US 7,119,085 B2Granted

Methods to treat alzheimer's disease

AssigneeElan Pharmaceuticals, Inc.

InventorsRoy Hom, Shumeye S. Mamo, Jay Tung, Andrea Gailunas, Varghese John, Lawrence Y. Fang

Life of this patent

Estimating the term…

Abstract

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII) useful in treating Alzheimer's disease and other similar diseases.

Drawings

Claims10

Dependent claims

A method for treating Alzheimer's disease comprising administering to a patient an effective therapeutic amount of a compound of the formula

where R1 is:
(I) C1–C6 alkyl, unsubstituted or substituted with one, two or three C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —NH2, —C≡N, —CF3, or —N3,
(II) —(CH2)1-2—S—CH3,
(III) —CH2—CH2—S—CH3,
(IV) —CH2—(C2–C6 alkenyl) unsubstituted or substituted by one —F,
(V) —(CH2)0-3—(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1–C3 alkyl,
(B) —CF3,
(C) —F, Cl, —Br and —I,
(D) C1–C3 alkoxy,
(E) —O—CF3,
(F) —NH2,
(G) —OH, or
(H) —C≡N,
(VI) —(CH2)n1—(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R1-heteroaryl group is bonded to —(CH2)0-3— by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1–C3 alkyl,
(2) —CF3,
(3) —F, Cl, —Br, or —I,
(4) C1–C3 alkoxy,
(5) —O—CF3,
(6) —NH2,
(7) —OH, or
(8) —C≡N,
with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) —(CH2)n1—(R1-heterocycle) where n1 is as defined above
and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) ═O,
(2) C1–C3 alkyl,
(3) —CF3,
(4) —F, Cl, —Br and —I,
(5) C1–C3 alkoxy,
(6) —O—CF3,
(7) —NH2,
(8) —OH, or
(9) —C≡N,
with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen;
where R2 is:
(I) —H,
(II) C1–C6 alkyl, or
(III) —(CH2)0-4—R2-1 where R2-1 is (C3–C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—,
(B) —SO2—,
(C) —(CR′R″)1-6 where R′ and R″ are the same or different and are —H or C —C4 alkyl,
(D) —CO—(CR′R″)1-6—XN-1 where XN-1 is —O—, —S— and —NR′R″— and where R′ and R″ are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1–C6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO2,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) —H,
(b) —C1–C6 alkyl unsubstituted or substituted with one
(i) —OH, or
(ii) —NH2,
(c) —C1–C6 alkyl unsubstituted or substituted with one to three —F, —Cl, —Br, or —I,
(d) —C3–C7 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C7 cycloalkyl),
(f) —(C1–C6 alkyl)-O—(C1–C3 alkyl),
(g) —C1–C6 alkenyl with one or two double bonds,
(h) —C1–C6 alkynyl with one or two triple bonds,
(i) —C1–C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl where R1-aryl is as defined above, or
(k) —R1-heteroaryl where R1-heteroaryl is as defined above,
(8) —CO—(C3–C12 alkyl),
(9) —CO—(C3–C6 cycloalkyl),
(10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above,
(11) —CO—R1-heterocycle where R1-heterocycle is as defined above,
(12) —CO—RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1–C3 alkyl,
(13) —CO—O—RN-5 where RN-5 is:
(a) C1–C6 alkyl, or
(b) —(CH2)0-2—(R1-aryl) where R1-aryl is as defined above,
(14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) —SO—(C1–C8 alkyl),
(16) —SO2—(C3–C12 alkyl),
(17) —NH—CO—O—RN-5 where RN-5 is as defined above,
(18) —NH—CO—N(C1–C3 alkyl)2,
(19) —N—CS—N(C1–C3 alkyl)2,
(20) —N(C1–C3 alkyl)-CO—RN-5 where RN-5 is as defined above,
(21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) —RN-4 where RN-4 is as defined above,
(23) —O—CO—(C1–C6 alkyl),
(24) —O—CO—N(C1–C3 alkyl)2,
(25) —O—CS—N(C1–C3 alkyl)2,
(26) —O—(C1–C6 alkyl),
(27) —O—(C2–C5 alkyl)-COOH,
(28) —S—(C1–C6 alkyl),
(29) C1–C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F,
(30) —O—(C1–C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, or
(31) —O-φ,
(B) —RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1–C6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO2,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) —H,
(b) —C1–C6 alkyl unsubstituted or substituted with one
(i) —OH, or
(ii) —NH2,
(c) —C1–C6 alkyl unsubstituted or substituted with 1, 2, or 3 —F, —Cl, —Br, or —I,
(d) —C3–C7 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C7 cycloalkyl),
(f) —(C1–C6 alkyl)-O—(C1–C3 alkyl),
