US 7,312,360 B2Granted

Substituted hydroxyethylamines

AssigneesElan Pharmaceuticals, Inc., Pharmacia & Upjohn Company

InventorsRuth TenBrink, Michel Maillard, Martha Warpehoski

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Abstract

Disclosed are compounds of the formula and the pharmaceutically acceptable salts thereof wherein the variables G, L, A, W, E, R2, R3, R4, R5, RN, and Rc are defined herein. These compounds interact with and inhibit the activity of the enzyme beta-secretase. These compounds are therefore useful in treating Alzheimer's disease and other similar diseases. Pharmaceutical compositions and methods of treatment of these diseases are also disclosed.

Claims11

Dependent claims

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
E is a bond;
RJ is H;
RK is H;
K is —(CR4R5)n—;
wherein R4 and R5 are independently hydrogen, halogen, C1–C6 alkoxy or C1–C4 alkyl optionally substituted with halogen, —CN, —CF3, or —OH;
n is 0, 1 or 2;
A is aryl optionally substituted with one, two or three independently selected R100 groups, where R100 is
(A) —NO2,
(B) —C≡N,
(C) —N(R)CO, where R and R′ are independently hydrogen, C1–C6 alkyl, —(CH2)0-2-aryl, or —(CH2)0-2-cycloalkyl, where each aryl or cycloalkyl is optionally substituted with halogen, hydroxy, C1–C6 alkyl, amino, mono(C1–C6)alkylamino, or di(C1–C6)alkylamino,
(D) —CO2—R25, where R25 is selected from the group consisting of:
(a) C1–C6 alkyl,
(b) —(CH2)0-2-cycloalkyl,
(c) —(CH2)0-2-aryl, where the aryl is optionally substituted with halogen, hydroxy, C1–C6 alkyl, amino, mono(C1–C6)alkylamino, or di(C1–C6)alkylamino, and
(d) hydrogen,
(E) —NH—CO2—R25,
(F) —O—(C2–C6 alkyl)—CO2H,
(G) —NRR′,
(H) —SR,
(I) —CH2OH,
(J) —C(O)—(C1–C6)alkyl,
(K) —C(O)NRR′,
(L) —SO2NRR′
(M) —CO2H,
(N) C1–C6 alkyl,
(O) C2–C6 alkenyl with one or two double bonds,
(P) —C2–C6 alkynyl with one or two triple bonds,
(Q) —CF3,
(R) —F, —Cl, —Br, —I,
(S) C1–C3 alkoxy,
(T) —OCF3,
(U) —NH2,
(V) —OH, or,
(W) —(CH2)0-2—O—(CH2)0-2—OH;
W is —S—, —S(O)—, —S(O)2—, —O—, or —N(R135)—, where R135 is C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, C3—C7 cycloalkyl, —(CH2)0—2—(aryl), —(CH2)0—2—(heteroaryl), or —(CH2)0—2—(heterocyclyl);
L is absent when G is absent, or L is —C(O)—, —S(O)—, —S2—, or —O—;
G is absent or C1–C10 alkyl;
R2 is selected from the group consisting of:
(I) hydrogen, and
(II) C1–C6alkyl;
R3 is selected from the group consisting of:
(I) —H, and
(II) C1–C6 alkyl;
RN is RN-1—XN—,
where XN is —CO—,
where RN-1 is RN-aryl wherein RN-aryl at each occurrence is independently phenyl;
naphthyl;
tetralinyl;
indanyl;
indenyl;
dihydronaphthyl;
or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl;
each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are:
(1) C1–C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b, wherein R1-a and R1-b at each occurrence are independently H or C1–C6 alkyl,
(2) —OH,
(3) —NO2,
(4) —F, —Cl, —Br, —I,
(5) —CO2H,
(6) —C≡N,
(7) —(CH2)0-4—CO—NRN-2RN-3, where RN-2 and RN-3 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C1–C8 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH,
(ii) —NH2, and
