Pyrrolidine glycosidase inhibitors
Compounds of formula (I) wherein A, W, R 3b , Z and p have the meaning according to the claims, can be employed, inter alia, for the treatment of taupathies and Alzheimer's disease.
1. A compound of formula (I)
wherein
A is:
or A is selected from the following groups, wherein at least one X is not CH:
X is N or CR′″;
X a is N, NR 3 , C, or CR′″;
X b is N or C;
Y is O, S, SO, or SO 2 ;
R′, R″ are, independently H, Hal or straight chain or branched alkyl having 1 to 12 carbon atoms;
R′″, R″″ are, independently, H, Hal, NR 3 R 4 , CHR 3 R 4 , OR 3 , CN or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , S(O)(NR 3 ′), N(SO)R 3 ′ CO, COO, OCO, CONR 3 , NR 3 CO,
and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , NO 2 ,
or R′, R″″ are, independently:
R 3 , R 4 are, independently, H, or a straight chain or branched alkyl group having 1 to 12 carbon atoms;
R 3a is a straight chain or branched alkyl group having 1 to 12 carbon atoms;
R 3b is independently selected from the group consisting of H, Hal, and a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O and NR 3 , and wherein 1 to 5 hydrogen atoms may be replaced by CN or Hal; or two R 3b substituents are bound to the same carbon atom and form together a cyclopropylidene radical;
W is R or Q;
Z is a six-membered aromatic or saturated ring, optionally containing one or two heteroatoms selected from N, O and S, which ring may be substituted by one or two substituents selected from R 7 , or Z may also be a single bond if W is Q;
Q is:
Z 1 is C, O, or NR 3 ;
Z 2 , Z 3 are, independently, CR 5 , CR 6 , or N;
Z 4 is N, CH, CON, or COCH;
Z 5 is 0, NR′, CHR 5 , SO 2 , S(O)(NR 3 ′), N(SO)R 3 ′,
Z 6 is CH 2 , CO, S(O)(NR 3 ′), N(SO)R 3 ′,
Z 7 is C(R 3 ′) 2 , S, O, or NR 3 ′;
p is 1, 2, or 3;
s is 0 or 1;
T is N, CH, or CR 7 ;
R 3 ′ is H or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from SO 2 , CO, and O; and wherein 1 to 5 hydrogen atoms may be replaced by Hal;
R, R 5 , R 6 , and R 7 are, independently, H, Hal, CN, OH, NR 3 R 4 , NO 2 , or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , S(O)(NR 3 ′), N(SO)R 3 ′, CO, COO, OCO, CONR 3 , NR 3 CO,
and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , NO 2 , OR 3 , Het, Ar, Cyc,
or R, R 5 , R 6 , and R 7 are Ar, Het, Cyc,
R 8 is H or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from SO, SO 2 , S(O)(NR 3 ′) N(SO)R 3 ′, CO, COO, OCO, CONR 3 , NR 3 CO,
and further wherein 1 to 5 hydrogen atoms may be replaced by CN, OR 3 , SR 3 , Hal, NR 3 R 4 , NO 2 ,
or R 8 is Ar, Het, Cyc,
Hal is F, Cl, Br, or I;
Het is a saturated, unsaturated or aromatic ring, being monocyclic or bicyclic or fused bicyclic and having 3 to 8 members and containing 1 to 4 heteroatoms selected from N, O, and S, which may be substituted by 1 to 3 substituents selected from R 5 , Hal, and OR 3 ;
Ar is a 6-membered carbocyclic aromatic ring or a fused or non-fused bicyclic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R 5 , OR 3 , and Hal;
Cyc is a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R 5 , Hal, and OH;
t and q are, independently, 0, 1, 2 or 3, with t+q≥1;
in its non-racemic form, or a solvate, salt, stereoisomer, tautomer, or compound of formula (I) wherein one or more H atoms are replaced by D (deuterium).
2. A compound according to claim 1 , having formula (Ia) or (Ib)
wherein A, W, R 3b , Z and p have the meaning according to claim 1 , or a solvate, salt, stereoisomer, tautomer, or compound of formula (Ia) or (Ib) wherein one or more H atoms are replaced by D (deuterium).