(g) —C1–C6 alkenyl with one or two double bonds,
(h) —C1–C6 alkynyl with one or two triple bonds,
(i) —C1–C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl where R1-aryl is as defined above, or
(k) —R1-heteroaryl where R1-heteroaryl is as defined above,
(8) —CO—(C3–C12 alkyl),
(9) —CO—(C3–C6 cycloalkyl),
(10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above,
(11) —CO—R1-heterocycle where R1-heterocycle is as defined above,
(12) —CO—RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1–C3 alkyl,
(13) —CO—O—RN-5 where RN-5 is:
(a) C1–C6 alkyl, or
(b) —(CH2)0-2—(R1-aryl) where R1-aryl is as defined above,
(14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) —SO—(C1–C8 alkyl),
(16) —SO2—(C3–C12 alkyl),
(17) —NH—CO—O—RN-5 where RN-5 is as defined above,
(18) —NH—CO—N(C1–C3 alkyl)2,
(19) —N—CS—N(C1–C3 alkyl)2,
(20) —N(C1–C3 alkyl)-CO—RN-5 where RN-5 is as defined above,
(21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) —RN-4 where RN-4 is as defined above,
(23) —O—CO—(C1–C6 alkyl),
(24) —O—CO—N(C1–C3 alkyl)2,
(25) —O—CS—N(C1–C3 alkyl)2,
(26) —O—(C1–C6 alkyl),
(27) —O—(C2–C5 alkyl)-COOH, or
(28) —S—(C1–C6 alkyl),
(C) —RN-aryl—RN-aryl where —RN-aryl is as defined above,
(D) —RN-aryl—RN-heteroaryl where —RN-aryl and —RN-heteroaryl are as defined above,
(E) —RN-heteroaryl—RN-aryl where —RN-aryl and —RN-heteroaryl are as defined above,
(F) —RN-heteroaryl—RN-heteroaryl where RN-heteroaryl is as defined above,
(G) —RN-aryl—O—RN-aryl where —RN-aryl is as defined above,
(H) —RN-aryl—S—RN-aryl where —RN-aryl is as defined above,
(I) —RN-heteroaryl—O—RN-heteroaryl where RN-heteroaryl is as defined above,
(J) —RN-heteroaryl—S—RN-heteroaryl where RN-heteroaryl is as defined above,
(K) —RN-aryl—CO—RN-aryl where —RN-aryl is as defined above,
(L) —RN-aryl—CO—RN-heteroaryl where —RN-aryl and RN-heteroaryl are as defined above,
(M) —RN-aryl—SO2—RN-aryl where —RN-aryl is as defined above,
(N) —RN-heteroaryl—CO—RN-heteroaryl where RN-heteroaryl is as defined above,
(O) —RN-heteroaryl—SO2—RN-heteroaryl where RN-heteroaryl is as defined above,
(P) —RN-aryl—O—(C1–C8 alkyl)-φ where RN aryl is as defined above,
(Q) —RN-aryl—S—(C1–C8 alkyl)-φ where RN-aryl is as defined above,
(R) —RN-heteroaryl—O—(C1–C8 alkyl)-φ where RN-heteroaryl is as defined above, or
(S) —RN-heteroaryl—S—(C1–C8 alkyl)-φ where RN-heteroaryl is as defined above,
(II) A-XN— where XN is —CO—,
wherein A is
(A) -T-E(Q)m′,
(1) where -T is
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) R′″ varies independently on each carbon and is H, (C1–C2) alkyl, phenyl, or phenyl(C1–C3)alkyl;
(2) -E is
(a) C1–C5 alkyl, but only if m′ does not equal 0,
(b) methylthioxy(C2–C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1–C8)alkyloxyphenyl, or
(j) C1–C6 alkoxy;
(3) -Q is
(a) C1–C3 alkyl,
(b) C1–C3 alkoxy,
(c) C1–C3 alkylthioxy,
(d) C1–C6 alkylacylamino,
(e) C1–C6 alkylacyloxy,
(f) amido (including primary, C1–C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1–C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1–C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1–C6 alkyl and phenyl esters),
(k) carboxy(C2–C5)alkoxy,
(l) carboxy(C2–C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) m′ is 0, 1, 2 or 3;
(B) -E(Q)m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3;
(C) -T-E wherein -E and -Q are as defined as above;
or
(D) -E wherein -E is as defined as above;
(III) —CO—(C1–C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(IV) —CO—(C1–C3 alkyl)-O—(C1–C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(V) —CO—(C1–C3 alkyl)-S—(C1–C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(VI) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is:
(A) —H,
(B) C1–C6 alkyl,
(C) C3–C7 cycloalkyl,
(D) C2–C6 alkenyl with one double bond,
(E) C2–C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above;
where B is —O—, —NH—, or —N(C1–C6 alkyl)-;
where RC is:
—(CH2)0-3—(C3–C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C1–C3 alkyl unsubstituted or substituted with 1, 2, 4, or 4 —F,
(B) —CO—OH,
(C) —CO—O—(C1–C4 alkyl),
(D) —OH, or
(E) C1–C6 alkoxy,
or a pharmaceutically acceptable salt thereof.