(iii) phenyl,
(c) —C1–C8 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, or —I,
(d) —C3–C8 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C8 cycloalkyl),
(f) —(C1–C6 alkyl)—O—(C1–C3 alkyl)
(g) —C2–C6 alkenyl,
(h) —C2–C6 alkynyl,
(i) —C1–C6 alkyl chain with one double bond and one triple bond, and
(j) —R1-aryl, wherein R1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C1–C6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR1-aR1-b, —C≡N, —CF3, and C1–C3 alkoxy,
(ii) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(iii) C2–C6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(iv) —F, Cl, —Br and —I,
(v) —C1–C6 alkoxy optionally substituted with 1, 2, or 3—F,
(vi) —OH,
(vii) —C≡N,
(viii) C3–C7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(ix) —CO—(C1–C4 alkyl),
(x) —SO2—NR1-aR1-b,
(xi) —CO—NR1-aR1-b, or
(xii) —SO2—(C1–C4 alkyl)
(8) —(CH2)0-4—CO—(C1–C12 alkyl),
(9) —(CH2)0-4—CO—(C2–C12 alkenyl),
(10) —(CH2)0-4—CO—(C2–C12 alkynyl),
(11) —(CH2)0-4—CO—(C3–C8 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO—RN-4 wherein RN-4 is optionally substituted with one, two, three, or four groups that are independently C1–C6 alkyl,
(14) —(CH2)0-4—CO—O—RN-5, where RN-5 is selected from the group consisting of:
(a) C1–C6 alkyl,
(b) —(CH2)0-2—(R1-aryl),
(c) C2–C6 alkenyl,
(d) C2–C6 alkynyl, and
(e) —(CH2)0-2—C3–C8 cycloalkyl,
(15) —(CH2)0-4—SO2—NRN-2RN-3,
(16) —(CH2)0-4—SO—(C1–C8 alkyl),
(17) —(CH2)0-4—SO2 (C1–C12 alkyl)
(18) —(CH2)0-4—SO2—(C3–C8 cycloalkyl),
(19) —(CH2)0-4—N(H or RN-5)—CO—O—RN-5,
(20) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2,
(21) —(CH2)0-4—N—CS—N(RN-5)2,
(22) —(CH2)0-4—N(H or RN-5)—CO—RN-2,
(23) —(CH2)0-4—NRN-2RN-3,
(24) —(CH2)0-4—RN-4,
(25) —(CH2)0-4—O—CO—(C1–C6 alkyl),
(26) —(CH2)0-4—O—CO—N(RN-5)2,
(27) —(CH2)0-4—O—CS—N(RN-5)2,
(28) —(CH2)0-4—O—(RN-5),
(29) —(CH2)0-4—O—(RN-5)—COOH,
(30) —(CH2)0-4—S—(RN-5),
(31) —(CH2)0-4—O—(C1–C6 alkyl optionally substituted with one, two, three, four, or five of —F),
(32) C3–C8 cycloalkyl,
(33) C2–C6 alkenyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —N1-aR1-b,
(34) C2–C6 alkynyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b,
(35) —(CH2)0-4—N(H or RN-5)—SO2—RN-2, or
(36) —(CH2)1-4—(C3–C8 cycloalkyl);
and
RC is selected from the group consisting of:
(I) —C1–C10 alkyl optionally substituted with one, two or three groups independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, —NR1-aR1-b, —OC═O NR1-aR1-b, —S(═O)0-2R1-a, —NR1-aC═O NR1-aR1-b, —C═O NR1-aR1-b, and —S(═O)2NR1-aR1-b wherein
(II) —(CH2)0-3—(C3–C8) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, —CO2H, —CO2—(C1–C4 alkyl), and —NR1-aR1-b
(III) —(CRC-xRC-y)0-4—RC-aryl where RC-x and RC-y are independently selected from the group consisting of
—H,
C1–C4 alkyl optionally substituted with 1 or 2 —OH,
C1–C4 alkoxy optionally substituted with 1, 2, or 3 halogen,
—(CH2)0-4—C3–C8 cycloalkyl,
C2–C6 alkenyl containing one or two double bonds,
C2–C6 alkynyl containing one or two triple bonds, and
phenyl, or
RC-x and RC-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms,
wherein RC-aryl at each occurrence is independently phenyl;
