ CONR ¹¹ R ² , where R ¹¹ and R ^{12 are} independently selected from H, substituted or unsubstituted C ^1-6 alkyl, substituted or unsubstituted C _2-6 alkynyl, and substituted or unsubstituted 5- or 6-membered N-containing heterocycle, condensed or non-condensed with substituted or unsubstituted 6-membered aryl; and (CH ₂ ) _m NHR ¹³ , where R ^{13 is} selected from substituted or unsubstituted C _1-6 alkyl and SO ₂ R ¹⁴ , where R ^{14 is} selected from substituted or unsubstituted C _1-6 alkyl and substituted or unsubstituted 6-membered aryl, am is from 1 to 6; R ⁵ and R ^{7 are} independently selected from H and halogen; and X represents O or S, under the following conditions: (i) at least one of R ² and R ^{3 is} not H; (ii) at least one of R ⁵ and R ⁷ is halogen; (iii) if X is O, R ⁵ and R ⁷ are Cl, and R ² is H, then R ^{3 is} not cyclopropyl or parafluorophenyl; and (iv) if X represents O, R ⁵ represents H, R ⁷ represents I, and R ² represents H, then R ^{3 is} not C _2-4 alkyl, their salts, hydrates, solvates, derivatives, prodrugs, tautomers and / or isomers. 2. The compound according to claim 1, which is a compound of formula IA

in which R ⁵ R ⁷ and X correspond to the definitions given in claim 1; and R ³ represents a substituted or unsubstituted C _2-4 alkyl; substituted or unsubstituted C _2-4 alkenyl; substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle, condensed or not condensed with substituted or unsubstituted 6-membered aryl or heteroaryl; (CH ₂ ) _n R ⁶ wherein n is 1 to 3 and R ⁶ is a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle; NR ⁸ R ⁹ in which R ⁸ is H and R ⁹ is H or substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted 6 membered aryl; NHCOR ¹⁰ , in which R ¹⁰ represents a substituted or unsubstituted C _1-4 alkyl or a substituted or unsubstituted 6-membered aryl. 3. The compound according to claim 2, in which R ³ represents a substituted or unsubstituted C _1-4 alkyl; substituted or unsubstituted C _2-4 alkenyl; substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle, condensed or not condensed with substituted or unsubstituted 6-membered aryl or heteroaryl, (CH ₂ ) _n R ⁶ , where n is from 1 to 3, and R ⁶ represents a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted saturated or unsaturated 5- or 6-membered N-containing heterocycle; or NR ⁸ R ⁹ where R ⁸ represents H, a R ⁹ —H, or substituted or unsubstituted C _1-4 alkyl, or substituted or unsubstituted 6-membered aryl. 4. The compound according to any one of claims 1 to 3, having the following form:

5. The compound according to claim 1, which is a compound of formula IB:

in which R ² , R ⁵ , R ⁷ and X correspond to the definition given in claim 1. 6. The compound according to claim 5, in which R ² represents CH ₂ NR ¹ R ⁴ , where R ¹ and R ^{4 are} independently selected from H, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C _3-6 cycloalkyl. 7. The compound according to any one of claims 1, 5 or 6, which has the following form:

8. The compound according to claim 1, which is a compound of formula 1C

in which R ⁵ , R ⁷ and X correspond to the definition given in claim 1; and R ^2C represents CH ₂ NR ¹ R ⁴ where R ¹ and R ^{4 are} independently selected from H and substituted or unsubstituted C _1-6 alkyl; and R ^3C is substituted or unsubstituted C _1-4 alkyl. 9. The compound of claim 8, which has the following form:

10. The compound according to claim 1, in which R ⁵ and R ⁷ are both halogen 11. The compound of claim 10, in which R ⁵ and R ⁷ are both chlorine. 12. The compound according to claim 1 for use as a medicine. 13. The compound of claim 12, wherein the drug is a neurotherapeutic or neuroprotective agent. 14. The compound of claim 12, wherein the drug is an anti-amyloidogenic agent. 15. A pharmaceutical or veterinary composition comprising a compound of formula I according to claim 1 and an excipient acceptable from a pharmaceutical or veterinary point of view. 16. The composition according to clause 15, which further includes another drug. 17. The composition according to clause 16, in which the other drug is an inhibitor of the active center of acetylcholinesterase, an antioxidant, anti-inflammatory agent or estrogen agent. 18. The use of the compounds of formula I according to claim 1 for the manufacture of a medicinal product for the treatment, mitigation and / or prevention of a neurological condition. 19. The application of claim 18, wherein the neurological condition is a neurodegenerative disorder. 20. The use according to claim 19, in which the neurodegenerative disorder is a neurodegenerative amyloidosis. 21. The use according to claim 19, in which the neurodegenerative disorder is sporadic or familial Alzheimer's disease, amyotrophic lateral sclerosis, cataract, Parkinson's disease, Creutzfeldt-Jakob disease and its new version, the so-called "mad cow disease", Huntinggon's disease, Friedrich ataxia , dementia with the formation of a Levy body, multisystem atrophy, Hallerboden-Spattz disease, diffuse Levy body disease, familial fatal insomnia, Gerimann Straussler Scheinker disease, hereditary hemorrhage in my g amiloidoizno-Dutch type, multiple sclerosis, tauopathies, motor neuropathy or prionovge disease. 22. The use of claim 21, wherein the neurodegenerative disorder is Parkinson's disease. 23. The use according to claim 19, in which the neurodegenerative disorder is a condition associated with β-amyloid protein (Aβ). 24. The use according to claim 23, wherein the condition associated with Aβ is Alzheimer's disease, or dementia with Down syndrome, or one of several types of autosomal dominant forms of familial Alzheimer's disease. 25. The application of claim 18, which slows down, decreases or stops the weakening of the subject's intelligence. 26. The use according to p. 18, which further comprises a separate, sequential or simultaneous administration of another drug. 27. The use of claim 26, wherein the other drug is an acetylcholinesperase active center inhibitor, antioxidant, anti-inflammatory agent, or estrogen agent. 28. The use of claim 18, wherein the compound of formula I is administered orally, topically or parenterally. 29. The compound of formula I according to claim 1 for use in therapy. 30. The compound of formula I according to claim 1 for the treatment, weakening and / or prevention of a neurological condition. 31. The compound of formula I according to claim 1 for use as an antiamyloidogenic agent. 32. A method of obtaining a compound of formula I according to claim 1, containing the following operations: (a) carrying out the reaction of a protected or unprotected compound of formula V

in which R ⁵ and R ⁷ correspond to the definition given in claim 1, with H ₂ NR ³ where R ³ corresponds to the definition given in claim 1, with the formation of a protected or unprotected compound of formula VII

(b) reduction of a compound of formula VII to form a protected or unprotected compound of formula VIII

cyclization of a compound of formula VIII to form a protected or unprotected compound of formula I in which R ² is H; or (d) cyclization of a compound of formula VIII in the presence of R ² CHO, R ² CO ₂ H or R ² C (OR ^X ) ₃ , where R ^X is substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted 6-membered aryl, and R ² corresponds to the definition given in claim 1. 33. The method of obtaining the compounds of formula I according to claim 1, where R ² represents H, containing the following operations: a) amination of a protected or unprotected compound of formula VI

in which R ⁵ and R ⁷ correspond to the definition given in claim 1, with the formation of a protected or unprotected compound of formula IX

b) reacting a compound of formula IX with R ³ -L or R ³ OSC ₂ R ^X where L is a leaving group, R ³ corresponds to the definition given in claim 1, and R ^X corresponds to the definition given in clause 32. 34. A method of obtaining a compound of formula I according to claim 1, containing the following operations: (a) reacting a protected or unprotected compound of formula VI according to claim 33 with a formylating agent to form a protected or unprotected compound of formula X

or protected or unprotected compounds of formula XI

(b) reacting a compound of formula X or XI with an acylating agent containing R ² to form a protected or unprotected compound of formula XII

where R ² corresponds to the definition given in claim 1, or the compounds of formula XIII

(c) carrying out the reaction of a compound of formula XII or XIII with H ₂ NR ³ , where R ³ corresponds to the definition given in claim 1. 35. A method of obtaining a compound of formula IV

where R ⁵ and R ^{7 are} independently selected from halogens, containing a diazotization step of a compound of formula III

where R ⁵ and R ⁷ correspond to their definition for the above formula IV. 36. The method of obtaining the compounds of formula V according to clause 32, where R ⁵ and R ⁷ correspond to the definition given in clause 35, containing the following operations: (a) diazotizing a compound of formula III according to claim 35 to form a compound of formula IV according to claim 35; and (b) nitration of a compound of formula IV. 37. The method of obtaining the compounds of formula VI according to clause 33, where R ⁵ and R ⁷ correspond to the definition given in clause 35, containing the following operations: (a) diazotizing a compound of formula III according to claim 35 to obtain a compound of formula IV according to claim 35, wherein R ⁵ and R ⁷ correspond to the definition given in claim 35; (b) nitration of a compound of formula IV to form a compound of formula V according to claim 32, wherein R ⁵ and R ⁷ correspond to the definition given in claim 35; and (c) reduction of a compound of formula V.