376 more elements

Dependencies are inferred from the claim text.

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US 7,119,085 B2Granted

Methods to treat alzheimer's disease

AssigneeElan Pharmaceuticals, Inc.

InventorsRoy Hom, Shumeye S. Mamo, Jay Tung, Andrea Gailunas, Varghese John, Lawrence Y. Fang

Life of this patent

Term ended 24 Jun 2023 (estimated)

Priority23 Mar 2000

Filed23 Mar 2001

Granted10 Oct 2006

Term ended24 Jun 2023

Priority23 Mar 2000

Granted10 Oct 2006

Term ended24 Jun 2023

Life of this patent

Estimating the term…

Abstract

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII) useful in treating Alzheimer's disease and other similar diseases.

Drawings

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Drawings

Claims10

Dependent claims

A method for treating Alzheimer's disease comprising administering to a patient an effective therapeutic amount of a compound of the formula

where R1 is:
(I) C1–C6 alkyl, unsubstituted or substituted with one, two or three C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —NH2, —C≡N, —CF3, or —N3,
(II) —(CH2)1-2—S—CH3,
(III) —CH2—CH2—S—CH3,
(IV) —CH2—(C2–C6 alkenyl) unsubstituted or substituted by one —F,
(V) —(CH2)0-3—(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1–C3 alkyl,
(B) —CF3,
(C) —F, Cl, —Br and —I,
(D) C1–C3 alkoxy,
(E) —O—CF3,
(F) —NH2,
(G) —OH, or
(H) —C≡N,
(VI) —(CH2)n1—(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the R1-heteroaryl group is bonded to —(CH2)0-3— by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1–C3 alkyl,
(2) —CF3,
(3) —F, Cl, —Br, or —I,
(4) C1–C3 alkoxy,
(5) —O—CF3,
(6) —NH2,
(7) —OH, or
(8) —C≡N,
with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) —(CH2)n1—(R1-heterocycle) where n1 is as defined above
and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) ═O,
(2) C1–C3 alkyl,
(3) —CF3,
(4) —F, Cl, —Br and —I,
(5) C1–C3 alkoxy,
(6) —O—CF3,
(7) —NH2,
(8) —OH, or
(9) —C≡N,
with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen;
where R2 is:
(I) —H,
(II) C1–C6 alkyl, or
(III) —(CH2)0-4—R2-1 where R2-1 is (C3–C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—,
(B) —SO2—,
(C) —(CR′R″)1-6 where R′ and R″ are the same or different and are —H or C —C4 alkyl,
(D) —CO—(CR′R″)1-6—XN-1 where XN-1 is —O—, —S— and —NR′R″— and where R′ and R″ are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1–C6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO2,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) —H,
(b) —C1–C6 alkyl unsubstituted or substituted with one
(i) —OH, or
(ii) —NH2,
(c) —C1–C6 alkyl unsubstituted or substituted with one to three —F, —Cl, —Br, or —I,
(d) —C3–C7 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C7 cycloalkyl),
(f) —(C1–C6 alkyl)-O—(C1–C3 alkyl),
(g) —C1–C6 alkenyl with one or two double bonds,
(h) —C1–C6 alkynyl with one or two triple bonds,
(i) —C1–C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl where R1-aryl is as defined above, or
(k) —R1-heteroaryl where R1-heteroaryl is as defined above,
(8) —CO—(C3–C12 alkyl),
(9) —CO—(C3–C6 cycloalkyl),
(10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above,
(11) —CO—R1-heterocycle where R1-heterocycle is as defined above,
(12) —CO—RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1–C3 alkyl,
(13) —CO—O—RN-5 where RN-5 is:
(a) C1–C6 alkyl, or
(b) —(CH2)0-2—(R1-aryl) where R1-aryl is as defined above,
(14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) —SO—(C1–C8 alkyl),
(16) —SO2—(C3–C12 alkyl),
(17) —NH—CO—O—RN-5 where RN-5 is as defined above,
(18) —NH—CO—N(C1–C3 alkyl)2,
(19) —N—CS—N(C1–C3 alkyl)2,
(20) —N(C1–C3 alkyl)-CO—RN-5 where RN-5 is as defined above,
(21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) —RN-4 where RN-4 is as defined above,
(23) —O—CO—(C1–C6 alkyl),
(24) —O—CO—N(C1–C3 alkyl)2,
(25) —O—CS—N(C1–C3 alkyl)2,
(26) —O—(C1–C6 alkyl),
(27) —O—(C2–C5 alkyl)-COOH,
(28) —S—(C1–C6 alkyl),
(29) C1–C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F,
(30) —O—(C1–C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, or
(31) —O-φ,
(B) —RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) β-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1–C6 alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO2,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) —H,
(b) —C1–C6 alkyl unsubstituted or substituted with one
(i) —OH, or
(ii) —NH2,
(c) —C1–C6 alkyl unsubstituted or substituted with 1, 2, or 3 —F, —Cl, —Br, or —I,
(d) —C3–C7 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C7 cycloalkyl),
(f) —(C1–C6 alkyl)-O—(C1–C3 alkyl),
(g) —C1–C6 alkenyl with one or two double bonds,
(h) —C1–C6 alkynyl with one or two triple bonds,
(i) —C1–C6 alkyl chain with one double bond and one triple bond,
(j) —R1-aryl where R1-aryl is as defined above, or
(k) —R1-heteroaryl where R1-heteroaryl is as defined above,
(8) —CO—(C3–C12 alkyl),
(9) —CO—(C3–C6 cycloalkyl),
(10) —CO—R1-heteroaryl where R1-heteroaryl is as defined above,
(11) —CO—R1-heterocycle where R1-heterocycle is as defined above,
(12) —CO—RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1–C3 alkyl,
(13) —CO—O—RN-5 where RN-5 is:
(a) C1–C6 alkyl, or
(b) —(CH2)0-2—(R1-aryl) where R1-aryl is as defined above,
(14) —SO2—NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) —SO—(C1–C8 alkyl),
(16) —SO2—(C3–C12 alkyl),
(17) —NH—CO—O—RN-5 where RN-5 is as defined above,
(18) —NH—CO—N(C1–C3 alkyl)2,
(19) —N—CS—N(C1–C3 alkyl)2,
(20) —N(C1–C3 alkyl)-CO—RN-5 where RN-5 is as defined above,
(21) —NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) —RN-4 where RN-4 is as defined above,
(23) —O—CO—(C1–C6 alkyl),
(24) —O—CO—N(C1–C3 alkyl)2,
(25) —O—CS—N(C1–C3 alkyl)2,
(26) —O—(C1–C6 alkyl),
(27) —O—(C2–C5 alkyl)-COOH, or
(28) —S—(C1–C6 alkyl),
(C) —RN-aryl—RN-aryl where —RN-aryl is as defined above,
(D) —RN-aryl—RN-heteroaryl where —RN-aryl and —RN-heteroaryl are as defined above,
(E) —RN-heteroaryl—RN-aryl where —RN-aryl and —RN-heteroaryl are as defined above,
(F) —RN-heteroaryl—RN-heteroaryl where RN-heteroaryl is as defined above,
(G) —RN-aryl—O—RN-aryl where —RN-aryl is as defined above,
(H) —RN-aryl—S—RN-aryl where —RN-aryl is as defined above,
(I) —RN-heteroaryl—O—RN-heteroaryl where RN-heteroaryl is as defined above,