3. A compound according to claim 1 , wherein Z is a single bond,
wherein T has the meaning given in claim 1 .
4. A compound according to claim 1 , wherein A is:
wherein R 3 , X, R′, R″ and R′″ have the meaning given in claim 1 .
5. A compound according to claim 1 , wherein Q is:
wherein X, R′″, R 3 , T, Z 5 , Z 6 , R 6 and R 7 have the meaning given in claim 1 .
6. A compound according to claim 1 , wherein R, R 5 , R 6 , R 7 , and R 8 , if present, are independently selected from H, CN, SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CH 2 CH 2 OH, SO 2 CH 2 CH 2 OCH 3 , S(O)(NR 3 ′)CH 3 , S(O)(NR 3 ′)CH 2 CH 3 , S(O)(NR 3 ′)CH 2 CH 2 OH, S(O)(NR 3 ′)CH 2 CH 2 OCH 3 , N(SO)R 3 ′CH 3 , N(SO)R 3 ′CH 2 CH 3 , N(SO)R 3 ′CH 2 CH 2 OH, N(SO)R 3 ′CH 2 CH 2 OCH 3 , Hal, NR 3 R 4 , NO 2 , R 3 ′-phenyl, R 3 ′-benzyl, CH 2 —(R 3 ′-pyridyl), O —(R 3 ′-phenyl), O—(R 3 ′-pyridyl), O-pyrimidinyl, O—(R 3 ′-benzyl), 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, alkoxy, hydroxyalkylene, alkoxyalkylene, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, NHCOCH 3 , NHCOphenyl, NHCOpyridyl, NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCOCH 2 CH 2 OH, CO—N-morpholinyl, CON(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , CO-1-piperidinyl, CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl, CH 2 —N-morpholinyl, CH 2 N(H)COCH 3 , CH 2 N(CH 3 )COCH 3 , CH 2 NH 2 , NH 2 , CH(OH)CH 3 , CH(OR 3 )CH 3 ,
wherein t+q is 2 or 3; and Z 7 , R 3 ′, R 3 , and R 4 have the meaning given in claim 1 .
7. A compound according to claim 1 , wherein Z is not a single bond and T, if present, is CH or CR 7 , wherein R 7 is Hal, CN, or alkyl having 1 to 6 carbon atoms, wherein 1 to 3 H-atoms may be replaced by Hal.
8. A compound according to claim 1 , wherein R 3b is H.
9. A compound selected from the group consisting of:
No.
Structure
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or solvate, salt or tautomer thereof.
10. A method of treating a neurodegenerative disease, diabetes, cancer, a cardiovascular disease, or stroke comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.
11. The method according to claim 10 , wherein the neurodegenerative disease is selected from the group consisting of one or more tauopathies, Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosis with cognitive impairment, Argyrophilic grain disease, Behavioural variant frontotemporal dementia, Bluit disease, Chronic traumatic encephalopathy, Corticobasal degeneration, Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17, Frontotemporal lobar degeneration, Ganglioglioma, Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glia tauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Lead encephalopathy, Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease type C, Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease, Parkinson's disease dementia, Postencephalitic parkinsonism, Primary progressive aphasia, Prion diseases (including Creutzfeldt-Jakob Disease, Progressive nonfluent aphasia, Variant Creutzfeldt-Jakob Disease), Fatal Familial Insomnia, Kuru, Progressive supercortical gliosis, Progressive supranuclear palsy, Semantic dementia, Steele-Richardson-Olszewski syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Tuberous sclerosis, Huntington's disease, and Parkinson's disease.
12. A method for treating a tauopathy, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.
13. A method for inhibiting a glycosidase, comprising contacting a system expressing the glycosidase with a compound of claim 1 under in vitro conditions such that the glycosidase is inhibited.
14. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with pharmaceutically tolerable adjuvants and/or excipients.
15. The method of claim 11 , wherein the neurodegenerative disease is selected from the group consisting of one or more tauopathies and Alzheimer's disease.
16. The pharmaceutical composition of claim 14 , further comprising one or more additional active ingredients.