DK2233474T3 - Kondenseret aminodihydrothiazinderivat - Google Patents
Kondenseret aminodihydrothiazinderivat Download PDFInfo
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- DK2233474T3 DK2233474T3 DK09701914.5T DK09701914T DK2233474T3 DK 2233474 T3 DK2233474 T3 DK 2233474T3 DK 09701914 T DK09701914 T DK 09701914T DK 2233474 T3 DK2233474 T3 DK 2233474T3
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- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
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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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Claims (14)
1. Forbindelse repræsenteret ved formlen (I):
(i) 5 eller et farmaceutisk acceptabelt salt deraf eller et solvat deraf, hvor ringen A er en C6-i4-arylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en 5- til 6- leddet heteroarylgruppe, som kan have 1 til 3 substituenter 3 valgt fra substituentgruppen a, eller en 9- til 10-leddet benzokondenseret heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen ex, L er en enkeltbinding, et oxygenatom, en formel -NReCO- (hvor Re er et hydrogenatom eller en Ci-6-alkylgruppe, som kan have 1 5 til 3 substituenter valgt fra substituentgruppen a) , en formel -NReSC>2- (hvor Re er et hydrogenatom eller en Ci-6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen ex) , en formel -NRe- (hvor Re er et hydrogenatom eller en Ci-6-alkylgruppe, som kan have 1 til 3 3 substituenter valgt fra substituentgruppen cx), en Ci_6- alkylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en C2-6_alkenylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, eller en C2-6-alkynylengruppe, som kan have 1 til 3 substituenter valgt 5 fra substituentgruppen cx, Ringen B er en C3_8-cycloalkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a, en C6-14- arylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, eller en 5- til 10-leddet heterocyklisk 3 gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, X er en methylengruppe, som kan have 1 til 2 substituenter valgt fra substituentgruppen a, Y er en enkeltbinding, -NRY- (hvor RY er et hydrogenatom, en Ci-6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en Ci-6~alkylcarbonylgruppe, som kan have 5 1 til 3 substituenter valgt fra substituentgruppen cx, en C6-14- arylcarbonylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en Ci-6_alkylsulf onylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a, en C6-i4_arylsulf onylgruppe, som kan have 1 til 3 substituenter 3 valgt fra substituentgruppen cx, en C6-i4~arylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a, eller en 5- til 10-leddet heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a), eller et oxygenatom, 5 Z er en enkeltbinding eller en Ci-3-alkylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, R1 og R2 hver uafhængigt er et hydrogenatom, en Ci_6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a, en Ci_6-alkylcarbonylgruppe, som kan have 3 1 til 3 substituenter valgt fra substituentgruppen cx, en C6-i4- arylcarbonylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en Ci-6~alkylsulfonylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en C6-i4_arylsulf onylgruppe, som kan have 1 til 3 substituenter 5 valgt fra substituentgruppen cx, en 3- til 10-leddet carbocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, eller en 5- til 10-leddet heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, og 3 R3, R4, R5 og R6 uafhængigt er et hydrogenatom, et halogenatom, en hydroxygruppe, en Ci-6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en C1-6-alkoxygruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen a, en 3- til 10-leddet carbocyklisk gruppe, 5 som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, eller en 5- til 10-leddet heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, [substituentgruppen α: et hydrogenatom, et halogenatom, en hydroxygruppe, en nitrogruppe, en Ci_6-alkylthiogruppe, en C6-i4~ arylgruppe, en C6-i4_aryloxycarbonylgruppe, en C6-14-arylcarbonylgruppe, en cyanogruppe, en C3-8_cycloalkoxygruppe, 5 en C3-8-cycloalkylgruppe, en C3_8-cycloalkylthiogruppe, en sulfonylaminogruppe (hvor sulfonylaminogruppen kan være substitueret med en Ci-6-alkylgruppe) , en C2-6_alkenylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen β, en C2-6-alkynylgruppe, som kan have 1 til 3 3 substituenter valgt fra substituentgruppen β, en carbamoylgruppe, som kan være substitueret med en eller to Ci_ 6-alkylgrupper, en Ci_6-alkoxygruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen β, en Ci-ξ-alkylgruppe, som kan have 1 til 3 substituenter valgt fra 5 substituentgruppen β, og en 5- til 10-leddet heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen β, substituentgruppen β: et halogenatom, en cyanogruppe, en hydroxygruppe, en Ci_6-alkoxygruppe, en Ci-6-alkylgruppe, en C3_ 3 8-cycloalkylgruppe og en oxogruppe].
2. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge krav 1, hvor Y er en enkeltbinding, og Z er en Ci-3-alkylengruppe, som kan have 1 til 3 5 substituenter valgt fra substituentgruppen a.
3. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge krav 1, hvor Y er et oxygenatom, og Z er en Ci_3-alkylengruppe, som kan have 1 til 3 substituenter 3 valgt fra substituentgruppen ex.
4. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge krav 1, hvor Y er et oxygenatom, og Z er en enkeltbinding.
5. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge krav 1, hvor Y er -NRY- (hvor RY er en Ci-6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en Ci_6-alkylcarbonylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en C6-i4_arylcarbonylgruppe, som kan have 1 til 3substituenter valgt fra substituentgruppen ex, en C6-i4_arylsulfonylgruppe, som 5 kan have 1 til 3 substituenter valgt fra substituentgruppen ex, en C6-i4~arylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen ex, eller en 5- til 10-leddet heterocyklisk gruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen ex) , et svovlatom, et sulfoxid eller en D sulfon, og Z er en enkeltbinding, en Ci-3-alkylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx.
6. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge et hvilket som helst af kravene 1-5, 5 hvor L er en enkeltbinding, en formel -NReCO- (hvor Re er et hydrogenatom eller en Ci_6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx) eller en formel -NReS02- (hvor Re er et hydrogenatom eller en Ci_6-alkylgruppe, som kan have 1 til 3 substituenter valgt fra 3 substituentgruppen cx) .
7. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge et hvilket som helst af kravene 1-5, hvor L er en enkeltbinding, et oxygenatom, en C1-6- 5 alkylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, en C2-6_alkenylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx, eller en C2-6-alkynylengruppe, som kan have 1 til 3 substituenter valgt fra substituentgruppen cx. D
8. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge et hvilket som helst af kravene 1-5, hvor L er en formel -NReCO- (hvor Re er et hydrogenatom eller en Ci_6-alkylgruppe, som kan have 1 til 3 substituenter valgt 5 fra substituentgruppen cx) .
9. Forbindelse eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge et hvilket som helst af kravene 1-8, hvor forbindelsen er valgt blandt følgende forbindelser: I) ( + )-N-{3-[(4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][l,3]thiazin-8a-yl]-4-fluorphenyl} - 5-chlorpyridin-2-carboxamid, 5 2) (+)-N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H- cyclopenta-[d][1,3]thiazin-7a-yl]-4-fluorphenyl}-5-chlorpyridin-2-carboxamid, 3) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopenta-[d][1,3]thiazin-7a-yl]-4-fluorphenyl}pyridin-2- 3 carboxamid, 4) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopenta-[d][1,3]thiazin-7a-yl]-4-fluorphenyl}-5-fluorpyridin-2-carboxamid, 5) N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-5 hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-fluorphenyl]-5- cyanopyridin-2-carboxamid, 6) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopenta[d][1,3]thiazin-7a-yl-4-fluorphenyl]-5- difluormethoxypyrazin-2-carboxamid, 3 7) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H- cyclopenta[d][l,3]thiazin-7a-yl)-4-fluorphenyl]-5-fluormethoxypyrazin-2-carboxamid, 8) N-[3-((4aR*, 7aS*)-2-amino-4a,5,6,7-tetrahydro-4H- cyclopenta[d][l,3]thiazin-7a-yl)-4-fluorphenyl]-5- 5 cyanopyridin-2-carboxamid, 9) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopenta[d][l,3]thiazin-7a-yl)-4-fluorphenyl]-5- fluormethoxypyridin-2-carboxamid, 10) N-[3-((4aS*,7aS*)-2-amino-4a,5,7,7a-tetrahydro-4H- 3 furo[3,4 — d] [1,3]thiazin-7a-yl)-4-fluorphenyl]-5-cyanopyridin- 2-carboxamid, II) N-[3-((4aS*,7aS*)-2-amino-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5- difluormethoxypyrazin-2-carboxamid, 5 12) N-[3-((4aS*, 7aS*)-2-amino-4a,5,7,7a-tetrahydro-4H- furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-chlorpyridin-2-carboxamid, 13) N-[3-((IS*,7aS*)-2-amino-4a,5,7,7a-tetrahydro-4H-furo[3,4- d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-fluormethoxypyrazin-2-carboxamid, 14) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4-fluorphenyl]-5-cyanopyridin-2- 