US 2006/0079533 A1Published application

Methods of treating alzheimer's disease

OwnerJames Nieman, Lawrence Fang +1inventors

InventorsJames Nieman, Lawrence Fang, barbara Jagodzinska

Life of this patent

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Abstract

Disclosed are methods for treating Alzheimer's disease, and other diseases, and/or inhibiting beta-secretase enzyme, and/or inhibiting deposition of A beta peptide in a mammal, by use of 3,4-disubstituted piperidinyl compounds of formula (I) wherein the variables R1, R2, R3, R4, Q, W, X, Z, m, and n are defined herein.

Claims21

Dependent claims

A method of treating or preventing Alzheimer's disease in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C)C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6CO—O, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which includes administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method of treating or preventing Alzheimer's disease in a patient in need of such treatment comprising administering a therapeutically effective amount of a composition comprising one or more pharmaceutically acceptable carriers and a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) —Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method for inhibiting beta-secretase activity, comprising contacting an effective amount for inhibition of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11) —, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11) —, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11) —, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method for inhibiting cleavage of an amyloid precursor protein (APP) isotype at a site in the APP isotype that is susceptible to cleavage, comprising contacting said APP isotype with an effective cleavage inhibitory amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C)C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6, where R6 is as defined above,
(J) —NR6SO2, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11) —, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11) —, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11) —, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A composition comprising beta-secretase complexed with a compound of formula (I), or a pharmaceutically acceptable salt thereof:

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibiting amount of a compound of formula (I):

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a hetero atom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

A method for treating or preventing a disease characterized by beta-amyloid deposits on or in the brain, comprising administering to a patient in need of such treatment or prevention an effective therapeutic amount of a compound of formula (I):

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C) C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6—CO—O—, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/472,868Filed 21 Mar 2002
Priority: 23 Mar 2001
Published: 13 Apr 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/497
Non-condensed pyrazines: containing further heterocyclic rings
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/445
Non condensed pyridines; Hydrogenated derivatives thereof: non condensed piperidines, e.g. piperocaine
A61K 31/453
Containing further heterocyclic ring systems: containing a six-membered ring with oxygen as a ring hetero atom

Family

Application60/278,371Us provisional application · filed 23 Mar 2001
Application60/308,729Us provisional application · filed 30 Jul 2001
US 2006/0079533 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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Abstract