naphthyl;
tetralinyl;
indanyl;
dihydronaphthyl;
or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently:
(1) C1–C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(2) —OH,
(3) —NO2,
(4) halogen,
(5) —CO2H,
(6) —C≡N,
(7) —(CH2)0-4—CO—NRN-2RN-3,
(8) —(CH2)0-4—CO—(C1–C12 alkyl),
(9) —(CH2)0-4—CO—(C2–C12 alkenyl),
(10) —(CH2)0-4—CO—(C2–C12 alkynyl),
(11) —(CH2)0-4—CO—(CH2)0-4 (C3–C7 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO2—RN-5,
(14) —(CH2)0-4—SO2—NRN-2RN-3
(15) —(CH2)0-4—SO—(C1–C8 alkyl),
(16) —(CH2)0-4—SO2—(C1–C12 alkyl),
(17) —(CH2)0-4—SO2—(C3–C7 cycloalkyl),
(18) —(CH2)0-4—N(H or RN-5)—CO2—RN-5,
(19) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2,
(20) —(CH2)0-4—N—CS—N(RN-5)2,
(21) —(CH2)0-4—N(—H or RN-5)—CO—RN-2,
(22) —(CH2)0-4—NRN-2RN-3,
(23) —(CH2)0-4—RN-4,
(24) —(CH2)0-4—O—CO—(C1–C6 alkyl),
(25) —(CH2)0-4—O—CO—N(RN-5)2,
(26) —(CH2)0-4—O—CS—N(RN-5)2,
(27) —(CH2)0-4—O—(RN-5),
(28) —(CH2)0-4—O—(RN-5)—COOH,
(29) —(CH2)0-4—S—(RN-5),
(30) —(CH2)0-4—O—(C1–C6 alkyl) wherein the alkyl group is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of F, Cl, Br, and I,
(31) —(CH2)0-4—(C3–C8 cycloalkyl),
(32) C2–C6 alkenyl optionally substituted with C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b,
(33) C2–C6 alkynyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b, or
(34) —(CH2)0-4—N(—H or RN-5)—SO2—RN-2;
(IV) —(CRc—xRc—y)0—4—Rc-aryl—R101—Rc—aryl, where R101 is a bond, (CH2)0—4, —O—, —NH—, or —N(C1—C6 alkyl);
(V) —[C(RC-1)(RC-2)]1-3—CO—N(RC-3)2 where RC-1 and RC-2 are the same or different and are selected from the group consisting of:
(A) —H,
(B) —C1–C6 alkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(C) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(D) C2–C6 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(E) —(CH2)1-2—S(O)0-2—(C1–C6 alkyl),
(F) —(CH2)0-4—C3–C7 cycloalkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(G) —(C1–C4 alkyl)—R1-aryl,
(H) —(CH2)1-4—RC-4—(CH2)0-4—R1-aryl where RC-4 is —O—, —S— or —NR(C1–C6 alkyl)—,
(I) —R1-aryl,
and where
RC-3 at each occurrence is independently:
(A) —H,
(B) —C1–C6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(C) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(D) C2–C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(E) —(CH2)0-4—C3–C7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(F) —R1-aryl,
(G) —(C1–C4 alkyl)—R1-aryl,
(VI) —CH(RC-aryl)2,
(VII) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to RC-aryl, where RC-aryl is as defined above where cyclopentyl, cyclohexyl, or -cycloheptyl can be optionally substituted with one or two —C1–C3 alkyl, —F, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, ═O, or —NR1-aR1-b,
(VIII) C2–C10 alkenyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(IX) C2–C10 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(X) —(CH2)0-1—CHRC-6—(CH2)0-1—RC-aryl wherein
RC-6 is —(CH2)0-6—OH,
(XI) —CH(—RC-aryl)—CO—O(C1–C4 alkyl),
(XII) —CH(—CH2OH)—CH(OH)—(C1–C6 alkyl)—NO2,
(XIII) —(C1–C6 alkyl)—O—(C1–C6 alkyl)—OH,
(XIV) —CH2—NH—CH2—CH(—O—CH2—CH3)2,
(XV) —H, and
(XVI) —(CH2)0-6—C(═NR1-a)(NR1-aR1-b).

