DK2803663T3 - Human protein tyrosin-phosphatase-inhibitorer og deres farmaceutiske anvendelse - Google Patents
Human protein tyrosin-phosphatase-inhibitorer og deres farmaceutiske anvendelse Download PDFInfo
- Publication number
- DK2803663T3 DK2803663T3 DK14166121.5T DK14166121T DK2803663T3 DK 2803663 T3 DK2803663 T3 DK 2803663T3 DK 14166121 T DK14166121 T DK 14166121T DK 2803663 T3 DK2803663 T3 DK 2803663T3
- Authority
- DK
- Denmark
- Prior art keywords
- phenyl
- butyl
- ethyl
- thiadiazol
- compound
- Prior art date
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- 108090000144 Human Proteins Proteins 0.000 title description 2
- 102000003839 Human Proteins Human genes 0.000 title description 2
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- -1 2-hydroxyphenyl Chemical group 0.000 claims description 112
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- BEHLMOQXOSLGHN-UHFFFAOYSA-N benzenamine sulfate Chemical compound OS(=O)(=O)NC1=CC=CC=C1 BEHLMOQXOSLGHN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 230000002792 vascular Effects 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
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- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
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- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 3
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- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
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- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
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Claims (10)
1. Forbindelse til anvendelse i behandling af vaskulær lækage-syndromer, hvilken forbindelse har formlen:
hvor R er en enhed valgt fra: i) hydrogen; ii) phenyl, 4-fluorphenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorphenyl, 2-(N,N-diethylamino)phenyl , 2-cyanophenyl, 2,6-di-tert-butylphenyl, og 3-methoxyphenyl; og iii) en heteroaryl-enhed valgt fra 1,2,3,4- tetrazol-l-yl, 1 ,2,3,4-tetrazol-5-yl, [l,2,3]triazol-4-yl, [l,2,3]triazol-5-yl, [l,2,4]triazol-4-yl, [l,2,4]triazol-5-yl, imidazol-2-yl, imidazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, [l,2,4]oxadiazol-3-yl, [l,2,4]oxadiazol-5-yl, [l,3,4]oxadiazol-2-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl, [l,2,4]thiadiazol-3-yl, [l,2,4]thiadiazol-5-yl, og [l,3,4]thiadiazol-2-yl; hvor heteroaryl-enheden kan være substitueret med en eller flere enheder valgt fra methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, terl-butyl, cyclopropylmethyl, methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, fluor, chlor, fluormethyl, difluormethyl, og trifluormethyl, Z er en substitueret eller ikke-substitueret [l,3,4]thiadiazol-2-yl-enhed med formlen:
R1 er valgt fra: i i) hydrogen; ii) ikke-substitueret C1-C6 lineær, forgrenet, eller cyklisk alkyl, eller substitueret C1-C6 lineær, forgrenet, eller cyklisk alkyl valgt fra hydroxymethyl, chlormethyl, trifluormethyl, aminomethyl, 1-chlorethyl, 2-hydroxyethyl, 1,2-difluorethyl, 2,2,2-trifluorethyl, 3- 1 carboxypropyl, og 2,3-dihydroxycyclobutyl; iii) ikke-substitueret C6 eller C10 aryl, eller substitueret C6 eller C10 aryl valgt fra 2-fluorphenyl, 3-fluorphenyl, 4-fluorphenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 2-methylphenyls 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 2-(N-methylamino)phenyl, 2-(7V//V-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N-diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,/V-dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 5-(7V//V-diethylamino)phenyl, 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N//V-dimethylamino)phenyl, 4-(N-ethylamino)phenyl, 4-f/V//V-diethylamino)phenyl, naphthylen-l-yl, og naphthylen-2-yl; iv) -OR4; v) -C(0)0R5; vi) -COR6; eller vii) -NR7C(0)0R8; R4 er hydrogen eller C1-C6 lineær, forgrenet, eller cyklisk alkyl; R5 er Ci-Ce lineær eller forgrenet alkyl, eller benzyl; R6 er Ci-Ce lineær, forgrenet, eller cyklisk alkyl, eller phenyl; R7 er hydrogen eller methyl; R8 er Ci-Ce lineær eller forgrenet alkyl, eller benzyl; L er en enhed med formel -[C(R9aR9b)]y-; R9a og R9b er hver uafhængigt hydrogen, Ci-Ce lineær eller forgrenet alkyl, eller phenyl; når L er en enhed med formlen -CH2-, kan R1 også vælges fra substitueret eller ikke-substitueret thiazol-4-yl, hvilke substitutioner er valgt fra methyl, ethyl, fluor, og chlor, og indekset x er 0 eller 1; indekset y er fra 1 til 4; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelsen til anvendelse ifølge krav 1, hvor R er valgt fra 1,2,3,4-tetrazolyl; [l,2,3]triazolyl; imidazolyl; pyrrolyl; oxazolyl; isoxazolyl; [l,2,4]-oxadiazolyl; [l,3,4-]oxadiazolyl; furanyl; thiophenyl; isothiazolyl; thiazolyl; [1,2,4]-thiadiazolyl; og [l,3,4]-thiadiazolyl; eller fra