where R1 is
(I) aryl, or
(II) heterocycle;
where R2 is
(I) phenyl,
(II) naphthyl,
(III) acenaphthyl,
(IV) cyclohexyl,
(V) pyridyl,
(VI) pyrimidinyl,
(VII) pyrazinyl,
(VIII) oxo-pyridinyl,
(IX) diazinyl,
(X) triazolyl,
(XI) thienyl,
(XII) oxazolyl,
(XIII) oxadiazolyl,
(XIV) thiazolyl,
(XV) pyrrolyl, or
(XVI) furyl,
optionally substituted by one, two, or three of halogen, hydroxy, cyano, trifluoromethyl, lower-alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, cyano-lower-alkyl, carboxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, lower-alkoxycarbonyloxy-lower-alkyl, lower-alkoxycarbonyl, lower alkoxy groups, lower-alkylenedioxy, or L1-T1-L2-T2-L3-T3-L4-T4-L5-U,
where L1, L2, L3, L4 and L5 are independently chosen from:
(A) a bond,
(B) C1-8-alkylene,
(C)C2-8-alkenylene,
(D) C2-8-alkynylene, or
(E) are absent,
where T1, T2, T3, and T4 are independently chosen from:
(A) a bond,
(B) —CH(OH)—,
(C) —CH(OR6)—, where R6 is hydrogen, lower-alkyl, lower-alkenyl, aryl-lower-alkyl, acyl, or together with the heteroatom to which they are attached are a 5- or 6-membered heterocyclic ring which can contain an additional N, O, or S atom or a SO or SO2 group and the additional N atom if present can be optionally substituted by lower-alkyl,
(D) —CH(NR5R6)—, where R5 is as defined for R6, and where R6 is as defined above,
(E) —CO—,
(F) —CR7R8—, where R7 and R8 together with the C atom to which they are attached form a three, four, five, six, or seven membered ring which can contain one or two O or S atoms or SO or SO2 groups,
(G) —O— or —NR6—, where R6 is as defined above,
(H) —S(O)0-2—,
(I) —SO2NR6—, where R6 is as defined above,
(J) —NR6SO2—, where R6 is as defined above,
(K) —CONR6—, where R6 is as defined above,
(L) —NR6CO—, where R6 is as defined above,
(M) —O—CO—,
(N) —CO—O—,
(O) —O—CO—O—,
(P) —O—CO—NR6—, where R6 is as defined above,
(Q) —NR6—CO—NR6—, where R6 are the same or different and are as defined above,
(R) —NR6CO—O, where R6 is as defined above, or
(S) are absent
where the bonds emanating from (B), (D), (E) and (G)-(R) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom, and not more than two of (B)-(F), three of (G)-(H) or one of (I)-(R) are present,
where U is:
(A) hydrogen,
(B) lower-alkyl,
(C) cycloalkyl,
(D) cyano,
(E) optionally substituted cycloalkyl,
(F) optionally substituted aryl, or
(G) optionally substituted heterocyclyl;
where R3 is:
(I) hydrogen,
(II) hydroxy,
(III) lower-alkoxy, or
(IV) lower-alkenyloxy;
where R4 is:
(I) hydrogen,
(II) lower-alkyl,
(III) lower-alkenyl,
(IV) lower-alkoxy,
(V) hydroxy-lower-alkyl,
(VI) lower-alkoxy-lower-alkyl,
(VII) benzyl,
(VIII) oxo, or
(IX) where R3 and R4 together are a bond, or R4a-Z1-X1—
where R4a is
(A) H—,
(B) lower-alkyl-,
(C) lower-alkenyl-,
(D) hydroxy-lower-alkyl-,
(E) polyhydroxy-lower-alkyl-,
(F) lower-alkyl-O-lower-alkyl-,
(G) aryl-,
(H) heterocyclyl-,
(I) arylalkyl-,
(J) heterocyclyloxylalkyl-,
(K) aryloxyalkyl-,
(L) heterocyclyloxylalkyl-,
(M) (R5R6)—N—(CH2)1-3—, where R5 and R6 are as defined above,
(N) (R5R6)—N—, where R5 and R6 are as defined above,
(O) lower-alkyl-S(O)0-2—,
(P) aryl-S(O)0-2—,
(Q) heterocyclyl-S(O)0-2—,
(R) HO—SO3— or a salt thereof,
(S) H2N—C(NH)—NH—, or
(T) NC—,
where the bonds emanating from (N)-(T) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom,
where Z1 is:
(A) a bond,
(B) lower-alkylene-,
(C) lower-alkenylene-,
(D) —O—,
(E) —N(R11)—, where R11 is hydrogen or lower-alkyl,
(F) —S(O)0-2—,
(G) —CO—,
(H) —O—CO—,
(I) —O—CO—O—,
(J) —O—CO—N(R11)O, where R11 is as defined above,
(K) —N(R11)—CO—O—, where R11 is as defined above,
(L) —CO—N(R11)—, where R11 is as defined above,
(M) —N(R11)—CO—, where R11 is as defined above,
(N) —N(R11)—CO—N(R11)—, where R11 are the same or different and are as defined above,
(O) —CH(OR9)—, where R9 is hydrogen, lower-alkyl, acyl or arylalkyl, or
(P) is absent
where the bonds emanating from (D) and (H)-(O) join to a C atom of the adjacent group and this C atom is saturated when the bond emanates from a heteroatom;
where X1 is:
(A) a bond,
(B) —O—,
(C) —N—(R11)—, where R11 is as defined above,
(D) —S(O)0-2—,
(E) —(CH2)1-3—, or
(F) is absent;
where Q is:
(I) ethylene, or
(II) is absent;
where X is:
(I) a bond,
(II) —O—,
(III) —S—,
(IV) —CH—R11—, where R11 is as defined above,
(V) —CHOR9—, where R9 is as defined above,
(VI) —O—CO,
(VII) —CO—, or
(VIII) C═NOR10—, where R10 is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen, with the bond emanating from an oxygen or sulfur atom joining to a saturated C atom of group Z or to R1;
where W is:
(I) —O—, or
(II) —S—;
where Z is:
(I) lower-alkylene,
(II) lower-alkenylene,
(III) hydroxy-lower-alkylidene,
(IV) —O—,
(V) —S—,
(VI) —O-Alk-, where Alk is a lower alkylene
(VII) —S-Alk-, where Alk is as defined above,
(VIII) -Alk-O—, where Alk is as defined above, or
(IX) -Alk-S, where Alk is as defined above;
where n is:
(I) one, or
(II) zero or one when X is —O—CO;
and
where m is 0 or 1;
with the provisos that
(I) X is —CH—R11— and either R2 contains a substituent L1-T1-L2-T2-L3-T3-L4-T4-L5-U or R4 is a substituent defined above other than hydrogen when Z is —O— or —S—,
(II) X is —CH—R11— when Z is —O-Alk- or —S-Alk-, and
(III) Z is lower-alkenylene, -Alk-O— or -Alk-S— when X is a bond.

149 more elements

Facts

Application

10/472,868Filed 21 Mar 2002

Priority

23 Mar 2001

Published

13 Apr 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/497
Non-condensed pyrazines: containing further heterocyclic rings
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/445
Non condensed pyridines; Hydrogenated derivatives thereof: non condensed piperidines, e.g. piperocaine
A61K 31/453
Containing further heterocyclic ring systems: containing a six-membered ring with oxygen as a ring hetero atom