202 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/313,849Filed 6 Dec 2002 · us provisional application
Priority: 6 Dec 2001
Published: US 2004/0044072 A14 Mar 2004
Granted: 25 Dec 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07C 233/36
With the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom: having the carbon atom of…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs

Family

Application60/338,452Us provisional application · filed 6 Dec 2001
US 2004/0044072 A1Pre-grant publication · published 4 Mar 2004
US 7,312,360 B2This patent

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

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Abstract

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
E is a bond;
RJ is H;
RK is H;
K is —(CR4R5)n—;
wherein R4 and R5 are independently hydrogen, halogen, C1–C6 alkoxy or C1–C4 alkyl optionally substituted with halogen, —CN, —CF3, or —OH;
n is 0, 1 or 2;
A is aryl optionally substituted with one, two or three independently selected R100 groups, where R100 is
(A) —NO2,
(B) —C≡N,
(C) —N(R)CO, where R and R′ are independently hydrogen, C1–C6 alkyl, —(CH2)0-2-aryl, or —(CH2)0-2-cycloalkyl, where each aryl or cycloalkyl is optionally substituted with halogen, hydroxy, C1–C6 alkyl, amino, mono(C1–C6)alkylamino, or di(C1–C6)alkylamino,
(D) —CO2—R25, where R25 is selected from the group consisting of:
(a) C1–C6 alkyl,
(b) —(CH2)0-2-cycloalkyl,
(c) —(CH2)0-2-aryl, where the aryl is optionally substituted with halogen, hydroxy, C1–C6 alkyl, amino, mono(C1–C6)alkylamino, or di(C1–C6)alkylamino, and
(d) hydrogen,
(E) —NH—CO2—R25,
(F) —O—(C2–C6 alkyl)—CO2H,
(G) —NRR′,
(H) —SR,
(I) —CH2OH,
(J) —C(O)—(C1–C6)alkyl,
(K) —C(O)NRR′,
(L) —SO2NRR′
(M) —CO2H,
(N) C1–C6 alkyl,
(O) C2–C6 alkenyl with one or two double bonds,
(P) —C2–C6 alkynyl with one or two triple bonds,
(Q) —CF3,
(R) —F, —Cl, —Br, —I,
(S) C1–C3 alkoxy,
(T) —OCF3,
(U) —NH2,
(V) —OH, or,
(W) —(CH2)0-2—O—(CH2)0-2—OH;
W is —S—, —S(O)—, —S(O)2—, —O—, or —N(R135)—, where R135 is C1—C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, C3—C7 cycloalkyl, —(CH2)0—2—(aryl), —(CH2)0—2—(heteroaryl), or —(CH2)0—2—(heterocyclyl);
L is absent when G is absent, or L is —C(O)—, —S(O)—, —S2—, or —O—;
G is absent or C1–C10 alkyl;
R2 is selected from the group consisting of:
(I) hydrogen, and
(II) C1–C6alkyl;
R3 is selected from the group consisting of:
(I) —H, and
(II) C1–C6 alkyl;
RN is RN-1—XN—,
where XN is —CO—,
where RN-1 is RN-aryl wherein RN-aryl at each occurrence is independently phenyl;
naphthyl;
tetralinyl;
indanyl;
indenyl;
dihydronaphthyl;
or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl;
each of which is optionally substituted with one, two or three of the following substituents which can be the same or different and are:
(1) C1–C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b, wherein R1-a and R1-b at each occurrence are independently H or C1–C6 alkyl,
(2) —OH,
(3) —NO2,
(4) —F, —Cl, —Br, —I,
(5) —CO2H,
(6) —C≡N,
(7) —(CH2)0-4—CO—NRN-2RN-3, where RN-2 and RN-3 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C1–C8 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH,
(ii) —NH2, and
(iii) phenyl,
(c) —C1–C8 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, or —I,
(d) —C3–C8 cycloalkyl,
(e) —(C1–C2 alkyl)-(C3–C8 cycloalkyl),