3. Forbindelsen til anvendelse ifølge krav 1, hvor R er phenyl eller thiophen-2-yl.
4. Forbindelsen til anvendelse ifølge krav 1, hvor R1 er valgt fra methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chlormethyl, trifluormethyl, aminomethyl, 1-chlorethyl, 2-hydroxyethyl, 1,2-difluorethyl, 2,2,2- trifluorethyl, 3-carboxypropyl, 2,3-dihydroxycyclobutyl.
5. Forbindelsen til anvendelse ifølge et hvilket som helst af kravene 1-4, hvor R1 er valgt fra methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, /so-butyl, tert-butyl, og cyclopropylmethyl.
6. Forbindelsen til anvendelse ifølge et hvilket som helst af kravene 1-5, hvor L har formlen -CH2-.
7. Forbindelsen til anvendelse ifølge krav 6, hvor R1 er valgt fra substitueret eller ikke-substitueret phenyl, naphthalen-l-yl, og thiazol-2-yl, hvilke substitutioner er valgt fra methyl, ethyl, fluor, og chlor.
8. Forbindelsen til anvendelse ifølge krav 1, hvor forbindelserne er salte omfattende anioner valgt fra chlorid, bromid, iodid, sulfat, bisulfat, carbonat, bicarbonat, phosphat, format, acetat, propionat, butyrat, pyruvat, laktat, oxalat, malonat, maleat, succinat, tartrat, fumarat, og citrat eller kationer valgt fra natrium, lithium, kalium, calcium, magnesium, og bismut.
9. Forbindelsen til anvendelse ifølge krav 1, hvor forbindelsen er valgt fra: (S)-4-(2-(5-Phenyl-l,3,4-thiadiazol-2-ylamino)-2-(2-phenylthiazol-4- yl)ethyl)-phenylsulfaminsyre; 4-((S)-2-(5-Propyl-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol- 4-yl)ethyl)phenylsulfaminsyre; 4-((S)-2-(5-Benzyl-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2- yl)thiazol-4-yl)ethyl)phenylsulfaminsyre; 4-((S)-2-(5-(Naphthalen-l-ylmethyl)-l,3,4-thiadiazol-2-ylamino)-2-(2- (thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfaminsyre; 4-((S)-2-(5-((Methoxycarbonyl)methyl)-l,3,4-thiadiazol-2-ylamino)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfaminsyre; og 4-((S)-2-(5-((2-Methylthiazol-4-yl)methyl)-l,3,4-thiadiazol-2-ylamino)-2- (2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenylsulfaminsyre.
10. Farmaceutisk sammensætning til anvendelse i behandling af vaskulær lækage-syndrom omfattende: A) en eller flere forbindelser ifølge krav 1; og B) en eller flere excipienser eller bærere.
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- 2007-06-27 ES ES14166121.5T patent/ES2660571T3/es active Active
- 2007-06-27 EP EP14166121.5A patent/EP2803663B1/en active Active
- 2007-06-27 WO PCT/US2007/014824 patent/WO2008002571A2/en not_active Ceased
-
2008
- 2008-12-23 IL IL196130A patent/IL196130A/en active IP Right Grant
-
2009
- 2009-01-23 ZA ZA2009/00558A patent/ZA200900558B/en unknown
- 2009-01-27 CO CO09007327A patent/CO6150143A2/es unknown
- 2009-05-18 US US12/467,430 patent/US8188125B2/en not_active Expired - Fee Related
-
2011
- 2011-12-01 US US13/309,452 patent/US8338615B2/en not_active Expired - Fee Related
-
2014
- 2014-10-03 CY CY20141100800T patent/CY1115588T1/el unknown
-
2015
- 2015-05-18 HK HK15104703.3A patent/HK1203960A1/en unknown
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