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US 2003/0114387 A1Published application
Gamma secretase inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsJose Luis Castro Pineiro, Timothy Harrison, Peter Alan Hunt, Alan John Nadin
Life of this patent
Estimating the term…
Abstract
Gamma-secretase inhibitors, useful in the treatment or prevention of Alzheimer's disease, are disclosed. The preferred compounds have, as the central portion of the molecule, the structure (a) and are diastereoisomers of known protease inhibitors.
Claims1
A compound of formula I or a pharmaceutically acceptable salt thereof:
- 22
- wherein:
- R1 is (1) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from:
- (i) hydroxy;
- (ii) carboxy;
- (iii) halogen;
- (iv) C1-4alkoxy;
- (v) C1-4alkoxycarbonyl;
- (vi) —NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1-5alkyl and C1-5alkoxyC1-5alkyl;
- (vii) —CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above;
- (viii) —N(R8)QR9 wherein:
- Q is C(O), C(S), SO2 or C(NH2);
- R8 is hydrogen or C1-4alkyl;
- and
- R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di(C1-4alkyl)amino wherein each alkyl group is independently chosen;
- (ix) C3-7cycloalkyl;
- (x) phenyl or naphthyl;
- a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S;
- a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms;
- each of which is optionally substituted by one to three groups independently chosen from:
- (a) halogen, cyano and nitro,
- (b) hydroxy,
- (c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
- (d) C1-4alkoxy,
- (e) NR6R7 wherein R6 and R7 are independently as defined above,
- (f) CO2R8 wherein R8 is independently as defined above,
- (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
- (h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
- (i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
- (j) N(R8)COR8′ wherein R8 is independently as defined above and R8′ is independently as defined for R8, and
- (k) NR8SO2R8′ wherein R8 and R8′ are independently as defined above;
- or
- (2) phenyl or naphthyl;
- a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S;
- a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms;
- each of which is optionally substituted by one to three groups independently chosen from:
- (a) halogen, cyano and nitro,
- (b) hydroxy,
- (c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
- (d) C1-4alkoxy,
- (e) NR6R7 wherein R6 and R7 are independently as defined above,
- (f) CO2R8 wherein R8 is independently as defined above,
- (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
- (h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
- (i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
- (j) N(R8)COR8′ wherein R8 and R8′ are independently as defined above, and
- (k) NR8SO2R8′ wherein R8 and R8′ are independently as defined above;
- R2 and R3 are independently chosen from C1-10alkyl, C1-10alkoxy, C2-10alkenyl, C2-10alkenyloxy, C2-10alkynyl or C2-10alkynyloxy;
- phenyl;
- naphthyl;
- a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S;
- a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
- and a group (CH2)pQ1 wherein Q1 is phenyl, naphthyl, a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S, and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms;
- and wherein each of R2 and R3 is independently optionally substituted by one to three groups independently chosen from:
- (a) halogen, cyano and nitro,
- (b) hydroxy,
- (c) C1-3alkyl, C2-3alkenyl and C2-3alkynyl,
- (d) C1-3alkoxy,
- (e) NR6R7 wherein R6 and R7 are independently as defined above,
- (f) CO2R8 wherein R8 is independently as defined above,
- (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
- (h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
- (i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
- (j) N(R8)COR8′ wherein R8 and R8′ are independently as defined above, and
- (k) NR8SO2R8′ wherein R8 and R8′ are independently as defined above;
- alternatively R3 may be hydrogen;
- R4 and R5 are independently chosen from hydrogen, C1-6alkyl, optionally substituted by halogen, hydroxy, thiol, amino, C1-4alkoxy, C1-4alkylthio, carboxy, C1-4alkoxycarbonyl and (CH2)qQ2 wherein Q2 is a five-membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatom optionally chosen from O, N, and S providing that not more than one heteroatom is O or S, a six-membered unsaturated heterocycle containing 1, 2 or 3 N atoms and phenyl and naphthyl, or a fused ring which is indolyl, each of the foregoing rings being optionally substituted with one to three groups independently chosen from hydroxy, C1-4alkyl, C1-4alkoxy, thiol, C1-4alkylthio, halogen, amino, carboxy, amido, CO2H and —NHC(NH2)2 and wherein each of the foregoing rings is optionally fused to a benzene ring;
- and
- A is:
- (1) hydrogen
- (2) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from:
- (i) hydroxy;
- (ii) carboxy;
- (iii) halogen;
- (iv) C1-4alkoxy;
- (v) C1-4alkoxycarbonyl;
- (vi) —NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1-5alkyl and C1-5alkoxyC1-5alkyl;
- (vii) —CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above;
- (viii) —N(R8)QR9 wherein:
- Q is C(O), C(S), SO2 or C(NH2);
- R8 is hydrogen or C1-4alkyl;
- and
- R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di(C1-4alkyl)amino wherein each alkyl group is independently chosen;
- (ix) C3-7cycloalkyl;
- (x) phenyl or naphthyl;
- a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S;
- a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms;
- each of which is optionally substituted by one to three groups independently chosen from:
- (a) halogen, cyano and nitro,
- (b) hydroxy,
- (c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
- (d) C1-4alkoxy,
- (e) NR6R7 wherein R6 and R7 are independently as defined above,
- (f) CO2R8 wherein R8 is independently as defined above,
- (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
- (h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
- (i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
- (j) N(R8)COR8′ wherein R8 is independently as defined above and R8′ is independently as defined for R8, and
- (k) NR8SO2R8′ wherein R8 and R8′ are independently as defined above;
- (3) a seven-membered heterocycle
- having an otherwise unsubstituted carbon atom at the point of attachment to the rest of the compound of formula I,
- having at a first atom alpha to the point of attachment a carbon atom which is unsubstituted or substituted by an oxygen or sulphur atom,
- having at a first atom beta to the point of attachment, which atom is alpha to the foregoing first atom alpha, a carbon atom or a nitrogen atom,
- having at a second atom alpha to the point of attachment a carbon atom, which is optionally substituted by oxygen, or a nitrogen atom,
- having at a second atom beta to the point of attachment, which atom is alpha to the foregoing second atom alpha, a carbon atom or a nitrogen atom,
- and having at the two remaining atoms carbon atoms;
- a double bond may be present between the second atom alpha and the second atom beta;
- the seven-membered heterocycle may be fused to one or two aromatic rings via any adjacent pair of atoms other than the point of attachment and the first atom alpha alone or in combination;
- the aromatic ring may be benzene or a five-membered heterocycle containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S
106 more elements
Dependencies are inferred from the claim text.