(J) —RN-heteroaryl—S—RN-heteroaryl where RN-heteroaryl is as defined above,
(K) —RN-aryl—CO—RN-aryl where —RN-aryl is as defined above,
(L) —RN-aryl—CO—RN-heteroaryl where —RN-aryl and RN-heteroaryl are as defined above,
(M) —RN-aryl—SO2—RN-aryl where —RN-aryl is as defined above,
(N) —RN-heteroaryl—CO—RN-heteroaryl where RN-heteroaryl is as defined above,
(O) —RN-heteroaryl—SO2—RN-heteroaryl where RN-heteroaryl is as defined above,
(P) —RN-aryl—O—(C1–C8 alkyl)-φ where RN aryl is as defined above,
(Q) —RN-aryl—S—(C1–C8 alkyl)-φ where RN-aryl is as defined above,
(R) —RN-heteroaryl—O—(C1–C8 alkyl)-φ where RN-heteroaryl is as defined above, or
(S) —RN-heteroaryl—S—(C1–C8 alkyl)-φ where RN-heteroaryl is as defined above,
(II) A-XN— where XN is —CO—,
wherein A is
(A) -T-E(Q)m′,
(1) where -T is
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) R′″ varies independently on each carbon and is H, (C1–C2) alkyl, phenyl, or phenyl(C1–C3)alkyl;
(2) -E is
(a) C1–C5 alkyl, but only if m′ does not equal 0,
(b) methylthioxy(C2–C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1–C8)alkyloxyphenyl, or
(j) C1–C6 alkoxy;
(3) -Q is
(a) C1–C3 alkyl,
(b) C1–C3 alkoxy,
(c) C1–C3 alkylthioxy,
(d) C1–C6 alkylacylamino,
(e) C1–C6 alkylacyloxy,
(f) amido (including primary, C1–C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1–C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1–C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1–C6 alkyl and phenyl esters),
(k) carboxy(C2–C5)alkoxy,
(l) carboxy(C2–C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) m′ is 0, 1, 2 or 3;
(B) -E(Q)m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3;
(C) -T-E wherein -E and -Q are as defined as above;
or
(D) -E wherein -E is as defined as above;
(III) —CO—(C1–C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(IV) —CO—(C1–C3 alkyl)-O—(C1–C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(V) —CO—(C1–C3 alkyl)-S—(C1–C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) —OH,
(B) —C1–C6 alkoxy,
(C) —C1–C6 thioalkoxy,
(D) —CO—O—RN-8 where RN-8 is —H, C1–C6 alkyl or -φ,
(E) —CO—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) —CO—RN-4 where RN-4 is as defined above,
(G) —SO2—(C1–C8 alkyl),
(H) —SO2—NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) —NH—CO—(C1–C6 alkyl),
(J) —NH—CO—O—RN-8 where RN-8 is as defined above,
(K) —NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) —RN-4 where RN-4 is as defined above,
(M) —O—CO—(C1–C6 alkyl),
(N) —O—CO—NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) —O—(C1–C5 alkyl)-COOH,
(VI) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is:
(A) —H,
(B) C1–C6 alkyl,
(C) C3–C7 cycloalkyl,
(D) C2–C6 alkenyl with one double bond,
(E) C2–C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above;
where B is —O—, —NH—, or —N(C1–C6 alkyl)-;
where RC is:
—(CH2)0-3—(C3–C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C1–C3 alkyl unsubstituted or substituted with 1, 2, 4, or 4 —F,
(B) —CO—OH,
(C) —CO—O—(C1–C4 alkyl),
(D) —OH, or
(E) C1–C6 alkoxy,
or a pharmaceutically acceptable salt thereof.

376 more elements

Dependencies are inferred from the claim text.

Description32,918 words

Summary11,324 words

#The present invention provides compounds, compositions, and methods for inhibiting β-secretase-mediated cleavage of beta amyloid precursor protein. More particularly, the invention relates to the use of the compounds, compositions, and methods of the invention to inhibit the production of beta-beta amyloid peptide and to treat or prevent disease characterized by beta-beta amyloid peptide deposits. Most particularly, the invention provides compounds, compositions, and methods for the treatment of Alzheimer's disease.

#Alzheimer's Disease (AD) is a degenerative brain disorder presented clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to profound mental deterioration and ultimately death. Individuals with AD exhibit characteristic beta amyloid deposits in the brain (beta amyloid plaques) and in cerebral blood vessels (beta amyloid angiopathy) as well as neurofibrillary tangles. On autopsy of AD patients, large numbers of these lesions are generally found in areas of the human brain important for memory and congnitive function. Smaller numbers are found in the brains of most aged humans not showing clinical symptoms of AD. Beta amyloid plaques and beta amyloid angiopathy also characterize the brains of individuals with Down's Syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage with Beta amyloidosis of the Dutch-Type, and other such disorders.

#Beta amyloid plaques are a defining feature of AD, now believed to be a causative precursor or factor in the development of disease. Beta amyloid plaques are predominantly composed of beta amyloid beta peptide (Aβ, also sometimes designated βA4).

Detailed description21,594 words

#The present invention provides hydroxyethylene compounds of formula (XII) which are useful in treating and preventing Alzheimer's disease. The anti-Alzheimer's hydroxyethylene compounds of formula (XII) are made by methods well known to those skilled in the art from starting compounds known to those skilled in the art. The process chemistry is well known to those skilled in the art. The most general process to prepare the hydroxyethylene compounds of formula (XII) is set forth in CHART A, as defined within. The chemistry is straight forward and in summary involves the steps of N-protecting an amino acid (I) starting material to produce the corresponding protected amino acid (II), amino-dehydroxylation of the protected amino acid (II) with the appropriate amine in the presence of a coupling agent to produce the corresponding protected amide (III), reduction of the protected amide to the corresponding aldehyde (IV), formation of the terminal olefin as described (V), peracid epoxidation of the olefin (V) to produce the corresponding epoxide (VI), opening of the epoxide (VI) with an amide (VII) to produce the corresponding protected alcohol (VIII), cyclization of the protected alcohol (VIII) to produce the protected lactone (IX) which then has the nitrogen protecting group removed to produce the corresponding amine (X), which is then reacted with an amide forming agent of the formula (RN-1—XN)2O or RN-1—XN—X2 or RN-1—XN—OH, for example, to produce the lactone (XI), opening of the lactone (XI) with a C-terminal amine, RC—NH2 to produce the anti-Alzheimer hydroxyethylene compounds of formula (XII). One skilled in the art will appreciate that these are all well known reactions in organic chemistry. A chemist skilled in the art, knowing the chemical structure of the biologically active hydroxyethylene compounds of formula (XII) would be able to prepare them by known methods from known starting materials without any additional information. The explanation below therefore is not necessary but is deemed helpful to those skilled in the art who desire to make the compounds of the present invention.

#The backbone of the compounds of the present invention is a hydroxyethylene moiety. It can be readily prepared by methods disclosed in the literature and known to those skilled in the art. For example, Henning, R. “Synthetic Routes to Different Classes of Natural Products and Analogs Thereof. Synthesis of Hydroxyethylene Isosteric Dipeptides.” In Organic Synthesis Highlights II; VCH: Weinheim, Germany, 1995; pp 251–259 discloses processes to prepare hydroxyethylene type compounds.