5 carboxamid, 15) N-[3-((4aS*, 8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4-fluorphenyl]-5- difluormethoxypyrazin-2-carboxamid, 16) N-[3-((4aS*, 8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-3 thia-l-azanaphthalen-8a-yl)-4-fluorphenyl]-5-chlorpyridin-2- carboxamid, 17) (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopenta[d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-cyanopyridin-2-carboxamid, 5 18) ( + )-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a, 5, 6, 7- tetrahydro-4H-cyclopenta[d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-cyanopyridin-2-carboxamid, 19) (+)-N-[3-((4aR*,9aS*)-2-amino-cyclohepta[d][1,3]thiazin- 9a-yl)-4-fluorphenyl]-5-cyanopyridin-2-carboxamid, 3 20) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H- cyclopenta-[d][1,3]thiazin-7a-yl)-4-methoxyphenyl]-5-chlorpyridin-2-carboxamid, 21) N-[3-((4aS*,7aS*)-2-amino-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5- 5 difluormethylpyrazin-2-carboxamid, 22) (4aR,7aS)-7a-[3-(2-fluor-pyridin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-ylamin, 23) (4aR*,7aS*)-7a-[3-(2-fluorpyridin-3-yl)phenyl]-6-pyrimidin-2-yl-4,4a,5,6,7,7a-hexahydropyrrolo[3,4- 3 d][1,3]thiazin-2-ylamin, 24) N-[3-((4aS*, 5R*, 7aS*)-2-amino-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-cyanopyridin-2-carboxamid, 25) N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5,7,7a-5 tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5- difluormethylpyrazin-2-carboxamid, 26) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4-fluorphenyl]-5- fluormethoxypyrazin-2-carboxamid, 27) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-difluormethoxypyrazin-2-carboxamid, 5 28) N-[3-((4aS, 5S, 7aS)-2-amino-5-fluormethyl-4a,5,7,7a- tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-difluormethylpyrazin-2-carboxamid, 29) N-[3-((4aS, 5S, 7aS)-2-amino-5-fluormethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5- D fluormethoxypyrazin-2-carboxamid, 30) N-[3-((4aS*,5S*,7aS*)-2-amino-5-fluormethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorphenyl]-5-cyanopyridin-2-carboxamid, 31) N-[3-((4aS*, 5S*, 8aS*)-2-amino-5-fluormethyl-4a,5,7,8-5 tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4- fluorphenyl]-5-cyanopyridin-2-carboxamid, 32) N-[3-((4aS*, 5S*, 8aS*)-2-amino-5-fluormethyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4- fluorphenyl]-5-fluormethoxypyrazin-2-carboxamid, D 33) N-[3-((4aS*,5S*,8aS*)-2-amino-5-fluormethyl-4a,5,7,8- tetrahydro-4H-6-oxa-3-thia-l-azanaphthalen-8a-yl)-4-fluorphenyl]-5-chlorpyridin-2-carboxamid, 34) N-[3-((4aS*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopenta[d][l,3]thiazin-7a-yl)-4-fluorphenyl]- 5-difluormethylpyrazin-2-carboxamid, 35) N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopenta[d][l,3]thiazin-7a-yl)-4-fluorphenyl]-5-difluormethylpyrazin-2-carboxamid og 36) N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluor-4a, 5, 6, 7-tetrahydro- 3 4H-cyclopenta-[d][l,3]thiazin-7a-yl)-4-fluorphenyl]-5- difluormethylpyrazin-2-carboxamid.
10. Forbindelse ifølge krav 1, N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-5 fluorphenyl]-5-difluormethylpyrazin-2-carboxamid, repræsenteret ved formlen:
c eller et farmaceutisk acceptabelt salt deraf.
11. Forbindelse ifølge krav 1, N-[3-((4aS, 5S, 7aS)-2-amino-5-5 fluormethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4- fluorphenyl]-5-difluormethylpyrazin-2-carboxamid, repræsenteret ved formlen:
eller et farmaceutisk acceptabelt salt deraf. D
12. Farmaceutisk sammensætning, som omfatter forbindelsen eller farmaceutisk acceptabelt salt deraf eller solvat deraf ifølge et hvilket som helst af kravene 1-11 som aktiv bestanddel.
13. Forbindelse ifølge et hvilket som helst af kravene 1-11 til anvendelse ved en fremgangsmåde til behandling af en neurodegenerativ sygdom.
14. Forbindelse til anvendelse ifølge krav 13, hvor den neurodegenerative sygdom er demens af Alzheimers type eller Downs syndrom.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2193908P | 2008-01-18 | 2008-01-18 | |
JP2008008680 | 2008-01-18 | ||
US8502408P | 2008-07-31 | 2008-07-31 | |
JP2008197204 | 2008-07-31 | ||
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