(f) —(C1–C6 alkyl)—O—(C1–C3 alkyl)
(g) —C2–C6 alkenyl,
(h) —C2–C6 alkynyl,
(i) —C1–C6 alkyl chain with one double bond and one triple bond, and
(j) —R1-aryl, wherein R1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C1–C6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR1-aR1-b, —C≡N, —CF3, and C1–C3 alkoxy,
(ii) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(iii) C2–C6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(iv) —F, Cl, —Br and —I,
(v) —C1–C6 alkoxy optionally substituted with 1, 2, or 3—F,
(vi) —OH,
(vii) —C≡N,
(viii) C3–C7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(ix) —CO—(C1–C4 alkyl),
(x) —SO2—NR1-aR1-b,
(xi) —CO—NR1-aR1-b, or
(xii) —SO2—(C1–C4 alkyl)
(8) —(CH2)0-4—CO—(C1–C12 alkyl),
(9) —(CH2)0-4—CO—(C2–C12 alkenyl),
(10) —(CH2)0-4—CO—(C2–C12 alkynyl),
(11) —(CH2)0-4—CO—(C3–C8 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO—RN-4 wherein RN-4 is optionally substituted with one, two, three, or four groups that are independently C1–C6 alkyl,
(14) —(CH2)0-4—CO—O—RN-5, where RN-5 is selected from the group consisting of:
(a) C1–C6 alkyl,
(b) —(CH2)0-2—(R1-aryl),
(c) C2–C6 alkenyl,
(d) C2–C6 alkynyl, and
(e) —(CH2)0-2—C3–C8 cycloalkyl,
(15) —(CH2)0-4—SO2—NRN-2RN-3,
(16) —(CH2)0-4—SO—(C1–C8 alkyl),
(17) —(CH2)0-4—SO2 (C1–C12 alkyl)
(18) —(CH2)0-4—SO2—(C3–C8 cycloalkyl),
(19) —(CH2)0-4—N(H or RN-5)—CO—O—RN-5,
(20) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2,
(21) —(CH2)0-4—N—CS—N(RN-5)2,
(22) —(CH2)0-4—N(H or RN-5)—CO—RN-2,
(23) —(CH2)0-4—NRN-2RN-3,
(24) —(CH2)0-4—RN-4,
(25) —(CH2)0-4—O—CO—(C1–C6 alkyl),
(26) —(CH2)0-4—O—CO—N(RN-5)2,
(27) —(CH2)0-4—O—CS—N(RN-5)2,
(28) —(CH2)0-4—O—(RN-5),
(29) —(CH2)0-4—O—(RN-5)—COOH,
(30) —(CH2)0-4—S—(RN-5),
(31) —(CH2)0-4—O—(C1–C6 alkyl optionally substituted with one, two, three, four, or five of —F),
(32) C3–C8 cycloalkyl,
(33) C2–C6 alkenyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —N1-aR1-b,
(34) C2–C6 alkynyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b,
(35) —(CH2)0-4—N(H or RN-5)—SO2—RN-2, or
(36) —(CH2)1-4—(C3–C8 cycloalkyl);
and
RC is selected from the group consisting of:
(I) —C1–C10 alkyl optionally substituted with one, two or three groups independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, —NR1-aR1-b, —OC═O NR1-aR1-b, —S(═O)0-2R1-a, —NR1-aC═O NR1-aR1-b, —C═O NR1-aR1-b, and —S(═O)2NR1-aR1-b wherein
(II) —(CH2)0-3—(C3–C8) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, —CO2H, —CO2—(C1–C4 alkyl), and —NR1-aR1-b
(III) —(CRC-xRC-y)0-4—RC-aryl where RC-x and RC-y are independently selected from the group consisting of
—H,
C1–C4 alkyl optionally substituted with 1 or 2 —OH,
C1–C4 alkoxy optionally substituted with 1, 2, or 3 halogen,
—(CH2)0-4—C3–C8 cycloalkyl,
C2–C6 alkenyl containing one or two double bonds,
C2–C6 alkynyl containing one or two triple bonds, and
phenyl, or
RC-x and RC-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms,
wherein RC-aryl at each occurrence is independently phenyl;
naphthyl;
tetralinyl;
indanyl;
dihydronaphthyl;
or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently:
(1) C1–C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, and —NR1-aR1-b,
(2) —OH,
(3) —NO2,
(4) halogen,
(5) —CO2H,
(6) —C≡N,
(7) —(CH2)0-4—CO—NRN-2RN-3,
(8) —(CH2)0-4—CO—(C1–C12 alkyl),
(9) —(CH2)0-4—CO—(C2–C12 alkenyl),