#CHART A, as defined within, sets forth a general method used in the present invention to prepare the appropriately substituted hydroxyethylene compounds of formula (XII). The anti-Alzheimer hydroxyethylene compounds of formula (XII) are prepared by starting with the corresponding amino acid (I). The amino acids (I) are well known to those skilled in the art or can be readily prepared from known compounds by methods well known to those skilled in the art. The hydroxyethylene compounds of formula (XII) have at least three enantiomeric centers which give 8 enantiomers, the S, S, R stereochemistry being preferred. The first of these enantiomeric centers derives from the amino acid starting material (I). It is preferred to commercially obtain or produce the desired enantiomer (S) rather than produce an enantiomerically impure mixture and then have to separate out the desired enantiomer (S). It is preferred to start the process with enantiomerically pure (S)-amino acid (I) of the same configuration as that of the hydroxyethylene product. For the amino acids (I), R1 is: (I) C1–C6 alkyl, unsubstituted or substituted with one, two or three C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —NH2, —C≡N, —CF3, or —N3, (II) —(CH2)1-2—S—CH3, (III) —CH2—CH2—S—CH3, (IV) —CH2—(C2–C6 alkenyl) unsubstituted or substituted by one —F, (V) —(CH2)0-3—(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different: (A) C1–C3 alkyl, (B) —CF3, (C) —F, Cl, —Br and —I, (D) C1–C3 alkoxy, (E) —O—CF3, (F) —NH2, (G) —OH, or (H) —C≡N, (VI) —(CH2)n1—(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is: (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D) indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl, (I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M) quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q) isoxazolyl, (R) pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl, (V) indazolyl, (W) benzothiazolyl, (X) benzimidazolyl, (Y) benzofuranyl, (Z) furanyl, (AA) thienyl, (BB) pyrrolyl, (CC) oxadiazolyl, (DD) thiadiazolyl, (EE) triazolyl, (FF) tetrazolyl, (GG) 1,4-benzodioxan (HH) purinyl, (II) oxazolopyridinyl, (JJ) imidazopyridinyl, (KK) isothiazolyl, (LL) naphthyridinyl, (MM) cinnolinyl, (NN) carbazolyl, (OO) β-carbolinyl, (PP) isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS) tetrahydroisoquinoline, (TT) isoindolinyl, (UU) isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW) isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl, where the R1-heteroaryl group is bonded to —(CH2)0-3— by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two: (1) C1–C3 alkyl, (2) —CF3, (3) —F, Cl, —Br, or —I, (4) C1–C3 alkoxy, (5) —O—CF3, (6) —NH2, (7) —OH, or (8) —C≡N, with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or (VII) —(CH2)n1—(R1-heterocycle) where n1 is as defined above and R1-heterocycle is: (A) morpholinyl, (B) thiomorpholinyl, (C) thiomorpholinyl S-oxide, (D) thiomorpholinyl S,S-dioxide, (E) piperazinyl, (F) homopiperazinyl, (G) pyrrolidinyl, (H) pyrrolinyl, (I) tetrahydropyranyl, (J) piperidinyl, (K) tetrahydrofuranyl, or (L) tetrahydrothiophenyl, where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two: (1) ═O, (2) C1–C3 alkyl, (3) —CF3, (4) —F, Cl, —Br and —I, (5) C1–C3 alkoxy, (6) —O—CF3, (7) —NH2, (8) —OH, or (9) —C≡N, with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen. Typically, R1 is (V) —(CH2)0-1—(R1-aryl) or (VI) —(CH2)n1—(R1-heteroaryl). It is preferred that R1 is (V) —(CH2)—(R1-aryl) or (VI) —(CH2)—(R1-heteroaryl). It is more preferred that R1 is —(CH2)—(R1-aryl) where R1-aryl is phenyl. It is even more preferred that R1 is —(CH2)—(R1-aryl) where R1-aryl is phenyl substituted with two —F. It is most preferred that the —F substitution is 3,5 on the phenyl ring.

Facts

Application: 09/816,876Filed 23 Mar 2001 · us provisional application
Priority: 23 Mar 2000
Published: US 2002/0019403 A114 Feb 2002
Granted: 10 Oct 2006
Term ended: 24 Jun 2023
Estimated · howhide
20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment, including 823 days of adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification25 codes

C07C 237/22
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: having nitrogen atoms of amino groups…
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

Application60/191,528Us provisional application · filed 23 Mar 2000
US 2002/0019403 A1Pre-grant publication · published 14 Feb 2002
US 7,119,085 B2This patent

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

Timeline

23 Mar 2000Priority claimedParent application 60/191,528
23 Mar 2001Application filedUS 09/816,876
28 Sep 2001Assigned to Elan Pharmaceuticals, Inc.assignment of assignor's interest
14 Feb 2002PublishedUS 2002/0019403 A1
10 Oct 2006GrantedUS 7,119,085 B2
24 Jun 2023Term endedEstimated, includes 823 days of adjustment

Citations

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