(10) —(CH2)0-4—CO—(C2–C12 alkynyl),
(11) —(CH2)0-4—CO—(CH2)0-4 (C3–C7 cycloalkyl),
(12) —(CH2)0-4—CO—R1-aryl,
(13) —(CH2)0-4—CO2—RN-5,
(14) —(CH2)0-4—SO2—NRN-2RN-3
(15) —(CH2)0-4—SO—(C1–C8 alkyl),
(16) —(CH2)0-4—SO2—(C1–C12 alkyl),
(17) —(CH2)0-4—SO2—(C3–C7 cycloalkyl),
(18) —(CH2)0-4—N(H or RN-5)—CO2—RN-5,
(19) —(CH2)0-4—N(H or RN-5)—CO—N(RN-5)2,
(20) —(CH2)0-4—N—CS—N(RN-5)2,
(21) —(CH2)0-4—N(—H or RN-5)—CO—RN-2,
(22) —(CH2)0-4—NRN-2RN-3,
(23) —(CH2)0-4—RN-4,
(24) —(CH2)0-4—O—CO—(C1–C6 alkyl),
(25) —(CH2)0-4—O—CO—N(RN-5)2,
(26) —(CH2)0-4—O—CS—N(RN-5)2,
(27) —(CH2)0-4—O—(RN-5),
(28) —(CH2)0-4—O—(RN-5)—COOH,
(29) —(CH2)0-4—S—(RN-5),
(30) —(CH2)0-4—O—(C1–C6 alkyl) wherein the alkyl group is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of F, Cl, Br, and I,
(31) —(CH2)0-4—(C3–C8 cycloalkyl),
(32) C2–C6 alkenyl optionally substituted with C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b,
(33) C2–C6 alkynyl optionally substituted with C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C3 alkoxy, or —NR1-aR1-b, or
(34) —(CH2)0-4—N(—H or RN-5)—SO2—RN-2;
(IV) —(CRc—xRc—y)0—4—Rc-aryl—R101—Rc—aryl, where R101 is a bond, (CH2)0—4, —O—, —NH—, or —N(C1—C6 alkyl);
(V) —[C(RC-1)(RC-2)]1-3—CO—N(RC-3)2 where RC-1 and RC-2 are the same or different and are selected from the group consisting of:
(A) —H,
(B) —C1–C6 alkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(C) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(D) C2–C6 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(E) —(CH2)1-2—S(O)0-2—(C1–C6 alkyl),
(F) —(CH2)0-4—C3–C7 cycloalkyl, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(G) —(C1–C4 alkyl)—R1-aryl,
(H) —(CH2)1-4—RC-4—(CH2)0-4—R1-aryl where RC-4 is —O—, —S— or —NR(C1–C6 alkyl)—,
(I) —R1-aryl,
and where
RC-3 at each occurrence is independently:
(A) —H,
(B) —C1–C6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(C) C2–C6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(D) C2–C6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(E) —(CH2)0-4—C3–C7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(F) —R1-aryl,
(G) —(C1–C4 alkyl)—R1-aryl,
(VI) —CH(RC-aryl)2,
(VII) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to RC-aryl, where RC-aryl is as defined above where cyclopentyl, cyclohexyl, or -cycloheptyl can be optionally substituted with one or two —C1–C3 alkyl, —F, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, ═O, or —NR1-aR1-b,
(VIII) C2–C10 alkenyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(IX) C2–C10 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C1–C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1–C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
(X) —(CH2)0-1—CHRC-6—(CH2)0-1—RC-aryl wherein
RC-6 is —(CH2)0-6—OH,
(XI) —CH(—RC-aryl)—CO—O(C1–C4 alkyl),
(XII) —CH(—CH2OH)—CH(OH)—(C1–C6 alkyl)—NO2,
(XIII) —(C1–C6 alkyl)—O—(C1–C6 alkyl)—OH,
(XIV) —CH2—NH—CH2—CH(—O—CH2—CH3)2,
(XV) —H, and
(XVI) —(CH2)0-6—C(═NR1-a)(NR1-aR1-b).

202 more elements

Facts

Application

10/313,849Filed 6 Dec 2002 · us provisional application

Priority

6 Dec 2001

Published

US 2004/0044072 A14 Mar 2004

Granted

25 Dec 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07C 233/36
With the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom: having the carbon atom of…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs