U.S. patent application number 11/548136 was filed with the patent office on 2008-03-06 for methods to treat alzheimer's disease.
This patent application is currently assigned to Elan Pharmaceuticals, Inc.. Invention is credited to Lawrence Y. Fang, Andrea Gailunas, Roy Hom, Varghese John, Shumeye S. Mamo, Jay Tung.
Application Number | 20080058336 11/548136 |
Document ID | / |
Family ID | 22705853 |
Filed Date | 2008-03-06 |
United States Patent
Application |
20080058336 |
Kind Code |
A1 |
Hom; Roy ; et al. |
March 6, 2008 |
Methods to Treat Alzheimer's Disease
Abstract
The present invention is directed toward substituted
hydroxyethylene compounds of formula (XII) ##STR00001## useful in
treating Alzheimer's disease and other similar diseases.
Inventors: |
Hom; Roy; (San Francisco,
CA) ; Mamo; Shumeye S.; (Oakland, CA) ; Tung;
Jay; (Belmont, CA) ; Gailunas; Andrea; (San
Francisco, CA) ; John; Varghese; (San Francisco,
CA) ; Fang; Lawrence Y.; (Foster City, CA) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE, 32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Elan Pharmaceuticals, Inc.
|
Family ID: |
22705853 |
Appl. No.: |
11/548136 |
Filed: |
October 10, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09816876 |
Mar 23, 2001 |
7119085 |
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11548136 |
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60191528 |
Mar 23, 2000 |
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Current U.S.
Class: |
514/237.5 ;
435/184; 514/255.01; 514/330; 514/374; 514/471; 514/506; 514/529;
514/538; 514/563; 514/567; 514/568; 514/625 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 261/20 20130101; C07D 307/52 20130101; C07C 271/18 20130101;
C07K 5/0207 20130101; C07D 295/13 20130101; A61P 25/28 20180101;
C07C 2603/74 20170501; C07D 295/185 20130101; C07C 271/14 20130101;
A61P 25/16 20180101; A61K 38/00 20130101; C07B 2200/07 20130101;
C07D 307/14 20130101; C07K 7/02 20130101; C07C 2601/14 20170501;
C07C 237/22 20130101; C07C 271/22 20130101; C07D 307/33
20130101 |
Class at
Publication: |
514/237.5 ;
435/184; 514/255.01; 514/330; 514/374; 514/471; 514/506; 514/529;
514/538; 514/563; 514/567; 514/568; 514/625 |
International
Class: |
A61K 31/5375 20060101
A61K031/5375; A61K 31/164 20060101 A61K031/164; A61K 31/192
20060101 A61K031/192; A61K 31/195 20060101 A61K031/195; A61K 31/215
20060101 A61K031/215; A61P 43/00 20060101 A61P043/00; C12N 9/99
20060101 C12N009/99; A61K 31/221 20060101 A61K031/221; A61K 31/341
20060101 A61K031/341; A61K 31/421 20060101 A61K031/421; A61K 31/445
20060101 A61K031/445 |
Claims
1. A method for inhibiting .beta.-secretase activity, comprising
exposing said .beta.-secretase to an effective inhibitory amount of
a hydroxyethylene compound of the formula ##STR00081## where
R.sub.1 is: (I) C.sub.1-C.sub.6 alkyl, unsubstituted or substituted
with one, two or three C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --NH.sub.2, --C.ident.N, --CF.sub.3, or --N.sub.3, (II)
--(CH.sub.2).sub.1-2--S--CH.sub.3, (III)
--CH.sub.2--CH.sub.2--S--CH.sub.3, (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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) C.sub.1-C.sub.3 alkyl, (B)
--CF.sub.3, (C) --F, Cl, --Br and --I, (D) C.sub.1-C.sub.3 alkoxy,
(E) --O--CF.sub.3, (F) --NH.sub.2, (G) --OH, or (H)--C.ident.N,
(VI) --(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0,
1, 2, or 3 and R.sub.1-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) .beta.-carbolinyl, (PP)
isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)
tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.1-heteroaryl group is bonded to
--(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: (1) C.sub.1-C.sub.3 alkyl, (2) --CF.sub.3, (3) --F, Cl,
--Br, or --I, (4) C.sub.1-C.sub.3 alkoxy, (5) --O--CF.sub.3, (6)
--NH.sub.2, (7) --OH, or (8) --C.ident.N, with the proviso that
when n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-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 R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: (1) .dbd.O, (2) C.sub.1-C.sub.3 alkyl,
(3) --CF.sub.3, (4) --F, Cl, --Br and --I, (5) C.sub.1-C.sub.3
alkoxy, (6) --O--CF.sub.3, (7) --NH.sub.2, (8) --OH, or (9)
--C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by nitrogen;
where R.sub.2 is: (I) --H, (II) C.sub.1-C.sub.6 alkyl, or (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
where R.sub.N is: (I) R.sub.N-1--X.sub.N-- where X.sub.N is: (A)
--CO--, (B) --SO.sub.2--, (C) --(CR'R'').sub.1-6 where R' and R''
are the same or different and are --H or C.sub.1-C.sub.4 alkyl, (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, (E) a
single bond; where R.sub.N-1 is: (A) R.sub.N-aryl where
R.sub.N-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)
C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or --I, (3) --OH, (4)
--NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one
to three --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl,
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, (8) --CO--(C.sub.3-C.sub.12 alkyl) (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), (10) --CO--R.sub.1-heteroaryl
where R.sub.1-heteroaryl is as defined above, (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5 where R.sub.N-5 is:
(a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, (28)
--S--(C.sub.1-C.sub.6 alkyl), (29) C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with 1, 2, 3, 4, or 5 --F, (30)
--O--(C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
3, 4, or 5 --F, or (31) --O-.phi., (B) --R.sub.N-heteroaryl where
R.sub.N-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)
.beta.-carbolinyl, (PP) isochromanyl, (QQ) chromanyl, (RR)
furazanyl, (SS) tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.N-heteroaryl group is bonded by any atom of the
parent R.sub.N-heteroaryl group substituted by hydrogen such that
the new bond to the R.sub.N-heteroaryl group replaces the hydrogen
atom and its bond, where heteroaryl is unsubstituted or substituted
with one or two: (1) C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or
--I, (3) --OH, (4) --NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
or 3 --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl, (e
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, (8) --CO--(C.sub.3-C.sub.12 alkyl), (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), (10) --CO--R.sub.1-heteroaryl
where R.sub.1-heteroaryl is as defined above, (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5 where R.sub.N-5 is:
(a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2 (C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, or (28)
--S--(C.sub.1-C.sub.6 alkyl), (C) --R.sub.N-aryl--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, (D)
--R.sub.N-aryl--R.sub.N-heteroaryl where --R.sub.N-aryl and
--R.sub.N-heteroaryl are as defined above, (E)
--R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl and
--R.sub.N-heteroaryl are as defined above, (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, (G) --R.sub.N-aryl--O--R.sub.N-aryl where
--R.sub.N-aryl is as defined above, (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, (M)
--R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is as
defined above, (N) --R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl
where R.sub.N-heteroaryl is as defined above, (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (P)
--R.sub.N-aryl--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl is
as defined above, (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, (II) A-X.sub.N-- where
X.sub.N is --CO--, wherein A is (A) -T-E(Q).sub.m', (1) where -T is
##STR00082## 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, (C.sub.1-C.sub.2) alkyl, phenyl, or
phenyl(C.sub.1-C.sub.3)alkyl; (2) -E is (a) C.sub.1-C.sub.5 alkyl,
but only if m' does not equal 0, (b)
methylthioxy(C.sub.2-C.sub.4)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 (C.sub.1-C.sub.8) alkyloxyphenyl, or (j)
C.sub.1-C.sub.6 alkoxy; (3) -Q is (a) C.sub.1-C.sub.3 alkyl, (b)
C.sub.1-C.sub.3 alkoxy, (c) C.sub.1-C.sub.3 alkylthioxy, (d)
C.sub.1-C.sub.6 alkylacylamino, (e) C.sub.1-C.sub.6 alkylacyloxy,
(f) amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), (g) C.sub.1-C.sub.6
alkylamino (h) phenylamino, (i) carbamyl (including C.sub.1-C.sub.6
alkyl and phenyl amides and esters), (j) carboxyl (including
C.sub.1-C.sub.6alkyl and phenyl esters), (k) carboxy
(C.sub.2-C.sub.5) alkoxy, (l) carboxy (C.sub.2-C.sub.5)
alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o)
hydroxyl; (4) m' is 0, 1, 2 or 3; (B) -E(Q).sub.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--(C.sub.1-C.sub.6alkyl) where alkyl
is unsubstituted or substituted with one or two: (A) --OH, (B)
--C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6 thioalkoxy, (D)
--CO--O--R.sub.N-8 where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or
-.phi., (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are the same or different and are as defined above, (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (IV) --CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or -.phi., (E) --CO--NR.sub.N-2R
.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different
and are as defined above, (F) --CO--R.sub.N-4 where R.sub.N-4 is as
defined above, (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (V) --CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or --(P, (E) --CO--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (F) --CO--R.sub.N-4 where R.sub.N-4 is as defined
above, (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is: (A)
--H, (B) C.sub.1-C.sub.6 alkyl, (C) C.sub.3-C.sub.7 cycloalkyl, (D)
C.sub.2-C.sub.6 alkenyl with one double bond, (E) C.sub.2-C.sub.6
alkynyl with one triple bond, (F) R.sub.1-aryl where R.sub.1-aryl
is as defined above, or (G) R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above; where B is --O--, --NH--,
or --N(C.sub.1-C.sub.6 alkyl)-; where R.sub.C is: (I)
--(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: (A) the alkyl chain
is unsubstituted or substituted with one --OH, (B) the alkyl chain
is unsubstituted or substituted with one C.sub.1-C.sub.6 alkoxy
unsubstituted or substituted with 1-5 --F, (C) the alkyl chain is
unsubstituted or substituted with one --O-.phi., (D) the alkyl
chain is unsubstituted or substituted with 1-5 --F, (E) the alkyl
chain is unsubstituted or substituted with a combination of up to
three atoms of oxygen and sulfur each such atom replacing one
carbon, (F) each K is: (1) H, (2) C.sub.1-C.sub.3 alkyl, (3)
C.sub.1-C.sub.3 alkoxy, (4) C.sub.1-C.sub.3 alkylthioxy, (5)
C.sub.1-C.sub.6 alkylacylamino, (6) C.sub.1-C.sub.6 alkylacyloxy,
(7) amido (8) C.sub.1-C.sub.6 alkylamino (9) phenylamino, (10)
carbamyl (11) carboxyl (12) carboxy (C.sub.2-C.sub.5) alkoxy, (13)
carboxy (C.sub.2-C.sub.5) alkylthioxy, (14) heterocyclylacyl, (15)
heteroarylacyl, (16) amino unsubstituted or substituted with
C.sub.1-C.sub.6 alkyl, (17) hydroxyl, or (18) carboxylmethyl ester;
(II) --(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K].sub.1-3
where K is as defined above and J is: (A) a 5 to 7 atom monocyclic
aryl group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7
atom heterocyclic group, (D) a 8 to 12 atom multicyclic
heterocyclic group, or (E) a 5 to 10 atom monocyclic or multicyclic
cycloalkyl group; (III) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7)
cycloalkyl where cycloalkyl can be unsubstituted or substituted
with one, two or three (A) C.sub.1-C.sub.3 alkyl unsubstituted or
substituted with 1, 2, 3, or 4 --F, --Cl, --Br, or --I, (B)
--CO--OH, (C) --CO--O--(C.sub.1-C.sub.4 alkyl), (D) --OH, or (E)
C.sub.1-C.sub.6 alkoxy, (IV) --(CH.sub.2).sub.2-6--OH, (V)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x and
R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.- and
R.sub.C-aryl is the same as R.sub.N-aryl, (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-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) isoxazolyl,
(Q) pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl,
(U) benzimidazolyl, (V) benzofuranyl, (W) furanyl, (X) thienyl, (Y)
pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)
tetrazolyl, (DD) 1,4-benzodioxan (EE) purinyl, (FF)
oxazolopyridinyl, (GG) imidazopyridinyl, (HH) isothiazolyl, (II)
naphthyridinyl, (JJ) cinnolinyl, (KK) carbazolyl, (LL)
.beta.-carbolinyl, (MM) isochromanyl, (NN) chromanyl, (OO)
furazanyl, (PP) tetrahydroisoquinoline, (QQ) isoindolinyl, (RR)
isobenzotetrahydrofuranyl, (SS) isobenzotetrahydrothienyl, (TT)
isobenzothiophenyl, (UU) benzoxazolyl, or (VV) pyridopyridinyl,
(VII) --(CH.sub.2).sub.0-4--R.sub.C-heterocycle where
R.sub.C-heterocycle is the same as R.sub.1-heterocycle, (VIII)
--C(R.sub.C-1) (R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: (A) --H, (B)
--C.sub.1-C.sub.6 alkyl, (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
R.sub.1-aryl, (D) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (E)
--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (F) --R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (G)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (H) --(CH.sub.2).sub.14--OH, (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or (K)
--R.sub.C-aryl where R.sub.C'-aryl is as defined above, and where
R.sub.C-3 is: (A) --H, (B) --C.sub.1-C.sub.6 alkyl, (C)
--R.sub.C'-aryl where R.sub.C'-aryl is as defined above, (D)
--R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above,
(E) --R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (IX) --CH(.phi.).sub.2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or
heteroaryl ring where heteroaryl is as defined above and phenyl and
heteroaryl are unsubstituted or substituted with one, two or three:
(A) C.sub.1-C.sub.3 alkyl, (B) --CF.sub.3, (C) --F, Cl, --Br and
--I, (D) C.sub.1-C.sub.3 alkoxy, (E) --OCF.sub.3, (F) --NH.sub.2,
(G) --OH, or (H) --C.ident.N, (XI) --CH.sub.2--C.ident.CH; (XII)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: (A) --OH, or (B) --CH.sub.2--OH; (XIII)
--CH(-.phi.)-CO--O(C.sub.1-C.sub.3 alkyl); (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; (XV)
--(CH.sub.2).sub.2-.phi.-(CH.sub.2).sub.2--OH; (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; (XVII)
--(C.sub.2-C.sub.8) alkynyl; or (XVIII) --H; or a pharmaceutically
acceptable salt thereof.
2-48. (canceled)
49. A method for treating or preventing a disease characterized by
beta-amyloid deposits in the brain comprising administering to a
patient an effective therapeutic amount of a hydroxyethylene
compound of the formula ##STR00083## where R.sub.1 is: (I)
C.sub.1-C.sub.6 alkyl, unsubstituted or substituted with one, two
or three C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--NH.sub.2, --C.ident.N, --CF.sub.3, or --N.sub.3, (II)
--(CH.sub.2).sub.1-2--S--CH.sub.3, (III)
--CH.sub.2--CH.sub.2--S--CH.sub.3, (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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) C.sub.1-C.sub.3 alkyl, (B)
--CF.sub.3, (C) --F, Cl, --Br and --I, (D) C.sub.1-C.sub.3 alkoxy,
(E) --O--CF.sub.3, (F) --NH.sub.2, (G) --OH, or (H) --C.ident.N,
(VI) --(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0,
1, 2, or 3 and R.sub.1-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) .beta.-carbolinyl, (PP)
isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)
tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.1-heteroaryl group is bonded to
--(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: (1) C.sub.1-C.sub.3 alkyl, (2) --CF.sub.3, (3) --F, Cl,
--Br, or --I, (4) C.sub.1-C.sub.3 alkoxy, (5) --O--CF.sub.3, (6)
--NH.sub.2, (7) --OH, or (8) --C.ident.N, with the proviso that
when n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-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 R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: (1) .dbd.O, (2) C.sub.1-C.sub.3 alkyl,
(3) --CF.sub.3, (4) --F, Cl, --Br and --I, (5) C.sub.1-C.sub.3
alkoxy, (6) --O--CF.sub.3, (7) --NH.sub.2, (8) --OH, or (9)
--C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by nitrogen;
where R.sub.2 is: (I) --H, (II) C.sub.1-C.sub.6 alkyl, or (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
where R.sub.N is: (I) R.sub.N-1--X.sub.N-- where X.sub.N is: (A)
--CO--, (B) --SO.sub.2--, (C) --(CR'R'').sub.1-6 where R' and R''
are the same or different and are --H or C.sub.1-C.sub.4 alkyl, (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, (E) a
single bond; where R.sub.N-1 is: (A) R.sub.N-aryl where
R.sub.N-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)
C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or --I, (3) --OH, (4)
--NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one
to three --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl,
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, (8) --CO--(C.sub.3-C.sub.12 alkyl), (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), (10) --CO--R.sub.1-heteroaryl
where R.sub.1-heteroaryl is as defined above, (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5 where R.sub.N-5 is:
(a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2 (C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, (28)
--S--(C.sub.1-C.sub.6 alkyl), (29) C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with 1, 2, 3, 4, or 5 --F, (30)
--O--(C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
3, 4, or 5 --F, or (31) --O-.phi., (B) --R.sub.N-heteroaryl where
R.sub.N-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)
.beta.-carbolinyl, (PP) isochromanyl, (QQ) chromanyl, (RR)
furazanyl, (SS) tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.N-heteroaryl group is bonded by any atom of the
parent R.sub.N-heteroaryl group substituted by hydrogen such that
the new bond to the R.sub.N-heteroaryl group replaces the hydrogen
atom and its bond, where heteroaryl is unsubstituted or substituted
with one or two: (1) C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or
--I, (3) --OH, (4) --NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
or 3 --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl, (e
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R-aryl where R.sub.1-aryl is as defined above, or (k)
--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined above,
(8) --CO--(C.sub.3-C.sub.12 alkyl), (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), (10) --CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl
is as defined above, (11) --CO--R.sub.1-heterocycle where
R.sub.1-heterocycle is as defined above, (12) --CO--R.sub.N-4 where
R.sub.N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl
or pyrrolidinyl where each group is unsubstituted or substituted
with one or two C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5
where R.sub.N-5 is: (a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, or (28)
--S--(C.sub.1-C.sub.6 alkyl), (C) --R.sub.N-aryl--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, (D)
--R.sub.N-aryl--R.sub.N-heteroaryl where --R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, (E)
--R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl and
--R.sub.N-heteroaryl are as defined above, (F)
R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl is
as defined above, (G) --R.sub.N-aryl--O--R.sub.N-aryl where
--R.sub.N-aryl is as defined above, (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, (M)
--R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is as
defined above, (N) --R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl
where R.sub.N-heteroaryl is as defined above, (O)
R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, (R)
--R.sub.N-heteroaryl--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, (II) A-X.sub.N-- where
X.sub.N is --CO--, wherein A is (A) -T-E-(Q).sub.m', (1) where -T
is ##STR00084## 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, (C.sub.1-C.sub.2) alkyl, phenyl, or
phenyl(C.sub.1-C.sub.3)alkyl; (2) -E is (a) C.sub.1-C.sub.5 alkyl,
but only if m' does not equal 0, (b)
methylthioxy(C.sub.2-C.sub.4)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 (C.sub.1-C.sub.8) alkyloxyphenyl, or (j)
C.sub.1-C.sub.6 alkoxy; (3) -Q is (a) C.sub.1-C.sub.3 alkyl, (b)
C.sub.1-C.sub.3 alkoxy, (c) C.sub.1-C.sub.3 alkylthioxy, (d)
C.sub.1-C.sub.6 alkylacylamino, (e) C.sub.1-C.sub.6 alkylacyloxy,
(f) amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), (g) C.sub.1-C.sub.6
alkylamino (h) phenylamino, (i) carbamyl (including C.sub.1-C.sub.6
alkyl and phenyl amides and esters), (j) carboxyl (including
C.sub.1-C.sub.6 alkyl and phenyl esters), (k)
carboxy(C.sub.2-C.sub.5) alkoxy, (l) carboxy (C.sub.2-C.sub.5)
alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o)
hydroxyl; (4) m' is 0, 1, 2 or 3; (B) -E(Q).sub.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--(C.sub.1-C.sub.6 alkyl) where
alkyl is unsubstituted or substituted with one or two: (A) --OH,
(B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6 thioalkoxy, (D)
--CO--O--R.sub.N-8 where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or
-.phi., (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are the same or different and are as defined above, (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (IV) --CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or -
.phi., (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are the same or different and are as defined above, (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (V) --CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or --(P, (E) --CO--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (F) --CO--R.sub.N-4 where R.sub.N-4 is as defined
above, (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is: (A)
--H, (B) C.sub.1-C.sub.6 alkyl, (C) C.sub.3-C.sub.7 cycloalkyl, (D)
C.sub.2-C.sub.6 alkenyl with one double bond, (E) C.sub.2-C.sub.6
alkynyl with one triple bond, (F) R.sub.1-aryl where R.sub.1-aryl
is as defined above, or (G) R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above; where B is --O--, --NH--,
or --N(C.sub.1-C.sub.6 alkyl)-; where R.sub.C is: (I)
--(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: (A) the alkyl chain
is unsubstituted or substituted with one --OH, (B) the alkyl chain
is unsubstituted or substituted with one C.sub.1-C.sub.6 alkoxy
unsubstituted or substituted with 1-5 --F, (C) the alkyl chain is
unsubstituted or substituted with one --O-.phi., (D) the alkyl
chain is unsubstituted or substituted with 1-5 --F, (E) the alkyl
chain is unsubstituted or substituted with a combination of up to
three atoms of oxygen and sulfur each such atom replacing one
carbon, (F) each K is: (1) H, (2) C.sub.1-C.sub.3 alkyl, (3)
C.sub.1-C.sub.3 alkoxy, (4) C.sub.1-C.sub.3 alkylthioxy, (5)
C.sub.1-C.sub.6 alkylacylamino, (6) C.sub.1-C.sub.6 alkylacyloxy,
(7) amido (8) C.sub.1-C.sub.6 alkylamino (9) phenylamino, (10)
carbamyl (11) carboxyl (12) carboxy(C.sub.2-C.sub.5) alkoxy, (13)
carboxy (C.sub.2-C5) alkylthioxy, (14) heterocyclylacyl, (15)
heteroarylacyl, (16) amino unsubstituted or substituted with
C.sub.1-C.sub.6 alkyl, (17) hydroxyl, or (18) carboxyl methyl
ester; (II)
--(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K].sub.1-3 where K
is as defined above and J is: (A) a 5 to 7 atom monocyclic aryl
group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atom
heterocyclic group, (D) a 8 to 12 atom multicyclic heterocyclic
group, or (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl
group; (III)--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl
where cycloalkyl can be unsubstituted or substituted with one, two
or three (A) C.sub.1-C.sub.3 alkyl unsubstituted or substituted
with 1, 2, 3, or 4 --F, --Cl, --Br, or --I, (B) --CO--OH, (C)
--CO--O--(C.sub.1-C.sub.4 alkyl), (D) --OH, or (E) C.sub.1-C.sub.6
alkoxy, (IV) --(CH.sub.2).sub.2-6--OH, (V)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x and
R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.- and
R.sub.C-aryl is the same as R.sub.N-aryl, (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-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) isoxazolyl,
(Q) pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl,
(U) benzimidazolyl, (V) benzofuranyl, (W) furanyl, (X) thienyl, (Y)
pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)
tetrazolyl, (DD) 1,4-benzodioxan (EE) purinyl, (FF)
oxazolopyridinyl, (GG) imidazopyridinyl, (HH) isothiazolyl, (II)
naphthyridinyl, (JJ) cinnolinyl, (KK) carbazolyl, (LL)
.beta.-carbolinyl, (MM) isochromanyl, (NN) chromanyl, (OO)
furazanyl, (PP) tetrahydroisoquinoline, (QQ) isoindolinyl, (RR)
isobenzotetrahydrofuranyl, (SS) isobenzotetrahydrothienyl, (TT)
isobenzothiophenyl, (UU) benzoxazolyl, or (VV) pyridopyridinyl,
(VII) --(CH.sub.2).sub.0-4--R.sub.C-heterocycle where
R.sub.C-heterocycle is the same as R.sub.1-heterocycle, (VIII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: (A) --H, (B)
--C.sub.1-C.sub.6 alkyl, (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
R.sub.1-aryl, (D) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (E)
--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (F) --R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (G)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (H) --(CH.sub.2).sub.1-4--OH, (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or (K)
--R.sub.C'-aryl where R.sub.C'-aryl is as defined above, and where
R.sub.C-3 is: (A) --H, (B) --C.sub.1-C.sub.6 alkyl, (C)
--R.sub.C'-aryl where R.sub.C'-aryl is as defined above, (D)
--R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above,
(E) --R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (IX) --CH(.phi.).sub.2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or
heteroaryl ring where heteroaryl is as defined above and phenyl and
heteroaryl are unsubstituted or substituted with one, two or three:
(A) C.sub.1-C.sub.3 alkyl, (B) --CF.sub.3, (C) --F, Cl, --Br and
--I, (D) C.sub.1-C.sub.3 alkoxy, (E) --OCF.sub.3, (F) --NH.sub.2,
(G) --OH, or (H) --C.ident.N, (XI) --CH.sub.2--C.ident.CH; (XII)
--(CH.sub.2).sub.01--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: (A) --OH, or (B) --CH.sub.2--OH; (XIII)
--CH(-.phi.)-CO--O(C.sub.1-C.sub.3 alkyl); (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; (XV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; (XVII)
--(C.sub.2-C.sub.8) alkynyl; or (XVIII) --H; or a pharmaceutically
acceptable salt thereof.
50-59. (canceled)
60. A composition comprising .beta.-secretase complexed with a
hydroxyethylene compound of the formula ##STR00085## where R.sub.1
is: (I) C.sub.1-C.sub.6 alkyl, unsubstituted or substituted with
one, two or three C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --NH.sub.2, --C.ident.N, --CF.sub.3, or --N.sub.3, (II)
--(CH.sub.2).sub.12--S--CH.sub.3, (III)
--CH.sub.2--CH.sub.2--S--CH.sub.3, (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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) C.sub.1-C.sub.3 alkyl, (B)
--CF.sub.3, (C) --F, Cl, --Br and --I, (D) C.sub.1-C.sub.3 alkoxy,
(E) --O--CF.sub.3, (F) --NH.sub.2, (G) --OH, or (H) --C.ident.N,
(VI) --(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0,
1, 2, or 3 and R.sub.1-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) .beta.-carbolinyl, (PP)
isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)
tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.1-heteroaryl group is bonded to
--(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: (1) C.sub.1-C.sub.3 alkyl, (2) --CF.sub.3, (3) --F, Cl,
--Br, or --I, (4) C.sub.1-C.sub.3 alkoxy, (5) --O--CF.sub.3, (6)
--NH.sub.2, (7) --OH, or (8) --C.ident.N, with the proviso that
when n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-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 R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: (1) .dbd.O, (2) C.sub.1-C.sub.3 alkyl,
(3) --CF.sub.3, (4) --F, Cl, --Br and --I, (5) C.sub.1-C.sub.3
alkoxy, (6) --O--CF.sub.3, (7) --NH.sub.2, (8) --OH, or (9)
--C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by nitrogen;
where R.sub.2 is: (I) --H, (II) C.sub.1-C.sub.6 alkyl, or (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
where R.sub.N is: (I) R.sub.N-1--X.sub.N-- where X.sub.N is: (A)
--CO--, (B) --SO.sub.2--, (C) --(CR'R'').sub.1-6 where R' and R''
are the same or different and are --H or C.sub.1-C.sub.4 alkyl, (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, (E) a
single bond; where R.sub.N-1 is: (A) R.sub.N-aryl where
R.sub.N-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)
C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or --I, (3) --OH, (4)
--NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one
to three --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl,
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, (8) --CO--(C.sub.3-C.sub.12 alkyl), (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), (10) --CO--R.sub.1-heteroaryl
where R.sub.1-heteroaryl is as defined above, (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5 where R.sub.N-5 is:
(a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl) 2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, (28)
--S--(C.sub.1-C.sub.6 alkyl), (29) C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with 1, 2, 3, 4, or 5 --F, (30)
--O--(C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
3, 4, or 5 --F, or (31) --O-.phi., (B) --R.sub.N-heteroaryl where
R.sub.N-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)
.beta.-carbolinyl, (PP) isochromanyl, (QQ) chromanyl, (RR)
furazanyl, (SS) tetrahydroisoquinoline, (TT) isoindolinyl, (UU)
isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)
isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl,
where the R.sub.N-heteroaryl group is bonded by any atom of the
parent R.sub.N-heteroaryl group substituted by hydrogen such that
the new bond to the R.sub.N-heteroaryl group replaces the hydrogen
atom and its bond, where heteroaryl is unsubstituted or substituted
with one or two: (1) C.sub.1-C.sub.6 alkyl, (2) --F, --Cl, --Br, or
--I, (3) --OH, (4) --NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: (a) --H, (b) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one (i) --OH, or (ii) --NH.sub.2,
(c) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2,
or 3 --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.7 cycloalkyl, (e
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl where R.sub.1-aryl is as defined above, or
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, (8) --CO--(C.sub.3-C.sub.12 alkyl), (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), (10) --CO--R.sub.1-heteroaryl
where R.sub.1-heteroaryl is as defined above, (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, (13) --CO--O--R.sub.N-5 where R.sub.N-5 is:
(a) C.sub.1-C.sub.6 alkyl, or (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1-C.sub.8
alkyl), (16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18)
--NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (20) --N(C.sub.1-C.sub.3
alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same
or different and are as defined above, (22) --R.sub.N-4 where
R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1-C.sub.6
alkyl), (24) --O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1-C.sub.6
alkyl), (27) --O--(C.sub.2-C.sub.5 alkyl)-COOH, or (28)
--S--(C.sub.1-C.sub.6 alkyl), (C) --R.sub.N-aryl--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, (D)
--R.sub.N-aryl--R.sub.N-heteroaryl where --R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, (E)
--R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl and
--R.sub.N-heteroaryl are as defined above, (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, (G) --R.sub.N-aryl--O--R.sub.N-aryl where
--R.sub.N-aryl is as defined above, (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, (M)
--R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where R.sub.N-aryl is as
defined above, (N) --R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl
where R.sub.N-heteroaryl is as defined above, (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, (O)--R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, (II) A-X.sub.N-- where
X.sub.N is --CO--, wherein A is (A) -T-E-(Q).sub.m', (1) where -T
is ##STR00086## 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, (C.sub.1-C.sub.2) alkyl, phenyl, or
phenyl(C.sub.1-C.sub.3)alkyl; (2) -E is (a) C.sub.1-C.sub.5 alkyl,
but only if m' does not equal 0, (b)
methylthioxy(C.sub.2-C.sub.4)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(C.sub.1-C.sub.8)alkyloxyphenyl, or (j)
C.sub.1-C.sub.6 alkoxy; (3) -Q is (a) C.sub.1-C.sub.3 alkyl, (b)
C.sub.1-C.sub.3 alkoxy, (c) C.sub.1-C.sub.3 alkylthioxy, (d)
C.sub.1-C.sub.6 alkylacylamino, (e) C.sub.1-C.sub.6 alkylacyloxy,
(f) amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), (g) C.sub.1-C.sub.6
alkylamino (h) phenylamino, (i) carbamyl (including C.sub.1-C.sub.6
alkyl and phenyl amides and esters), (j) carboxyl (including
C.sub.1-C.sub.6alkyl and phenyl esters), (k) carboxy
(C.sub.2-C.sub.5) alkoxy, (l) carboxy (C.sub.2-C.sub.5)
alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o)
hydroxyl; (4) m' is 0, 1, 2 or 3; (B) -E(Q).sub.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--(C.sub.1-C.sub.6 alkyl) where
alkyl is unsubstituted or substituted with one or two: (A) --OH,
(B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6 thioalkoxy, (D)
--CO--O--R.sub.N-8 where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or
-.phi., (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are the same or different and are as defined above, (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (IV) --CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or -.phi., (E) --CO--NR.sub.N-2R.sub.N-3
where R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above,
(F) --CO--R.sub.N-4 where R.sub.N-4 is as defined above, (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (V) --CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3
alkyl) where alkyl is unsubstituted or substituted with one or two
(A) --OH, (B) --C.sub.1-C.sub.6 alkoxy, (C) --C.sub.1-C.sub.6
thioalkoxy, (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or -.phi., (E) --CO--NR.sub.N-2R.sub.N-3
where R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (F) --CO--R.sub.N-4 where R.sub.N-4 is as defined
above, (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (J) --NH--CO--O--R.sub.N-8 where
R.sub.N-8 is as defined above, (K) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, (L) --R.sub.N-4 where R.sub.N-4 is as defined above,
(M) --O--CO--(C.sub.1-C.sub.6 alkyl), (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or (O) --O--(C.sub.1-C.sub.5
alkyl)-COOH, (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is: (A)
--H, (B) C.sub.1-C.sub.6 alkyl, (C) C.sub.3-C.sub.7 cycloalkyl, (D)
C.sub.2-C.sub.6 alkenyl with one double bond, (E) C.sub.2-C.sub.6
alkynyl with one triple bond, (F) R.sub.1-aryl where R.sub.1-aryl
is as defined above, or (G) R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above; where B is --O--, --NH--,
or --N(C.sub.1-C.sub.6 alkyl)-; where R.sub.C is: (I)
--(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: (A) the alkyl chain
is unsubstituted or substituted with one --OH, (B) the alkyl chain
is unsubstituted or substituted with one C.sub.1-C.sub.6 alkoxy
unsubstituted or substituted with 1-5 --F, (C) the alkyl chain is
unsubstituted or substituted with one --O-.phi., (D) the alkyl
chain is unsubstituted or substituted with 1-5 --F, (E) the alkyl
chain is unsubstituted or substituted with a combination of up to
three atoms of oxygen and sulfur each such atom replacing one
carbon, (F) each K is: (1) H, (2) C.sub.1-C.sub.3 alkyl, (3)
C.sub.1-C.sub.3 alkoxy, (4) C.sub.1-C.sub.3 alkylthioxy, (5)
C.sub.1-C.sub.6 alkylacylamino, (6) C.sub.1-C.sub.6 alkylacyloxy,
(7) amido (8) C.sub.1-C.sub.6 alkylamino (9) phenylamino, (10)
carbamyl (11) carboxyl (12) carboxy(C.sub.2-C.sub.5) alkoxy, (13)
carboxy (C.sub.2-C.sub.5) alkylthioxy, (14) heterocyclylacyl, (15)
heteroarylacyl, (16) amino unsubstituted or substituted with
C.sub.1-C.sub.6 alkyl, (17) hydroxyl, or (18) carboxyl methyl
ester; (II)
--(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K].sub.1-3 where K
is as defined above and J is: (A) a 5 to 7 atom monocyclic aryl
group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atom
heterocyclic group, (D) a 8 to 12 atom multicyclic heterocyclic
group, or (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl
group; (III) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl
where cycloalkyl can be unsubstituted or substituted with one, two
or three (A) C.sub.1-C.sub.3 alkyl unsubstituted or substituted
with 1, 2, 3, or 4 --F, --Cl, --Br, or --I, (B) --CO--OH, (C)
--CO--O--(C.sub.1-C.sub.4 alkyl) (D) --OH, or (E) C.sub.1-C.sub.6
alkoxy, (IV) --(CH.sub.2).sub.2-6--OH, (V)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x and
R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.- and
R.sub.C-aryl is the same as R.sub.N-aryl, (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-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) isoxazolyl,
(Q) pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl,
(U) benzimidazolyl, (V) benzofuranyl, (W) furanyl, (X) thienyl, (Y)
pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)
tetrazolyl, (DD) 1,4-benzodioxan (EE) purinyl, (FF)
oxazolopyridinyl, (GG) imidazopyridinyl, (HH) isothiazolyl, (II)
naphthyridinyl, (JJ) cinnolinyl, (KK) carbazolyl, (LL)
.beta.-carbolinyl, (MM) isochromanyl, (NN) chromanyl, (OO)
furazanyl, (PP) tetrahydroisoquinoline, (QQ) isoindolinyl, (RR)
isobenzotetrahydrofuranyl, (SS) isobenzotetrahydrothienyl, (TT)
isobenzothiophenyl, (UU) benzoxazolyl, or (VV) pyridopyridinyl,
(VII) --(CH.sub.2).sub.0-4--R.sub.C-heterocycle where
R.sub.C-heterocycle is the same as R.sub.1-heterocycle, (VIII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: (A) --H, (B)
--C.sub.1-C.sub.6 alkyl, (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
R.sub.1-aryl, (D) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (E)
--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (F) --R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, (G)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (H) --(CH.sub.2).sub.14--OH, (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or (K)
--R.sub.C'-aryl where R.sub.C'-aryl is as defined above, and where
R.sub.C-3 is: (A) --H, (B) --C.sub.1-C.sub.6 alkyl, (C)
--R.sub.C'-aryl where R.sub.C'-aryl is as defined above, (D)
--R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above,
(E) --R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, (IX) --CH(.phi.).sub.2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or
heteroaryl ring where heteroaryl is as defined above and phenyl and
heteroaryl are unsubstituted or substituted with one, two or three:
(A) C.sub.1-C.sub.3 alkyl, (B) --CF.sub.3, (C) --F, Cl, --Br and
--I, (D) C.sub.1-C.sub.3 alkoxy, (E) --OCF.sub.3, (F) --NH.sub.2,
(G) --OH, or (H) --C.ident.N, (XI) --CH.sub.2--C.ident.CH; (XII)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: (A) --OH, or (B) --CH.sub.2--OH; (XIII)
--CH(-.phi.)-CO--O(C.sub.1-C.sub.3 alkyl) (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; (XV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; (XVII)
--(C.sub.2-C.sub.8) alkynyl; or (XVIII) --H; or a pharmaceutically
acceptable salt thereof.
61. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of invention under 35
U.S.C. .sctn.119(e) from U.S. provisional application No.
60/191,528, filed Mar. 23, 2000.
FIELD OF THE INVENTION
[0002] The present invention provides compounds, compositions, and
methods for inhibiting .beta.-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.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's Disease (AD) is a degenerative brain disorder
presented clinically by progressive loss of memory, cognition,
reasoning, judgment, 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 cognitive
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.
[0004] 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 (A.beta., also sometimes designated
.beta.A4).
[0005] Several isotypes of APP are known to date, including
"normal" APP-695, APP-751, and APP770, having a sequence of 695,
751, and 770 amino acids, respectively. The identification of
mutations in the beta amyloid precursor protein gene that cause
familial, early onset AD implicate beta amyloid metabolism in the
pathology of the disease. Such reported mutations include the
double Swedish mutation (SW), changing Lys.sup.595 and Met.sup.596
to Asp.sup.595-Leu.sup.596, and mutations altering Val.sup.717 to
Gly, Ile, or Phe.
[0006] A.beta. peptide is derived by proteolysis of the beta
amyloid precursor protein (APP) and is comprised of 39-42 amino
acids. Several proteases called secretases are involved in the
processing of APP. Deposition of A.beta. in areas of the brain
responsible for cognitive activities is a major factor in the
development of AD. Cleavage of APP at the N-terminus of the
.beta.A4 peptide by .beta.-secretase and at the C-terminus by one
or more .gamma.-secretases constitutes the beta amyloidogenic
pathway, i.e. the pathway by which A.beta. is formed. Cleavage of
APP by .alpha.-secretase and the same or a different
.gamma.-secretase produces .alpha.-sAPP, a secreted form of APP
that does not result in beta amyloid plaque formation. This
alternate .alpha.-sAPP pathway precludes the formation of A.beta.
peptide. It has been proposed that A.beta. accumulates as a result
of processing of APP by .beta.-secretase, and that therefore
inhibition of the activity of this enzyme is desirable for the
treatment of AD. In vivo processing of APP at the .beta.-secretase
site is thought to be the rate-limiting step in A.beta. production,
and is thus a therapeutic target for the treatment of AD. See, for
example, Sabbagh et. al., 1997, Alz. Dis. Rev. 3:1-19). A
description of the proteolytic processing fragments of APP can be
found, for example, in U.S. Pat. Nos. 5,441,870, 5,721,130, and
5,942,400.
[0007] Several lines of evidence indicate that progressive cerebral
deposition of particular beta amyloidogenic peptides,
.beta.-amyloid peptides, (A.beta.), play a seminal role in the
pathogenesis of AD and can precede cognitive symptoms by years or
decades. See, for example, Selkoe, 1991, Neuron 6:487. Recently, it
has been shown that A.beta. is released from neuronal cells grown
in culture and is present in cerebrospinal fluid (CSF) of both
normal individuals and AD patients. See, for example, Seubert et
al., 1992, Nature 359:325-327.
[0008] An aspartyl protease has been identified as the enzyme
responsible for processing of APP at the .beta.-secretase cleavage
site. The .beta.-secretase enzyme has been disclosed using varied
nomenclature, including BACE and Asp. See, for example, Sindha et.
al., 1999, Nature 402:537-554 (p 501) and published PCT application
WO00/17369 (hAsp2a and hAsp2b).
[0009] At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimeres disease.
Therefore, there is an urgent need for pharmaceutical agents
capable of slowing the progression of Alzheimer's disease and/or
preventing it in the first place.
[0010] Compounds that are effective inhibitors of .beta.-secretase,
that inhibit .beta.-secretase-mediated cleavage of APP, that are
effective inhibitors of A.beta. production, and/or are effective to
reduce beta amyloid beta deposits or plaques are needed for the
treatment and prevention of disease characterized by beta amyloid
beta deposits or plaques, such as AD.
SUMMARY OF INVENTION
[0011] The present invention provides compounds, compositions, and
methods for inhibiting .beta.-secretase-mediated cleavage of beta
amyloid precursor protein. More particularly, the compounds,
compositions, and methods of the invention are effective to inhibit
the production of beta-beta amyloid peptide and to treat or prevent
disease characterized by beta-beta amyloid peptide deposits.
[0012] Most particularly, the compounds, compositions, and methods
of the invention are effective for treating humans who have
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 Beta amyloidosis of the Dutch-Type, for
treating cerebral beta 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, diffuse Lewis body type of Alzheimer's
disease.
[0013] The inhibitory activities of the compounds of the invention
can be demonstrated, for example, using one or more of the assays
described herein or in the prior art.
[0014] The compounds (XII) of the invention possess
.beta.-secretase inhibitory activity:
##STR00002##
[0015] where R.sub.1 is: [0016] (I) C.sub.1-C.sub.6 alkyl, [0017]
(II) C.sub.1-C.sub.6 alkyl-5-alkyl [0018] (III) C.sub.1-C.sub.6
alkyl-(C.sub.2-C.sub.6 alkenyl), [0019] (IV)
--(CH.sub.2).sub.0-6-alkyl --(R.sub.1-aryl) where R.sub.1-aryl is
unsubstituted or substituted with: [0020] (A) C.sub.1-C.sub.6
alkyl, [0021] (B) --CF.sub.3, [0022] (C) --F, Cl, --Br or --I,
[0023] (D) C.sub.1-C.sub.3 alkoxy, [0024] (E) --O--CF.sub.3, [0025]
(F) --NH.sub.2, [0026] (G) --OH, or [0027] (H)--C.ident.N, [0028]
(V) --(CH.sub.2).sub.0-6-alkyl-(R.sub.1-heteroaryl) where
R.sub.1-heteroaryl is: [0029] (A) pyridinyl, [0030] (B)
pyrimidinyl, [0031] (C) quinolinyl, [0032] (D) indenyl, [0033] (E)
indanyl, [0034] (F) benzothiophenyl, [0035] (G) indolyl, [0036] (H)
indolinyl, [0037] (I) pyridazinyl, [0038] (J) pyrazinyl, [0039] (K)
isoindolyl, [0040] (L) isoquinolyl, [0041] (M) quinazolinyl, [0042]
(N) quinoxalinyl, [0043] (O) phthalazinyl, [0044] (P) imidazolyl,
[0045] (Q) isoxazolyl, [0046] (R) pyrazolyl, [0047] (S) oxazolyl,
[0048] (T) thiazolyl, [0049] (U) indolizinyl, [0050] (V) indazolyl,
[0051] (W) benzothiazolyl, [0052] (X) benzimidazolyl, [0053] (Y)
benzofuranyl, [0054] (Z) furanyl, [0055] (AA) thienyl, [0056] (BB)
pyrrolyl, [0057] (CC) oxadiazolyl, [0058] (DD) thiadiazolyl, [0059]
(EE) triazolyl, [0060] (FF) tetrazolyl, [0061] (GG) 1,4-benzodioxan
[0062] (HH) purinyl, [0063] (II) oxazolopyridinyl, [0064] (JJ)
imidazopyridinyl, [0065] (KK) isothiazolyl, [0066] (LL)
naphthyridinyl, [0067] (MM) cinnolinyl, [0068] (NN) carbazolyl,
[0069] (OO) .beta.-carbolinyl, [0070] (PP) isochromanyl, [0071]
(QQ) chromanyl, [0072] (RR) furazanyl, [0073] (SS)
tetrahydroisoquinoline, [0074] (TT) isoindolinyl, [0075] (UU)
isobenzotetrahydrofuranyl, [0076] (VV) isobenzotetrahydrothienyl,
[0077] (WW) isobenzothiophenyl, [0078] (XX) benzoxazolyl, or [0079]
(YY) pyridopyridinyl, where the R.sub.1-heteroaryl group is bonded
to -alkyl- by any ring atom of the parent R.sub.N-heteroaryl group
substituted by hydrogen such that the new bond to the
R.sub.1-heteroaryl group replaces the hydrogen atom and its bond,
where R.sub.1-heteroaryl is unsubstituted or substituted with:
[0080] (1) C.sub.1-C.sub.3 alkyl, [0081] (2) --CF.sub.3, [0082] (3)
--F, Cl, --Br, or I, [0083] (4) C.sub.1-C.sub.3 alkoxy, [0084] (5)
--O--CF.sub.3, [0085] (6) --NH.sub.2, [0086] (7) --OH, or [0087]
(8) --C.ident.N, [0088] (VI) --(R.sub.1-heteroaryl) where
R.sub.1-heteroaryl is as defined above, [0089] (VII)
--C.sub.1-C.sub.5 alkyl-(R.sub.1-heterocycle) where
R.sub.1-heterocycle is: [0090] (A) morpholinyl, [0091] (B)
thiomorpholinyl, [0092] (C) thiomorpholinyl S-oxide, [0093] (D)
thiomorpholinyl S,S-dioxide, [0094] (E) piperazinyl, [0095] (F)
homopiperazinyl, [0096] (G) pyrrolidinyl, [0097] (H) pyrrolinyl,
[0098] (I) tetrahydropyranyl, [0099] (J) piperidinyl, [0100] (K)
tetrahydrofuranyl, or [0101] (L) tetrahydrothiophenyl, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where R.sub.1-heterocycle is unsubstituted or substituted
with: [0102] (1) .dbd.O, [0103] (2) C.sub.1-C.sub.3 alkyl, [0104]
(3) --CF.sub.3, [0105] (4) --F, Cl, --Br or --I, [0106] (5)
C.sub.1-C.sub.3 alkoxy, [0107] (6) --CF.sub.3, [0108] (7)
--NH.sub.2, [0109] (8) --OH, or [0110] (9) --C.ident.N, or [0111]
(VIII) --R.sub.1-heterocycle with R.sub.1-heterocycle as defined
above;
[0112] where R.sub.2 is: [0113] (I) --H, [0114] (II) alkyl, or
[0115] (III) --C.sub.1-C.sub.5 alkyl-R.sub.2-1 where R.sub.2-1 is
cycloalkyl, R.sup.1-aryl or R.sub.1-heteroaryl where R.sub.1-aryl
and R.sub.1-heteroaryl are as defined above,
[0116] where R.sub.N is: [0117] (I) R.sub.N-1--X.sub.N-- where
X.sub.N is: [0118] (A) --CO--, [0119] (B) --SO.sub.2--, [0120]
(C)--(CR'R'').sub.1-6 where R' and R'' are the same or different
and are --H or C.sub.1-C.sub.4 alkyl, [0121] (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
or --NR'R''-- and where R' and R'' are as defined above, or [0122]
(E) a single bond;
[0123] where R.sub.N-1 is: [0124] (A) R.sub.N-aryl where
R.sub.N-aryl is unsubstituted or substituted with: [0125] (1)
C.sub.1-C.sub.6 alkyl, [0126] (2) --F, --Cl, --Br, or --I, [0127]
(3) --OH, [0128] (4) --NO.sub.2, [0129] (5) --CO--OH, [0130] (6)
--C.ident.N, [0131] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [0132] (a) --H,
[0133] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with [0134] (i) --OH, or [0135] (ii) --NH.sub.2, [0136] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with --F,
--Cl, --Br, or --I, [0137] (d) --C.sub.3-C.sub.7 cycloalkyl, [0138]
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [0139]
(f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0140]
(g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds, [0141]
(h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds, [0142]
(i) --C.sub.1-C.sub.6 alkyl chain with one double bond and one
triple bond, [0143] (j) --R.sub.1-aryl where R.sub.1-aryl is as
defined above, or [0144] (k) --R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [0145] (8)
--CO--(C.sub.3-C.sub.12 alkyl), [0146] (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), [0147] (10) --CO--R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [0148] (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, [0149] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with C.sub.1-C.sub.3
alkyl, [0150] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [0151]
(a) alkyl, or [0152] (b) --(CH.sub.2).sub.0-2--(R.sub.1-aryl) where
R.sub.1-aryl is as defined above, [0153] (14)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
as defined above, [0154] (15) --SO--(C.sub.1-C.sub.8 alkyl), [0155]
(16) --SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0156] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0157]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0158] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0159] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [0160] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [0161] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[0162] (23) --CO--(C.sub.1-C.sub.6 alkyl), [0163] (24)
O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0164] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0165] (26)
--O--(C.sub.1-C.sub.6 alkyl), [0166] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, [0167] (28) --S--(C.sub.1-C.sub.6 alkyl), [0168] (29)
C.sub.1-C.sub.6 alkyl unsubstituted or substituted with halo,
[0169] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or
substituted with halo), or [0170] (31) --O-.phi., [0171] (B)
--R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [0172] (A)
pyridinyl, [0173] (B) pyrimidinyl, [0174] (C) quinolinyl, [0175]
(D) indenyl, [0176] (E) indanyl, [0177] (F) benzothiophenyl, [0178]
(G) indolyl, [0179] (H) indolinyl, [0180] (I) pyridazinyl, [0181]
(J) pyrazinyl, [0182] (K) isoindolyl, [0183] (L) isoquinolyl,
[0184] (M) quinazolinyl, [0185] (N) quinoxalinyl, [0186] (O)
phthalazinyl, [0187] (P) imidazolyl, [0188] (Q) isoxazolyl, [0189]
(R) pyrazolyl, [0190] (S) oxazolyl, [0191] (T) thiazolyl, [0192]
(U) indolizinyl, [0193] (V) indazolyl, [0194] (W) benzothiazolyl,
[0195] (X) benzimidazolyl, [0196] (Y) benzofuranyl, [0197] (Z)
furanyl, [0198] (AA) thienyl, [0199] (BB) pyrrolyl, [0200] (CC)
oxadiazolyl, [0201] (DD) thiadiazolyl, [0202] (EE) triazolyl,
[0203] (FF) tetrazolyl, [0204] (GG) 1,4-benzodioxan [0205] (HH)
purinyl, [0206] (II) oxazolopyridinyl, [0207] (JJ)
imidazopyridinyl, [0208] (KK) isothiazolyl, [0209] (LL)
naphthyridinyl, [0210] (MM) cinnolinyl, [0211] (NN) carbazolyl,
[0212] (OO) .beta.-carbolinyl, [0213] (PP) isochromanyl, [0214]
(QQ) chromanyl, [0215] (RR) furazanyl, [0216] (SS)
tetrahydroisoquinoline, [0217] (TT) isoindolinyl, [0218] (UU)
isobenzotetrahydrofuranyl, [0219] (VV) isobenzotetrahydrothienyl,
[0220] (WW) isobenzothiophenyl, [0221] (XX) benzoxazolyl, or [0222]
(YY) pyridopyridinyl, where the R.sub.N-heteroaryl group is bonded
by any atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.N-heteroaryl group
replaces the hydrogen atom and its bond, where .sub.N-heteroaryl is
unsubstituted or substituted with: [0223] (1) C.sub.1-C.sub.6
alkyl, [0224] (2) --F, --Cl, --Br, or --I, [0225] (3) --OH, [0226]
(4) --NO.sub.2, [0227] (5) --CO--OH, [0228] (6) --C.ident.N, [0229]
(7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: [0230] (a) --H, [0231] (b)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with: [0232]
(i) --OH, or [0233] (ii) --NH.sub.2, [0234] (c) --C.sub.1-C.sub.6
alkyl substituted or substituted with --F, --Cl, --Br, or --I,
[0235] (d) --C.sub.3-C.sub.7 cycloalkyl, [0236] (e
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [0237] (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0238] (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, [0239] (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, [0240] (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, [0241] (j) --R.sub.1-aryl where R.sub.1-aryl is as defined
above, or [0242] (k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl
is as defined above, [0243] (8) --CO--(C.sub.3-C.sub.12 alkyl),
[0244] (9) --CO--(C.sub.3-C.sub.6 cycloalkyl), [0245] (10)
--CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [0246] (11) --CO--R.sub.1-heterocycle where
R.sub.1-heterocycle is as defined above, [0247] (12)
--CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl or pyrrolidinyl where each group is
unsubstituted or substituted with C.sub.1-C.sub.3 alkyl, [0248]
(13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [0249] (a)
C.sub.1-C.sub.6 alkyl, or [0250] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [0251] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [0252] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [0253] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0254] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0255]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0256] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0257] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [0258] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [0259] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[0260] (23) --CO--(C.sub.1-C.sub.6 alkyl), [0261] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0262] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0263] (26)
--O--(C.sub.1-C.sub.6 alkyl), [0264] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, or [0265] (28) --S--(C.sub.1-C.sub.6 alkyl), [0266]
(C) --R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [0267] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where
--R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above,
[0268] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl
and --R.sub.N-heteroaryl are as defined above, [0269] (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [0270] (G) --R.sub.N-aryl--O--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [0271] (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [0272] (I) --R.sub.N-heteroaryl--OR.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0273] (J)
--R.sub.N-heteraryl--S--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [0274] (K) --R.sub.N-aryl--CO--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [0275] (L)
--R.sub.N-aryl--CO--R.sub.N-heteroaryl where --R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, [0276] (M)
--R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is as
defined above, [0277] (N)
--R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0278] (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0279] (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, [0280] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, [0281] (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or [0282] (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, [0283] (II)
--CO--(C.sub.1-C.sub.6 alkyl) where alkyl is unsubstituted or
substituted with: [0284] (A) --OH, [0285] (B) --C.sub.1-C.sub.6
alkoxy, [0286] (C) --C.sub.1-C.sub.6 thioalkoxy, [0287] (D)
--CO--O--R.sub.N-8 where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or
[0288] (E) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3
are the same or different and are as defined above, [0289] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0290] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0291] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [0292] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0293] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0294]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0295] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0296] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0297] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [0298] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0299] (III)
--CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with: [0300] (A) --OH, [0301]
(B) --C.sub.1-C.sub.6 alkoxy, [0302] (C) --C.sub.1-C.sub.6
thioalkoxy, [0303] (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or [0304] (E) --CO--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are the same or different and are as
defined above, [0305] (F) --CO--R.sub.N-4 where R.sub.N-4 is as
defined above, [0306] (G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
[0307] (H) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are the same or different and are as defined above,
[0308] (I) --NH--CO--(C.sub.1-C.sub.6 alkyl), [0309] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0310]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0311] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0312] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0313] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [0314] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0315] (IV)
--O--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3 alkyl) where alkyl
is: [0316] (A) --OH, [0317] (B) --C.sub.1-C.sub.6 alkoxy, [0318]
(C) --C.sub.1-C.sub.6 thioalkoxy, [0319] (D) --CO--O--R.sub.N-8
where R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or -.phi., [0320] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0321] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0322] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0323] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [0324] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0325] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0326]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0327] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0328] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0329] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [0330] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0331] (V)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is
selected from the group consisting of: [0332] (A) --H, [0333] (B)
C.sub.1-C.sub.6 alkyl, [0334] (C) C.sub.3-C.sub.7 cycloalkyl,
[0335] (D) C.sub.2-C.sub.6 alkenyl with one double bond, [0336] (E)
C.sub.2-C.sub.6 alkynyl with one triple bond, [0337] (F)
R.sub.1-aryl where R.sub.1-aryl is as defined above, or [0338] (G)
R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined
above;
[0339] where B is --O--, --NH--, or --N(C.sub.1-C.sub.6
alkyl)-;
[0340] where R.sub.C is: [0341] (I) C.sub.1-C.sub.8 alkyl
unsubstituted or substituted with --OH, --O-.phi., halo, or
(C.sub.1-C.sub.6 alkoxy unsubstituted or substituted with halo),
[0342] (II) --(CH.sub.2).sub.0-3-alkyl-(C.sub.3-C.sub.7) cycloalkyl
where cycloalkyl is unsubstituted or substituted with: [0343] (A)
C.sub.1-C.sub.3 alkyl unsubstituted or substituted with --F, --Cl,
--Br, or --I, [0344] (B) --CO--OH, [0345] (C)
--CO--O--(C.sub.1-C.sub.4 alkyl), [0346] (D) --OH, or [0347] (E)
C.sub.1-C.sub.6 alkoxy, [0348] (III) --(CH.sub.2).sub.2-6--OH,
[0349] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.-
and R.sub.C-aryl is the same as R.sub.N-aryl, [0350] (V)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-heteroaryl
is the same as R.sub.N-heteroaryl, [0351] (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heterocycle where R.sub.C-heterocycle
is: [0352] (A) pyridinyl, [0353] (B) pyrimidinyl, [0354] (C)
quinolinyl, [0355] (D) indenyl, [0356] (E) indanyl, [0357] (F)
benzothiophenyl, [0358] (G) indolyl, [0359] (H) indolinyl, [0360]
(I) pyridazinyl, [0361] (J) pyrazinyl, [0362] (K) isoindolyl,
[0363] (L) isoquinolyl, [0364] (M) quinazolinyl, [0365] (N)
quinoxalinyl, [0366] (O) phthalazinyl, [0367] (P) isoxazolyl,
[0368] (Q) pyrazolyl, [0369] (R) indolizinyl, [0370] (S) indazolyl,
[0371] (T) benzothiazolyl, [0372] (U) benzimidazolyl, [0373] (V)
benzofuranyl, [0374] (W) furanyl, [0375] (X) thienyl, [0376] (Y)
pyrrolyl, [0377] (Z) oxadiazolyl, [0378] (AA) thiadiazolyl, [0379]
(BB) triazolyl, [0380] (CC) tetrazolyl, [0381] (DD) 1,4-benzodioxan
[0382] (EE) purinyl, [0383] (FF) oxazolopyridinyl, [0384] (GG)
imidazopyridinyl, [0385] (HH) isothiazolyl, [0386] (II)
naphthyridinyl, [0387] (JJ) cinnolinyl, [0388] (KK) carbazolyl,
[0389] (LL) .beta.-carbolinyl, [0390] (MM) isochromanyl, [0391]
(NN) chromanyl, [0392] (OO) furazanyl, [0393] (PP)
tetrahydroisoquinoline, [0394] (QQ) isoindolinyl, [0395] (RR)
isobenzotetrahydrofuranyl, [0396] (SS) isobenzotetrahydrothienyl,
[0397] (TT) isobenzothiophenyl, [0398] (UU) benzoxazolyl, or [0399]
(VV) pyridopyridinyl, [0400] (VII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: [0401] (A) --H, [0402]
(B) --C.sub.1-C.sub.6 alkyl, [0403] (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-aryl where R.sub.C'-aryl is as defined for
R.sub.1-aryl, [0404] (D) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, [0405] (E) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [0406] (F)
--R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above,
[0407] (G) --R.sub.C-heterocycle where R.sub.C-heterocycle is as
defined above, [0408] (H) --(CH.sub.2).sub.1-4--OH, [0409] (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH--, or --NR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is
defined above, [0410] (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroar-
yl where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or
[0411] (K) --R.sub.C-aryl where R.sub.C'-aryl is as defined
above,
[0412] and where R.sub.C-3 is: [0413] (A) --H, [0414] (B)
--C.sub.1-C.sub.6 alkyl, [0415] (C) --R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, [0416] (D) --R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, [0417] (E)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, [0418] (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-aryl where
R.sub.C-aryl is as defined above, [0419] (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or [0420] (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [0421] (VIII)
--CH(.phi.).sub.2, [0422] (IX) -cyclopentyl or -cyclohexyl ring
fused to a phenyl or heteroaryl ring where heteroaryl is as defined
above and phenyl and heteroaryl are unsubstituted or substituted
with: [0423] (A) C.sub.1-C.sub.3 alkyl, [0424] (B) --CF.sub.3,
[0425] (C) --F, Cl, --Br or --I, [0426] (D) C.sub.1-C.sub.3 alkoxy,
[0427] (E) --OCF.sub.3, [0428] (F) --NH.sub.2, [0429] (G) --OH, or
[0430] (H) --CN, [0431] (X) --CH.sub.2--C.ident.CH; [0432] (XI)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: [0433] (A) --OH, or [0434] (B) --CH.sub.2--OH; [0435]
(XII) --CH(-.phi.)--CO--O(C.sub.1-C.sub.3 alkyl); [0436] (XIII)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; [0437] (XIV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; [0438] (XV)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; [0439]
(XVI) --(C.sub.2-C.sub.8) alkynyl; or [0440] (XVII) --H; and
pharmaceutically acceptable salts thereof.
[0441] Also disclosed are hydroxyethylene compounds of the formula
(XII)
##STR00003##
[0442] where R.sub.1 is: [0443] (I) C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted with one, two or three C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --C.ident.N,
--CF.sub.3, or --N.sub.3, [0444] (II)
--(CH.sub.2).sub.1-2--S--CH.sub.3, [0445] (III)
--CH.sub.2--CH.sub.2--S--CH.sub.3, [0446] (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, [0447] (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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: [0448] (A) C.sub.1-C.sub.3 alkyl, [0449]
(B) --CF.sub.3, [0450] (C) --F, Cl, --Br and --I, [0451] (D)
C.sub.1-C.sub.3 alkoxy, [0452] (E) --O--CF.sub.3, [0453] (F)
--NH.sub.2, [0454] (G) --OH, or [0455] (H) --C.ident.N, [0456] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0, 1, 2,
or 3 and R.sub.1-heteroaryl is: [0457] (A) pyridinyl, [0458] (B)
pyrimidinyl, [0459] (C) quinolinyl, [0460] (D) indenyl, [0461] (E)
indanyl, [0462] (F) benzothiophenyl, [0463] (G) indolyl, [0464] (H)
indolinyl, [0465] (I) pyridazinyl, [0466] (J) pyrazinyl, [0467] (K)
isoindolyl, [0468] (L) isoquinolyl, [0469] (M) quinazolinyl, [0470]
(N) quinoxalinyl, [0471] (O) phthalazinyl, [0472] (P) imidazolyl,
[0473] (Q) isoxazolyl, [0474] (R) pyrazolyl, [0475] (S) oxazolyl,
[0476] (T) thiazolyl, [0477] (U) indolizinyl, [0478] (V) indazolyl,
[0479] (W) benzothiazolyl, [0480] (X) benzimidazolyl, [0481] (Y)
benzofuranyl, [0482] (Z) furanyl, [0483] (AA) thienyl, [0484] (BB)
pyrrolyl, [0485] (CC) oxadiazolyl, [0486] (DD) thiadiazolyl, [0487]
(EE) triazolyl, [0488] (FF) tetrazolyl, [0489] (GG) 1,4-benzodioxan
[0490] (HH) purinyl, [0491] (II) oxazolopyridinyl, [0492] (JJ)
imidazopyridinyl, [0493] (KK) isothiazolyl, [0494] (LL)
naphthyridinyl, [0495] (MM) cinnolinyl, [0496] (NN) carbazolyl,
[0497] (OO) .beta.-carbolinyl, [0498] (PP) isochromanyl, [0499]
(QQ) chromanyl, [0500] (RR) furazanyl, [0501] (SS)
tetrahydroisoquinoline, [0502] (TT) isoindolinyl, [0503] (UU)
isobenzotetrahydrofuranyl, [0504] (VV) isobenzotetrahydrothienyl,
[0505] (WW) isobenzothiophenyl, [0506] (XX) benzoxazolyl, or [0507]
(YY) pyridopyridinyl, where the R.sub.1-heteroaryl group is bonded
to --(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: [0508] (1) C.sub.1-C.sub.3 alkyl, [0509] (2) --CF.sub.3,
[0510] (3) --F, Cl, --Br, or --I, [0511] (4) C.sub.1-C.sub.3
alkoxy, [0512] (5) --O--CF.sub.3, [0513] (6) --NH.sub.2, [0514] (7)
--OH, or [0515] (8) --C.ident.N, with the proviso that when n.sub.1
is zero R.sub.1-heteroaryl is not bonded to the carbon chain by
nitrogen, or [0516] (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is: [0517] (A) morpholinyl,
[0518] (B) thiomorpholinyl, [0519] (C) thiomorpholinyl S-oxide,
[0520] (D) thiomorpholinyl S,S-dioxide, [0521] (E) piperazinyl,
[0522] (F) homopiperazinyl, [0523] (G) pyrrolidinyl, [0524] (H)
pyrrolinyl, [0525] (I) tetrahydropyranyl, [0526] (J) piperidinyl,
[0527] (K) tetrahydrofuranyl, or [0528] (L) tetrahydrothiophenyl,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: [0529] (1) .dbd.O, [0530] (2)
C.sub.1-C.sub.3 alkyl, [0531] (3) --CF.sub.3, [0532] (4) --F, Cl,
--Br and --I, [0533] (5) C.sub.1-C.sub.3 alkoxy, [0534] (6)
--CF.sub.3, [0535] (7) --NH.sub.2, [0536] (8) --OH, or [0537] (9)
--C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen;
[0538] where R.sub.2 is: [0539] (I) --H, [0540] (II)
C.sub.1-C.sub.6 alkyl, or [0541] (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
[0542] where R.sub.N is: [0543] (1) R.sub.N-1--X.sub.N-- where
X.sub.N is: [0544] (A) --O--, [0545] (B) --SO.sub.2--,
[0546] (C) --(CR'R'').sub.1-6 where R' and R'' are the same or
different and are --H or C.sub.1-C.sub.4 alkyl, [0547] (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, [0548]
(E) a single bond;
[0549] where R.sub.N-1 is: [0550] (A) R.sub.N-aryl where
R.sub.N-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: [0551] (1)
C.sub.1-C.sub.6 alkyl, [0552] (2) --F, --Cl, --Br, or --I, [0553]
(3) --OH, [0554] (4) --NO.sub.2, [0555] (5) --CO--OH, [0556] (6)
--C.ident.N, [0557] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [0558] (a) --H,
[0559] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [0560] (i) --OH, or [0561] (ii) --NH.sub.2, [0562] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one to
three --F, --Cl, --Br, or --I, [0563] (d) --C.sub.3-C.sub.7
cycloalkyl, [0564] (e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7
cycloalkyl), [0565] (f) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0566] (g) --C.sub.1-C.sub.6
alkenyl with one or two double bonds, [0567] (h) --C.sub.1-C.sub.6
alkynyl with one or two triple bonds, [0568] (i) --C.sub.1-C.sub.6
alkyl chain with one double bond and one triple bond, [0569] (j)
--R.sub.1-aryl where R.sub.1-aryl is as defined above, or [0570]
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [0571] (8) --CO--(C.sub.3-C.sub.12 alkyl), [0572] (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), [0573] (10)
--CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [0574] (II) --CO--R.sub.1-heteroaryl where
R.sub.1-heterocycle is as defined above, [0575] (12)
--CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl or pyrrolidinyl where each group is
unsubstituted or substituted with one or two C.sub.1-C.sub.3 alkyl,
[0576] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [0577] (a)
C.sub.1-C.sub.6 alkyl, or [0578] (b)
(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as defined
above, [0579] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are as defined above, [0580] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [0581] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0582] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0583]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0584] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0585] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [0586] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [0587] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[0588] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [0589] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0590] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0591] (26)
--O--(C.sub.1-C.sub.6 alkyl), [0592] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, [0593] (28) --S--(C.sub.1-C.sub.6 alkyl), [0594] (29)
C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4,
or 5 --F, [0595] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or
substituted with 1, 2, 3, 4, or 5 --F, or [0596] (31) --O-.phi.,
[0597] (B) R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [0598]
(A) pyridinyl, [0599] (B) pyrimidinyl, [0600] (C) quinolinyl,
[0601] (D) indenyl, [0602] (E) indanyl, [0603] (F) benzothiophenyl,
[0604] (G) indolyl, [0605] (H) indolinyl, [0606] (I) pyridazinyl,
[0607] (J) pyrazinyl, [0608] (K) isoindolyl, [0609] (L)
isoquinolyl, [0610] (M) quinazolinyl, [0611] (N) quinoxalinyl,
[0612] (O) phthalazinyl, [0613] (P) imidazolyl, [0614] (Q)
isoxazolyl, [0615] (R) pyrazolyl, [0616] (S) oxazolyl, [0617] (T)
thiazolyl, [0618] (U) indolizinyl, [0619] (V) indazolyl, [0620] (W)
benzothiazolyl, [0621] (X) benzimidazolyl, [0622] (Y) benzofuranyl,
[0623] (Z) furanyl, [0624] (AA) thienyl, [0625] (BB) pyrrolyl,
[0626] (CC) oxadiazolyl, [0627] (DD) thiadiazolyl, [0628] (EE)
triazolyl, [0629] (FF) tetrazolyl, [0630] (GG) 1,4-benzodioxan
[0631] (HH) purinyl, [0632] (II) oxazolopyridinyl, [0633] (JJ)
imidazopyridinyl, [0634] (KK) isothiazolyl, [0635] (LL)
naphthyridinyl, [0636] (MM) cinnolinyl, [0637] (NN) carbazolyl,
[0638] (OO) .beta.-carbolinyl, [0639] (PP) isochromanyl, [0640]
(QQ) chromanyl, [0641] (RR) furazanyl, [0642] (SS)
tetrahydroisoquinoline, [0643] (TT) isoindolinyl, [0644] (UU)
isobenzotetrahydrofuranyl, [0645] (VV) isobenzotetrahydrothienyl,
[0646] (WW) isobenzothiophenyl, [0647] (XX) benzoxazolyl, or [0648]
(YY) pyridopyridinyl, where the R.sub.N-heteroaryl group is bonded
by any atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.N-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
unsubstituted or substituted with one or two: [0649] (1)
C.sub.1-C.sub.6 alkyl, [0650] (2) --F, --Cl, --Br, or --I, [0651]
(3) --OH, [0652] (4) --NO.sub.2, [0653] (5) --CO--OH, [0654] (6)
--C.ident.N, [0655] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [0656] (a) --H,
[0657] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [0658] (i) --OH, or [0659] (ii) --NH.sub.2, [0660] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, or
3 --F, --Cl, --Br, or --I, [0661] (d) --C.sub.3-C.sub.7 cycloalkyl,
[0662] (e --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
[0663] (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
[0664] (g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds,
[0665] (h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds,
[0666] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [0667] (j) --R.sub.1-aryl where R.sub.1-aryl is as
defined above, or [0668] (k) --R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [0669] (8)
--CO--(C.sub.3-C.sub.12 alkyl), [0670] (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), [0671] (10) --CO--R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [0672] (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, [0673] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, [0674] (13) --CO--O--R.sub.N-5 where
R.sub.N-5 is: [0675] (a) C.sub.1-C.sub.6 alkyl, or [0676] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [0677] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [0678] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [0679] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [0680] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [0681]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0682] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0683] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [0684] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [0685] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[0686] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [0687] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [0688] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [0689] (26)
--O--(C.sub.1-C.sub.6 alkyl), [0690] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, or [0691] (28) --S--(C.sub.1-C.sub.6 alkyl), [0692]
(C)--R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [0693] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where
--R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above,
[0694] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl
and --R.sub.N-heteroaryl are as defined above, [0695] (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [0696] (G) --R.sub.N-aryl--O--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [0697] (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [0698] (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0699] (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0700] (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [0701] (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, [0702]
(M) --R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is
as defined above, [0703] (N)
--R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0704]
(O)--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [0705] (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, [0706] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, [0707] (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or [0708] (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, [0709] (II) A-X.sub.N--
where X.sub.N is --CO--,
[0710] wherein A is [0711] (A) -T-E-(Q).sub.m', [0712] (1) where -T
is
[0712] ##STR00004## [0713] where [0714] (a) x=1 when y=1 and x=2
when y=0, [0715] (b) m is 0, 1, 2 or 3, [0716] (c) the values of x
and y vary independently on each carbon when m is 2 and 3, and
[0717] (d) R''' varies independently on each carbon and is H,
(C.sub.1-C.sub.2) alkyl, phenyl, or phenyl(C.sub.1-C.sub.3)alkyl;
[0718] (2) -E is [0719] (a) C.sub.1-C.sub.5 alkyl, but only if m'
does not equal 0, [0720] (b) methylthioxy(C.sub.2-C.sub.4)alkyl,
[0721] (c) an aryl group having 5 to 7 atoms when monocyclic or
having 8 to 12 atoms when fused, [0722] (d) a heterocyclic group
having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when
fused, [0723] (e) a mono or fused ring cycloalkyl group having 5 to
10 carbon atoms, [0724] (f) biphenyl, [0725] (g) diphenyl ether,
[0726] (h) diphenylketone, [0727] (i)
phenyl(C.sub.1-C.sub.8)alkyloxyphenyl, or [0728] (j)
C.sub.1-C.sub.6 alkoxy; [0729] (3) -Q is [0730] (a) C.sub.1-C.sub.3
alkyl, [0731] (b) C.sub.1-C.sub.3 alkoxy, [0732] (c)
C.sub.1-C.sub.3 alkylthioxy, [0733] (d) C.sub.1-C.sub.6
alkylacylamino, [0734] (e) C.sub.1-C.sub.6 alkylacyloxy, [0735] (f)
amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), [0736] (g) C.sub.1-C.sub.6
alkylamino [0737] (h) phenylamino, [0738] (i) carbamyl (including
C.sub.1-C.sub.6 alkyl and phenyl amides and esters), [0739] (j)
carboxyl (including C.sub.1-C.sub.6 alkyl and phenyl esters),
[0740] (k) carboxy(C.sub.2-C.sub.5)alkoxy, [0741] (l)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [0742] (m) heterocyclylacyl,
[0743] (n) heteroarylacyl, or [0744] (o) hydroxyl; [0745] (4) m' is
0, 1, 2 or 3; [0746] (B) -E(Q).sub.m'' wherein E and -Q are as
defined as above and m'' is 0, 1, 2, or 3; [0747] (C) -T-E wherein
-E and -Q are as defined as above; or [0748] (D) -E wherein -E is
as defined as above; [0749] (III) --CO--(C.sub.1-C.sub.6 alkyl)
where alkyl is unsubstituted or substituted with one or two: [0750]
(A) --OH, [0751] (B) --C.sub.1-C.sub.6 alkoxy, [0752] (C)
--C.sub.1-C.sub.6 thioalkoxy, [0753] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [0754] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0755] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0756] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0757] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [0758] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0759] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0760]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0761] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0762] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0763] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or [0764] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0765] (IV)
--CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [0766] (A)
--OH, [0767] (B) --C.sub.1-C.sub.6 alkoxy, [0768] (C)
--C.sub.1-C.sub.6 thioalkoxy, [0769] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or -.phi., [0770] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0771] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0772] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0773] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [0774] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0775] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0776]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0777] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0778] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0779] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [0780] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0781] (V)
--CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [0782] (A)
--OH, [0783] (B) --C.sub.1-C.sub.6 alkoxy, [0784] (C)
--C.sub.1-C.sub.6 thioalkoxy, [0785] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [0786] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0787] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [0788] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0789] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [0790] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0791] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [0792]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [0793] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [0794] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0795] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [0796] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0797] (VI)
--CO--CH(--(CH.sub.2).sub.0-2--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.N-a-
ryl/R.sub.N-heteroaryl) where R.sub.N-aryl and R.sub.N-heteroaryl
are as defined above, where R.sub.N-10 is: [0798] (A) --H, [0799]
(B) C.sub.1-C.sub.6 alkyl, [0800] (C) C.sub.3-C.sub.7 cycloalkyl,
[0801] (D) C.sub.2-C.sub.6 alkenyl with one double bond, [0802] (E)
C.sub.2-C.sub.6 alkynyl with one triple bond, [0803] (F)
R.sub.1-aryl where R.sub.1-aryl is as defined above, or [0804] (G)
R.sub.N-heteroaryl where R.sub.N-heteroaryl is as defined
above;
[0805] where B is --O--, --NH--, or --N(C.sub.1-C.sub.6
alkyl)-;
[0806] where R.sub.C is: [0807] (I)
--(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: [0808] (A) the alkyl
chain is unsubstituted or substituted with one --OH, [0809] (B) the
alkyl chain is unsubstituted or substituted with one
C.sub.1-C.sub.6 alkoxy unsubstituted or substituted with 1-5 --F,
[0810] (C) the alkyl chain is unsubstituted or substituted with one
--O-.phi., [0811] (D) the alkyl chain is unsubstituted or
substituted with 1-5 --F, [0812] (E) the alkyl chain is
unsubstituted or substituted with a combination of up to three
atoms of oxygen and sulfur each such atom replacing one carbon,
[0813] (F) each K is: [0814] (1) H, [0815] (2) C.sub.1-C.sub.3
alkyl, [0816] (3) C.sub.1-C.sub.3 alkoxy, [0817] (4)
C.sub.1-C.sub.3 alkylthioxy, [0818] (5) C.sub.1-C.sub.6
alkylacylamino, [0819] (6) C.sub.1-C.sub.6 alkylacyloxy, [0820] (7)
amido [0821] (8) C.sub.1-C.sub.6 alkylamino [0822] (9) phenylamino,
[0823] (10) carbamyl [0824] (11) carboxyl [0825] (12)
carboxy(C.sub.2-C.sub.5)alkoxy, [0826] (13)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [0827] (14) heterocyclylacyl,
[0828] (15) heteroarylacyl, [0829] (16) amino unsubstituted or
substituted with C.sub.1-C.sub.6 alkyl, [0830] (17) hydroxyl, or
[0831] (18) carboxylmethyl ester; [0832] (II)
--(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K].sub.1-3 where K
is as defined above and J is: [0833] (A) a 5 to 7 atom monocyclic
aryl group, [0834] (B) a 8 to 12 atom multicyclic aryl group,
[0835] (C) a 5 to 7 atom heterocyclic group, [0836] (D) a 8 to 12
atom multicyclic heterocyclic group, or [0837] (E) a 5 to 10 atom
monocyclic or multicyclic cycloalkyl group; [0838] (III)
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl where cycloalkyl
can be unsubstituted or substituted with one, two or three [0839]
(A) C.sub.1-C.sub.3 alkyl unsubstituted or substituted with 1, 2,
3, or 4 --F, --Cl, --Br, or --I, [0840] (B) --CO--OH, [0841] (C)
--CO--O--(C.sub.1-C.sub.4 alkyl), [0842] (D) --OH, or [0843] (E)
C.sub.1-C.sub.6 alkoxy, [0844] (IV) --(CH.sub.2).sub.2-6--OH,
[0845] (V) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.-
and R.sub.C-aryl is the same as R.sub.N-aryl, [0846] (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-heteroaryl
is: [0847] (A) pyridinyl, [0848] (B) pyrimidinyl, [0849] (C)
quinolinyl, [0850] (D) indenyl, [0851] (E) indanyl, [0852] (F)
benzothiophenyl, [0853] (G) indolyl, [0854] (H) indolinyl, [0855]
(I) pyridazinyl, [0856] (J) pyrazinyl, [0857] (K) isoindolyl,
[0858] (L) isoquinolyl, [0859] (M) quinazolinyl, [0860] (N)
quinoxalinyl, [0861] (O) phthalazinyl, [0862] (P) isoxazolyl,
[0863] (Q) pyrazolyl, [0864] (R) indolizinyl, [0865] (S) indazolyl,
[0866] (T) benzothiazolyl, [0867] (U) benzimidazolyl, [0868] (V)
benzofuranyl, [0869] (W) fliranyl, [0870] (X) thienyl, [0871] (Y)
pyrrolyl, [0872] (Z) oxadiazolyl, [0873] (AA) thiadiazolyl, [0874]
(BB) triazolyl, [0875] (CC) tetrazolyl, [0876] (DD) 1,4-benzodioxan
[0877] (EE) purinyl, [0878] (FF) oxazolopyridinyl, [0879] (GG)
imidazopyridinyl, [0880] (HH) isothiazolyl, [0881] (II)
naphthyridinyl, [0882] (JJ) cinnolinyl, [0883] (KK) carbazolyl,
[0884] (LL) .beta.-carbolinyl, [0885] (MM) isochromanyl, [0886]
(NN) chromanyl, [0887] (OO) furazanyl, [0888] (PP)
tetrahydroisoquinoline, [0889] (QQ) isoindolinyl, [0890] (RR)
isobenzotetrahydrofuranyl, [0891] (SS) isobenzotetrahydrothienyl,
[0892] (TT) isobenzothiophenyl, [0893] (UU) benzoxazolyl, or [0894]
(VV) pyridopyridinyl, [0895] (VII)
--(CH.sub.2).sub.0-4--R.sub.C-heterocycle where R.sub.C-heterocycle
is the same as R.sub.1-heterocycle, [0896] (VIII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: [0897] (A) --H, [0898]
(B) --C.sub.1-C.sub.6 alkyl, [0899] (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
[0900] (D) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl where
R.sub.C-heteroaryl is as defined above, [0901] (E)
--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle where
R.sub.C-heterocycle is as defined above, [0902] (F)
--R.sub.C-hetcroaryl where R.sub.C-heteroaryl is as defined above,
[0903] (G) --R.sub.C-heterocycle where R.sub.C-heterocycle is as
defined above, [0904] (H) --(CH.sub.2).sub.1-4--OH, [0905] (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, [0906] (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or
[0907] (K) --R.sub.C-aryl where R.sub.C'-aryl is as defined
above,
[0908] and where R.sub.C-3 is: [0909] (A) --H, [0910] (B)
--C.sub.1-C.sub.6 alkyl, [0911] (C) --R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, [0912] (D) --R.sub.C'-heteroaryl
where R.sub.C-heteroaryl is as defined above, [0913] (E)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, [0914] (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where
R.sub.C-aryl is as defined above, [0915] (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or [0916] (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [0917] (IX)
--CH(.phi.).sub.2, [0918] (X) -cyclopentyl or -cyclohexyl ring
fused to a phenyl or heteroaryl ring where heteroaryl is as defined
above and phenyl and heteroaryl are unsubstituted or substituted
with one, two or three: [0919] (A) C.sub.1-C.sub.3 alkyl, [0920]
(B) --CF.sub.3, [0921] (C)--F, Cl, --Br and --I, [0922] (D)
C.sub.1-C.sub.3 alkoxy, [0923] (E) --OCF.sub.3, [0924] (F)
--NH.sub.2, [0925] (G) --OH, or [0926] (H) --C.ident.N, [0927] (XI)
--CH.sub.2--C.ident.CH; [0928] (XII)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: [0929] (A) --OH, or [0930] (B) --CH.sub.2--OH; [0931]
(XIII) CH(.phi.)--CO--O(C.sub.1-C.sub.3 alkyl); [0932] (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; [0933] (XV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; [0934] (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; [0935]
(XVII) --(C.sub.2-C.sub.8) alkynyl; or [0936] (XVIII) --H; or a
pharmaceutically acceptable salt thereof.
[0937] Additionally disclosed are compounds of the formula
##STR00005##
[0938] where R.sub.1 is: [0939] (V) --CH.sub.2-phenyl, where phenyl
is substituted with two --F in the 3- and 5-positions giving
3,5-difluorophenyl, or [0940] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl), where n1 and
R.sub.1-heteroaryl are as defined above; and
[0941] PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl,
formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl,
bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-p-toluoyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluoylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobornyloxycarbonyl, -phenyl-C(.dbd.N)--H, or
1-piperidyloxycarbonyl.
[0942] Additionally disclosed are epoxide compounds of the
formula
##STR00006##
where R.sub.1 is: [0943] (A) --CH.sub.2-.phi. where -.phi. is
substituted with two --F, [0944] (B)
--(CH.sub.2).sub.n1--R.sub.1-heteroaryl where n.sub.1 is 0, 1, 2,
or 3 and R.sub.1-hetroaryl is: [0945] (A) pyridinyl, [0946] (B)
pyrimidinyl, [0947] (C) quinolinyl, [0948] (D) indenyl, [0949] (E)
indanyl, [0950] (F) benzothiophenyl, [0951] (G) indolyl, [0952] (H)
indolinyl, [0953] (I) pyridazinyl, [0954] (J) pyrazinyl, [0955] (K)
isoindolyl, [0956] (L) isoquinolyl, [0957] (M) quinazolinyl, [0958]
(N) quinoxalinyl, [0959] (O) phthalazinyl, [0960] (P) imidazolyl,
[0961] (Q) isoxazolyl, [0962] (R) pyrazolyl, [0963] (S) oxazolyl,
[0964] (T) thiazolyl, [0965] (U) indolizinyl, [0966] (V) indazolyl,
[0967] (W) benzothiazolyl, [0968] (X) benzimidazolyl, [0969] (Y)
benzofuranyl, [0970] (Z) furanyl, [0971] (AA) thienyl, [0972] (BB)
pyrrolyl, [0973] (CC) oxadiazolyl, [0974] (DD) thiadiazolyl, [0975]
(EE) triazolyl, [0976] (FF) tetrazolyl, [0977] (GG) 1,4-benzodioxan
[0978] (HH) purinyl, [0979] (II) oxazolopyridinyl, [0980] (JJ)
imidazopyridinyl, [0981] (KK) isothiazolyl, [0982] (LL)
naphthyridinyl, [0983] (MM) cinnolinlyl, [0984] (NN) carbazolyl,
[0985] (OO) .beta.-carbolinyl, [0986] (PP) isochromanyl, [0987]
(QQ) chromanyl, [0988] (RR) furazanyl, [0989] (SS)
tetrahydroisoquinoline, [0990] (TT) isoindolinyl, [0991] (UU)
isobenzotetrahydrofuranyl, [0992] (VV) isobenzotetrahydrothienyl,
[0993] (WW) isobenzothiophenyl, [0994] (XX) benzoxazolyl, or [0995]
(YY) pyridopyridinyl, [0996]
(C)--(CH.sub.2).sub.n1--R.sub.1-heterocycle where n.sub.1 is 0, 1,
2, or 3 and R.sub.1-heterocycle is: [0997] (A) morpholinyl, [0998]
(B) thiomorpholinyl, [0999] (C) thiomorpholinyl S-oxide, [1000] (D)
thiomorpholinyl S,S-dioxide, [1001] (E) piperazinyl, [1002] (F)
homopiperazinyl, [1003] (G) pyrrolidinyl, [1004] (H) pyrrolinyl,
[1005] (I) tetrahydropyranyl, [1006] (J) piperidinyl, [1007] (K)
tetrahydrofuranyl, or [1008] (L) tetrahydrothiophenyl, and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl,
trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,
iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,
4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,
4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,
2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,
2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,
1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,
1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluoylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobornyloxycarbonyl, -phenyl-C(.dbd.N)--H, or
1-piperidyloxycarbonyl.
[1009] Additionally disclosed are compounds of the formula
##STR00007##
where R.sub.1 is: [1010] (V) --CH.sub.2-phenyl, where phenyl is
substituted with two --F in the 3- and 5-positions giving
3,5-difluorophenyl, or [1011] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl), where n1 and
R.sub.1-heteroaryl are as defined above;
[1012] where R.sub.2 is as defined in claim 1; and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl,
trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,
iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,
4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,
4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,
2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,
2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1,1-yloxycarbonyl,
1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,
1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluoylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobornyloxycarbonyl, -phenyl-C(.dbd.N)--H, or
1-piperidyloxycarbonyl.
[1013] Additionally disclosed are amine compounds of the
formula
##STR00008##
[1014] where R.sub.1 is: [1015] (V) --CH.sub.2-phenyl, where phenyl
is substituted with two --F in the 3- and S-positions giving
3,5-difluorophenyl, or [1016] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl), where n1 and
R.sub.1-heteroaryl are as defined above; and
[1017] where R.sub.2 is as defined in claim 1.
[1018] Additionally disclosed are lactone compounds of the
formula
##STR00009##
[1019] where R.sub.1 is: [1020] (I) C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted with one, two or three C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --C(N, --CF.sub.3,
or --N.sub.3, [1021] (II) --(CH.sub.2).sub.1-2--S--CH.sub.3, [1022]
(III) --CH.sub.2--CH.sub.2--S--CH.sub.3, [1023] (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, [1024] (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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: [1025] (A) C.sub.1-C.sub.3 alkyl, [1026]
(B) --CF.sub.3, [1027] (C) --F, Cl, --Br and --I, [1028] (D)
C.sub.1-C.sub.3 alkoxy, [1029] (E) --O--CF.sub.3, [1030] (F)
--NH.sub.2, [1031] (G) --OH, or [1032] (H) --C.ident.N, [1033] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0, 1, 2,
or 3 and R.sub.1-heteroaryl is: [1034] (A) pyridinyl, [1035] (B)
pyrimidinyl, [1036] (C) quinolinyl, [1037] (D) indenyl, [1038] (E)
indanyl, [1039] (F) benzothiophenyl, [1040] (G) indolyl, [1041] (H)
indolinyl, [1042] (I) pyridazinyl, [1043] (J) pyrazinyl, [1044] (K)
isoindolyl, [1045] (L) isoquinolyl, [1046] (M) quinazolinyl, [1047]
(N) quinoxalinyl, [1048] (O) phthalazinyl, [1049] (P) imidazolyl,
[1050] (Q) isoxazolyl, [1051] (R) pyrazolyl, [1052] (S) oxazolyl,
[1053] (T) thiazolyl, [1054] (U) indolizinyl, [1055] (V) indazolyl,
[1056] (W) benzothiazolyl, [1057] (X) benzimidazolyl, [1058] (Y)
benzofuranyl, [1059] (Z) furanyl, [1060] (AA) thienyl, [1061] (BB)
pyrrolyl, [1062] (CC) oxadiazolyl, [1063] (DD) thiadiazolyl, [1064]
(EE) triazolyl, [1065] (FF) tetrazolyl, [1066] (GG) 1,4-benzodioxan
[1067] (HH) purinyl, [1068] (II) oxazolopyridinyl, [1069] (JJ)
imidazopyridinyl, [1070] (KK) isothiazolyl, [1071] (LL)
naphthyridinyl, [1072] (MM) cinnolinyl, [1073] (NN) carbazolyl,
[1074] (OO) .beta.-carbolinyl, [1075] (PP) isochromanyl, [1076]
(QQ) chromanyl, [1077] (RR) fuirazanyl, [1078] (SS)
tetrahydroisoquinoline, [1079] (TT) isoindolinyl, [1080] (UU)
isobenzotetrahydrofiaranyl, [1081] (VV) isobenzotetrahydrothienyl,
[1082] (WW) isobenzothiophenyl, [1083] (XX) benzoxazolyl, or [1084]
(YY) pyridopyridinyl, where the R.sub.1-heteroaryl group is bonded
to --(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: [1085] (1) C.sub.1-C.sub.3 alkyl, [1086] (2) --CF.sub.3,
[1087] (3) --F, Cl, --Br, or --I, [1088] (4) C.sub.1-C.sub.3
alkoxy, [1089] (5) --O--CF.sub.3, [1090] (6) --NH.sub.2, [1091] (7)
--OH, or [1092] (8) --C.ident.N, with the proviso that when n.sub.1
is zero R.sub.1-heteroaryl is not bonded to the carbon chain by
nitrogen, or [1093] (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is: [1094] (A) morpholinyl,
[1095] (B) thiomorpholinyl, [1096] (C) thiomorpholinyl S-oxide,
[1097] (D) thiomorpholinyl S,S-dioxide, [1098] (E) piperazinyl,
[1099] (F) homopiperazinyl, [1100] (G) pyrrolidinyl, [1101] (H)
pyrrolinyl, [1102] (I) tetrahydropyranyl, [1103] (J) piperidinyl,
[1104] (K) tetrahydrofuranyl, or [1105] (L) tetrahydrothiophenyl,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: [1106] (1) .dbd.O, [1107] (2)
C.sub.1-C.sub.3 alkyl, [1108] (3) --CF.sub.3, [1109] (4) --F, Cl,
--Br and --I, [1110] (5) C.sub.1-C.sub.3 alkoxy, [1111] (6)
--O--CF.sub.3, [1112] (7) --NH.sub.2, [1113] (8) --OH, or [1114]
(9) --C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen;
[1115] where R.sub.2 is: [1116] (I) --H, [1117] (II)
C.sub.1-C.sub.6 alkyl, or [1118] (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
[1119] where R.sub.N is: [1120] (I) R.sub.N-1--X.sub.N-- where
X.sub.N is: [1121] (A) --CO--, [1122] (B) --SO.sub.2--, [1123]
(C)--(CR'R'').sub.1-6 where R' and R'' are the same or different
and are --H or C.sub.1-C.sub.4 alkyl, [1124] (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, [1125]
(E) a single bond;
[1126] where R.sub.N-1 is: [1127] (A) R.sub.N-aryl where
R.sub.N-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: [1128] (1)
C.sub.1-C.sub.6 alkyl, [1129] (2) --F, --Cl, --Br, or --I, [1130]
(3) --OH, [1131] (4) --NO.sub.2, [1132] (5) --CO--OH, [1133] (6)
--C.ident.N, [1134] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [1135] (a) --H,
[1136] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [1137] (i) --OH, or [1138] (ii) --NH.sub.2, [1139] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one to
three --F, --Cl, --Br, or --I, [1140] (d) --C.sub.3-C.sub.7
cycloalkyl, [1141] (e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7
cycloalkyl), [1142] (f) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), [1143] (g) --C.sub.1-C.sub.6
alkenyl with one or two double bonds, [1144] (h) --C.sub.1-C.sub.6
alkynyl with one or two triple bonds, [1145] (i) --C.sub.1-C.sub.6
alkyl chain with one double bond and one triple bond, [1146] (j)
--R.sub.1-aryl where R.sub.1-aryl is as defined above, or [1147]
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [1148] (8) --CO--(C.sub.3-C.sub.12 alkyl), [1149] (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), [1150] (10)
--CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [1151] (11) --CO--R.sub.1-heterocycle where
R.sub.1-heterocycle is as defined above, [1152] (12)
--CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl or pyrrolidinyl where each group is
unsubstituted or substituted with one or two C.sub.1-C.sub.3 alkyl,
[1153] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [1154] (a)
C.sub.1-C.sub.6 alkyl, or [1155] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [1156] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [1157] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [1158] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [1159] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [1160]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1161] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1162] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [1163] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [1164] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[1165] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [1166] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1167] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1168] (26)
--O--(C.sub.1-C.sub.6 alkyl), [1169] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, [1170] (28) --S--(C.sub.1-C.sub.6 alkyl), [1171] (29)
C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4,
or 5 --F, [1172] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or
substituted with 1, 2, 3, 4, or 5 --F, or [1173] (31) --O-.phi.,
[1174] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [1175]
(A) pyridinyl, [1176] (B) pyrimidinyl, [1177] (C) quinolinyl,
[1178] (D) indenyl, [1179] (E) indanyl, [1180] (F) benzothiophenyl,
[1181] (G) indolyl, [1182] (H) indolinyl, [1183] (I) pyridazinyl,
[1184] (J) pyrazinyl, [1185] (K) isoindolyl, [1186] (L)
isoquinolyl, [1187] (M) quinazolinyl, [1188] (N) quinoxalinyl,
[1189] (O) phthalazinyl, [1190] (P) imidazolyl, [1191] (Q)
isoxazolyl, [1192] (R) pyrazolyl, [1193] (S) oxazolyl, [1194] (T)
thiazolyl, [1195] (U) indolizinyl, [1196] (V) indazolyl, [1197] (W)
benzothiazolyl, [1198] (X) benzimidazolyl, [1199] (Y) benzofuranyl,
[1200] (Z) furanyl, [1201] (AA) thienyl, [1202] (BB) pyrrolyl,
[1203] (CC) oxadiazolyl, [1204] (DD) thiadiazolyl, [1205] (EE)
triazolyl, [1206] (FF) tetrazolyl, [1207] (GG) 1,4-benzodioxan
[1208] (HH) purinyl, [1209] (II) oxazolopyridinyl, [1210] (JJ)
imidazopyridinyl, [1211] (KK) isothiazolyl, [1212] (LL)
naphthyridinyl, [1213] (MM) cinnolinyl, [1214] (NN) carbazolyl,
[1215] (OO) .beta.-carbolinyl, [1216] (PP) isochromanyl, [1217]
(QQ) chromanyl, [1218] (RR) fuirazanyl, [1219] (SS)
tetrahydroisoquinoline, [1220] (TT) isoindolinyl, [1221] (UU)
isobenzotetrahydrofuranyl, [1222] (VV) isobenzotetrahydrothienyl,
[1223] (WW) isobenzothiophenyl, [1224] (XX) benzoxazolyl, or [1225]
(YY) pyridopyridinyl, where the R.sub.N-heteroaryl group is bonded
by any atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.N-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
unsubstituted or substituted with one or two: [1226] (1)
C.sub.1-C.sub.6 alkyl, [1227] (2) --F, --Cl, --Br, or --I, [1228]
(3) --OH, [1229] (4) --NO.sub.2, [1230] (5) --CO--OH, [1231] (6)
--C.ident.N, [1232] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [1233] (a) --H,
[1234] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [1235] (i) --OH, or [1236] (ii) --NH.sub.2, [1237] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, or
3 --F, --Cl, --Br, or --I, [1238] (d) --C.sub.3-C.sub.7 cycloalkyl,
[1239] (e --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
[1240] (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
[1241] (g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds,
[1242] (h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds,
[1243] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [1244] (j) --R.sub.1-aryl where R.sub.1-aryl is as
defined above, or [1245] (k) --R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [1246] (8)
--CO--(C.sub.3-C.sub.12 alkyl), [1247] (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), [1248] (10) --CO--R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [1249] (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, [1250] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, [1251] (13) --CO--O--R.sub.N-5 where
R.sub.N-5 is: [1252] (a) C.sub.1-C.sub.6 alkyl, or [1253] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [1254] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [1255] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [1256] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [1257] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [1258]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1259] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1260] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [1261] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [1262] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[1263] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [1264] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1265] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1266] (26)
--O--(C.sub.1-C.sub.6 alkyl), [1267] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, or [1268] (28) --S--(C.sub.1-C.sub.6 alkyl), [1269]
(C) --R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [1270] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where
--R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above,
[1271] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl
and --R.sub.N-heteroaryl are as defined above, [1272] (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [1273] (G) --R.sub.N-aryl--O--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [1274] (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [1275] (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1276] (J)
--R.sub.N-heteroaryl--SR.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [1277] (K) --R.sub.N-aryl--CO--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [1278] (L)
--R.sub.N-aryl--CO--R.sub.N-heteroaryl where --R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, [1279] (M)
--R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is as
defined above, [1280] (N)
--R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1281] (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1282] (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where RNaryl is as
defined above, [1283] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, [1284] (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or [1285] (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, [1286] (II) A-X.sub.N--
where X.sub.N is --CO--,
[1287] wherein A is [1288] (A) -T-E-(Q)m', [1289] (1) where -T
is
[1289] ##STR00010## where [1290] (a) x=1 when y=1 and x=2 when y=0,
[1291] (b) m is 0, 1, 2 or 3, [1292] (c) the values of x and y vary
independently on each carbon when m is 2 and 3, and [1293] (d) R'''
varies independently on each carbon and is H, (C1-C2) alkyl,
phenyl, or phenyl(C1-C3)alkyl; [1294] (2) -E is [1295] (a)
C.sub.1-C.sub.5 alkyl, but only if m' does not equal 0, [1296] (b)
methylthioxy(C.sub.2-C.sub.4)alkyl, [1297] (c) an aryl group having
5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
[1298] (d) a heterocyclic group having 5 to 7 atoms when monocyclic
or having 8 to 12 atoms when fused, [1299] (e) a mono or fused ring
cycloalkyl group having 5 to 10 carbon atoms, [1300] (f) biphenyl,
[1301] (g) diphenyl ether, [1302] (h) diphenylketone, [1303] (i)
phenyl(C.sub.1-C.sub.8)alkyloxyphenyl, or [1304] (j)
C.sub.1-C.sub.6 alkoxy; [1305] (3) -Q is [1306] (a) C.sub.1-C.sub.3
alkyl, [1307] (b) C.sub.1-C.sub.3 alkoxy, [1308] (c)
C.sub.1-C.sub.3 alkylthioxy, [1309] (d) C.sub.1-C.sub.6
alkylacylamino, [1310] (e) C.sub.1-C.sub.6 alkylacyloxy, [1311] (f)
amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), [1312] (g) C.sub.1-C.sub.6
alkylamino [1313] (h) phenylamino, [1314] (i) carbamyl (including
C.sub.1-C.sub.6 alkyl and phenyl amides and esters), [1315] (j)
carboxyl (including C.sub.1-C.sub.6 alkyl and phenyl esters),
[1316] (k) carboxy(C.sub.2-C.sub.5)alkoxy, [1317] (l)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [1318] (m) heterocyclylacyl,
[1319] (n) heteroarylacyl, or [1320] (o) hydroxyl; [1321] (4) m' is
0, 1, 2 or 3; [1322] (B) -E(Q).sub.m'' wherein E and -Q are as
defined as above and m'' is 0, 1, 2, or 3; [1323] (C) -T-E wherein
-E and -Q are as defined as above; or [1324] (D) -E wherein -E is
as defined as above; [1325] (III) --CO--(C.sub.1-C.sub.6 alkyl)
where alkyl is unsubstituted or substituted with one or two: [1326]
(A) --OH, [1327] (B) --C.sub.1-C.sub.6 alkoxy, [1328] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1329] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [1330] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1331] (F) --CO--RNA4
where R.sub.N-4 is as defined above, [1332] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1333] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1334] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1335] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1336]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1337] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1338] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [1339] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or [1340] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [1341] (IV)
--CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [1342] (A)
--OH, [1343] (B) --C.sub.1-C.sub.6 alkoxy, [1344] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1345] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [1346] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1347] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [1348] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1349] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1350] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1351] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1352]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1353] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1354] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [1355] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [1356] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [1357] (V)
--CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [1358] (A)
--OH, [1359] (B) --C.sub.1-C.sub.6 alkoxy, [1360] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1361] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [1362] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1363] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [1364] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1365] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1366] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1367] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1368]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1369] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1370] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl),
[1371] (N) --O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the
same or different and are as defined above, or
[1372] (O) --O--(C.sub.1-C.sub.5 alkyl)-COOH, [1373] (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is:
[1374] (A) --H, [1375] (B) C.sub.1-C.sub.6 alkyl, [1376] (C)
C.sub.3-C.sub.7 cycloalkyl, [1377] (D) C.sub.2-C.sub.6 alkenyl with
one double bond, [1378] (E) C.sub.2-C.sub.6 alkynyl with one triple
bond, [1379] (F) R.sub.1-aryl where R.sub.1-aryl is as defined
above, or [1380] (G) R.sub.N-heteroaryl where R.sub.N-heteroaryl is
as defined above.
[1381] Disclosed is a method of treating a patient who has, or in
preventing a patient from getting, a disease or condition selected
from Alzheimer's disease, mild cognitive impairment, Down's
syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the
Dutch-Type, cerebral amyloid angiopathy, degenerative dementia,
diffuse Lewy body type of Alzheimer's disease or central or
peripheral amyloid diseases and who is in need of such treatment
which comprises administration of a therapeutically effective
amount of a hydroxyethylene compound of formula (XII)
##STR00011##
where R.sub.1 is: [1382] (I) C.sub.1-C.sub.6 alkyl, unsubstituted
or substituted with one, two or three C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --NH.sub.2, --C.ident.N, --CF.sub.3, or
--N.sub.3, [1383] (II) --(CH.sub.2).sub.1-2--S--CH.sub.3, [1384]
(III) --CH.sub.2--CH.sub.2--S--CH.sub.3, [1385] (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, [1386] (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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: [1387] (A) C.sub.1-C.sub.3 alkyl, [1388]
(B) --CF.sub.3, [1389] (C) --F, Cl, --Br and --I, [1390] (D)
C.sub.1-C.sub.3 alkoxy, [1391] (E) --O--CF.sub.3, [1392] (F)
--NH.sub.2, [1393] (G) --OH, or [1394] (H) --C.ident.N, [1395] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0, 1, 2,
or 3 and R.sub.1-heteroaryl is: [1396] (A) pyridinyl, [1397] (B)
pyrimidinyl, [1398] (C) quinolinyl, [1399] (D) indenyl, [1400] (E)
indanyl, [1401] (F) benzothiophenyl, [1402] (G) indolyl, [1403] (H)
indolinyl, [1404] (I) pyridazinyl, [1405] (J) pyrazinyl, [1406] (K)
isoindolyl, [1407] (L) isoquinolyl, [1408] (M) quinazolinyl, [1409]
(N) quinoxalinyl, [1410] (O) phthalazinyl, [1411] (P) imidazolyl,
[1412] (Q) isoxazolyl, [1413] (R) pyrazolyl, [1414] (S) oxazolyl,
[1415] (T) thiazolyl, [1416] (U) indolizinyl, [1417] (V) indazolyl,
[1418] (W) benzothiazolyl, [1419] (X) benzimidazolyl, [1420] (Y)
benzofuranyl, [1421] (Z) furanyl, [1422] (AA) thienyl, [1423] (BB)
pyrrolyl, [1424] (CC) oxadiazolyl, [1425] (DD) thiadiazolyl, [1426]
(EE) triazolyl, [1427] (FF) tetrazolyl, [1428] (GG) 1,4-benzodioxan
[1429] (HH) purinyl, [1430] (II) oxazolopyridinyl, [1431] (JJ)
imidazopyridinyl, [1432] (KK) isothiazolyl, [1433] (LL)
naphthyridinyl, [1434] (MM) cinnolinyl, [1435] (NN) carbazolyl,
[1436] (OO) .beta.-carbolinyl, [1437] (PP) isochromanyl, [1438]
(QQ) chromanyl, [1439] (RR) fiurazanyl, [1440] (SS)
tetrahydroisoquinoline, [1441] (TT) isoindolinyl, [1442] (UU)
isobenzotetrahydrofuranyl, [1443] (VV) isobenzotetrahydrothienyl,
[1444] (WW) isobenzothiophenyl, [1445] (XX) benzoxazolyl, or [1446]
(YY) pyridopyridinyl, where the R.sub.1-heteroaryl group is bonded
to --(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: [1447] (1) C.sub.1-C.sub.3 alkyl, [1448] (2) --CF.sub.3,
[1449] (3) --F, Cl, --Br, or --I, [1450] (4) C.sub.1-C.sub.3
alkoxy, [1451] (5) --O--CF.sub.3, [1452] (6) --NH.sub.2, [1453] (7)
--OH, or [1454] (8) --C.ident.N, with the proviso that when n.sub.1
is zero R.sub.1-heteroaryl is not bonded to the carbon chain by
nitrogen, or [1455] (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is: [1456] (A) morpholinyl,
[1457] (B) thiomorpholinyl, [1458] (C) thiomorpholinyl S-oxide,
[1459] (D) thiomorpholinyl S,S-dioxide, [1460] (E) piperazinyl,
[1461] (F) homopiperazinyl, [1462] (G) pyrrolidinyl, [1463] (H)
pyrrolinyl, [1464] (I) tetrahydropyranyl, [1465] (J) piperidinyl,
[1466] (K) tetrahydrofluranyl, or [1467] (L) tetrahydrothiophenyl,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: [1468] (1) .dbd.O, [1469] (2)
C.sub.1-C.sub.3 alkyl, [1470] (3) --CF.sub.3, [1471] (4) --F, Cl,
--Br and --I, [1472] (5) C.sub.1-C.sub.3 alkoxy, [1473] (6)
O--CF.sub.3, [1474] (7) --NH.sub.2, [1475] (8) --OH, or [1476] (9)
--C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen;
[1477] where R.sub.2 is: [1478] (I) --H, [1479] --(II)
C.sub.1-C.sub.6 alkyl, or [1480] (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
[1481] where R.sub.N is: [1482] (I) R.sub.N-1--X.sub.N-- where
X.sub.N is: [1483] (A) --CO--, [1484] (B) --SO.sub.2--, [1485]
(C)--(CR'R'').sub.1-6 where R' and R'' are the same or different
and are --H or C.sub.1-C.sub.4 alkyl, [1486] (D)
--CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is --O--, --S--
and --NR'R''-- and where R' and R'' are as defined above, [1487]
(E) a single bond;
[1488] where R.sub.N-1 is: [1489] (A) R.sub.N-aryl where
R.sub.N-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: [1490] (1)
C.sub.1-C.sub.6 alkyl, [1491] (2) --F, --Cl, --Br, or --I, [1492]
(3) --OH, [1493] (4) --NO.sub.2, [1494] (5) --CO--OH, [1495] (6)
--C.ident.N, [1496] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [1497] (a) --H,
[1498] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [1499] (i) --OH, or [1500] (ii) --NH.sub.2, [1501] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one to
three --F, --Cl, --Br, or --I, [1502] (d) --C.sub.3-C.sub.7
cycloalkyl, [1503] (e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7
cycloalkyl), [1504] (f) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), [1505] (g) --C.sub.1-C.sub.6
alkenyl with one or two double bonds, [1506] (h) --C.sub.1-C.sub.6
alkynyl with one or two triple bonds, [1507] (i) --C.sub.1-C.sub.6
alkyl chain with one double bond and one triple bond, [1508] (j)
--R.sub.1-aryl where R.sub.1-aryl is as defined above, or [1509]
(k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [1510] (8) --CO--(C.sub.3-C.sub.12 alkyl), [1511] (9)
--CO--(C.sub.3-C.sub.6 cycloalkyl), [1512] (10)
--CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [1513] (11) --CO--R.sub.1-heterocycle where
R.sub.1-heterocycle is as defined above, [1514] (12)
--CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl or pyrrolidinyl where each group is
unsubstituted or substituted with one or two C.sub.1-C.sub.3 alkyl,
[1515] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [1516] (a)
C.sub.1-C.sub.6 alkyl, or [1517] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [1518] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [1519] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [1520] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [1521] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [1522]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1523] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1524] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [1525] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [1526] (22) --R.sub.N-4 where RNA is as defined above,
[1527] (23) O--CO--(C.sub.1-C.sub.6 alkyl), [1528] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1529] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1530] (26)
--O--(C.sub.1-C.sub.6 alkyl), [1531] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, [1532] (28) --S--(C.sub.1-C.sub.6 alkyl), [1533] (29)
C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4,
or 5 --F, [1534] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or
substituted with 1, 2, 3, 4, or 5 --F, or [1535] (31) --O-.phi.,
[1536] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [1537]
(A) pyridinyl, [1538] (B) pyrimidinyl, [1539] (C) quinolinyl,
[1540] (D) indenyl, [1541] (E) indanyl, [1542] (F) benzothiophenyl,
[1543] (G) indolyl, [1544] (H) indolinyl, [1545] (I) pyridazinyl,
[1546] (J) pyrazinyl, [1547] (K) isoindolyl, [1548] (L)
isoquinolyl, [1549] (M) quinazolinyl, [1550] (N) quinoxalinyl,
[1551] (O) phthalazinyl, [1552] (P) imidazolyl, [1553] (Q)
isoxazolyl, [1554] (R) pyrazolyl, [1555] (S) oxazolyl, [1556] (T)
thiazolyl, [1557] (U) indolizinyl, [1558] (V) indazolyl, [1559] (W)
benzothiazolyl, [1560] (X) benzimidazolyl, [1561] (Y) benzofuranyl,
[1562] (Z) furanyl, [1563] (AA) thienyl, [1564] (BB) pyrrolyl,
[1565] (CC) oxadiazolyl, [1566] (DD) thiadiazolyl, [1567] (EE)
triazolyl, [1568] (FF) tetrazolyl, [1569] (GG) 1,4-benzodioxan
[1570] (HH) purinyl, [1571] (II) oxazolopyridinyl, [1572] (JJ)
imidazopyridinyl, [1573] (KK) isothiazolyl, [1574] (LL)
naphthyridinyl, [1575] (MM) cinnolinyl, [1576] (NN) carbazolyl,
[1577] (OO) .beta.-carbolinyl, [1578] (PP) isochromanyl, [1579]
(QQ) chromanyl, [1580] (RR) farazanyl, [1581] (SS)
tetrahydroisoquinoline, [1582] (TT) isoindolinyl, [1583] (UU)
isobenzotetrahydrofuranyl, [1584] (VV) isobenzotetrahydrothienyl,
[1585] (WW) isobenzothiophenyl, [1586] (XX) benzoxazolyl, or [1587]
(YY) pyridopyridinyl, where the R.sub.N-heteroaryl group is bonded
by any atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.N-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
unsubstituted or substituted with one or two: [1588] (1)
C.sub.1-C.sub.6 alkyl, [1589] (2) --F, --Cl, --Br, or --I, [1590]
(3) --OH, [1591] (4) --NO.sub.2, [1592] (5) --CO--OH, [1593] (6)
--C.ident.N, [1594] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [1595] (a) --H,
[1596] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [1597] (i) --OH, or [1598] (ii) --NH.sub.2, [1599] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, or
3 --F, --Cl, --Br, or --I, [1600] (d) --C.sub.3-C.sub.7 cycloalkyl,
[1601] (e --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
[1602] (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
[1603] (g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds,
[1604] (h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds,
[1605] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [1606] (j) --R.sub.1-aryl where R.sub.1-aryl is as
defined above, or [1607] (k) --R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [1608] (8)
--CO--(C.sub.3-C.sub.12 alkyl), [1609] (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), [1610] (10) --CO--R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [1611] (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined
above, [1612] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, [1613] (13) --CO--O--R.sub.N-5 where
R.sub.N-5 is: [1614] (a) C.sub.1-C.sub.6 alkyl, or [1615] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [1616] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [1617] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [1618] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [1619] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [1620]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1621] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1622] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [1623] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [1624] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[1625] (23) --CO--(C.sub.1-C.sub.6 alkyl), [1626] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [1627] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [1628] (26)
--O--(C.sub.1-C.sub.6 alkyl), [1629] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, or [1630] (28) --S--(C.sub.1-C.sub.6 alkyl), [1631]
(C) --R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [1632] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where
--R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above,
[1633] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl
and --R.sub.N-heteroaryl are as defined above, [1634] (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [1635] (G) --R.sub.N-aryl--O--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [1636] (H)
--R.sub.N-aryl--SR.sub.N-aryl where --R.sub.N-aryl is as defined
above, [1637] (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1638] (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1639] (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [1640] (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, [1641]
(M) --R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where --R.sub.N-aryl is
as defined above, [1642] (N)
--R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1643] (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [1644] (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, [1645] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, [1646] (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or [1647] (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, [1648] (II) A-X.sub.N--
where X.sub.N is --CO--,
[1649] wherein A is [1650] (A) -T-E-(O).sub.m', [1651] (1) where -T
is
[1651] ##STR00012## [1652] where [1653] (a) x=1 when y=1 and x=2
when y=0, [1654] (b) m is 0, 1, 2 or 3, [1655] (c) the values of x
and y vary independently on each carbon when m is 2 and 3, and
[1656] (d) R''' varies independently on each carbon and is H,
(C.sub.1-C.sub.2) alkyl, phenyl, or phenyl(C.sub.1-C.sub.3)alkyl;
[1657] (2) -E is [1658] (a) C.sub.1-C.sub.5 alkyl, but only if m'
does not equal 0, [1659] (b) methylthioxy(C.sub.2-C.sub.4)alkyl,
[1660] (c) an aryl group having 5 to 7 atoms when monocyclic or
having 8 to 12 atoms when fused, [1661] (d) a heterocyclic group
having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when
fused, [1662] (e) a mono or fused ring cycloalkyl group having 5 to
10 carbon atoms, [1663] (f) biphenyl, [1664] (g) diphenyl ether,
[1665] (h) diphenylketone, [1666] (i)
phenyl(C.sub.1-C.sub.8)alkyloxyphenyl, or [1667] (j)
C.sub.1-C.sub.6 alkoxy; [1668] (3) -Q is [1669] (a) C.sub.1-C.sub.3
alkyl, [1670] (b) C.sub.1-C.sub.3 alkoxy, [1671] (c)
C.sub.1-C.sub.3 alkylthioxy, [1672] (d) C.sub.1-C.sub.6
alkylacylamino, [1673] (e) C.sub.1-C.sub.6 alkylacyloxy, [1674] (f)
amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), [1675] (g) C.sub.1-C.sub.6
alkylamino [1676] (h) phenylamino, [1677] (i) carbamyl (including
C.sub.1-C.sub.6 alkyl and phenyl amides and esters), [1678] (j)
carboxyl (including C.sub.1-C.sub.6 alkyl and phenyl esters),
[1679] (k) carboxy(C.sub.2-C.sub.5)alkoxy, [1680] (l)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [1681] (m) heterocyclylacyl,
[1682] (n) heteroarylacyl, or [1683] (o) hydroxyl; [1684] (4) m' is
0, 1, 2 or 3; [1685] (B) -E(Q).sub.m'' wherein E and -Q are as
defined as above and m'' is 0, 1, 2, or 3; [1686] (C) -T-E wherein
-E and -Q are as defined as above; or [1687] (D) -E wherein -E is
as defined as above; [1688] (III) --CO--(C.sub.1-C.sub.6 alkyl)
where alkyl is unsubstituted or substituted with one or two: [1689]
(A) --OH, [1690] (B) --C.sub.1-C.sub.6 alkoxy, [1691] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1692] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [1693] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1694] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [1695] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1696] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1697] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1698] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1699]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1700] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1701] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [1702] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or [1703] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [1704] (IV)
--CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [1705] (A)
--OH, [1706] (B) --C.sub.1-C.sub.6 alkoxy, [1707] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1708] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or -.phi., [1709] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1710] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [1711] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1712] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1713] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1714] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1715]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1716] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1717] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [1718] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [1719] (O)
--O--(C.sub.1-C.sub.5 alkyl) --COOH, [1720] (V)
--CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [1721] (A)
--OH, [1722] (B) --C.sub.1-C.sub.6 alkoxy, [1723] (C)
--C.sub.1-C.sub.6 thioalkoxy, [1724] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [1725] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1726] (F)
--CO--R.sub.N-4 where RNA is as defined above, [1727] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [1728] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [1729] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [1730] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [1731]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [1732] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [1733] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [1734] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [1735] (O)
--O--(C.sub.1-C.sub.5 alkyl) --COOH, [1736] (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is:
[1737] (A) --H, [1738] (B) C.sub.1-C.sub.6 alkyl, [1739] (C)
C.sub.3-C.sub.7 cycloalkyl, [1740] (D) C.sub.2-C.sub.6 alkenyl with
one double bond, [1741] (E) C.sub.2-C.sub.6 alkynyl with one triple
bond, [1742] (F) R.sub.1-aryl where R.sub.1-aryl is as defined
above, or [1743] (G) R.sub.N-heteroaryl where R.sub.N-heteroaryl is
as defined above;
[1744] where B is --O--, --NH--, or --N(C.sub.1-C.sub.6
alkyl)-;
[1745] where R.sub.C is: [1746] (I)
--(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: [1747] (A) the alkyl
chain is unsubstituted or substituted with one --OH, [1748] (B) the
alkyl chain is unsubstituted or substituted with one
C.sub.1-C.sub.6 alkoxy unsubstituted or substituted with 1-5 --F,
[1749] (C) the alkyl chain is unsubstituted or substituted with one
--O-.phi., [1750] (D) the alkyl chain is unsubstituted or
substituted with 1-5 --F, [1751] (E) the alkyl chain is
unsubstituted or substituted with a combination of up to three
atoms of oxygen and sulfur each such atom replacing one carbon,
[1752] (F) each K is: [1753] (1) H, [1754] (2) C.sub.1-C.sub.3
alkyl, [1755] (3) C.sub.1-C.sub.3 alkoxy, [1756] (4)
C.sub.1-C.sub.3 alkylthioxy, [1757] (5) C.sub.1-C.sub.6
alkylacylamino, [1758] (6) C.sub.1-C.sub.6 alkylacyloxy, [1759] (7)
amido [1760] (8) C.sub.1-C.sub.6 alkylamino [1761] (9) phenylamino,
[1762] (10) carbamyl [1763] (11) carboxyl [1764] (12)
carboxy(C.sub.2-C.sub.5)alkoxy, [1765] (13)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [1766] (14) heterocyclylacyl,
[1767] (15) heteroarylacyl, [1768] (16) amino unsubstituted or
substituted with C.sub.1-C.sub.6 alkyl, [1769] (17) hydroxyl, or
[1770] (18) carboxyl methyl ester; [1771] (II)
--(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K]I.sub.3 where K is
as defined above and J is: [1772] (A) a 5 to 7 atom monocyclic aryl
group, [1773] (B) a 8 to 12 atom multicyclie aryl group, [1774] (C)
a 5 to 7 atom heterocyclic group, [1775] (D) a 8 to 12 atom
multicyclic heterocyclic group, or [1776] (E) a 5 to 10 atom
monocyclic or multicyclic cycloalkyl group; [1777] (III)
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl where cycloalkyl
can be unsubstituted or substituted with one, two or three [1778]
(A) C.sub.1-C.sub.3 alkyl unsubstituted or substituted with 1, 2,
3, or 4 --F, --Cl, --Br, or --I, [1779] (B) --CO--OH, [1780] (C)
--CO--O--(C.sub.1-C.sub.4 alkyl), [1781] (D) --OH, or [1782] (E)
C.sub.1-C.sub.6 alkoxy, [1783] (IV) --(CH.sub.2).sub.2-6--OH,
[1784] (V) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.-
and R.sub.C-aryl is the same as R.sub.N-aryl, [1785] (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-heteroaryl
is: [1786] (A) pyridinyl, [1787] (B) pyrimidinyl, [1788] (C)
quinolinyl, [1789] (D) indenyl, [1790] (E) indanyl, [1791] (F)
benzothiophenyl, [1792] (G) indolyl, [1793] (H) indolinyl, [1794]
(I) pyridazinyl, [1795] (J) pyrazinyl, [1796] (K) isoindolyl,
[1797] (L) isoquinolyl, [1798] (M) quinazolinyl, [1799] (N)
quinoxalinyl, [1800] (O) phthalazinyl, [1801] (P) isoxazolyl,
[1802] (Q) pyrazolyl, [1803] (R) indolizinyl, [1804] (S) indazolyl,
[1805] (T) benzothiazolyl, [1806] (U) benzimidazolyl, [1807] (V)
benzofuranyl, [1808] (W) furanyl, [1809] (X) thienyl, [1810] (Y)
pyrrolyl, [1811] (Z) oxadiazolyl, [1812] (AA) thiadiazolyl, [1813]
(BB) triazolyl, [1814] (CC) tetrazolyl, [1815] (DD) 1,4-benzodioxan
[1816] (EE) purinyl, [1817] (FF) oxazolopyridinyl, [1818] (GG)
imidazopyridinyl, [1819] (HH) isothiazolyl, [1820] (II)
naphthyridinyl, [1821] (JJ) cinnolinyl, [1822] (KK) carbazolyl,
[1823] (LL) .beta.-carbolinyl, [1824] (MM) isochromanyl, [1825]
(NN) chromanyl, [1826] (OO) furazanyl, [1827] (PP)
tetrahydroisoquinoline, [1828] (QQ) isoindolinyl, [1829] (RR)
isobenzotetrahydrofuranyl, [1830] (SS) isobenzotetrahydrothienyl,
[1831] (TT) isobenzothiophenyl, [1832] (UU) benzoxazolyl, or [1833]
(VV) pyridopyridinyl, [1834] (VII)
--(CH.sub.2).sub.0-4--R.sub.C-heterocycle where R.sub.C-heterocycle
is the same as R.sub.1-heterocycle [1835] (VIII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: [1836] (A) --H, [1837]
(B) --C.sub.1-C.sub.6 alkyl, [1838] (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
R.sub.1-aryl: [1839] (D) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, [1840] (E) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [1841] (F)
--R.sub.C-hetroaryl where R.sub.C-heteroaryl is as defined above,
[1842] (G) --R.sub.C-heterocycle where R.sub.C-heterocycle is as
defined above, [1843] (H) --(CH.sub.2).sub.1-4--OH, [1844] (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, [1845] (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or
[1846] (K) --R.sub.C'-aryl where R.sub.C'-aryl is as defined
above,
[1847] and where R.sub.C-3 is: [1848] (A) --H, [1849] (B)
--C.sub.1-C.sub.6 alkyl, [1850] (C) --R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, [1851] (D) --R.sub.C-hetroaryl
where R.sub.C-heteroaryl is as defined above, [1852] (E)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, [1853] (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-aryl where
R.sub.C'-aryl is as defined above, [1854] (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-hetcroaryl is as defined
above, or [1855] (H)--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-hetercycle is as defined above, [1856] (IX)
--CH(.phi.).sub.2, [1857] (X) -cyclopentyl or -cyclohexyl ring
fused to a phenyl or heteroaryl ring where heteroaryl is as defined
above and phenyl and heteroaryl are unsubstituted or substituted
with one, two or three: [1858] (A) C.sub.1-C.sub.3 alkyl, [1859]
(B) --CF.sub.3, [1860] (C) --F, Cl, --Br and --I, [1861] (D)
C.sub.1-C.sub.3 alkoxy, [1862] (E) --OCF.sub.3, [1863] (F)
--NH.sub.2, [1864] (G) --OH, or [1865] (H) --C.ident.N, [1866] (XI)
--CH.sub.2--C.ident.CH; [1867] (XII)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.01-.phi. where
R.sub.C-5 is; [1868] (A) --OH, or [1869] (B) --CH.sub.2--OH; [1870]
(XIII) --CH(.phi.)--CO--O(C.sub.1-C.sub.3 alkyl); [1871] (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; [1872] (XV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; [1873] (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; [1874]
(XVII) --(C.sub.2-C.sub.8) alkynyl; or [1875] (XVIII) --H; or a
pharmaceutically acceptable salt thereof.
[1876] Disclosed is the use of a hydroxyethylene compound of
formula (XII)
##STR00013##
[1877] where R.sub.1, R.sub.2, R.sub.C, and R.sub.N are as defined
immediately above, and pharmaceutically acceptable salts thereof
for the manufacture of a medicament for use in treating a patient
who has, or in preventing a patient from getting, a disease or
condition selected from Alzheimer's disease, mild cognitive
impairment, Down's syndrome, Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy,
degenerative dementia, diffuse Lewy body type of Alzheimer's
disease or central or peripheral amyloid diseases and who is in
need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
[1878] 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 (R.sub.N-1--X.sub.N).sub.2O or
R.sub.N-1--X.sub.N--X.sub.2 or R.sub.N-1--X.sub.N--OH, for example,
to produce the lactone (XI), opening of the lactone (XI) with a
C-terminal amine, R.sub.C--NH.sub.2 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.
[1879] 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.
[1880] 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), R.sub.1 is: [1881] (I) C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted with one, two or three C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --C.ident.N,
--CF.sub.3, or --N.sub.3, [1882] (II)
--(CH.sub.2).sub.1-2--S--CH.sub.3, [1883] (III)
--CH.sub.2--CH.sub.2--S--CH.sub.3, [1884] (IV)
--CH.sub.2--(C.sub.2-C.sub.6 alkenyl) unsubstituted or substituted
by one --F, [1885] (V) --(CH.sub.2).sub.0-3--(R.sub.1-aryl) where
R.sub.1-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: [1886] (A) C.sub.1-C.sub.3 alkyl, [1887]
(B) --CF.sub.3, [1888] (C) --F, Cl, --Br and --I, [1889] (D)
C.sub.1-C.sub.3 alkoxy, [1890] (E) --O--CF.sub.3, [1891] (F)
--NH.sub.2, [1892] (G) --OH, or [1893] (H) --C.ident.N, [1894] (VI)
--(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is 0, 1, 2,
or 3 and R.sub.1-heteroaryl is: [1895] (A) pyridinyl, [1896] (B)
pyrimidinyl, [1897] (C) quinolinyl, [1898] (D) indenyl, [1899] (E)
indanyl, [1900] (F) benzothiophenyl, [1901] (G) indolyl, [1902] (H)
indolinyl, [1903] (I) pyridazinyl, [1904] (J) pyrazinyl, [1905] (K)
isoindolyl, [1906] (L) isoquinolyl, [1907] (M) quinazolinyl, [1908]
(N) quinoxalinyl, [1909] (O) phthalazinyl, [1910] (P) imidazolyl,
[1911] (Q) isoxazolyl, [1912] (R) pyrazolyl, [1913] (S) oxazolyl,
[1914] (T) thiazolyl, [1915] (U) indolizinyl, [1916] (V) indazolyl,
[1917] (W) benzothiazolyl, [1918] (X) benzimidazolyl, [1919] (Y)
benzofuranyl, [1920] (Z) furanyl, [1921] (AA) thienyl, [1922] (BB)
pyrrolyl, [1923] (CC) oxadiazolyl, [1924] (DD) thiadiazolyl, [1925]
(EE) triazolyl, [1926] (FF) tetrazolyl, [1927] (GG) 1,4-benzodioxan
[1928] (HH) purinyl, [1929] (II) oxazolopyridinyl, [1930] (JJ)
imidazopyridinyl, [1931] (KK) isothiazolyl, [1932] (LL)
naphthyridinyl, [1933] (MM) cinnolinyl, [1934] (NN) carbazolyl,
[1935] (OO) .beta.-carbolinyl, [1936] (PP) isochromanyl, [1937]
(QQ) chromanyl, [1938] (RR) furazanyl, [1939] (SS)
tetrahydroisoquinoline, [1940] (TT) isoindolinyl, [1941] (UU)
isobenzotetrahydrofuranyl, [1942] (VV) isobenzotetrahydrothienyl,
[1943] (WW) isobenzothiophenyl, [1944] (XX) benzoxazolyl, or [1945]
(YY) pyridopyridinyl, where the R.sub.1-heteroaryl group is bonded
to --(CH.sub.2).sub.0-3-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is unsubstituted or substituted with one
or two: [1946] (1) C.sub.1-C.sub.3 alkyl, [1947] (2) --CF.sub.3,
[1948] (3) --F, Cl, --Br, or --I, [1949] (4) C.sub.1-C.sub.3
alkoxy, [1950] (5) --O--CF.sub.3, [1951] (6) --NH.sub.2, [1952] (7)
--OH, or [1953] (8) --C.ident.N, with the proviso that when n.sub.1
is zero R.sub.1-heteroaryl is not bonded to the carbon chain by
nitrogen, or [1954] (VII)
--(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is: [1955] (A) morpholinyl,
[1956] (B) thiomorpholinyl, [1957] (C) thiomorpholinyl S-oxide,
[1958] (D) thiomorpholinyl S,S-dioxide, [1959] (E) piperazinyl,
[1960] (F) homopiperazinyl, [1961] (G) pyrrolidinyl, [1962] (H)
pyrrolinyl, [1963] (I) tetrahydropyranyl, [1964] (J) piperidinyl,
[1965] (K) tetrahydrofairanyl, or [1966] (L) tetrahydrothiophenyl,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heteroaryl group replaces the hydrogen
atom and its bond, where heterocycle is unsubstituted or
substituted with one or two: [1967] (1) .dbd.O, [1968] (2)
C.sub.1-C.sub.3 alkyl, [1969] (3) CF.sub.3, [1970] (4) --F, Cl,
--Br and --I, [1971] (5) C.sub.1-C.sub.3 alkoxy, [1972] (6)
--O--CF.sub.3, [1973] (7) --NH.sub.2, [1974] (8) --OH, or [1975]
(9) --C.ident.N, with the proviso that when n.sub.1 is zero
R.sub.1-heterocycle is not bonded to the carbon chain by nitrogen.
Typically, R.sub.1 is (V) --(CH.sub.2).sub.0-1--(R.sub.1-aryl) or
(VI) --(CH.sub.2).sub.n1--(R.sub.1-heteroaryl). It is preferred
that R.sub.1 is (V) --(CH.sub.2)--(R.sub.1-aryl) or (VI)
--(CH.sub.2)--(R.sub.1-heteroaryl). It is more preferred that
R.sub.1 is --(CH.sub.2)--(R.sub.1-aryl) where R.sub.1-aryl is
phenyl. It is even more preferred that R.sub.1 is
--(CH.sub.2)--(R.sub.1-aryl) where R.sub.1-aryl is phenyl
substituted with two --F. It is most preferred that the --F
substitution is 3,5 on the phenyl ring.
[1976] When R.sub.1 is R.sub.1-heteroaryl or R.sub.1-heterocycle
the bond from the R.sub.1-heteroaryl or R.sub.1-heterocycle group
to the --(CH.sub.2).sub.n1-- group can be from any ring atom which
has an available valence provided that such bond does not result in
formation of a charged species or unstable valence. This means that
the R.sub.1-heteroaryl or R.sub.1-heterocycle group is bonded to
--(CH.sub.2).sub.n1-- by any ring atom of the parent
R.sub.1-heteroaryl or R.sub.1-heterocycle group which was
substituted by hydrogen such that the new bond to the
R.sub.1-heteroaryl or R.sub.1-heterocycle group replaces the
hydrogen atom and its bond.
[1977] The first step of the process is to protect the free amino
group of the (S)-amino acid (I) with an amino protecting group to
produce the (S)-protected amino acid (II) by methods well known to
those skilled in the art. Amino protecting groups are well known to
those skilled in the art. See for example, "Protecting Groups in
Organic Synthesis", John Wiley and sons, New York, N.Y., 2nd ed.,
1991, Chapter 7; "Protecting Groups in Organic Chemistry", Plenum
Press, New York, N.Y., 1973, Chapter 2. The function of the amino
protecting group is to protect the free amino functionality
(--NH.sub.2) during subsequent reactions on the (S)-amino acid (I)
which would not proceed well either because the amino group would
react and be functionalized in a way that is inconsistent with its
need to be free for subsequent reactions or the free amino group
would interfere in the reaction. When the amino protecting group is
no longer needed, it is removed by methods well known to those
skilled in the art. By definition the amino protecting group must
be readily removable as is known to those skilled in the art by
methods well known to those skilled in the art. Suitable amino
PROTECTING GROUPs include t-butoxycarbonyl, benzyloxycarbonyl,
formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl,
bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluoylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobornyloxycarbonyl, -phenyl-C(.dbd.N)--H, and
1-piperidyloxycarbonyl. It is preferred that the protecting group
be t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ), it is more
preferred that the protecting group be t-butoxycarbonyl. One
skilled in the art will understand the preferred methods of
introducing a t-butoxycarbonyl or benzyloxycarbonyl protecting
group and may additionally consult T. W. Green and P. G. M. Wuts in
"Protective Groups in Organic Chemistry, John Wiley and Sons, 2nd
ed., 1991, at 327-335 for guidance.
[1978] The (S)-protected amino acid (II) is transformed to the
corresponding (S)-protected amide compound (III) by means well
known to those skilled in the art for the production of an amide
from a carboxylic acid and an amine or hydroxylamine. The means and
reaction conditions for producing the (S)-protected amide compound
(III) include, for example, the use of a coupling agent such as,
for example, dicyclohexylcarbodiimide, 1,1-carbonyldiimidazole,
POCl.sub.3, TiCl.sub.4, SO.sub.2ClF, benzotriazol-1-yl diethyl
phosphate, or N,N,N',N'-tetramethyl(succinimido)uronium
tetrafluoroborate in the presence of an amine or hydroxylamine.
1,1-Carbonyldiimidazole is a preferred coupling agent and
N-methyl-O-methylhydroxylamine is a preferred hydroxylamine. The
reaction is carried out for a period of time between 1 hour and 3
days at temperatures ranging from -78.degree. to elevated
temperature up to the reflux point of the solvent employed. It is
preferred to conduct the reaction between 0.degree. and
50.degree..
[1979] The (S)-protected amide compound (III) is then reduced by
means well known to those skilled in the art for reduction of a
amide to the corresponding aldehyde, affording the corresponding
aldehyde (IV). The means and reaction conditions for reducing the
(S)-protected amide compound (III) to the corresponding aldehyde
(IV) include, for example, sodium borohydride, lithium borohydride,
borane, diisobutylaluminum hydride, and lithium aluminium hydride.
Lithium aluminium hydride is the preferred reducing agent. The
reductions are carried out for a period of time between 1 hour and
3 days at temperatures ranging from -78.degree. to room
temperature. It is preferred to conduct the reduction between
-20.degree. and room temperature. The preferred combination of
reducing agents and reaction conditions needed are known to those
skilled in the art, see for example, Larock, R. C. in Comprehensive
Organic Transformations, VCH Publishers, 1989.
[1980] The aldehyde (IV) is transformed to the corresponding olefin
(V) by means known to those skilled in the art. An example of such
a reaction is the reaction of the aldehyde (IV) with a phosphorous
ylide to produce the desired olefin. Such phosphorous ylides
include methyltriphenylphosphonium bromide. Reaction conditions
include temperatures ranging from -100.degree. up to the reflux
temperature of the solvent employed; preferred temperature ranges
are between -100.degree. and 0.degree..
[1981] Peracid epoxidation of the olefin (V) affords the epoxide
(VI). Other methods for the conversion of an olefin to an epoxide
are known to those skilled in the art. The means for producing the
epoxide (VI) include, for example, the use of a peracid such as,
for example, peracetic acid, perbenzoic, trifluoroperacetic acid,
3,5-dinitroperoxybenzoic acid, and m-chloroperbenzoic acid.
[1982] The epoxide (VI) is then reacted with the appropriate amide
(VII) by means known to those skilled in the art which opens the
epoxide to produce the desired corresponding protected alcohol
(VIII). Reaction of the epoxide (VI) with the amide (VII) produces
a mixture of enantiomers. This enantiomeric mixture is then
separated by means known to those skilled in the art such as
selective low-temperature recrystallization or chromatographic
separation, most preferably by HPLC, employing commercially
available chiral columns. The enantiomer that is used in the
remainder of the process of CHART A is the (S,S,R)-alcohol
(VIII).
[1983] The protected-alcohol (VIII) is transformed to the
corresponding protected lactone (IX) by means known to those
skilled in the art. A preferred means is by reaction with an acid
catalyst, for example, but not limited to, p-toluenesulfonic acid
and the like. Reactions are conducted at temperatures ranging from
-78.degree. up to the reflux temperature of the solvent employed;
preferred temperature ranges are between 0.degree. and
50.degree..
[1984] The amine moiety or the protected lactone (IX) is
deprotected to the corresponding amine (X) by means known to those
skilled in the art for removal of amine protecting group. Suitable
means for removal of the amine protecting group depends on the
nature of the protecting group. Those skilled in the art, knowing
the nature of a specific protecting group, know which reagent is
preferable for its removal. For example, it is preferred to remove
the preferred protecting group, BOC, by dissolving the protected
lactone (IX) in a trifluoroacetic acid/dichloromethane mixture.
When complete, the solvents are removed under reduced pressure to
give the corresponding lactone (as the corresponding salt, i.e.
trifluoroacetic acid salt) which is used without further
purification. However, if desired, the lactone can be purified
farther by means well known to those skilled in the art, such as
for example, recrystallization. Further, if the non-salt form is
desired that also can be obtained by means known to those skilled
in the art, such as for example, preparing the free base amine via
treatment of the salt with mild basic conditions. Additional BOC
deprotection conditions and deprotection conditions for other
protecting groups can be found in T. W. Green and P. G. M. Wuts in
"Protective Groups in Organic Chemistry, John Wiley and Sons, 1991,
p. 309 and following. Chemically suitable salts include
trifluoroacetate, and the anion of mineral acids such as chloride,
sulfate, phosphate; preferred is trifluoroacetate.
[1985] The amine (X) is then reacted with an appropriately
substituted-amide-forming-agent such as anhydride, acyl halide, or
acid of the formula (R.sub.N-1--X.sub.N).sub.2O or
R.sub.N-1--X.sub.N--X.sub.2 or R.sub.N-1--X.sub.N--OH by
nitrogen-acylation means known to those skilled in the art to
produce the corresponding lactone (XI). Nitrogen acylation
conditions for reaction of the amine (X) with an amide forming
agent to produce the corresponding lactone (XI) are known to those
skilled in the art and can be found in R. C. Larock in
Comprehensive Organic Transformations, VCH Publishers, 1989, p.
981, 979, and 972. R.sub.N includes: [1986] (I)
R.sub.N-1--X.sub.N-- where X.sub.N is: [1987] (A) --CO--, [1988]
(B) --SO.sub.2--, [1989] (C) --(CR'R'').sub.1-6 where R' and R''
are the same or different and are --H or C.sub.1-C.sub.4 alkyl,
[1990] (D) --CO--(CR'R'').sub.1-6--X.sub.N-1 where X.sub.N-1 is
--O--, --S-- and --NR'R''-- and where R' and R'' are as defined
above, [1991] (E) a single bond; [1992] where R.sub.N-1 is: [1993]
(A) R.sub.N-aryl where R.sub.N-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: [1994] (1) C.sub.1-C.sub.6 alkyl, [1995] (2)
--F, --Cl, --Br, or --I, [1996] (3) --OH, [1997] (4) --NO.sub.2,
[1998] (5) --CO--OH, [1999] (6) --C.ident.N, [2000] (7)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are: [2001] (a) --H, [2002] (b)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with one (i)
--OH, or (ii) --NH.sub.2, [2003] (c) --C.sub.1-C.sub.6 alkyl
unsubstituted or substituted with one to three --F, --Cl, --Br, or
--I, [2004] (d) --C.sub.3-C.sub.7 cycloalkyl, [2005] (e)
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [2006] (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [2007] (g)
--C.sub.1-C.sub.6 alkenyl with one or two double bonds, [2008] (h)
--C.sub.1-C.sub.6 alkynyl with one or two triple bonds, [2009] (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, [2010] (j) --R.sub.1-ayrl where R.sub.1-aryl is as defined
above, or [2011] (k) --R.sub.1-heteroaryl where R.sub.1-heteroaryl
is as defined above, [2012] (8) --CO--(C.sub.3-C.sub.12 alkyl),
[2013] (9) --CO--(C.sub.3-C.sub.6 cycloalkyl), [2014] (10)
--CO--R.sub.1-heteroaryl where R.sub.1-heteroaryl is as defined
above, [2015] (11) --CO--R.sub.1-heterocycle where
R.sub.1-heterocycle is as defined above, [2016] (12)
--CO--R.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl or pyrrolidinyl where each group is
unsubstituted or substituted with one or two C.sub.1-C.sub.3 alkyl,
[2017] (13) --CO--O--R.sub.N-5 where R.sub.N-5 is: [2018] (a)
C.sub.1-C.sub.6 alkyl, or [2019] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [2020] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [2021] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [2022] (16)
--SO.sub.2--(C.sub.3-C.sub.12 alkyl), [2023] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [2024]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [2025] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [2026] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [2027] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [2028] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[2029] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [2030] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [2031] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [2032] (26)
--O--(C.sub.1-C.sub.6 alkyl), [2033] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, [2034] (28) --S--(C.sub.1-C.sub.6 alkyl), [2035] (29)
C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4,
or 5 --F, [2036] (30) --O--(C.sub.1-C.sub.6 alkyl unsubstituted or
substituted with 1, 2, 3, 4, or 5 --F, or [2037] (31) --O-.phi.,
[2038] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is: [2039]
(A) pyridinyl, [2040] (B) pyrimidinyl, [2041] (C) quinolinyl,
[2042] (D) indenyl, [2043] (E) indanyl, [2044] (F) benzothiophenyl,
[2045] (G) indolyl, [2046] (H) indolinyl, [2047] (I) pyridazinyl,
[2048] (J) pyrazinyl, [2049] (K) isoindolyl, [2050] (L)
isoquinolyl, [2051] (M) quinazolinyl, [2052] (N) quinoxalinyl,
[2053] (O) phthalazinyl, [2054] (P) imidazolyl, [2055] (Q)
isoxazolyl, [2056] (R) pyrazolyl, [2057] (S) oxazolyl, [2058] (T)
thiazolyl, [2059] (U) indolizinyl, [2060] (V) indazolyl, [2061] (W)
benzothiazolyl, [2062] (X) benzimidazolyl, [2063] (Y) benzofuranyl,
[2064] (Z) furanyl, [2065] (AA) thienyl, [2066] (BB) pyrrolyl,
[2067] (CC) oxadiazolyl, [2068] (DD) thiadiazolyl, [2069] (EE)
triazolyl, [2070] (FF) tetrazolyl, [2071] (GG) 1,4-benzodioxan
[2072] (HH) purinyl, [2073] (II) oxazolopyridinyl, [2074] (JJ)
imidazopyridinyl, [2075] (KK) isothiazolyl, [2076] (LL)
naphthyridinyl, [2077] (MM) cinnolinyl, [2078] (NN) carbazolyl,
[2079] (OO) .beta.-carbolinyl, [2080] (PP) isochromanyl, [2081]
(QQ) chromanyl, [2082] (RR) furazanyl, [2083] (SS)
tetrahydroisoquinoline, [2084] (TT) isoindolinyl, [2085] (UU)
isobenzotetrahydrofuranyl, [2086] (VV) isobenzotetrahydrothienyl,
[2087] (WW) isobenzothiophenyl, [2088] (XX) benzoxazolyl, or [2089]
(YY) pyridopyridinyl, where the R.sub.N-heteroaryl group is bonded
by any atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.N-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
unsubstituted or substituted with one or two: [2090] (1)
C.sub.1-C.sub.6 alkyl, [2091] (2) --F, --Cl, --Br, or --I, [2092]
(3) --OH, [2093] (4) --NO.sub.2, [2094] (5) --CO--OH, [2095] (6)
--C.ident.N, [2096] (7) --CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 are the same or different and are: [2097] (a) --H,
[2098] (b) --C.sub.1-C.sub.6 alkyl unsubstituted or substituted
with one [2099] (i) --OH, or [2100] (ii) 13 NH.sub.2, [2101] (c)
--C.sub.1-C.sub.6 alkyl unsubstituted or substituted with 1, 2, or
3 --F, --Cl, --Br, or --I, [2102] (d) --C.sub.3-C.sub.7 cycloalkyl,
[2103] (e --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
[2104] (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
[2105] (g) --C.sub.1-C.sub.6 alkenyl with one or two double bonds,
[2106] (h) --C.sub.1-C.sub.6 alkynyl with one or two triple bonds,
[2107] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [2108] (j) --R.sub.1-aryl where R.sub.1-aryl is as
defined above, or [2109] (k) --R.sub.1-heteroaryl where
R.sub.1-heteroaryl is as defined above, [2110] (8)
--CO--(C.sub.3-C.sub.12 alkyl), [2111] (9) --CO--(C.sub.3-C.sub.6
cycloalkyl), [2112] (10) --CO--R.sub.1-heteroaryl where
R.sup.1-heteroaryl is as defined above, [2113] (11)
--CO--R.sub.1-heterocycle where R.sub.1-heterocycle is as defined 4
above, [2114] (12) --CO--R.sub.N-4 where R.sub.N-4 is morpholinyl,
thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where
each group is unsubstituted or substituted with one or two
C.sub.1-C.sub.3 alkyl, [2115] (13) --CO--O--R.sub.N-5 where
R.sub.N-5 is: [2116] (a) C.sub.1-C.sub.6 alkyl, or [2117] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) where R.sub.1-aryl is as
defined above, [2118] (14) --SO.sub.2--NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined above, [2119] (15)
--SO--(C.sub.1-C.sub.8 alkyl), [2120] (16)
--SO.sub.2(C.sub.3-C.sub.12 alkyl), [2121] (17)
--NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, [2122]
(18) --NH--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [2123] (19)
--N--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [2124] (20)
--N(C.sub.1-C.sub.3 alkyl)-CO--R.sub.N-5 where R.sub.N-5 is as
defined above, [2125] (21) --NR.sub.N-2R.sub.N-3 where R.sub.N-2
and R.sub.N-3 can be the same or different and are as defined
above, [2126] (22) --R.sub.N-4 where R.sub.N-4 is as defined above,
[2127] (23) --O--CO--(C.sub.1-C.sub.6 alkyl), [2128] (24)
--O--CO--N(C.sub.1-C.sub.3 alkyl).sub.2, [2129] (25)
--O--CS--N(C.sub.1-C.sub.3 alkyl).sub.2, [2130] (26)
--O--(C.sub.1-C.sub.6 alkyl), [2131] (27) --O--(C.sub.2-C.sub.5
alkyl)-COOH, or [2132] (28) --S--(C.sub.1-C.sub.6 alkyl), [2133]
(C) --R.sub.N-aryl--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [2134] (D) --R.sub.N-aryl--R.sub.N-heteroaryl where
--R.sub.N-aryl and --R.sub.N-heteroaryl are as defined above,
[2135] (E) --R.sub.N-heteroaryl--R.sub.N-aryl where --R.sub.N-aryl
and --R.sub.N-heteroaryl are as defined above, [2136] (F)
--R.sub.N-heteroaryl--R.sub.N-heteroaryl where R.sub.N-heteroaryl
is as defined above, [2137] (G) --R.sub.N-aryl--O--R.sub.N-aryl
where --R.sub.N-aryl is as defined above, [2138] (H)
--R.sub.N-aryl--S--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [2139] (I) --R.sub.N-heteroaryl--O--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [2140] (J)
--R.sub.N-heteroaryl--S--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [2141] (K)
--R.sub.N-aryl--CO--R.sub.N-aryl where --R.sub.N-aryl is as defined
above, [2142] (L) --R.sub.N-aryl--CO--R.sub.N-heteroaryl where
--R.sub.N-aryl and R.sub.N-heteroaryl are as defined above, [2143]
(M) --R.sub.N-aryl--SO.sub.2--R.sub.N-aryl where R.sub.N-aryl is as
defined above, [2144] (N)
--R.sub.N-heteroaryl--CO--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [2145] (O)
--R.sub.N-heteroaryl--SO.sub.2--R.sub.N-heteroaryl where
R.sub.N-heteroaryl is as defined above, [2146] (P)
--R.sub.N-aryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where R.sub.N-aryl
is as defined above, [2147] (Q) --R.sub.N-aryl--S--(C.sub.1-C.sub.8
alkyl)-.phi. where R.sub.N-aryl is as defined above, [2148] (R)
--R.sub.N-heteroaryl--O--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, or [2149] (S)
--R.sub.N-heteroaryl--S--(C.sub.1-C.sub.8 alkyl)-.phi. where
R.sub.N-heteroaryl is as defined above, [2150] (II) A-X.sub.N--
where X.sub.N is --CO--,
[2151] wherein A is [2152] (A) T-E-(Q).sub.m', [2153] (1) where -T
is
[2153] ##STR00014## [2154] where [2155] (a) x=1 when y=1 and x 2
when y=0, [2156] (b) m is 0, 1, 2 or 3, [2157] (c) the values of x
and y vary independently on each carbon when m is 2 and 3, and
[2158] (d) R''' varies independently on each carbon and is H,
(C.sub.1-C.sub.2) alkyl, phenyl, or phenyl(C.sub.1-C.sub.3)alkyl;
[2159] (2) -E is [2160] (a) C.sub.1-C.sub.5 alkyl, but only if m'
does not equal 0, [2161] (b) methylthioxy(C.sub.2-C.sub.4)alkyl,
[2162] (c) an aryl group having 5 to 7 atoms when monocyclic or
having 8 to 12 atoms when fused, [2163] (d) a heterocyclic group
having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when
fused, [2164] (e) a mono or fused ring cycloalkyl group having 5 to
10 carbon atoms, [2165] (f) biphenyl, [2166] (g) diphenyl ether,
[2167] (h) diphenylketone, [2168] (i)
phenyl(C.sub.1-C.sub.8)alkyloxyphenyl, or [2169] (j)
C.sub.1-C.sub.6 alkoxy; [2170] (3) -Q is [2171] (a) C.sub.1-C.sub.3
alkyl, [2172] (b) C.sub.1-C.sub.3 alkoxy, [2173] (c)
C.sub.1-C.sub.3 alkylthioxy, [2174] (d) C.sub.1-C.sub.6
alkylacylamino, [2175] (e) C.sub.1-C.sub.6 alkylacyloxy, [2176] (f)
amido (including primary, C.sub.1-C.sub.6 alkyl and phenyl
secondary and tertiary amino moieties), [2177] (g) C.sub.1-C.sub.6
alkylamino [2178] (h) phenylamino, [2179] (i) carbamyl (including
C.sub.1-C.sub.6 alkyl and phenyl amides and esters), [2180] (j)
carboxyl (including C.sub.1-C.sub.6 alkyl and phenyl esters),
[2181] (k) carboxy(C.sub.2-C.sub.5)alkoxy, [2182] (l)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [2183] (m) heterocyclylacyl,
[2184] (n) heteroarylacyl, or [2185] (o) hydroxyl;
[2186] (4) m' is 0, 1, 2 or 3; [2187] (B) -E(Q).sub.m'' wherein E
and -Q are as defined as above and m'' is 0, 1, 2, or 3; [2188] (C)
-T-E wherein -E and -Q are as defined as above; or
[2189] (D) -E wherein -E is as defined as above; [2190] (III)
--CO--(C.sub.1-C.sub.6 alkyl) where alkyl is unsubstituted or
substituted with one or two: [2191] (A) --OH, [2192] (B)
--C.sub.1-C.sub.6 alkoxy, [2193] (C) --C.sub.1-C.sub.6 thioalkoxy,
[2194] (D) --CO--O--R.sub.N-8 where R.sub.N-8 is --H,
C.sub.1-C.sub.6 alkyl or -.phi., [2195] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2196] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [2197] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [2198] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [2199] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [2200] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [2201]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2202] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [2203] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [2204] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 is the same or
different and are as defined above, or [2205] (O)
--O--(C.sub.1-C.sub.5 alkyl) --COOH, [2206] (IV)
--CO--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [2207] (A)
--OH, [2208] (B) --C.sub.1-C.sub.6 alkoxy, [2209] (C)
--C.sub.1-C.sub.6 thioalkoxy, [2210] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [2211] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2212] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [2213] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [2214] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [2215] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [2216] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [2217]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2218] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [2219] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [2220] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [2221] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [2222] (V)
--CO--(C.sub.1-C.sub.3 alkyl)-S--(C.sub.1-C.sub.3 alkyl) where
alkyl is unsubstituted or substituted with one or two [2223] (A)
--OH, [2224] (B) --C.sub.1-C.sub.6 alkoxy, [2225] (C)
--C.sub.1-C.sub.6 thioalkoxy, [2226] (D) --CO--O--R.sub.N-8 where
R.sub.N-8 is --H, C.sub.1-C.sub.6 alkyl or [2227] (E)
--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2228] (F)
--CO--R.sub.N-4 where R.sub.N-4 is as defined above, [2229] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [2230] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are
the same or different and are as defined above, [2231] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [2232] (J)
--NH--CO--O--R.sub.N-8 where R.sub.N-8 is as defined above, [2233]
(K) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the
same or different and are as defined above, [2234] (L) --R.sub.N-4
where R.sub.N-4 is as defined above, [2235] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [2236] (N)
--O--CO--NR.sub.N-8R.sub.N-8 where the R.sub.N-8 are the same or
different and are as defined above, or [2237] (O)
--O--(C.sub.1-C.sub.5 alkyl) --COOH, [2238] (VI)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) where R.sub.N-aryl and
R.sub.N-heteroaryl are as defined above, where R.sub.N-10 is:
[2239] (A) --H, [2240] (B) C.sub.1-C.sub.6 alkyl, [2241] (C)
C.sub.3-C.sub.7 cycloalkyl, [2242] (D) C.sub.2-C.sub.6 alkenyl with
one double bond, [2243] (E) C.sub.2-C.sub.6 alkynyl with one triple
bond, [2244] (F) R.sub.1-aryl where R.sub.1-aryl is as defined
above, or [2245] (G) R.sub.N-heteroaryl where R.sub.N-heteroaryl is
as defined above.
It is preferred that R.sub.N is R.sub.N-1--X.sub.N-- where X.sub.N
is --CO--, where R.sub.N--, is R.sub.N-aryl where R.sub.N-aryl is
phenyl substituted with one --CO--NR.sub.N-2R.sub.N-3 where the
substitution on phenyl is 1,3-,
[2246] R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, where
R.sub.N-1 is R.sub.N-aryl where R.sub.N-aryl is phenyl substituted
with one C.sub.1 alkyl and with one --CO--NR.sub.N-2R.sub.N-3 where
the substitution on the phenyl is 1,3,5-, or
[2247] R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, where
R.sub.N-1 is R.sub.N-heteroaryl where R.sub.N-heteroaryl is
substituted with one --CO--NR.sub.N-2R.sub.N-3. It is further
preferred that R.sub.N-2 and R.sub.N-3 are the same and are C.sub.3
alkyl.
[2248] It is further preferred that:
[2249] R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, where
R.sub.N-1 is R.sub.N-aryl where R.sub.N-aryl is phenyl substituted
with one --CO--NR.sub.N-2R.sub.N-3 where the substitution on phenyl
is 1,3-,
[2250] R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, where
R.sub.N-1 is R.sub.N-aryl where R.sub.N-aryl is phenyl substituted
with one C.sub.1 alkyl and with one --CO--NR.sub.N-2R.sub.N-3 where
the substitution on the phenyl is 1,3,5-.
[2251] It is preferred that X.sub.N is (A) --CO-- and (B)
--SO.sub.2--; it is more preferred that X.sub.N be --CO--.
[2252] The nitrogen-acylation of primary amines to produce
secondary amides is one of the oldest known reactions. The amide
forming agents, (R.sub.N-1--X.sub.N).sub.2O or
R.sub.N-1--X.sub.N--X.sub.2 or R.sub.N-1--X.sub.N--OH are known to
those skilled in the art and are commercially available or can be
readily prepared from known starting materials by methods known in
the literature. X.sub.2 includes --Cl, --Br; it is preferred that
X.sub.2 is --Cl. It is preferred to use an isophthalic acid
acylating agent of the formula R.sub.N-2R.sub.N-3N--CO-.phi.-CO--
or a methylisophthalic acid acylating agent
R.sub.N-2R.sub.N-3N--CO--(CH.sub.3--).phi.-CO-- where the
substitution is 5-methyl-1,3-isophthalic acid. The more preferred
5-methyl-1,3-isophthalic acid is
3-[(N,N-dipropylamino)carbonyl]-5-methylbenzoic acid. These
compounds are preferably prepared as set forth as follows. An
ester, preferably the methyl ester of isophthalate or methyl
5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture.
1,1'-Carbonyldilmidazole is then added at 0-100.degree.. Next the
desired amine (H--NR.sub.N-2R.sub.N-3) is added. After stirring at
0-100.degree. the reaction mixture is partitioned between a
saturated aqueous solution with a pH of 3 to 9 and a water
immiscible organic solvent. The aqueous layer is separated and
extracted twice more with the organic solvent. The organic extracts
are combined and then washed with an aqueous solution and dried.
Filtration of the drying agent and removal of solvents by reduced
pressure gives crude ester of the desired
R.sub.N-2R.sub.N-3N--CO-.phi.-CO--O--CH.sub.3 or a
methylisophthalic acid acylating agent
R.sub.N-2R.sub.N-3N--CO--(CH.sub.3--).phi.-CO--O--CH.sub.3--.
Purification of the ester can be achieved via chromatography on
silica gel eluting with a suitable solvent The isophthalate ester
or methylisophthalate ester of the mono-alkyl or di-alkyl amide is
then treated with an aqueous solution of base such as alkali
hydroxide in a minimum amount of THF/methanol/water and stirred at
20-70.degree. with monitoring. The solvents are removed under
reduced pressure and subsequently partitioned between water and a
water immiscible organic solvent. The aqueous phase is separated
and extracted once more with a water immiscible organic solvent.
The aqueous phase was then acidified to pH.ltoreq.3. The mixture
obtained is then extracted three times with ethyl acetate. These
combined organic extracts are then dried. The drying agent is
removed by filtration and the organic solvent remove under reduced
pressure to gave crude product. The crude mono- or di-alkyl amide
isophthalate/methylisophthalate is used as such in the next
reaction with the amine (X) to produce the lactone (XI).
[2253] When it is desired to produce a primary amide, R.sub.N-2 and
R.sub.N-3 are both --H, the following procedure is preferred. An
ester of isophthalate or methyl 5-methyl-1,3-isophthalate is
dissolved in a THF/DMF mixture. CDI is then added at 0-100.degree..
Ammonia gas is then bubbled into the mixture with monitoring. The
reaction is cooled to 0.degree. for the duration of the ammonia
addition. The reaction is left stirring under a balloon of ammonia
at 0-100.degree. with monitoring. The reaction is partitioned
between a aqueous solution with a pH of 3 to 9 and a water
immiscible organic solvent. The phases are separated and the
aqueous phase is extracted twice more with a water immiscible
organic solvent. The organic extracts are washed with an aqueous
solution and dried. Removal of solvents under reduced pressure
gives crude ester of the desired H.sub.2N--CO-.phi.-CO--O(Alkyl) or
a methylisophthalic acid acylating agent
H.sub.2N--CO--(CH.sub.3--).phi.-CO--O(Alkyl). Purification of the
crude ester can be achieved via chromatography on silica gel
eluting with isopropanol/chloroform. The isophthalate ester or
methylisophthalate ester of the primary amide is then treated with
an aqueous solution of base such as alkali hydroxide in a minimum
amount of THF/methanol/water and stirred at 0-100.degree. with
monitoring. The solvents are removed under reduced pressure and
subsequently partitioned between water and a water immiscible
organic solvent. The aqueous phase is separated and extracted once
more with a water immiscible organic solvent. The aqueous phase is
then acidified until pH.ltoreq.3. The mixture obtained is then
extracted three times with a water immiscible organic solvent.
These combined organic extracts are dried and the organic solvent
removed under reduced pressure to gave crude product. The primary
amide isophthalate/methylisophthalate is used as such in the next
reaction with (X) to produce (XI).
[2254] When it is desired that the amine be cyclized to be a group
such as morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl, etc
the following procedure is followed. An ester of isophthalate or
methyl 5-methyl-1,3-isophthalate is dissolved in a suitable organic
solvent and a catalytic amount or DMF is added. The mixture is
cooled to -20.degree. to below rt and then oxalyl chloride is
added. The mixture is stirred with monitoring and the solvents
removed under reduced pressure. The acid chloride is left under
vacuum overnight. The crude acid chloride is dissolved in a
suitable organic solvent and cooled to -20.degree. to below rt
before the addition of the cyclic amine and N-methyl piperidine.
The reaction mixture is stirred at -20.degree. to below rt with
monitoring before the solvents are removed. The residue is diluted
with water and water immiscible organic solvent and the phases are
separated. The aqueous phase is extracted twice more with water
immiscible organic solvent, and the combined organic extracts are
washed with an aqueous solution and dried. Removal of solvents
under reduced pressure gives the crude product. The crude
cyclicamide is then treated with an aqueous base such as alkali
hydroxide a minimum amount of THF/methanol/water and stirred
overnight at 0-100.degree.. The solvents are removed under reduced
pressure and subsequently partitioned between water and a water
immiscible organic solvent. The aqueous phase is extracted once
more with a water immiscible organic solvent. Removal of water from
the aqueous phase under reduced pressure gives the desired cyclic
amide product.
[2255] The lactone (XI) may then be reacted with the appropriately
substituted C-terminal amine, R.sub.C--NH.sub.2 by means known to
those skilled in the art which opens the lactone to produce the
desired hydroxyethylene end product (XII). The substituted
C-terminal amines, R.sub.C--NH.sub.2 of this invention are
commercially available or are known to those skilled in the art and
can be readily prepared from known compounds. R.sub.C includes:
[2256] (I) --(C.sub.1-C.sub.10)alkyl-K.sub.1-3 in which: [2257] (A)
the alkyl chain is unsubstituted or substituted with one --OH,
[2258] (B) the alkyl chain is unsubstituted or substituted with one
C.sub.1-C.sub.6 alkoxy unsubstituted or substituted with 1-5 --F,
[2259] (C) the alkyl chain is unsubstituted or substituted with one
--O-.phi., [2260] (D) the alkyl chain is unsubstituted or
substituted with 1, 2, 3, 4 or 5 --F, [2261] (E) the alkyl chain is
unsubstituted or substituted with a combination of up to three
atoms of oxygen and sulfur each such atom replacing one carbon,
[2262] (F) each K is: [2263] (1) H, [2264] (2) C.sub.1-C.sub.3
alkyl, [2265] (3) C.sub.1-C.sub.3 alkoxy, [2266] (4)
C.sub.1-C.sub.3 alkylthioxy, [2267] (5) C.sub.1-C.sub.6
alkylacylamino, [2268] (6) C.sub.1-C.sub.6 alkylacyloxy, [2269] (7)
amido [2270] (8) C.sub.1-C.sub.6 alkylamino [2271] (9) phenylamino,
[2272] (10) carbamyl [2273] (11) carboxyl [2274] (12)
carboxy(C.sub.2-C.sub.5)alkoxy, [2275] (13)
carboxy(C.sub.2-C.sub.5)alkylthioxy, [2276] (14) heterocyclylacyl,
[2277] (15) heteroarylacyl, [2278] (16) amino unsubstituted or
substituted with C.sub.1-C.sub.6 alkyl, [2279] (17) hydroxyl, or
[2280] (18) carboxyl methyl ester; [2281] (II)
--(CH.sub.2).sub.0-3-J-[(--(CH.sub.2).sub.0-3--K].sub.1-2 where K
is as defined above and J is: [2282] (A) a 5 to 7 atom monocyclic
aryl group, [2283] (B) a 8 to 12 atom multicyclic aryl group,
[2284] (C) a 5 to 7 atom heterocyclic group, [2285] (D) a 8 to 12
atom multicyclic heterocyclic group, or [2286] (E) a 5 to 10 atom
monocyclic or multicyclic cycloalkyl group; [2287] (III)
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl where cycloalkyl
can be unsubstituted or substituted with one, two or three [2288]
(A) C.sub.1-C.sub.3 alkyl unsubstituted or substituted with 1, 2,
3, or 4 --F, --Cl, --Br, or --I, [2289] (B) --CO--OH, [2290]
(C)--CO--O--(C.sub.1-C.sub.4 alkyl), [2291] (D) --OH, or [2292] (E)
C.sub.1-C.sub.6 alkoxy, [2293] (IV) --(CH.sub.2).sub.2-6--OH,
[2294] (V) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are --H, C.sub.1-C.sub.4 alkyl and .phi.-
and R.sub.C-aryl is the same as R.sub.N-aryl, [2295] (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl where R.sub.C-heteroaryl
is: [2296] (A) pyridinyl, [2297] (B) pyrimidinyl, [2298] (C)
quinolinyl, [2299] (D) indenyl, [2300] (E) indanyl, [2301] (F)
benzothiophenyl, [2302] (G) indolyl, [2303] (H) indolinyl, [2304]
(I) pyridazinyl, [2305] (J) pyrazinyl, [2306] (K) isoindolyl,
[2307] (L) isoquinolyl, [2308] (M) quinazolinyl, [2309] (N)
quinoxalinyl, [2310] (O) phthalazinyl, [2311] (P) isoxazolyl,
[2312] (Q) pyrazolyl, [2313] (R) indolizinyl, [2314] (S) indazolyl,
[2315] (T) benzothiazolyl, [2316] (U) benzimidazolyl, [2317] (V)
benzofuranyl, [2318] (W) fliranyl, [2319] (X) thienyl, [2320] (Y)
pyrrolyl, [2321] (Z) oxadiazolyl, [2322] (AA) thiadiazolyl, [2323]
(BB) triazolyl, [2324] (CC) tetrazolyl, [2325] (DD) 1,4-benzodioxan
[2326] (EE) purinyl, [2327] (FF) oxazolopyridinyl, [2328] (GG)
imidazopyridinyl, [2329] (HH) isothiazolyl, [2330] (II)
naphthyridinyl, [2331] (JJ) cinnolinyl, [2332] (KK) carbazolyl,
[2333] (LL) .beta.-carbolinyl, [2334] (MM) isochromanyl, [2335]
(NN) chromanyl, [2336] (OO) furazanyl, [2337] (PP)
tetrahydroisoquinoline, [2338] (QQ) isoindolinyl, [2339] (RR)
isobenzotetrahydrofuranyl, [2340] (SS) isobenzotetrahydrothienyl,
[2341] (TT) isobenzothiophenyl, [2342] (UU) benzoxazolyl, or [2343]
(VV) pyridopyridinyl, [2344] (VII)
--(CH.sub.2).sub.0-4--R.sub.C-heterocycle where R.sub.C-heterocycle
is the same as R.sub.1-heterocycle, [2345] (VIII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3 where R.sub.C-1 and
R.sub.C-2 are the same or different and are: [2346] (A) --H, [2347]
(B) --C.sub.1-C.sub.6 alkyl, [2348] (C) --(C.sub.1-C.sub.4
alkyl)-R.sub.C'-aryl where R.sub.C'-aryl is as defined above for
R.sub.1-aryl, [2349] (D) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, [2350] (E) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [2351] (F)
--R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined above,
[2352] (G) --R.sub.C-heterocycle where R.sub.C-heterocycle is as
defined above, [2353] (H) --(CH.sub.2).sub.1-4--OH, [2354] (I)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C'-aryl
where R.sub.C-4 is --O--, --S--, --NH-- or --NHR.sub.C-5-- where
R.sub.C-5 is C.sub.1-C.sub.6 alkyl, and where R.sub.C'-aryl is as
defined above, [2355] (J)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.1-4--R.sub.C-heteroaryl
where R.sub.C-4 and R.sub.C-heteroaryl are as defined above, or
[2356] (K) --R.sub.C'-aryl where R.sub.C'-aryl is as defined
above,
[2357] and where R.sub.C-3 is: [2358] (A) --H, [2359] (B)
--C.sub.1-C.sub.6 alkyl, [2360] (C) --R.sub.C-aryl where
R.sub.C'-aryl is as defined above, [2361] (D) --R.sub.C-heteroaryl
where R.sub.C-heteroaryl is as defined above, [2362] (E)
--R.sub.C-heterocycle where R.sub.C-heterocycle is as defined
above, [2363] (F) --(C.sub.1-C.sub.4 alkyl)-R.sub.C'-aryl where
R.sub.C'-aryl is as defined above, [2364] (G) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl where R.sub.C-heteroaryl is as defined
above, or [2365] (H) --(C.sub.1-C.sub.4 alkyl)-R.sub.C-heterocycle
where R.sub.C-heterocycle is as defined above, [2366] (IX)
--CH(.phi.).sub.2, [2367] (X) -cyclopentyl or -cyclohexyl ring
fused to a phenyl or heteroaryl ring where heteroaryl is as defined
above and phenyl and heteroaryl are unsubstituted or substituted
with one, two or three: [2368] (A) C.sub.1-C.sub.3 alkyl, [2369]
(B) CF.sub.3, [2370] (C) --F, Cl, --Br and --I, [2371] (D)
C.sub.1-C.sub.3 alkoxy, [2372] (E) --OCF.sub.3, [2373] (F)
--NH.sub.2, [2374] (G) --OH, or [2375] (H) --C.ident.N, [2376] (XI)
--CH.sub.2--C.ident.CH; [2377] (XII)
--(CH.sub.2).sub.0-1--CHR.sub.C-5--(CH.sub.2).sub.0-1-.phi. where
R.sub.C-5 is: [2378] (A) --OH, or [2379] (B) --CH.sub.2--OH; [2380]
(XIII) --CH(-.phi.)--CO--O(C.sub.1-C.sub.3 alkyl); [2381] (XIV)
--CH(--CH.sub.2--OH)--CH(--OH)-.phi.-NO.sub.2; [2382] (XV)
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--OH; [2383] (XVI)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; [2384]
(XVII) --(C.sub.2-C.sub.8) alkynyl; or [2385] (XVIII) --H.
Typically, R.sub.C is:
[2385] [2386] (I) --C.sub.1-C.sub.8 alkyl, [2387] (II)
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7) cycloalkyl, [2388] (III)
--(CH.sub.2).sub.0-3--OH, [2389] (IV)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl, [2390] (V)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl, [2391]
(VI)--(CH.sub.2).sub.0-4--R.sub.C-heterocycle, [2392] (VII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3, [2393] (IX)
-cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl
ring where heteroaryl is as defined above and phenyl and heteroaryl
are unsubstituted or substituted with one or two: [2394] (A)
C.sub.1-C.sub.3 alkyl, [2395] (B) --CF.sub.3, [2396] (C)--F, Cl,
--Br or --I, [2397] (D) C.sub.1-C.sub.3 alkoxy, [2398] (E)
--OCF.sub.3, or [2399] (XVI) --H.
It is preferred that R.sub.C is:
[2399] [2400] (II) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.7)
cycloalkyl, [2401] (IV)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl, [2402] (V)
--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl, [2403] (VI)
--(CH.sub.2).sub.0-4--R.sub.C-heterocycle, [2404] (VII)
--C(R.sub.C-1)(R.sub.C-2)--CO--NH--R.sub.C-3, or [2405] (IX)
-cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl
ring.
It is more preferred that R.sub.C is:
[2405] [2406] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl,
[2407] (V) --(CH.sub.2).sub.0-4--R.sub.C-heteroaryl, [2408] (VI)
--(CH.sub.2).sub.0-4 --R.sub.C-heterocycle, or [2409] (IX)
-cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl
ring.
It is most preferred that R.sub.C is:
[2409] [2410] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl
where R.sub.C-aryl is phenyl, [2411] (V)
--CH.sub.2--R.sub.C-heteroaryl, [2412] (VI)
--CH.sub.2--R.sub.C-heterocycle, or [2413] (IX) -cyclohexyl ring
fused to a phenyl ring. Further, it is preferred that when R.sub.C
is phenyl, it is substituted in the 3-position or
3,5-positions.
[2414] Suitable reaction conditions for opening the lactone (XI) to
produce the desired hydroxyethylene end product (XII) include those
of the AlMe.sub.3-mediated coupling reaction disclosed in the
literature procedure of S. F. Martin et al., Tetrahedron Lett.
1998, 39, 1517-1520. When the substituted C-terminal amine is a
1-amino-3,5-cis-dimethyl cyclohexyldicarboxylate it is preferrably
prepared as follows. To dimethyl-5-isophthalate in acetic acid and
methanol, is added rhodium in alumina in a high-pressure bottle.
The bottle is saturated with hydrogen at 55 psi and shaken for one
week of time. The mixture is then filtered through a thick layer of
celite cake and rinsed with methanol three times, the solvents are
removed under reduced pressure (with heat) to give a concentrate.
The concentrate is triturated with ether and filtered again to give
the desired C-terminal amine. When the substituted C-terminal amine
is 1-amino-3,5-cis-dimethoxy cyclohexane it is preferably following
the general procedure above and making non-critical variations but
starting wth 3,5-dimethoxyaniline. When the substituted C-terminal
amine is an aminomethyl group where the substituent on the methyl
group is an aryl group, for example
NH.sub.2--CH.sub.2--R.sub.C-aryl, and
NH.sub.2--CH.sub.2--R.sub.C-aryl is not commercially available it
is preferrably prepared as follows. A suitable starting material is
the (appropriately substituted) aralkyl compound. The first step is
bromination of the alkyl substitutent via methods known to those
skilled in the art, see for example R. C. Larock in Comprehensive
Organic Transformations, VCH Publishers, 1989, p. 313. Next the
alkyl halide is reacted with azide to produce the
aryl-(alkyl)-azide. Last the azide is reduced to the corresponding
amine by hydrogen/catalyst to give the C-terminal amine of formula
NH.sub.2--CH.sub.2--R.sub.C-aryl.
[2415] CHART B, as defined within, sets forth a process for
production of the amide
[2416] (VII). Preparation of the amide (VIII) starts with the
reaction of an appropriate amino-indanol (XIV) with an appropriate
haloketone (XII) to afford the hydroxy indane (XV). The
amino-indanol (XIV) and haloketone (XII) 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 X
substituent of the haloketone is typically F, Cl, Br, or I.
Preferably X is Cl. For the amino haloketone (XII), R.sub.2 is:
[2417] (I) --H, [2418] (II) C.sub.1-C.sub.6 alkyl, or [2419] (III)
--(CH.sub.2).sub.0-4--R.sub.2-1 where R.sub.2-1 is
(C.sub.3-C.sub.6)cycloalkyl, R.sub.1-aryl or R.sub.1-heteroaryl
where R.sub.1-aryl and R.sub.1-heteroaryl are as defined above,
[2420] Certain hydroxyethylene compounds of formula (XII) contain
acidic functionality capable of forming base addition salts.
Additionally, certain hydroxyethylene compounds of formula (XII)
contain basic functionality capable of forming acid addition salts.
For example, certain hydroxyethylene compounds of formula (XII) are
amines and as such form salts when reacted with acids.
Pharmaceutically acceptable salts are prefer-red over the
corresponding hydroxyethylene compounds of formula (XII) since they
produce compounds which are more water soluble, stable and/or more
crystalline. Pharmaceutically acceptable salts are any salt which
retains the activity of the parent compound and does not impart any
deleterious or undersirable effect on the subject to whom it is
administered and in the context in which it is administered.
Pharmaceutically acceptable salts include salts of both inorganic
and organic acids. The preferred pharmaceutically acceptable salts
include salts of the following acids: hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic,
CH.sub.3--(CH.sub.2).sub.n1--COOH where n.sub.1 is 0 thru 4,
HOOC--(CH.sub.2).sub.n1--COOH where n is as defined above,
HOOC--CH.dbd.CH--COOH, and .phi.-COOH. Additionally, preferred
pharmaceutically acceptable salts include salts of the following
bases: triethanolamine, N-methylglucamine, diethanolamine,
ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, and
carbonate, bicarbonate, phosphonate, or hydroxide salts of an
alkali or alkaline earth metal. For other acceptable salts, see
Int. J. Pharm., 33, 201-217 (1986).
[2421] Preferred hydroxyethylene compounds of formula (XII),
include, for example, [2422]
N-[(1S,2S,4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5
dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide-
, [2423]
6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-
-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid, [2424]
5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-e-
thyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid, [2425]
4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-e-
thyl-4-(S)-hydroxyhexanoylamino]-butyric acid, [2426]
3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-e-
thyl-4-(S)-hydroxyhexanoylamino]-propionic acid, [2427]
8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-e-
thyl-4-(S)-hydroxyhexanoylamino]-octanoic acid, [2428]
8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-
-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,
[2429]
N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]--
N,N-dipropyl-isophthalamide, [2430]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexy-
l]-N,N-dipropyl-isophthalamide, [2431]
N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-
-N,N-dipropyl-isophthalamide, [2432]
N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-h-
ydroxy-hexyl]-N,N-dipropyl-isophthalamide, [2433]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl-
)-hexyl]-N,N-dipropyl-isophthalamide, [2434]
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(-
S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, [2435]
N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydro-
xy-hexyl]-N,N-dipropyl-isophthalamide, [2436]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarba-
moyl)-hexyl]-N,N-dipropyl-isophthalamide, [2437]
4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R-
)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid methyl ester, [2438]
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2--
(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, [2439]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid, [2440]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid, [2441]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid, [2442]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamnoyl-benzoylami-
no)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarbox-
ylic acid, [2443]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,
[2444]
4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoy-
l-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid, [2445]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-be-
nzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexaneca-
rboxylic acid, [2446]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-be-
nzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexaneca-
rboxylic acid methyl ester, [2447]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethy-
lcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, [2448]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pent-
yl]-5-methyl-N,N-dipropyl-isophthalamide, [2449]
N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S-
)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, [2450]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-y-
lmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,
[2451]
N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydr-
oxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, [2452]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-y-
l-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, [2453]
N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl-
]-5-methyl-N,N-dipropyl-isophthalamide, [2454]
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hyd-
roxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, [2455]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pen-
tyl]-5-methyl-N,N-dipropyl-isophthalamide, [2456]
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-
-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or [2457]
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-
-pentyl]-5-methyl-N,N-dipropyl-isophthalamide.
[2458] Additional preferred hydroxyethylene compounds of formula
(XII) include, for example those of the following formulae:
##STR00015## ##STR00016##
[2459] Most preferred hydroxyethylene compounds of formula (XII),
include, for example,
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid. [2460]
6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-e-
thyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid, [2461]
8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-
-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,
[2462]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid [2463]
4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoy-
l-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid, and [2464]
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamin-
o)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid.
[2465] The hydroxyethylene compounds of formula (XII), and
pharmaceutically acceptable salts thereof, are useful for treating
humans suffering from Alzheimer's disease, for helping prevent or
delay the onset of Alzheimer's disease, for treating patients with
MCI (mild cognitive impairment) 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 lobal
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, diffuse Lewy body type Alzheimer's disease. It
is preferred the disease is Alzheimer's disease.
[2466] When treating these diseases, the hydroxyethylene compounds
of formula (XII) can either be used individually or in combination
as is best for the patient.
[2467] With regard to these diseases the term "treating" means that
the hydroxyethylene compounds of formula (XII) can be used in
humans with existing disease. The hydroxyethylene compounds of
formula (XII) will delay or slow the progression of the disease
thereby giving the individual a more useful life span.
[2468] The term "preventing" means that if the compounds of the
present invention are administered to those who do not now have the
disease but who would normally get the disease or be at increased
risk for the disease, they will not get the disease. In addition,
"preventing" also includes delaying the development of the disease
in an individual who will ultimately get the disease or would be at
risk for the disease. By delaying the onset of the disease, the
hydroxyethylene compounds of formula (XII) have prevented the
individual from getting the disease during the period in which the
individual would normally have gotten the disease or reduce the
rate of development of the disease or some of its effects but for
the administration of the hydroxyethylene compounds of formula
(XII) up to the time the individual ultimately gets the disease.
Preventing also includes administration of the compounds of the
invention to those individuals thought to be predisposed to the
disease due to familial history and/or due to the presence of one
or more biological markers for the disease such as a known genetic
mutation of APP or by analysis of APP cleavage products in body
tissues or fluids.
[2469] In treating or preventing the above diseases the
hydroxyethylene compounds of formula (XII) are administered in a
therapeutically effective amount. The therapeutically effective
amount will vary depending on the particular compound used and the
route of administration as is known to those skilled in the
art.
[2470] In treating a patient with any of the diagnosed above
conditions a physician may administer hydroxyethylenes of formula
(XII) immediately and continue indefinitely.
[2471] In treating patients who do not at the present have
Alzheimer's disease, but who are believed to be at substantial risk
for Alzheimer's disease, the physician should start treatment when
the patient first experiences early pre-Alzheimer's symptoms such
as, memory or cognitive problems associated with aging. In
addition, there are some patients who may be diagnosed with
Alzheimer's through the detection of the genetic marker APOE4 or
other biological indicators that are predictive for Alzheimer's
disease. In these situations, even though the patient does not have
symptoms of the disease, the administration of the hydroxyethylene
compounds of formula (XII) may be started before they appear and
treatment continued indefinitely to prevent or delay the outset of
the disease.
[2472] The hydroxyethylene compounds of formula (XII) can be
administered orally, parenterally (IV, IM, depo-IM, SQ and
depo-SQ), sublingually, intranasally (inhalation), intrathecally,
topically and rectally. The invention here is the novel
hydroxyethylene compounds of formula (XII). Dosage forms known to
those skilled in the art are suitable for delivery of the novel
hydroxyethylene compounds of formula (XII).
[2473] Hydroxyethylene compounds of formula (XII) may be
administered enterally or parenterally. When administered orally,
hydroxyethylene compounds of formula (XII) can be administered in
usual dosage forms for oral administration as is well known to
those skilled in the art. These dosage forms include the usual
solid unit dosage forms of tablets and capsules as well as liquid
dosage forms such as solutions, suspensions and elixirs. When the
solid dosage forms are used, it is preferred that they be of the
sustained release type so that the hydroxyethylene compounds of
formula (XII) need to be administered only once or twice daily.
[2474] The oral dosage forms are administered to the patient 1, 2,
3, or 4 times daily. It is preferred that the hydroxyethylene
compounds of formula (XII) be administered either three or fewer
times, more preferably once or twice daily. Hence, it is preferred
that the hydroxyethylene compounds of formula (XII) be administered
in oral dosage form. It is preferred that whatever oral dosage form
is used, that it be designed so as to protect the hydroxyethylene
compounds of formula (XII) from the acidic environment of the
stomach. Enteric coated tablets are well known to those skilled in
the art. In addition, capsules filled with small spheres each
coated to protect from the acidic stomach, are also well known to
those skilled in the art. When administered orally the
therapeutically effective amount is from about 0.1 mg/day to about
1,000 mg/day. It is preferred that the oral dosage is from about 1
mg/day to about 100 mg/day. It is more preferred that the oral
dosage is from about 5 mg/day to about 50 mg/day. It is understood
that while a patient may be started on one dose, that dose may have
to be varied over time as the patient's condition changes.
[2475] Hydroxyethylene compounds of formula (XII) may also be
advantageously delivered in a nano crystal dispersion formulation.
Preparation of such formulations is described in U.S. Pat. No.
5,145,684. And nano crystalline dispersions of, for example, HIV
protease inhibitors and their method of use are described in U.S.
Pat. No. 6,045,829. The nano crystalline formulations typically
afford greater bioavailability of drug compounds.
[2476] In addition, the hydroxyethylene compounds of formula (XII)
can be administered parenterally. When administered parenterally
they can be administered IV, IM, depo-IM, SC or depo-SC. When
administered parenterally, the hydroxyethylene compounds of formula
(XII) should deliver a therapeutically effective amount about 0.5
to about 100 mg/day, preferably from about 5 to about 50 mg daily.
When a depo formulation is used for injection once a month or once
every two weeks, the dose should be about 0.5 mg/day to about 50
mg/day or on a monthly amount the dose for one month should be from
about 15 mg to about 1,500 mg. Because of the forgetfulness of the
patients with Alzheimer's disease, it is preferred that the
parenteral dosage form be a depo-IM injection.
[2477] The hydroxyethylene compounds of formula (XII) can be given
sublingually. When given sublingually, the hydroxyethylene
compounds of formula (XII) should be given one thru four times
daily in the same amount as for IM administration.
[2478] The hydroxyethylene compounds of formula (XII) can be given
intranasally. When given by this route of administration, the
appropriate dosage forms are a nasal spray or dry powder as is
known to those skilled in the art. The dosage of the
hydroxyethylene compounds of formula (XII) for intranasal
administration is the same as for IM administration.
[2479] The hydroxyethylene compounds of formula (XII) can be given
intrathecally. When given by this route of administration the
appropriate dosage form can be a parenteral dosage form as is known
to those skilled in the art. The dosage of the hydroxyethylene
compounds of formula (XII) for intrathecal administration is the
same as for IM administration.
[2480] The hydroxyethylene compounds of formula (XII) can be given
topically. When given by this route of administration, the
appropriate dosage form is a cream, ointment or patch. Because of
the amount of the hydroxyethylene compounds of formula (XII) needed
to administered the patch is preferred. Further, two or more
patches may be needed. When administered topically, the dosage is
from about 0.5 mg/day to about 200 mg/day. However, the amount that
can be delivered by a patch is limited. Therefore, two or more
patches may be required. The number and size of the patch is not
important, what is important is that a therapeutically effective
amount of the hydroxyethylene compounds of formula (XII) be
delivered as is known to those skilled in the art. The
hydroxyethylene compounds of formula (XII) can be administered
rectally by suppository as is known to those skilled in the art.
When administered by suppository, the therapeutically effective
amount is from about 0.5 mg to about 500 mg.
[2481] The hydroxyethylene compounds of formula (XII) can be
administered by implants as is known to those skilled in the art.
When administering a hydroxyethylene compound of formula (XII) by
implant, the therapeutically effective amount is the same as for
depot administration.
[2482] Again, the invention here is a new method of using
hydroxyethylene compounds of formula (XII) and hydroxyethylene
compounds of formula (XII). Given a particular hydroxyethylene
compound of formula (XII), and a desired dosage form, one skilled
in the art would know how to prepare the appropriate dosage form
for the hydroxyethylene compounds of formula (XII).
[2483] The hydroxyethylene compounds of formula (XII) are used in
the same manner by the same routes of administration using the same
pharmaceutical dosage forms and at the same dosing schedule for
treating patients with MCI (mild cognitive impairment) 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
[2484] 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, diffuse Lewy body type of Alzheimer's disease.
The hydroxyethylene compounds of formula (XII) can be used with
each other or with other agents used to treat or prevent the
conditions listed above. Such agents include gamma-secretase
inhibitors, anti-amyloid vaccines and pharmaceutical agents such as
donepezil hydrochloride (ARICEPT.TM. Tablets), tacrine
hydrochloride (COGNEX.TM. Capsules) or other acetylcholine esterase
inhibitors and with direct or indirect neurotropic agents of the
future.
Inhibition of APP Cleavage
[2485] The compounds of the invention inhibit cleavage of APP at
the .beta.-secretase cleavage site, Met595-Asp596 for the APP695
isoform. While not wishing to be bound by a particular theory,
inhibition of .beta.-secretase acitivity is thought to inhibit
production of beta amyloid beta peptide (A.beta.). Inhibitory
activity is demonstrated in one of a variety of inhibition assays,
whereby cleavage of an APP substrate in the presence of a secretase
enzyme is analyzed in the presence of the inhibitory compound,
under conditions normally sufficient to result in cleavage at the
.beta.-secretase cleavage site. Reduction of APP cleavage at the
.beta.-secretase cleavage site compared with an untreated or
inactive control is correlated with inhibitory activity. Assay
systems that can be used to demonstrate efficacy of the compound
inhibitors of the invention are known. Representative assay systems
are described, for example, in U.S. Pat. No. 5,942,400.
[2486] The enzymatic activity of .beta.-secretase and the
production of A.beta. can be analyzed in vitro or in vivo, using
natural, mutated, and/or synthetic APP substrates, natural,
mutated, and/or synthetic enzyme, and the test compound. The
analysis may involve primary or secondary cells expressing native,
mutant, and/or synthetic APP and enzyme, or may utilize transgenic
animal models expressing the substrate and enzyme. Detection of
enzymatic activity can be by analysis of one or more of the
cleavage products, for example, by immunoassay, fluorometric or
chromogenic assay, HPLC, or other means of detection. Inhibitory
compounds are determined as those having the ability to decrease
the amount of .beta.-secretase cleavage product produced in
comparison to a control, where .beta.-secretase mediated cleavage
in the reaction system is observed and measured in the absence of
inhibitory compounds.
.beta.-Secretase
[2487] Various forms of .beta.-secretase enzyme are known, and are
available and useful for assay of enzyme activity and inhibition of
enzyme activity. These include native, recombinant, and synthetic
forms of the enzyme. Human ASP2a and Asp2b has been characterized,
for example, in published PCT patent applications WO98/22597 and
WO00/17369, as well as synthetic forms of the enzyme.
[2488] The compounds of the invention inhibit 50% of the
.beta.-secretase enzymatic acitivity at a concentration of from
about 0.1 nM to about 200 .mu.M, preferably at a concentration of
from about 10 nM to about 100 .mu.M, more preferably from about 100
.mu.M to about 50 .mu.M, and most preferably from about 1 .mu.M to
about 10 .mu.M.
APP Substrate
[2489] Assays that demonstrate inhibition of
.beta.-secretase-mediated cleavage of APP can utilize any of the
known forms of APP, including the 695 amino acid "normal" isotype
described by Kang et. al., 1987, Nature 325:733-6, the 770 amino
acid isotype described by Kitaguchi et. al., 1981, Nature
331:530-532, and variants such as the Swedish Mutation (KM670-1NL)
(APP-SW), the London Mutation (V7176F), and others. See, for
example, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature
Genet. 1:233-234, for a review of known variant mutations.
Additional useful substrates include the dibasic amino acid
modification, APP-KK disclosed, for example, in WO 00/17369,
fragments of APP, and synthetic peptides containing the
.beta.-secretase cleavage site, wild type (WT) or mutated form,
e.g., SW, as described, for example, in U.S. Pat. No.
5,942,400.
[2490] The APP substrate may also be a fusion peptide, formed of a
peptide having the .beta.-secretase cleavage site fused to a
peptide that confers a characteristic useful for enzymatic assay,
for example, isolation and/or detection properties.
[2491] One useful assay utilizes a fusion peptide having maltose
binding protein (MBP) fused to the C-terminal 125 amino acids of
APP-SW. The MBP portion is captured on an assay substrate by
anti-MBP capture antibody. Incubation of the captured fusion
protein in the presence of .beta.-secretase results in cleavage of
the substrate at the .beta.-secretase cleavage site. Analysis of
the cleavage activity can be, for example, by immunoassay of
cleavage products. One such immunoassay detects a unique epitope
exposed at the carboxy terminus of the cleaved fusion protein, for
example, using the antibody SW192. This assay is described, for
example, in U.S. Pat. No. 5,942,400.
Cellular Assay
[2492] Cells expressing an APP substrate and an active
.beta.-secretase can be incubated in the presence of a compound
inhibitor to demonstrate inhibition of enzymatic activity as
compared with a control. Activity of .beta.-secretase can be
measured by analysis of one or more APP cleavage products. For
example, cellular inhibition of .beta.-secretase activity would be
expected to decrease release of the cleavage product, A.beta..
[2493] Human cell lines that normally process A.beta. from APP
provide a useful means to assay inhibitory activities of the
compounds of the invention. Production and release of A.beta.
and/or other cleavage products into the culture medium can be
measured, for example by immunoassay, such as Western blot or
enzyme-linked immoassay (EIA or ELISA).
[2494] Primary neuronal cell cultures from human brain or from
brain tissue obtained from transgenic animals expressing APP,
particurly human APP, and capable of processing APP to detectable
A.beta. are also useful cells for assay of .beta.-secretase
cleavage activity. For example, primary human neuronal cell
cultures derived from human embryonic tissues express endogenous
.beta.-secretase and endogenous APP. Enzymatic activity is assayed
in the presence of the inhibitory compound, and cleavage products,
such as A.beta., are measured. Another useful primary cell culture
system employs cells derived from brain tissue of transgenic mice,
for example, from PD-APP mice expressing a transgenic APP having a
mutation at V717 or the Swedish mutation.
[2495] Although both neural and non-neural cells process and
release A.beta., levels of endogenous .beta.-secretase activity are
low and often difficult to detect by EIA. The use of cell types
known to have enhanced .beta.-secretase activity, enhanced
processing of APP to A.beta., and/or enhanced production of A.beta.
are therefore preferred. For example, transfection of cells with
the Swedish Mutant form of APP (APP-SW); with APP-KK; or with
APP-SW-KK provides cells having enhanced .beta.-secretase activity
and producing amounts of A.beta. that can be readily measured.
Antibodies
[2496] Products characteristic of APP cleavage can be measured by
immunoassay using various antibodies, as described, for example, in
Pirttila et. al., 1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No.
5,612,486. Useful antibodies to detect A.beta. include, for
example, the monoclonal antibody 6E10 (Senetek, St. Louis, Mo.)
that specifically recognizes an epitope on amino acids 1-16 of the
A.beta. peptide; antibodies 162 and 164 (New York State Insititute
for Basic Research, Staten Island, N.Y.) that are specific for
hA.beta. 1-40 and 1-42, respectively. Another useful antibody is SW
92, as discussed above, that recognizes an epitope uncovered on the
C-termial cleavage fragment following APP-SW cleavage mediated by
.beta.-secretase.
Animal Models
[2497] Animal models useful in testing the compounds of the
invention include those expressing elevated levels of A.beta.,
demonstrating an enhanced amount of A.beta. deposits, and/or
increased number or size of beta amyloid plaques as compared with
control animals. Such animal models include transgenic mammals.
Suitable transgenic animals include rodents transformed with a
variant or modified APP that results in a measured amount A.beta.
in the animal that is greater than that produced in a
non-transformed control. Examples of suitable transgenic animal
models include a mouse transformed with APP-SW, described, for
example, in U.S. Pat. Nos. 5,877,399, 5,612,486, and 5,850,003.
Other suitable animals are transformed with V717 APP, as described,
for example, in U.S. Pat. No. 5,877,015, and in Ganes et. al.,
1995, Nature 373:523.
[2498] Cleavage of APP at the .beta.-secretase cleavage site can be
analyzed in these animals by measure of cleavage fragments in the
animal's brain tissues, and possibly cerebral fluids, as well as by
analysis of beta amyloid plaques and assessment of necrosis in the
animal's brain tissues.
[2499] On contacting an APP substrate with a .beta.-secretase
enzyme in the presence of an inhibitory compound of the invention
and under conditions sufficient to permit enzymatic mediated
cleavage of APP and/or release of A.beta. from the substrate, the
of the invention are effective to reduce .beta.-secretase-mediated
cleavage of APP at the .beta.-secretase cleavage site and/or
effective to reduce released amounts of A.beta.. Where such
contacting is the administration of the inhibitory compounds of the
invention to an animal model, for example, as described above, the
compounds are effective to reduce A.beta. deposition in brain
tissues of the animal, and to reduce the number and/or size of beta
amyloid plaques. Where such administration is to a human subject,
the compounds are effective to inhibit or slow the progression of
disease characterized by enhanced amounts of A.beta., to slow the
progression of AD in the, and/or to prevent onset or development of
AD in a patient at risk for the disease.
Assay Systems
[2500] Assays for determining APP cleavage at the .beta.-secretase
cleavage site are well known in the art. Exemplary assays, are
described, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400,
and described in the Examples below.
Cell Free Assays
[2501] Exemplary assays that can be used to demonstrate the
inhibitory activity of the compounds of the invention are
described, for example, in WO00/17369 and U.S. Pat. No. 5,942,400.
Such assays can be performed in cell-free incubations or in
cellular incubations using cells expressing a .beta.-secretase and
an APP substrate having a secretase cleavage site.
[2502] An APP substrate containing the 13-secretase cleavage site
of APP, for example, a complete APP or variant, an APP fragment, or
a recombinant or synthetic APP substrate containing the amino acid
sequence: KM-DA or NL-DA, is incubated in the presence of a
.beta.-secretase enzyme, for example human (h) Asp2a, hAsp2b, a
fragment thereof, or a synthetic or recombinant polypeptide variant
of hAsp2a or hAsp2b having .beta.-secretase activity and effective
to cleave the .beta.-secretase cleavage site of APP, under
incubation conditions suitable for the cleavage activity of the
enzyme. Suitable substrates optionally include derivatives that may
be fusion proteins or peptides that contain the substrate peptide
and a modification useful to facilitate the purification or
detection of the peptide or its .beta.-secretase cleavage products.
Useful modifications include the insertion of a known antigenic
epitope for antibody binding; the linking of a label or detectable
moiety, the linking of a binding substrate, and the like.
[2503] Suitable incubation conditions for a cell-free in vitro
assay include, for example: approximately 200 nM-10 .mu.M
substrate, approximately 10-200 pM enzyme, and approximately 0.1
nM-10 .mu.M inhibitor compound, in aqueous solution, at an
approximate pH of 4-7, at approximately 37.degree. C., for a time
period of approximately 10 minutes to 3 hours. These incubation
conditions are exemplary only, and can be varied as required for
the particular assay components and/or desired measurement system.
Optimization of the incubation conditions for the particular assay
components should account for the specific .beta.-enzyme used and
its pH optimum, any additional enzymes and/or markers that might be
used in the assay, and the like. Such optimization is routine and
will not require undue experimentation.
Cellular Assays
[2504] Numerous cell-based assays to analyze .beta.-secretase
activity and/or processing of APP to release A.beta.. In one
embodiment, cells that naturally express .beta.-secretase are used.
Alternatively, cells are modified to express a recombinant
.beta.-secretase, for example, hAsp2a, hAsp2b, or a recombinant or
synthetic variant enzyme as discussed above.
[2505] The APP substrate may be added to the culture medium or
expressed in the cells. Cells that naturally express APP, variant
or mutant forms of APP, or cells transformed to express an isoform
of APP, mutant or variant APP, recombinant or synthetic APP, APP
fragment, or synthetic APP peptide or fusion protein containing the
.beta.-secretase APP cleavage site can be used, provided that the
expressed APP is permitted to contact the enzyme and enzymatic
cleavage activity can be analyzed.
[2506] Contact of an APP substrate with a .beta.-secretase enzyme
within the cell and in the presence or absence of a compound
inhibitor of the invention can be used to demonstrate the
inhibitory activity. .beta.-secretase activity or function, for
example, as measured by cleavage of the APP substrate and detection
of fragments and/or markers, can take numerous forms, as discussed
above for non-cellular assays. Preferably, assay in the presence of
a useful inhibitory compound provides at least about 30%, most
preferably at least about 50% inhibition of the enzymatic activity,
as compared with a non-inhibited control.
[2507] In such assays, for example, the cells expressing APP and
.beta.-secretase are incubated in a culture medium under conditions
to permit processing of the APP by the enzyme and release of
A.beta. into the medium and accumulation of other fragments of APP
in cell lysates. The inhibitory activity of the compounds of the
invention can be demonstrated by incubating the cells in the
presence and absence of the compound. On exposure of the cells to
the compound inhibitor, the amount of A.beta. released into the
medium and/or the amount of CTF99 fragments of APP in the cell
lysates is reduced as compared with the control. The cleavage
products of APP can be analyzed, for example, by immune reactions
with specific antibodies, as discussed above.
[2508] Preferred cells for analysis of .beta.-secretase activity
include primary human neuronal cells, primary transgenic animal
neuronal cells, where the transgene is APP, and other cells such as
those of a stable 293 cell line expressing APP, for example,
APP-SW. In the cellular assay, cells are incubated in the presence
or absence of the inhibitor, under conditions suitable for
.beta.-secretase enzymatic activity at it's cleavage site on the
APP substrate. Cell supernatant is harvested, and analyzed for
cleavage fragments, for example using immunoassay.
In Vivo Assays: Animal Models
[2509] Various animal models can be used to analyze
.beta.-secretase activity and/or processing of APP to release
A.beta., as described above. For example, transgenic animals
expressing APP substrate and .beta.-secretase enzyme can be used to
demonstrate inhibitory activity of the compounds of the invention.
Preferred are animals that exhibit characteristics associated with
the pathophysiology of AD. Certain transgenic animal models for AD
have been described, for example, in U.S. Pat. Nos. 5,877,399,
5,612,486, 5,387,742, 5,720,936, and 5,811,633.
[2510] Administration of the compound inhibitors of the invention
to the transgenic mice described herein provides an alternative
method for demonstrating the inhibitory activity of the compound
inhibitors. Administration of the compound inhibitor in a
pharmaceutally effective carrier and via an administrative route
that reaches the target tissue in an appropriate therapeutic amount
is preferred. Inhibition of .beta.-secretase-mediated cleavage of
APP and of A.beta. release can be measured by analysis of the
cleavage products in the body fluids or tissues of the animal.
Analysis of brain tissues for A.beta. deposits or plaques is also
made.
[2511] It should be apparent to one skilled in the art that the
exact dosage and frequency of administration will depend on the
particular hydroxyethylene compounds of formula (XII) administered,
the particular condition being treated, the severity of the
condition being treated, the age, weight, general physical
condition of the particular patient, and other medication the
individual may be taking as is well known to administering
physicians who are skilled in this art.
DEFINITIONS AND CONVENTIONS
[2512] The definitions and explanations below are for the terms as
used throughout this entire document including both the
specification and the claims.
I. Conventions for Formulas and Definitions of Variables
[2513] The chemical formulas representing various compounds or
molecular fragments in the specification and claims may contain
variable substituents in addition to expressly defined structural
features. These variable substituents are identified by a letter or
a letter followed by a numerical subscript, for example, "Z.sub.1"
or "R.sub.i" where "i" is an integer. These variable substituents
are either monovalent or bivalent, that is, they represent a group
attached to the formula by one or two chemical bonds. For example,
a group Z.sub.1 would represent a bivalent variable if attached to
the formula CH.sub.3--C(=Z.sub.1)H. Groups R.sub.i and R.sub.j
would represent monovalent variable substituents if attached to the
formula CH.sub.3--CH.sub.2--C(R.sub.i)(R.sub.j)H.sub.2. When
chemical formulas are drawn in a linear fashion, such as those
above, variable substituents contained in parentheses are bonded to
the atom immediately to the left of the variable substituent
enclosed in parenthesis. When two or more consecutive variable
substituents are enclosed in parentheses, each of the consecutive
variable substituents is bonded to the immediately preceding atom
to the left which is not enclosed in parentheses. Thus, in the
formula above, both R.sub.i and R.sub.j are bonded to the preceding
carbon atom. Also, for any molecule with an established system of
carbon atom numbering, such as steroids, these carbon atoms are
designated as C.sub.1, where "i" is the integer corresponding to
the carbon atom number. For example, C.sub.6 represents the 6
position or carbon atom number in the steroid nucleus as
traditionally designated by those skilled in the art of steroid
chemistry. Likewise the term "R.sub.6" represents a variable
substituent (either monovalent or bivalent) at the C.sub.6
position.
[2514] Chemical formulas or portions thereof drawn in a linear
fashion represent atoms in a linear chain. The symbol "--" in
general represents a bond between two atoms in the chain. Thus
CH.sub.3--O--CH.sub.2--CH(R.sub.1)--CH.sub.3 represents a
2-substituted-1-methoxypropane compound. In a similar fashion, the
symbol "=" represents a double bond, e.g.,
CH.sub.2.dbd.C(R.sub.i)--O--CH.sub.3, and the symbol ".ident."
represents a triple bond, e.g.,
HC.ident.C--CH(R.sub.i)--CH.sub.2--CH.sub.3. Carbonyl groups are
represented in either one of two ways: --CO-- or --C(.dbd.O)--,
with the former being preferred for simplicity.
[2515] A rigid cyclic (ring) structure for any compounds herein
defines an orientation with respect to the plane of the ring for
substituents attached to each carbon atom of the rigid cyclic
compound. For saturated compounds which have two substituents
attached to a carbon atom which is part of a cyclic system,
--C(X.sub.1)(X.sub.2)-- the two substituents may be in either an
axial or equatorial position relative to the ring and may change
between axial/equatorial. However, the position of the two
substituents relative to the ring and each other remains fixed.
While either substituent at times may lie in the plane of the ring
(equatorial) rather than above or below the plane (axial), one
substituent is always above the other. In chemical structural
formulas depicting such compounds, a substituent (X.sub.1) which is
"below" another substituent (X.sub.2) will be identified as being
in the alpha (.alpha.) configuration and is identified by a broken,
dashed or dotted line attachment to the carbon atom, i.e., by the
symbol " - - - " or " . . . ". The corresponding substituent
attached "above" (X.sub.2) the other (X.sub.1) is identified as
being in the beta (.beta.) configuration and is indicated by an
unbroken line attachment to the carbon atom.
[2516] When a variable substituent is bivalent, the valences may be
taken together or separately or both in the definition of the
variable. For example, a variable R.sub.1 attached to a carbon atom
as --C(.dbd.R.sub.i)-- might be bivalent and be defined as oxo or
keto (thus forming a carbonyl group (--CO--) or as two separately
attached monovalent variable substituents .alpha.-R.sub.i-j and
.beta.-R.sub.i-k. When a bivalent variable, R.sub.i, is defined to
consist of two monovalent variable substituents, the convention
used to define the bivalent variable is of the form
".alpha.-R.sub.1-j:.beta.-R.sub.1-k" or some variant thereof. In
such a case both .alpha.-R.sub.i-j and .beta.-R.sub.i-k are
attached to the carbon atom to give
--C(.alpha.-R.sub.i-j)(.beta.-R.sub.i-k)--. For example, when the
bivalent variable R.sub.6, --C(.dbd.R.sub.6)-- is defined to
consist of two monovalent variable substituents, the two monovalent
variable substituents are .alpha.-R.sub.6-1:.beta.-R.sub.6-2, . . .
.alpha.-R.sub.6-9:.beta.-R.sub.6-10, etc, giving
--C(.alpha.-R.sub.6-1)(.beta.-R.sub.6-2)--, . . .
--C(.alpha.-R.sub.6-9)(.beta.-R.sub.6-10)--, etc. Likewise, for the
bivalent variable R.sub.11, --C(.dbd.R.sub.11)--, two monovalent
variable substituents are .alpha.-R.sub.11-1:.beta.-R.sub.11-2. For
a ring substituent for which separate .alpha. and .beta.
orientations do not exist (e.g. due to the presence of a carbon
carbon double bond in the ring), and for a substituent bonded to a
carbon atom which is not part of a ring the above convention is
still used, but the .alpha. and .beta. designations are
omitted.
[2517] Just as a bivalent variable may be defined as two separate
monovalent variable substituents, two separate monovalent variable
substituents may be defined to be taken together to form a bivalent
variable. For example, in the formula
--C.sub.1(R.sub.i)H--C.sub.2(R.sub.j)H--(C.sub.1 and C.sub.2 define
arbitrarily a first and second carbon atom, respectively) R.sub.i
and R.sub.j may be defined to be taken together to form (1) a
second bond between C.sub.1 and C.sub.2 or (2) a bivalent group
such as oxa (--O--) and the formula thereby describes an epoxide.
When R.sub.i and R.sub.j are taken together to form a more complex
entity, such as the group --X--Y--, then the orientation of the
entity is such that C.sub.1 in the above formula is bonded to X and
C.sub.2 is bonded to Y. Thus, by convention the designation " . . .
R.sub.i and R.sub.j are taken together to form
--CH.sub.2--CH.sub.2--O--CO-- . . . " means a lactone in which the
carbonyl is bonded to C.sub.2. However, when designated " . . .
R.sub.j and R.sub.i are taken together to form
--CO--O--CH.sub.2--CH.sub.2-- the convention means a lactone in
which the carbonyl is bonded to C.sub.1.
[2518] The carbon atom content of variable substituents is
indicated in one of two ways. The first method uses a prefix to the
entire name of the variable such as "C.sub.1-C.sub.4", where both
"1" and "4" are integers representing the minimum and maximum
number of carbon atoms in the variable. The prefix is separated
from the variable by a space. For example, "C.sub.1-C.sub.4 alkyl"
represents alkyl of 1 through 4 carbon atoms, (including isomeric
forms thereof unless an express indication to the contrary is
given). Whenever this single prefix is given, the prefix indicates
the entire carbon atom content of the variable being defined. Thus
C.sub.2-C.sub.4 alkoxycarbonyl describes a group
CH.sub.3--(CH.sub.2).sub.n-0-CO-- where n is zero, one or two. By
the second method the carbon atom content of only each portion of
the definition is indicated separately by enclosing the
"C.sub.i-C.sub.j" designation in parentheses and placing it
immediately (no intervening space) before the portion of the
definition being defined. By this optional convention
(C.sub.1-C.sub.3)alkoxycarbonyl has the same meaning as
C.sub.2-C.sub.4 alkoxycarbonyl because the "C.sub.1-C.sub.3" refers
only to the carbon atom content of the alkoxy group. Similarly
while both C.sub.2-C.sub.6 alkoxyalkyl and
(C.sub.1-C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl define alkoxyalkyl
groups containing from 2 to 6 carbon atoms, the two definitions
differ since the former definition allows either the alkoxy or
alkyl portion alone to contain 4 or 5 carbon atoms while the latter
definition limits either of these groups to 3 carbon atoms.
[2519] When the claims contain a fairly complex (cyclic)
substituent, at the end of the phrase naming/designating that
particular substituent will be a notation in (parentheses) which
will correspond to the same name/designation in one of the CHARTS
which will also set forth the chemical structural formula of that
particular substituent.
[2520] It is to be understood that the recitation of numerical
ranges by endpoints includes all numbers and fractions subsumed
within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80,
4, and 5).
[2521] It is to be understood that all numbers and fractions
thereof are presumed to be modified by the term "about."
[2522] It is to be understood that "a" as used herein includes both
the singular and plural.
[2523] The general definitions used herein have the following
meanings within the scope of the present invention.
II. Definitions
[2524] All temperatures are in degrees Celsius.
[2525] TLC refers to thin-layer chromatography.
[2526] psi refers to pounds/in.sup.2.
[2527] HPLC refers to high pressure liquid chromatography.
[2528] THF refers to tetrahydrofuran.
[2529] DMF refers to dimethylformamide.
[2530] EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
[2531] NBS refers to N-bromosuccinimide.
[2532] TEA refers to triethylamine.
[2533] BOC refers to 1,1-dimethylethoxy carbonyl or
t-butoxycarbonyl, --CO--O--C(CH.sub.3).sub.3.
[2534] CBZ refers to benzyloxycarbonyl, CO--O--CH.sub.2-.phi..
[2535] TFA refers to trifluoracetic acid, CF.sub.3--COOH.
[2536] CDI refers to 1,1'-carbonyldiimidazole.
[2537] Saline refers to an aqueous saturated sodium chloride
solution.
[2538] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[2539] CMR refers to C-13 magnetic resonance spectroscopy, chemical
shifts are reported in ppm (.delta.) downfield from TMS.
[2540] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (d) downfield
from TMS.
[2541] -.phi. refers to phenyl (C.sub.6H.sub.5).
[2542] MS refers to mass spectrometry expressed as m/e, m/z or
mass/charge unit. MH.sup.+ refers to the positive ion of a parent
plus a hydrogen atom. EI refers to electron impact. CI refers to
chemical ionization. FAB refers to fast atom bombardment.
[2543] HRMS refers to high resolution mass spectrometry.
[2544] Ether refers to diethyl ether.
[2545] "APP", amyloid precursor protein, is defined as any APP
polypeptide, including APP variants, mutations, and isoforms, for
example as disclosed in U.S. Pat. No. 5,766,846.
[2546] "A.beta.", beta amyloid beta peptide, is defined as any
peptide resulting from beta-secretase mediated cleavage of APP,
including peptides of 39, 40, 41, 42, and 43 amino acids, and
extending from the beta-secretase cleavage site to amino acids 39,
40, 41, 42, or 43.
[2547] ".beta.-secretase" is an aspartyl protease that mediates
cleavage of APP at the amino-terminal edge of A.beta.. Human
.beta.-secretase is described, for example, in WO00/17369.
[2548] A compound of the invention is any compound described herein
having inhibitory activity against a .beta.-secretase enzyme;
against the production of A.beta.; against the production of beta
amyloid deposits or plaques; or against the development or
progression of neurodegenerative disease such as AD, measured, for
example, by one or more of the assays described herein.
[2549] Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[2550] When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
[2551] When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v).
[2552] BOP refers to
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate.
[2553] TBDMSCI refers to t-butyldimethylsilyl chloride.
[2554] TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid
ester.
[2555] Trisomy 21 refers to Down's Syndrome.
Ac=acetyl (methylcarbonyl)
[2556] aq.=aqueous bd=broad doublet bs=broad singlet
c=concentration (g/mL) cc=cubic centimeter d=doublet
DCM=dichloromethane=methylene chloride=CH.sub.2Cl.sub.2
[2557] de=diastereomeric excess
EDTA=ethylene diamine tetraacetic acid
[2558] eq.=equivalents
EtOAc=ethyl acetate
EtOH=ethanol
[2559] g=grams
HOBT=1-hydroxybenzotriazole
[2560] h=hour
IC.sub.50=inhibitory concentration of a compound that reduces
enzyme activity by half.
[2561] iso=an alkyl chain having the ending group 2-methylpropyl,
i.e. --CH(CH.sub.3).sub.2.
IM=intramuscularly
IV=intravenously
SC=subcutaneously
L=liter
LDA=lithium diisopropyl amide
[2562] m=multiplet max=maximum mg=milligram mL=milliliter
mm=millimeter mM=millimolar mmol=millimole mp=melting point
MeOH=methanol
[2563] meq=milliequivalent
MsOH=methanesulfonic acid
[2564] n=normal, i.e. unbranched, e.g. n-Pr is
--CH.sub.2--CH.sub.2--CH.sub.3
N=normal
[2565] ng=nanogram nm=nanometers
OD=optical density
PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
[2566] pg=picogram pM=picoMolar
R.sub.f=ratio of movement of a substance on a thin layer
chromatogram in comparison to the movement of the solvent
front.
[2567] .delta.=units of measurement in nuclear magnetic resonance
spectroscopy which are relative to a standard, e.g. tetramethyl
silane. q=quartet quint.=quintet rpm=rotations per minute s=singlet
t=triplet t or tert=tertiary in an alkyl chain, e.g. t-butyl is
--C(CH.sub.3).sub.3.
.mu.L=microliter
.mu.M=micromolar (an expression of concentration in
micromoles/liter)
[2568] s=singlet t=triplet
UV=ultraviolet
[2569] Unless otherwise indicated, all functional group radicals
(e.g., alkyl, aryl, cycloalkyl, cyclic heteroaryl, heterocycle,
etc.) can be substituted or unsubstituted. Substituted functional
group radicals can be substituted with one or more substituents,
unless indicated otherwise. Suitable substituents for substituted
functional group radicals generally include halogen, hydroxy,
alkoxy, alkyl, aryl, arylalkyl, alkylaryl, arylalkoxy, and the
like. It will be understood that the terminology "X radical
substituted by a/an Y" includes the "X" radical being substituted
by two or more "Y", unless indicated otherwise.
[2570] "Alkyl" refers to linear or branched, saturated aliphatic
hydrocarbon radicals, such as, for example, methyl, ethyl, propyl,
butyl, octyl, isopropyl, tert-butyl, sec-pentyl, and the like.
[2571] "Cycloalkyl" refers to cyclic aliphatic hydrocarbon
radicals, such as, for example, 3- to 8-member hydrocarbon rings
(e.g., cyclohexyl or cyclopentyl), bicyclic 4- to 10-member
hydrocarbon ring systems, and a tricyclic 8- to 14-member
hydrocarbon ring systems. Monocyclic cycloalkyl groups include, for
example, cyclohexane and cyclopentane. Multicyclic cycloalkyl
groups include cyclohexyl, cyclopentyl, and
1,2,3,4-tetrahydrohaphthyl for example.
[2572] "Heterocycle" refers to cyclic, non-aromatic radicals
containing at least two carbon atoms and 1 to 3 heteroatoms
selected from O, N, and S as members of at least one ring. Examples
of such radicals include 3- to 8-member rings; bicyclic 4- to
10-member ring systems, and tricyclic 8- to 14-member ring systems,
where at least one ring (and in some instances each of the rings)
of any of these examples contains 1 to 3 heteroatoms selected from
O, N, and S as members of the ring. Monocyclic heterocyclic groups
include morpholinyl, piperazinyl, and tetrahydrofuranyl, for
example. Multicyclic heterocyclic groups include
decahydroquinoline, cyclohexene oxide, and
3-amino-3-azabicyclo[3.3.0]octane, for example.
[2573] "Alkylene` refers to bivalent, linear or branched, saturated
aliphatic hydrocarbon radicals, such as, for example, methylene,
ethylene, propylene, butylene, octylene, isopropylene,
tert-butylene, sec-pentylene, and the like.
[2574] "Alkenyl" refers to linear or branched aliphatic hydrocarbon
radicals containing at least one double bond, such as, for example,
ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-methyl-1-propenyl,
and the like.
[2575] "Alkynyl" refers to linear or branched aliphatic hydrocarbon
radicals containing at least one triple bond, such as, for example,
ethynyl (acetyl), 1-propynyl, 2-propynyl, 1-butynyl, and the
like.
[2576] "Aryl" refers to cyclic aromatic hydrocarbon radicals having
a single ring, such as phenyl, multiple rings, such as biphenyl,
and multiple condensed rings, such as naphthyl and anthryl.
Monocyclic aryl groups include phenyl, for example. Multicyclic
aryl groups include naphthyl and anthryl, for example.
[2577] "Amine" includes primary, secondary and tertiary amines
which may be in straight or branched chains or, in the case of
secondary and tertiary amines within rings (e.g. morpholine and
piperazine).
[2578] "Heteroaryl" refers to a cyclic aromatic rings having 1 to 4
hetero atoms selected from S, O, and N; and aromatic 7 to 10
membered organic stable bicyclic rings having 1 to 5 hetero atoms
selected from S, O, and N. Examples of such radicals include 3- to
8-member rings; bicyclic 4- to 10-member ring systems; and
tricyclic 8- to 14-member ring systems, where at least one ring
(and in some instances each of the rings) of any of these examples
contains 1 to 3 heteroatoms selected from O, N, and S as members of
the ring.
[2579] "Acyloxy" refers to the groups R--C(O)O--, substituted
R--C(O)O--, cycloalkyl-C(O)O--, aryl-C(O)O--, and
heterocyclic-C(O)O where R=alkyl, and alkyl, cycloalkyl, aryl, and
heterocyclic are as defined herein.
[2580] "Acylamino" refers to the groups R--C(O)N--, substituted
R--C(O)N--, cycloalkyl-C(O)N--, aryl-C(O)N--, and
heterocyclic-C(O)N-- where R=alkyl, and alkyl, cycloalkyl, aryl,
and heterocyclic are as defined herein.
[2581] "Amide" and "amido" refer to a functional group containing a
carbon atom double-bonded to an oxygen atom and additionally singly
bonded to a nitrogen atom [--C(O)--N]. "Primary" amide describes an
unsubstituted amide group [--C(O)--NH.sub.2]. "Secondary" and
"tertiary" amides are amides in which nitrogen is substituted with
one and two non-hydrogen groups respectively. The term "lactam"
refers to a cyclized amide, i.e. a secondary or tertiary amide
wherein the carbonyl carbon and the nitrogen atom are adjacent
members of a ring.
[2582] "Halogen" refers to fluoro, chloro, bromo, and iodo
radicals.
[2583] "Lactone" refers to cyclized ester of a carboxylic acid.
[2584] "Thio" refers to the replacement of oxygen by sulfur in a
defined radical. Examples of thio compound include alkylthioxy
compounds (e.g. alkyl-S--).
[2585] "Thioxyalkyl" refers to the divalent radical --S-alkyl-,
where alkyl is as defined above. Examples of thioxyalkyl moietites
include alkyl-5-alkyl moieties, such as
CH.sub.3--S--CH.sub.2CH.sub.2--
[2586] "Alkoxy" refers to the radical --O-alkyl with alkyl as
defined above. Alkoxy groups include, for example, methoxy, ethoxy,
propoxy, isopropoxy, and the like.
[2587] "Arylalkyl" and "aralkyl" refer to an alkyl radical
substituted with an aryl.
[2588] "Alkylaryl" refers to an aryl radical substituted with an
alkyl.
[2589] All the terms "carboxyl", "carboxylic acid", "carboxylate"
and "carbamoyl" are terms referring to functional groups containing
a carbon atom double-bonded to an oxygen atom [C.dbd.O, also called
an acyl or a carbonyl group, represented in linear notation as
--C(O)--] and additionally single-bonded to another oxygen atom
[--C(O)--O--], and in the case of carbamoyl, additionally a
nitrogen atom is also bonded to the carbonyl carbon to give
--N--C(O)--O--. Carboxyl, carboxylate and carbamate include the
corresponding pharmaceutically acceptable C.sub.1-C.sub.6 alkyl and
C.sub.6-C.sub.10 aryl esters and secondary and tertiary amides.
[2590] Combinations of these terms for functional group radicals
are also used. Typically, the last term in the designation contains
the radical that bonds to the remainder of the chemical structure.
For example, "haloalkyl" refers to an alkyl radical substituted by
a halogen, "cycloalkylalkyl" refers to alkyl radical substituted by
a cycloalkyl, and "alkylcycloalkyl" refers to a cycloalkyl radical
substituted by an alkyl.
##STR00017## ##STR00018## ##STR00019##
##STR00020##
EXAMPLES
[2591] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. The following detailed
examples describe how to prepare the various compounds and/or
perform the various processes of the invention and are to be
construed as merely illustrative, and not limitations of the
preceding disclosure in any way whatsoever. Those skilled in the
art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
[2592] Preparations of the novel compounds of the present invention
utilizing the hydroxyethylene isostere are illustrated in the
following examples, which are not, however, intended to be any
limitation thereof.
Methods of Synthesis
[2593] The following reaction schemes illustrate methods of
construction of the hydroxyethylene dipeptide isosteres provided in
examples 1-13. Variations of starting materials may be used in
these reactions to prepare hydroxyethylene cores having other side
chain groups. Substitutions of available starting materials to
achieve the desired side chain variants will be apparent to one of
ordinary skill in the art.
##STR00021##
Alternatively hydroxyethylenes may be prepared by the method
described below. Synthesis of the Boc-3,5-difluorophenylalanine
threo epoxide starting material was adapted from the procedure of
Luly, J R, et al. J. Org. Chem. 1987, 52, 1487-1492 for the
synthesis of Boc-phenylalanine threo epoxide (Scheme II). The
starting material utilized in the preparation of
Boc-3,5-difluorophenylalanine threo epoxide was Boc protected
1-3,5-difluorophenylalanine available from Synthetech, Inc. (1290
Industrial Way, P.O. Box 646, Albany, OR97321 USA).
##STR00022##
[2594] The chiral amine synthesis, the initial alkylation step and
further manipulation to the lactone were accomplished based on
literature procedures as follows: Dragovich, P S, et al. J. Med.
Chem. 1999, 42, 1203-1222; Askin, D., et al. J. Org. Chem. 1992,
57, 2771-2773. Cleavage of the Boc protecting group and subsequent
coupling of the acid was accomplished using the procedures for
deprotection of the amine and EDC coupling given below.
Ring-opening of the lactone to the final product was accomplished
using a AlMe.sub.3-mediated coupling step according to the
literature procedure of S. F. Martin et al., Tetrahedron Lett.
1998, 39, 1517-1520.
Removal of a Boc-Protecting Group from a Protected Amine to
Generate Free Amine:
[2595] For example, the Boc-protected alpha-amino lactone
intermediate of either Scheme I or II was dissolved in a
trifluoroacetic acid/dichloromethane (1/1) solution. The reaction
was monitored by TLC to confirm the consumption of starting
material at which time the solvents were removed under reduced
pressure to yield the free amine, which was used without further
purification.
Coupling Deprotected Amine with a Selected N-Terminal Capping
Group:
[2596] For example, 2-(N,N-dipropyl) amidobenzoic acid (1.0 equiv.)
was dissolved in 30 mL of dry dichloromethane, then HOBT (2.0
equiv.), functionalized .alpha.-amino lactone from the step above
(1.0 equiv.) and TEA (5 equiv.) were added and all was stirred for
20 minutes. EDC (1.2 equiv.) was added and the mixture was stirred
overnight under an atmosphere of nitrogen. The reaction was then
diluted with water and extracted with EtOAc (3.times.). The organic
layers were washed with aqueous citric acid (2.times.), sat. NaHCO3
(2.times.), brine, then dried over MgSO.sub.4, and the solvent was
removed under vacuum. The product of this step may then be
subjected to a lactone ring aminolysis to provide the desired amide
bond.
TABLE-US-00001 TABLE 1 Enzyme inhibition assay results for
structures having the peptide backbone: (XII) ##STR00023## Example
R.sub.N R.sub.C 1 ##STR00024## ##STR00025## 2 ##STR00026##
##STR00027## 3 ##STR00028## ##STR00029## 4 ##STR00030##
##STR00031## 5 ##STR00032## ##STR00033## 6 ##STR00034##
##STR00035## 7 ##STR00036## ##STR00037## 8 ##STR00038##
##STR00039## 9 ##STR00040## ##STR00041## 10 ##STR00042##
##STR00043## 11 ##STR00044## ##STR00045## 12 ##STR00046##
##STR00047## 13 ##STR00048## ##STR00049## Examples 1-6: R2 =
--CH(CH.sub.3).sub.2 and R1 = --CH.sub.2CH(CH.sub.3).sub.2 * Assay
procedure described in the Example 70 Examples 7-10: R2 =
--CH.sub.2CH.sub.3 and R1 = --CH.sub.2-3,5-difluorophenyl Example
11: R2 = benzyl and R1 = --CH.sub.2-3,5-difluorophenyl Examples 12:
R2 = propyl and R1 = --CH.sub.2-3,5-difluorophenyl Examples 13: R1
= methyl and R2 = --CH.sub.2-3,5-difluorophenyl
Example 1
[2597] This compound was prepared employing the amino and hydroxy
protected hydroxyethylene prepared via Scheme I. The compound was
prepared standard resin supported peptide synthetic methods using
standard HOBt, EDC coupling procedures described under Scheme II.
Boc-Phe was esterified to the resin support. The Boc protecting
group was removed from the Phe by treatment with trifluoroacetic
acid in dichloromethane (TFA/DCM) and then coupled with Boc-Glu
(mono ester) as described above. The cycle of amino deprotection
and HOBt/EDC coupling was repeated with Boc-Ala, then with the
protected hydroxyethylene moiety of Scheme I and then Boc-Met and
finally Ac-Val. The glutamyl ester was removed via LiOH hydrolysis.
The silyl group was removed from the hydroxyl function by treatment
with tetra-t-butylammonium fluoride [(t-Bu).sub.4NF] in THF.
TABLE-US-00002 Molecular Formula C.sub.41H.sub.68N.sub.6O.sub.9S
Molecular Weight 821.10 Mass spec (MH+) 821
Example 2
[2598] p-Aminomethylbenzoic acid methyl ester (commercially
available) was coupled with the hydroxyethylene moiety of Scheme I
using standard EDC/HOBt coupling. The Boc protecting group was
removed from the N-terminal and then subsequently coupled with
Boc-Val-Met. The methyl ester was hydroylzed as described above and
silyl group was removed from the hydroxyl function by treatment
with tetra-t-butylammonium fluoride [(t-Bu).sub.4NF] in THF.
TABLE-US-00003 Molecular Formula C.sub.35H.sub.58N.sub.4O.sub.8S
Molecular Weight 694.927 tlc Rf (solvent) Rf = 0.28 in 5%
Methanol/dichloromethane Purification: 5% Methanol/dichloromethane
Mass spec (MH+) 695
Example 3
[2599] The hydroxyethylene moiety of Scheme I was coupled with the
dimethyl ester of 3,5-dicarboxycyclohexylamine as prepared in
Scheme VI A. This intermediate was in turn deprotected at the
N-terminal with TFA/DCM and then coupled with the
alpha-hydroxy-naphthylacetic acid. The methyl esters were
hydrolyzed with LiOH and then the silyl group was removed from the
hydroxyl function by treatment with tetra-t-butylammonium fluoride
[(t-Bu).sub.4NF] in THF.
TABLE-US-00004 Molecular Weight 584.7 tlc Rf (solvent) 0.15 (10%
MeOH/CH2Cl2) Purification: Flash chromatography Mass spec (M + H+)
(CI) 584.7
Example 4
[2600] The protected hydroxyethylene as produced in Scheme I was
coupled with the dimethyl ester of 3,5-dicarboxycyclohexylamine
(Scheme VI A). The diester was hydrolyzed with LiOH and the silyl
protecting group removed by treatment with tetra-t-butylammonium
fluoride [(t-BU).sub.4NF] in THF.
TABLE-US-00005 Molecular Formula C.sub.25 H.sub.44 N.sub.2 O.sub.8
Molecular Weight 500.6 tlc Rf (solvent) 0.15 (5%
MeOH/CH.sub.2Cl.sub.2) Purification: Acid/base extraction Mass spec
(M - H+) (CI) 498.7
Example 5
Diastereomeric at the .alpha.-hydroxy-naphthylacetyl
[2601] The hydroxyethylene moiety of Scheme I was coupled with the
methyl 3-(1-aminopropyl)-4-benzoate (commercially available). This
intermediate was in turn deprotected at the N-terminus with TFA/DCM
(1:1) and then coupled with the alpha-hydroxy-naphthylacetic acid.
The methyl ester was hydrolyzed with LiOH and then the silyl group
was removed from the hydroxyl function by treatment with
tetra-t-butylammonium fluoride [(t-Bu).sub.4NF] in THF.
TABLE-US-00006 Molecular Formula C.sub.34H.sub.44N.sub.2O.sub.6
Molecular Weight 576.73 tlc Rf (solvent) Rf = 0.12 in 10%
Methanol/dichloromethane Purification: 10% Methanol/dichloromethane
Mass spec (MH+) 577
Example 6
[2602] This pentapeptide isostere was prepared to test the efficacy
of the .alpha.-hydroxy-naphthylacetic acid as an N-terminal group
peptidomimetic in an oligopeptide sequence that demonstrated good
activity (see Ex. 1). The hydroxyethylene moiety was prepared via
the method of Scheme I. Resin supported synthesis was employed to
prepare the molecule by bonding Boc-Phg to a resin support and then
sequentially constructed by removal of the Boc protecting group and
HOBt/EDC coupling in turn with glutamic acid methyl ester, valine,
the hydroxyethylene isostere of Scheme I and finally with
.alpha.-hydroxy-naphthylacetic acid. The product was then cleaved
from the solid support and protecting groups were removed as
described in the examples above.
TABLE-US-00007 Molecular Formula C.sub.41H.sub.54N.sub.4O.sub.10
Molecular Weight 762.9 Purification: 500 analytical HPLC trace
(Gradient: 20-50% [B] in 30 minutes, [A] Buffer = 0.1% TFA/H2O; [B]
Buffer = 0.1% TFA/Acetonitrile) revealed two diastereomers eluting
at 19.4 and 21.0 minutes Mass spec 763.6 (785.6) [801.6] (M + Na+)
[M + K+]
[2603] The preparation of examples 1-6, as described in Table 1
above, is outlined in Scheme I.
Example 7
[2604] After the C-termninal coupling was accomplished as described
above, the lactone was subjected to aminolysis at refluxing
temperatures with 3,5-dimethylcyclohexylamine in the presence of
AIMe.sub.3 and a suitable organic solvent to provide the subject
compound.
TABLE-US-00008 Molecular Formula C36H51F2N3O6 Molecular Weight 659
tlc Rf (solvent) 0.15 (5% iPrOH/CHCl3) Purification: Flash
chromatography Mass spec (M + H+) (CI) 660.4
Example 8
[2605] After the C-terminal coupling was accomplished as described
above, the lactone was subjected to aminolysis at refluxing
temperatures with 6-aminohexanoic acid in the presence of
AlMe.sub.3 and a suitable organic solvent to provide the subject
compound.
TABLE-US-00009 Molecular Formula
C.sub.34H.sub.47F.sub.2N.sub.3O.sub.6 Molecular Weight 631 tlc Rf
(solvent) 0.15 (5% MeOH/CH2Cl2) Purification: Flash chromatography
Mass spec (M + H+) (CI) 632.2
Example 9
[2606] After the C-terminal coupling was accomplished as described
above, the lactone was subjected to aminolysis at refluxing
temperatures with 8-aminooctanoic acid in the presence of
AlMe.sub.3 and a suitable organic solvent which was then dissolved
in MeOH and treated with HCl gas to provide the desired methyl
ester.
TABLE-US-00010 Molecular Formula
C.sub.37H.sub.53F.sub.2N.sub.3O.sub.6 Molecular Weight 673 tlc Rf
(solvent) 0.4 (5% iPrOH/CHCl.sub.3) Purification: Flash
chromatography Mass spec (M + H+) (CI) 674.4
Example 10
[2607] After the C-terminal coupling was accomplished as described
above, the lactone was subjected to aminolysis at refluxing
temperatures with 4-carboxycyclohexylmethylamine in the presence of
AlMe.sub.3 and a suitable organic solvent to provide the subject
compound.
TABLE-US-00011 Molecular Formula C.sub.36H.sub.49F.sub.2N.sub.3O6
Molecular Weight 657 tlc Rf (solvent) 0.3 (10%
MeOH/CH.sub.2Cl.sub.2) Purification: Flash chromatography Mass spec
(M + H+) (CI) 658.4
Example 11
[2608] The subject compound was prepared as in Example 10 except
that in the first step of preparation of the chiral oxazolidine
intermediate, 3-phenylpropionyl chloride (Aldrich Chemical) was
substituted for n-butanoyl chloride.
TABLE-US-00012 Molecular Formula
C.sub.41H.sub.51F.sub.2N.sub.3O.sub.6 Molecular Weight 719.86 Mass
spec (M + Na+) 743
Example 12
[2609] The subject compound was prepared as in Example 10 except
that in the first step 25 of preparation of the chiral oxazolidine
intermediate, n-pentanoyl chloride was substituted for n-butanoyl
chloride.
TABLE-US-00013 Molecular Formula
C.sub.37H.sub.51F.sub.2N.sub.3O.sub.6 Molecular Weight 671.37 Mass
spec (M + Na+) 694.37
Example 13
[2610] The subject compound was prepared as in Example 10 except
that in the first step of preparation of the chiral oxazolidine
intermediate, n-propionyl chloride was substituted for n-butanoyl
chloride.
TABLE-US-00014 Molecular Formula
C.sub.35H.sub.47F.sub.2N.sub.3O.sub.6 Molecular Weight 643.34 Mass
spec (M + Na+) 666.34
[2611] The compound formulae referred to in Examples 14-22
correspond to those recited in CHART A. Furthermore, the following
examples relate to those compounds recited in CHART A where
R.sub.1=--(CH.sub.2)3,5-difluorobenzyl, R.sub.2=Et,
R.sub.N.dbd.N',N'-dipropylisophthalamide,
R.sub.C=anti-4-aminomethylcyclohexanecarboxylic acid, and
PROTECTING GROUP is Boc. The identity of the R.sub.2 substituent is
determined by the starting material (i.e. compounds of formula
(XIII)) used in the synthesis of the intermediate (VII) as is
outlined in CHART B. The intermediate (VII), prepared according to
CHART B, is then incorporated into the synthetic scheme for the
preparation of hydroxyethylene compounds of formula (XII), as
outlined in CHART A, by reaction with the epoxide (VI).
Example 14
(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamic
acid tert-butyl ester (III)
[2612]
(L)-2-tert-Butoxycarbonylamino-3-(3,5-difluorophenyl)-propionic
acid (Synthetech Inc., II, 2.66 g, 8.83 mmol) was dissolved in a
mixture of dry THF (5 mL) and dry DMF (2 mL) at rt.
1,1-Carbonyldiimidazole (1.71 g, 10.6 mmol) was added in one
portion to this solution. After gas evolution ceased, a solution of
N-methyl-O-methylhydroxylamine hydrochloride (0.955 g, 9.79 mmol)
and diisopropylethylamine (1.6 mL, 9.19 mmol) in DMF (4 mL) was
added at rt by syringe. This was stirred at rt for 17 h, whereupon
the reaction was quenched with 10% citric acid. The mixture was
extracted with EtOAc. The organic extract was washed (saturated
NaHCO.sub.3, saturated NaCl), dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (30% EtOAc/hexanes elution) to give an oil as
product: M+Na+ 367.1.
Example 15
(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl
ester (IV)
[2613]
(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carba-
mic acid tert-butyl ester (III, 2.56 g) was dissolved in dry THF
(50 mL) and cooled to 0.degree. C. To this mixture was added powder
lithium aluminum hydride (285 mg) in portions over 5 min. The
resulting suspension was stirred at 0.degree. C. for 1 h. Reaction
was quenched at 0.degree. C. by slow addition of saturated citric
acid until gas evolution ceased, followed by dropwise addition of
10% aqueous citric acid (30 mL). This was then allowed to warm to
rt. The layers were separated and the aqueous extracted with
Et.sub.2O. The combined organic extracts were washed (saturated
NaHCO.sub.3, saturated NaCl), dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure to give a solid, which was used
without further purification.
Example 16
(L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butyl ester
(V)
[2614] Potassium hydride (35% suspension in mineral oil, 1.76 g)
was suspended in a mixture of dry THF (20 mL) and DMSO (4 mL), and
was cooled to 0.degree. C. 1,1,1,3,3,3-Hexamethyldisilazane (4.0
mL) was added by syringe, and the mixture was stirred for 45 min at
0.degree. C. Methyltriphenylphosphonium bromide (5.57 g) was added,
and the resulting yellow slurry was stirred at 0.degree. C. for 1
h, whereupon the mixture was cooled to -78.degree. C. A solution of
(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl
ester (IV, 2.2 g) in THF (15 mL) at -78.degree. C. was added by
cannula. The resulting suspension was stirred at -78.degree. C. for
15 min, then was allowed to warm to rt for 16 h. MeOH (2 mL) and
half-saturated sodium bicarbonate solution (100 mL) were added, and
the mixture was extracted with EtOAc (2.times.50 mL). The combined
organic extracts were washed (water, saturated NaCl) dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (10-20%
Et.sub.2O/hexanes) to give a solid as product: M+Na+ 306.1.
Example 17
(1S,2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid
tert-butyl ester (VI)
[2615] (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butyl
ester (V, 3.3 g) was dissolved in CH.sub.2Cl.sub.2 (130 mL) and
m-chloroperbenzoic acid (50-55% pure, 16.0 g) was added with
stirring at rt. After 23 h, the reaction mixture was diluted with
Et.sub.2O, washed (10% Na.sub.2SO.sub.3, saturated NaHCO.sub.3,
saturated NaCl), dried (MgSO.sub.4), filtered, and concentrated
under reduced pressure to give a solid: M+Na+ 322.1.
Example 18
(1S,2S,4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro--
3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid
tert-butyl ester (VIII)
[2616] (1S,2S)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic
acid tert-butyl ester (VI, 113 mg) and
1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-buta-
n-1-one (VII, 94 mg) were combined in dry THF (3 mL), and cooled to
-78.degree. C. To this solution was added BuLi (2.5 M in hexanes,
0.32 mL) over 5 min., whereupon the solution was allowed to warrn
to 0.degree. C. for 1.5 h. The reaction mixture was partitioned
between 0.5 N HCl (4 mL) and 1:1 EtOAc/hexanes (2.times.4 mL). The
combined organic layers were dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (20-30% EtOAc/hexanes) to give an oil: MH+
559.1.
Example 19
[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-
-ethyl]-carbamic acid tert-butyl ester (IX)
[2617]
(1S,2S,4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-d-
ihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic
acid tert-butyl ester (VIII, 60 mg) was dissolved in 5:1
toluene/CH.sub.2Cl.sub.2 (3 mL), and p-toluenesulfonic acid
monohydrate (23 mg) was added. This was stirred at rt for 18 h. The
mixture was then filtered, and partitioned between half-saturated
NaHCO.sub.3 (3 mL) and 1:1 EtOAc/hexanes (2.times.3 mL). The
combined organic layers were dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure. Flash chromatography of the
residue afforded desired product as a solid: MH+ 370.2.
Example 20
[2618]
5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-on-
e (X)
[2619]
[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2--
(S)-yl)-ethyl]-carbamic acid tert-butyl ester (IX, 313 mg) was
dissolved in CH.sub.2Cl.sub.2 (1 mL) at rt, whereupon CF.sub.3COOH
(1 mL) was added. This was stirred at rt for 1 h, then concentrated
under reduced pressure. This was used in the next reaction without
further purification.
Example 21
N-{2-(3,5-Difluorophenyl)-(1S,2S,4R)-[1-(4-ethyl-5-oxotetrahiydrofuran-2-y-
l]ethyl}-N',N'-dipropylisophthalamide (XI)
[2620]
5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-on-
e (X, 228 mg theoretical) was combined with triethylamine (0.7 mL)
in dry DMF (2 mL) at 0.degree. C. N,N-Dipropylisophthalamic acid
(242 mg) was added and dissolved. 1-Hydroxybenzotriazole (224 mg)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(320 mg) were added in succession. The mixture was stirred at
0.degree. C. for 5 min., then allowed to warm to rt for 4 h. This
was then diluted with 10% citric acid, and extracted 3.times. with
EtOAc. The combined organic extracts were washed (saturated
NaHCO.sub.3, saturated NaCl), dried (MgSO.sub.4), filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (40% EtOAc/hexanes elution) to give a solid:
MH+ 501.3.
Example 22
4-(anti)-{[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)--
2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-methyl}cyclohexanecarboxylic
acid (XII)
[2621] Anti-4-Aminomethylcyclohexanecarboxylic acid (57 mg) was
suspended in 1,2-dichloroethane (2 mL), and cooled to 0.degree. C.
Trimethylaluminum (2.0 M in toluene, 0.21 mL) was added, followed
by a solution of
N-{2-(3,5-Difluorophenyl)-(1S,2S,4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-y-
l)]ethyl}-N',N'-dipropylisophthalamide (XI, 30 mg) in
1,2-dichloroethane (1 mL). This was then warmed to reflux for 1.5
h, whereupon the reaction mixture was cooled to 0.degree. C., and
the reaction quenched with 3 N HCl (2 mL). The slurry was stirred
at 0.degree. C. for 30 min, and then extracted with 3.times.5 mL
10% iPrOH/CHCl.sub.3. The combined organic extracts were dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (5-10%
MeOH/CH.sub.2Cl.sub.2 elution) to give a solid: MH+ 658.4.
[2622] The compound formulae referred to in Examples 23-24
correspond to those recited in CHART B. Furthermore, the following
examples relate to those compounds recited in CHART B
R.sub.2=Et.
Example 23
N-(1S,2R)-(2-Hydroxyindan-1-yl)-butyramide (XV)
[2623] (1S,2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved
with triethylamine (1.5 mL) in dry THF (45 mL), and cooled to
0.degree. C. Butyryl chloride (XIII, 1.05 mL) was added by syringe,
and the resultant solution stirred 0.degree. C. for 20 min,
whereupon the reaction mixture was partitioned between
half-saturated NH.sub.4Cl (45 mL) and EtOAc (2.times.45 mL). The
combined organic layers were dried dried (MgSO.sub.4), filtered,
and concentrated under reduced pressure to give a solid, which was
taken to the next reaction without further purification.
Example 24
1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-butan-
-1-one (VII)
[2624] N-(1S,2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and
2-methoxypropene (5 mL) were combined with CH.sub.2Cl.sub.2 (70 mL)
at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min
at rt, the reaction mixture was partitioned between half-saturated
NaHCO.sub.3 (30 mL) and CH.sub.2Cl.sub.2 (2.times.30 mL). The
combined organic layers were dried dried (MgSO.sub.4), filtered,
and concentrated under reduced pressure to give an oil as product:
MH+ 260.1.
[2625] Examples 25-30 recited below relate to the synthesis for
N-terminus capping groups.
Example 25
Hydroxylated and Benzylated N-Terminal Capping Groups
[2626] The making of hydroxylated and benzylated N-terminal capping
groups from aromatic acetic acid starting materials is illustrated
in Scheme III below. Moersch, G W and Zwiesler, M L. (Synthesis,
1971, 647-648, ref. I in Scheme III) demonstrate a synthesis useful
for preparing an arylalkylhydroxycarboxylic acid N-terminus capping
group. The procedure here provides alpha hydroxylation of
1-naphthylacetic acid, using lithium diethylamine and oxygen. Hon,
Yung-Son, Chang, Rong-Chi, Chau, Tay-Yuan (Heterocycles, 1990, Vol.
31, No. 10, 1745-1750, ref. 2 in Scheme III) demonstrate a
synthesis of the corresponding benzyl ether from the
.alpha.-hydroxyaromatic by esterification of the carboxy function
and etherification with benzyl bromide. Either the .alpha.-hydroxy
acid or the benzyl ether derivative is suitable as a N-terminal
cap.
##STR00050##
Example 26
Preparation of Carboxybenzamides
##STR00051##
[2628] Methyl isophthalate (Aldrich Chemical, Milwaukee, Wis., (1
equiv, 11.1 mmol) was dissolved in 50:50 THF:DMF (20 mL) before the
addition of 1,1' carbonyldiimidazole (CDJ) (1.2 equiv, 13.3 mmol)
at ambient temperature. Upon addition of CDI, an evolution of gas
(CO.sub.2), was observed. After gas evolution subsided
(approximately one minute or less), the amine (1.2 equiv, 13.3
mmol) was added. After 12 h of stirring at ambient temperature, the
reaction was partitioned between saturated aqueous NH.sub.4Cl and
ethyl acetate, and the aqueous layer was extracted twice more with
ethyl acetate. The organic extracts were then washed with saturated
aqueous solutions of NaHCO.sub.3 and NaCl, and dried over anhydrous
MgSO.sub.4 or NaSO.sub.4. Filtration of the drying agent and
removal of solvents in vacuo gave the crude white solid or clear
oil. Purification of these compounds If needed was achieved via
chromatography on silica gel with 30-40% ethyl acetate in
hexanes.
[2629] The methyl isophthalate mono-alkyl or di-alkyl amide was
then treated with LiOH.H.sub.2O (3 equiv, 33.3 mmol) in a minimum
amount of 1:2:1 THF:MeOH:H.sub.2O and allowed to stir overnight at
ambient temperature. After 12 h, the solvents were removed in vacuo
and subsequently partitioned between H.sub.2O and ethyl acetate. If
emulsions prohibit separation of the two layers, a small amount of
brine was added to aid in separation. The aqueous layer was
extracted once more with ethyl acetate (to remove any unreacted
starting material). The aqueous layer was then acidified with
concentrated HCl until pH.ltoreq.3. The cloudy-white acidic aqueous
solution thus obtained was then extracted three times with ethyl
acetate. These combined organic extracts were dried over anhydrous
MgSO.sub.4 or NaSO.sub.4. Filtration of the drying agent and
removal of solvents in vacuo gave a solid. The mono- or di-alkyl
amide isophthalate was used crude in the next reaction.
Example 27
Preparation of Carboxybenzamides
##STR00052##
[2630] Methyl isophthalate (1 equiv, 11.1 mmol) was dissolved in
50:50 THF:DMF (20 mL) before the addition of 1,1'
carbonyldiimidazole (CDI) (1.2 equiv, 13.3 mmol) at ambient
temperature. Upon addition of CDI, evolution of gas (CO.sub.2), was
observed. After gas evolution subsided (approximately one minute or
less), the amine (1.2 equiv, 13.3 mmol) dissolved in DMF and
diisopropylethyl amine (1.2 equiv, 13.3 mmol) was added. After 12 h
of stirring at ambient temperature, the reaction was partitioned
between saturated aqueous NH.sub.4Cl and ethyl acetate, and the
aqueous layer was extracted twice more with ethyl acetate. The
organic extracts were then washed with saturated aqueous solutions
of NaHCO.sub.3 and NaCl, and dried over anhydrous MgSO.sub.4 or
NaSO.sub.4. Filtration of the drying agent and removal of solvents
in vacuo gave a solid or oil. Purification of these compounds
ifneeded was achieved via chromatography on silica gel with 30-40%
ethyl acetate in hexanes.
[2631] The methyl isophthalate mono-alkyl or di-alkyl amide (1
equiv, 11.1 mmol) was then treated with LiOH.H.sub.2O (3 equiv,
33.3 mmol) in a minimum amount of 1:2:1 THF:MeOH:H.sub.2O and
allowed to stir overnight at ambient temperature. After 12 h, the
solvents were removed in vacuo and subsequently partitioned between
H.sub.2O and ethyl acetate. If emulsions prohibit separation of the
two layers, a small amount of brine was added to aid in separation.
The aqueous layer was extracted once more with ethyl acetate (to
remove any unreacted starting material). The aqueous layer was then
acidified with concentrated HCl until pH.ltoreq.3. The cloudy-white
acidic aqueous solution thus obtained was then extracted three
times with ethyl acetate. These combined organic extracts were
dried over anhydrous MgSO.sub.4 or Na.sub.2SO.sub.4. Filtration of
the drying agent and removal of solvents in vacuo gave a solid. The
mono- or di-alkyl amide isophthalate was used crude in the next
reaction.
Example 28
Preparation of Primary Amide
##STR00053##
[2633] Methyl isophthalate (1 equiv, 11.1 mmol) was dissolved in
50:50 THF:DMF (20 mL) before the addition of 1,1'
carbonyldiimidazole (CDI) (1.2 equiv, 13.3 mmol) at ambient
temperature. Upon addition of CDI, an evolution of gas (CO.sub.2),
was observed. After five minutes, ammonia gas was bubbled into the
solution through a syringe needle for 1 h. Since the reaction was
heating up due to an exotherm, the reaction was cooled to 0.degree.
C. for the duration of the hour. The reaction was then left
stirring under a balloon of ammonia overnight at ambient
temperature. After 12 h, the reaction was partitioned between
saturated aqueous NH.sub.4Cl and ethyl acetate, and the aqueous
layer was extracted twice more with ethyl acetate. The organic
extracts were then washed with saturated aqueous solutions of
NaHCO.sub.3 and NaCl, and dried over anhydrous MgSO.sub.4 or
NaSO.sub.4. Filtration of the drying agent and removal of solvents
in vacuo gave a solid or oil. Purification via chromatography on
silica gel with 5% isopropanol in chloroform gave the desired
primary amide.
[2634] The methyl isophthalate primary amide (7.26 mmol) was then
treated with LiOH.H.sub.2O (3 equiv, 21.8 mmol) in a minimum amount
of 1:2:1 THF:MeOH:H.sub.2O and allowed to stir overnight at ambient
temperature. After 12 h, the solvents were removed in vacuo and
subsequently partitioned between H.sub.2O and ethyl acetate. The
aqueous layer was extracted once more with ethyl acetate (to remove
any unreacted starting material). The aqueous layer was then
acidified with concentrated HCl until pH.ltoreq.3. The cloudy-white
acidic aqueous solution thus obtained was then extracted three
times with ethyl acetate. These combined organic extracts were
dried over anhydrous MgSO.sub.4 or NaSO.sub.4. Filtration of the
drying agent and removal of solvents in vacuo gave a solid. The
mono- or di-alkyl amide isophthalate was used crude in the next
reaction.
Example 29
Preparation of Heterocyclic Amides
##STR00054##
[2636] Methyl isophthalate (1.2 equiv, 2.78 mmol) was dissolved in
dry CH.sub.2Cl.sub.2 and three drops of DMF (catalytic). The
solution was cooled to 0.degree. C. before the drop-wise addition
of oxalyl chloride (2 equiv, 4.63 mmol). The mixture was stirred at
0.degree. C. for 1 h. The mixture never dissolved. After 1 h, the
solvents were removed in vacuo. The acid chloride was left under
vacuum overnight.
[2637] The crude acid chloride (1 equiv, 2.78 mmol) was dissolved
in dry CH.sub.2Cl.sub.2 and cooled to 0.degree. C. before the
addition of NEt.sub.3 (5 equiv, 11.6 mmol) and N-methyl piperidine
(6 equiv, 13.9 mmol). The reaction was stirred at 0.degree. C. for
2 h before the solvents were removed in vacuo. The residue was
diluted with H.sub.2O and ethyl acetate and the layers were
separated. The aqueous layer was extracted twice more with ethyl
acetate, and the combined organic extracts were washed with
saturated aqueous NaHCO.sub.3, and dried over anhydrous MgSO.sub.4.
Filtration of the drying agent and removal of solvents in vacuo
gave the crude product.
[2638] The crude amide (1 equiv, 2.19 mmol) was then treated with
LiOH.H.sub.2O (1 equiv, 2.19 mmol) in a minimum amount of 1:2:1
THF:MeOH:H.sub.2O and allowed to stir overnight at ambient
temperature. After 12 h, the solvents were removed in vacuo and
subsequently partitioned between H.sub.2O and ethyl acetate. The
aqueous layer was extracted once more with ethyl acetate (to remove
any unreacted starting material.) Removal of H.sub.2O from aqueous
layer in vacuo gave a solid.
Example 30
Preparation of Aromatic .alpha.-hydroxy Acids
Illustrated by the Preparation with
.alpha.-hydroxy-.alpha.-(2-biphenyl)acetic acid
##STR00055##
[2640] A solution of CH.sub.2Cl.sub.2 (25 mL) and oxalyl chloride
(2 mL, 21.16 mmol) was placed in a 100-mL round bottom flask kept
under nitrogen. The oxalyl chloride solution was stirred at -50 to
-60.degree. C. Me.sub.2SO (2.5 mL, 35.82 mmol) was dissolved in
CH.sub.2Cl.sub.2 (SmL). The Me.sub.2SO was added dropwise to the
stirred oxalyl chloride solution at -50 to -60.degree. C. The
reaction mixture was stirred for 2 min and the 2-phenylbenzyl
alcohol (16.28 mmol in 10 mL CH.sub.2Cl.sub.2) was added within 5
min; stirring was continued for an additional 60 min. TEA (11.30
mL, 81.4 mmol) was added and the reaction mixture was stirred for
60 min and then allowed to warm to room temperature. Water (60 mL)
was then added and the aqueous layer was reextracted with
additional CH.sub.2Cl.sub.2 (60 mL). The organic layers were
combined, washed with saturated NaCl solution (120 mL), and dried
over anhydrous MgSO.sub.4. The filtered solution was concentrated
in a rotary evaporator to dryness. The oil was chromatographed on
silica gel (98:2 hexanes:EtOAc) to give 1.
[2641] A mixture of 5.46 mmol of aromatic aldehyde (1) in 10 mL of
CHCl.sub.3 and .beta.-cyclodextrins (CDs) (0.11 mmol) and
triethylbenzylammonium chloride (TEBA) (0.273 mmol) in a flask
equipped with a magnetic stirrer and dropping funnel was stirred
for 20 minute at 50.degree. C. Then 10 g of sodium hydroxide
dissolved in 10 mL of water was added dropwise to the flask with
stirring. After completion of this addition, the reaction was
continued for 8 h with the temperature maintained at 50.degree. C.
Then enough of distilled water was added to dissolve the
precipitate formed during the reaction, and the resulting solution
was thoroughly washed with ether, adjusted to pH 3 with dilute
hydrochloric acid and extracted with 3.times.30 mL of ether. The
extract was dried with anhydrous sodium sulfate, then evaporated to
dryness and the remaining precipitate was subjected to column
chromatography on silica gel using DCM:MeOH:AcOH (95:5:1) to give
2.
[2642] Examples 31 and 32 recited below relate to the synthesis for
N-terminus capping groups.
Example 31
1-Amino-3,5-cis,cis-dimethyl Cyclohexyldicarboxylate
[2643] To 10 g (47.85 mmole) of dimethyl-5-isophthalate in 25 ml of
acetic acid and 50 ml of methanol was added 5 g of 5% rhodium in
alumina in a high-pressure bottle, which was saturated with
hydrogen at 55 psi and shaken for one week of time.
##STR00056##
[2644] The mixture was then filtered thirough a thick layer of
Celite cake and rinse with methanol three times, the solvents was
concentrated and the crude solid was triturated with diethyl ether
and filtered again, it afforded 1-amino-3,5-cis,cis-cdimethyl
cyclohexyldicarboxylate, reverse phase HPLC has shown a purity of
94.4%.
Example 32
1-Amino-3,5-cis,cis-dimethoxy Cyclohexane
[2645] To 10 g (65.36 mmole) of 3,5-dimethoxyaniline was reacted as
described in the procedure above and afforded
1-amino-3,5-cis,cis-dimethoxy cyclohexane.
##STR00057##
[2646] Following the general procedure as outlined in Examples
14-22 and making non-critical variations the following substitute
amines of formula (XII) are obtained. These substitute amines of
formula (XII) are listed in Tables 2, 3, and 4 as Examples.
TABLE-US-00015 TABLE 2 ##STR00058## Example MH+ C-terminus (X)
N-[(1S, 2S,
4R)-1-(3,5-Difluorobenzyl)-4-(syn,syn)-(3,5-dimethoxycyclohexylcarbamoyl)-
-2-hydroxyhexyl]-N,N-dipropylisophathalamide 33 660.4 ##STR00059##
6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et-
hyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid 34 632
NH(CH.sub.2).sub.5CO.sub.2H
5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et-
hyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid 35 618.3
NH(CH.sub.2).sub.4CO.sub.2H
4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et-
hyl-4-(S)-hydroxyhexanoylamino]-butyric acid 36 603.7
NH(CH.sub.2).sub.3CO.sub.2H
3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et-
hyl-4-(S)-hydroxyhexanoylamino]-propionic acid 37 590.3
NH(CH.sub.2).sub.2CO.sub.2H
8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et-
hyl-4-(S)-hydroxyhexanoylamino]-octanoic acid 38 660.4
NH(CH.sub.2).sub.7CO.sub.2H
8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)--
ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester 39
674.4 NH(CH.sub.2).sub.7CO.sub.2Me
N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N-
,N-dipropyl-isophthalamide 40 574.3 NHBu
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoylhexyl]-
-N,N-dipropyl-isophthalamide 41 574.5 NHiBu
N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]--
N,N-dipropyl-isophthalamide 42 608.3 NHBn
N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hy-
droxy-hexyl]-N,N-dipropyl-isophthalamide 43 614.3 ##STR00060##
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-
-hexyl]-N,N-dipropyl-isophthalamide 44 586.3 ##STR00061##
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S-
)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 45 589.3 ##STR00062##
N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydrox-
y-hexyl]-N,N-dipropyl-isophthalamide 46 588.1 ##STR00063##
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbam-
oyl)-hexyl]-N,N-dipropyl-isophthalamide 47 576.3 ##STR00064##
4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-
-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid methyl ester 48 672.0 ##STR00065##
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(-
S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 49 608.0
##STR00066##
TABLE-US-00016 TABLE 3 ##STR00067## Example MH+ X
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino-
)-2- 50 658.4 Et
(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino-
)-4- 51 644.3 Me
(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino-
)-4- 52 672.3 nPr
(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino-
)-4- 53 686.3 iBu
(S)-hydroxy-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic
acid
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino-
)-4- 54 630.3 H
(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid
4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-
- 55 720.3 Bn
benzoylamino)-4-(S)-hydroxy-hexanoylamino]methyl)-cyclohexanecarboxylic
acid
TABLE-US-00017 TABLE 4 ##STR00068## Example MH+ X Y
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-ben-
zoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecar-
boxylic acid 56 672.2 ##STR00069## Et
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-ben-
zoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecar-
boxylic acid methyl ester 57 686 ##STR00070## Et
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethyl-
carbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 58 631.2
##STR00071## Me
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-penty-
l]-5-methyl-N,N-dipropyl-isophthalamide 59 574.3 ##STR00072## Me
N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-
-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 60 617.3
##STR00073## Me
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-yl-
methyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide 61
602.3 ##STR00074## Me
N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydro-
xy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 62 652.3
##STR00075## Me
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-
-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 63 588.3
##STR00076## Me
N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-
-5-methyl-N,N-dipropyl-isophthalamide 64 608.3 NHBn Me
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydr-
oxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 65 626.3
NH-(4-F)-Bn Me
TABLE-US-00018 TABLE 5 ##STR00077## Example MH+ X
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pent-
yl]-5-methyl-N,N-dipropyl-isophthalamide 66 622.3 ##STR00078##
N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)--
hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide 67 598.3
##STR00079##
N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)--
pentyl]-5-methy-N,N-dipropyl-isophthalamide 68 556.3
##STR00080##
Example 69
Benzyl (1S)-2-(3,5-difluorophenyl)-1-[(2R)-oxiranyl]ethylcarbamate
(VI)
[2647] Following the general procedure of EXAMPLE 17 and making non
critical variations but starting with the alcohol (IV) Benzyl
(1S,2R)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate,
the title compound is obtained.
Example 70
Enzyme Inhibition Assay
[2648] The compounds of the invention were analyzed for inhibitory
activity by use of the MBP-C125 assay. This assay determines the
relative inhibition of .beta.-secretase cleavage of a model APP
substrate, MPB-C125SW, by the compounds assayed as compared with an
untreated control. A detailed description of the assay parameters
can be found, for example, in U.S. Pat. No. 5,942,400. Briefly, the
substrate is a fusion peptide formed of maltose binding protein
(MBP) and the carboxy terminal 125 amino acids of APP-SW, the
Swedish mutation. Human brain .beta.-Secretase was prepared from
partially purified concentrated human brain tissue as described in
Sindha et. al., 1999, Nature 402:537-554 and maintained in 0.20%
Triton. Alternatively, recombinant full length enzyme (amino acids
1-501) was prepared from 293 cells expressing the transgenic
enzyme.
[2649] Inhibition data was obtained from an ELISA which uses an
anti-MBP capture antibody deposited on precoated and blocked
96-well high binding plates, followed by incubation with diluted
enzyme reaction supernatant, incubation with the anti-SW192
specific biotinylated reporter antibody, and incubation with
streptavidin/alkaline phosphatase. Cleavage of the intact
MBP-C125SW fusion protein results in the generation of a truncated
amino-terminal fragment, with the new SW-192 antibody-positive
epitope exposed at the carboxy terminus. Detection was effected by
a fluorescent substrate signal on cleavage by the phosphatase.
ELISA only detected cleavage following Leu 596 at the substrate's
APP-SW 751 mutation site.
[2650] Compounds were diluted in a 1:1 dilution series to a
six-point concentration curve (two wells per concentration) which
took up one 96-plate row per compound tested.
Procedure:
[2651] Each of the test compounds was weighed out into a vial and
DMSO was added to make up a 10 mM solution. To obtain a final
compound concentration of 200 .mu.M at the high point of a 6-point
dilution curve, 100 .mu.L of the 10 mM solution was added to well
C1 of a 96-well V-bottom plate. Fifty .mu.L of DMSO was added to
odd wells of row C across the plate and 1:1 serial dilutions were
made. 10 .mu.L of each dilution was added to each of two wells on
row C of a corresponding V-bottom plate to which 190 .mu.L of 52 mM
NaOAc/7.9% DMSO, pH 4.5 were pre-added. The NaOAc diluted compound
plate was spun down to pellet precipitant and 20 .mu.L/well was
transferred to a corresponding flat-bottom plate to which 30 .mu.L
of ice-cold enzyme-substrate mixture (2.5 .mu.L MBP-C125SW
substrate, 0.03 .mu.L enzyme and 24.5 ice cold 0.09% TX100 per 30
.mu.l) was added. The compound concentration in the final enzyme
reaction was thus 50 times less than the starting concentration.
The final reaction mixture of 200 .mu.M compound for the highest
curve point was in 5% DMSO, 20 mM NaAc, 0.06% TX100, at pH 4.5. The
enzyme reaction was started by warming the plates to 37.degree. C.
After 90 minutes at 37.degree. C., 200 .mu.L/well cold specimen
diluent was added to stop the reaction and 20 .mu.L/well was
transferred to a corresponding anti-MBP antibody coated ELISA plate
for capture, containing 80 .mu.L/well specimen diluent. This
reaction was incubated overnight at 4.degree. C. and the ELISA was
developed the next day after a 2 hr. incubation with anti-192SW
antibody, followed by Streptavidin-A.beta. conjugate and
flourescent substrate. The signal was read on a fluorescent plate
reader.
Results:
[2652] Relative compound inhibition potency was determined by
calculating the concentration of compound that showed a
fifty-percent reduction in detected signal (IC.sub.50) compared to
the enzyme reaction signal in the control wells with no added
compound.
[2653] For the purpose of grouping inhibitor activities of the
compounds of the present invention disclosed in the data tables of
this specification, the inhibitory activities have been ranked by
their IC.sub.50 concentrations according to following order:
Group I: compounds having an IC.sub.50 less than 10 .mu.M;
Group II: compounds having an IC.sub.50 of from 10 .mu.M to and
including 100 .mu.M;
Group III: compounds having an IC.sub.50 of from 100 .mu.M to and
including 200 .mu.M;
Group IV: compounds having an IC.sub.50 of greater than 200
.mu.M.
Example 71
Cell Free Inhibition Assay Utilizing APP-KK
[2654] The synthetic APP substrate, Biotin-KVEANY-EVEGERC(oregon
green)KK, having N-terminal biotin and made fluorescent by the
covalent attachment of oregon green at the Cys residue was used.
The N-terminal biotin is used to anchor the peptide to a substrate
assay plate. Incubation was conducted under the following
conditions: 10 .mu.M APP substrate; 50 nM enzyme (hAsp2a), pH 4.5,
37.degree. C., for 2 hours. Activity of the .beta.-secretase enzyme
is detected as the loss of oregon green fluorophore, on the
opposite side of the cleavage site from the Biotin anchor is
released on cleavage of the substrate.
[2655] Incubation in the presence or absence of compound inhibitor
demonstrates specific inhibition of .beta.-secretase enzymatic
cleavage of its APP substrate.
Example 72
.beta.-Secretase Inhibition
P26-P4'SW Assay
[2656] The P26-P4'sw substrate is a peptide of the sequence:
TABLE-US-00019 (SEQ ID NO:1)
(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF.
[2657] The P26-P1 standard has the sequence:
TABLE-US-00020 (SEQ ID NO: 2)
(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL.
[2658] Peptides were prepared by Anaspec, Inc. (San Jose, Calif.)
using solid phase synthesis with boc-amino acids. Biotin was
coupled to the terminal cysteine sulfhydryl by Anaspec, Inc. after
synthesis of the peptide, using EZ-link Iodoacetyl-LC-Biotin
(Pierce). Peptides are stored as 0.8-1.0 mM stocks in 5 mM Tris,
with the pH adjusted to around neutral (pH 6.5-7.5) with sodium
hydroxide.
[2659] For the enzyme assay, the substrate concentration can vary
from 0-200 .mu.M. Specifically for testing compounds for inhibitory
activity, substrate concentration can be 1.0 .mu.M. Compounds to be
tested are added in DMSO, with a final DMSO concentration of 5%; in
such experiments, the controls also receive 5% DMSO. Concentration
of enzyme is varied, to give product concentrations with the linear
range of the ELISA assay (125-2000 .mu.M, after dilution).
[2660] These components are incubated in 20 mM sodium acetate, pH
4.5, 0.06% Triton X-100, at 37 degrees C. for 1 to 3 hours. Samples
are diluted 5-fold in specimen diluent (for example, 145.4 mM
sodium chloride, 9.51 mM sodium phosphate, 7.7 mM sodium azide,
0.05% Triton X-405, 6 gm/liter bovine serum albumin, pH 7.4) to
quench the reaction, then diluted further for the ELISA as
needed.
[2661] For the ELISA, Costar High Binding 96-well assay plates
(Corning, Inc., Corning, N.Y.) are coated with SW 192 monoclonal
antibody from clone 16A7, or a clone of similar affinity. P26-P1
standards are diluted in specimen diluent to a final concentration
of 0 to 2 nM. Diluted samples and standards (100 .mu.l) are
incubated on the SW192 plates at 4 degrees C. for 24 hours. The
plates are washed 4 times in TTBS buffer (150 mM sodium chloride,
25 mM Tris, 0.05% Tween 20, pH 7.5), then incubated with 0.1
ml/well of streptavidin--alkaline phosphate (Roche Molecular
Biochemicals, Indianapolis, Ind.) diluted 1:3000 in specimen
diluent. After incubating for one hour at room temperature, the
plate is washed 4 times in TTBS, and incubated with fluorescent
substrate solution A (31.2 gm/liter 2-amino-2-methyl-1-propanol, 30
mg/liter, adjusted to pH 9.5 with HCl). Fluorescent values are read
after 30 minutes.
[2662] Compounds that are effective inhibitors of .beta.-secretase
activity demonstrate reduced cleavage as compared to a control.
Example 36
Assays Using Synthetic Oligopeptide-Substrates
[2663] Synthetic oligopeptides are prepared which incorporate the
known cleavage site of .beta.-secretase, and optionally detectable
tags, such as fluorescent or chromogenic moieties. Examples of such
peptides, as well as their production and detection methods are
described in allowed U.S. Pat. No. 5,942,400, herein incorporated
by reference. Cleavage products can be detected using high
performance liquid chromatography, or fluorescent or chromogenic
detection methods appropriate to the peptide to be detected,
according to methods well known in the art.
[2664] By way of example, one such peptide has the sequence SEVNL
DAEF (SEQ ID NO: 3), and the cleavage site is between residues 5
and 6. Another preferred substrate has the sequence
ADRGLTTRPGSGLTNIKTEEISEVNLDAE F (SEQ ID NO: 4), and the cleavage
site is between residues 26 and 27.
[2665] These synthetic APP substrates are incubated in the presence
of .beta.-secretase under conditions sufficient to result in
.beta.-secretase mediated cleavage of the substrate. Comparison of
cleavage results in the presence of the compound inhibitor results
to a control provides a measure of the compound's inhibitory
activity.
Example 73
Inhibition of .beta.-Secretase Activity
Cellular Assay
[2666] An exemplary assay for the analysis of inhibition of
.beta.-secretase activity utilizes the human embryonic kidney cell
line HEKp293 (ATCC Accession No. CRL-1573) stably transfected with
APP751 containing the naturally occurring double mutation
Lys651Met52 to Asn651Leu652 (numbered for APP751), commonly called
the Swedish mutation and shown to overproduce A.beta. (Citron et.
al., 1992, Nature 360:672-674). The cells were plated in 96 well
plates and in Dulbecco's Modified Eagle's medium (DMEM, Sigma
D-6546) containing 10% fetal bovine serum. After cells are
established (1 day post plating), cells are incubated in the
presence/absence of the inhibitory compound (diluted in DMSO) at
the desired concentration, generally from 0.25 to 5.0 .mu.g/ml, and
with a final concentration of DMSO ranging from 0.1 to 0.5%. After
incubation at 37.degree. C. for two hours, the media is aspirated
from the cells and is replaced with fresh compound for an
additional 2 hour incubation. At the end of the treatment period,
each cell plate is centrifuged at 1100 rpm for 5 minutes at room
temperature.
[2667] Conditioned media is analyzed for .beta.-secretase activity
by analysis of release of the peptide fragment A.beta. into the
culture medium by immunoassay. Using specific antibodies to detect
cleavage product, for example, A.beta., the enzymatic activity is
measured in the presence and absence of the compound inhibitors to
demonstrate specific inhibition of .beta.-secretase mediated
cleavage of APP substrate.
Example 74
Inhibition of .beta.-Secretase Activity in Primary Neuronal Cells
and Human Fetal Brain Tissue
[2668] Inhibition of .beta.-secretase activity in primary neuronal
cells in mice and fetal brain tissue in humans is assayed as
follows.
Media Preparation
[2669] Mouse neuronal media without KCl is supplemented with the
following: 25 ml fetal bovine serum (FBS, Sigma F-2422 or JRH
Biosciences, 12103-78P), heat inactivated for 1 hour at 56.degree.
C.; and 25 ml Chang's supplement (Irvine Scientific C104). Final
concentrations in 500 ml of mouse neuronal media without KCl is 5%
FBS, 5% Chang's supplement.
[2670] Human neuronal media without KCl is supplemented with the
following: 10 ml of 50.times. stock B27 solution (Gibco 17504-036).
Final concentration in 500 ml human neuronal media without KCl is
1.times. B27.
Preparation of Cell Culture Plates
[2671] Polyethyleneimine (PEI) solution (50% w/v, obtained from
Sigma, P-3143) is diluted 1:10 with tissue culture grade water to
yield 5% (w/v) diluted solution. The PEI diluted solution is then
filter sterilized, using a 0.45 .mu.m filter. Filter sterilized PEI
is further diluted 1:100 with sodium borate buffer (150 mM, pH 8.5,
sterile) to yield 0.05% (w/v) working solution.
[2672] Cell culture plates (24-well flat-bottom, Corning 25820, or
6-well flat-bottom, Corning 25810) are prepared for culture as
follows. PEI working solution is added in an amount of 300
.mu.l/well in 24-well plates, or 1.5 ml/well in 6 well plates to
coat at approximately 80 .mu.g/cm.sup.2. The coated plates are
incubated overnight at room temperature. Next, the plates are
aspirated and washed twice with 500 .mu.l/well (for 24-well plates)
or 2.5 ml/well (for 6-well plates) PBS (1.times. phosphate-buffered
saline, pH 7.5, sterile). The plates are then aspirated and
incubated with neuronal media without KCl plus 10% PBS (500
.mu.l/well, 24 well; or 2.5 ml/well, 6-well) at 37.degree. C. for
at least one hour. After incubation, the plates can be used
immediately, or stored under sterile conditions at 37.degree. C.
for up to one week (media should be discarded prior to
seeding).
Preparation of PDAPP Mouse Cortical Cultures
[2673] Wild type, Swiss Webster female mice are mated with
homozygotic PDAPP male mice. Sixteen to seventeen days post mating,
pregnant females are euthanized by carbon dioxide suffocation.
Under sterile conditions, fetuses are removed and decapitated.
Fetal brains are removed, and the cerebral cortices are dissected
away from the rest of the brain tissue using a dissecting
microscope. Cortical tissues are transferred to a 35 mm tissue
culture dish (Corning 25000) containing ice cold Hanks buffered
salt solution (HBSS, Sigma H9269).
[2674] Cortical tissues from ten mouse brains are pooled by
transferring to a 50 ml polypropylene conical tube (Falcon 2070),
and washed twice with 25 ml cold HBSS. Tissues are resuspended in 5
ml cold CMF HBSS (Calcium- and magnesium-free HBSS, Sigma H-9394)
plus 0.5 ml DNase stock solution (Sigma D-4527, 1 .mu.g/ml in CMF
HBSS) to yield approximately 100 .mu.g/ml final concentration of
DNase. Tissue is triturated with a 5 ml pipette until the
suspension becomes homogeneous (approximately 20-30 times). The
cell suspension is centrifuged in a clinical centrifuge for three
minutes at approximately 600.times.g. The cell pellet is
resuspended in 2.5 ml trypsin-EDTA (1.times. trypsin-EDTA, Sigma
T-3924), and incubated at 37.degree. C. for five minutes.
[2675] Neuronal media plus 10% FBS (Sigma F-2422 or JRH Biosciences
12103-78P) is added in an amount of 10 ml to 1 ml DNase stock
solution. The solution is mixed gently and incubated at room
temperature for three minutes. The cell suspension is filterd by
passage through a sterile nylon screen (100 .mu.m pore size, Falcon
2360). The filtrate is centrifuged in a clinical centrifuge for
three minutes at approximately 600.times.g.
[2676] The cell pellet is recovered and resuspended in 5 ml
complete mouse media, prepared as described above. Cells are
counted with a hemacytometer by mixing 50 .mu.l cell suspension
with 450 .mu.l trypan blue solution (0.4%, Sigma T-8154). Cells are
diluted to 1.2.times.10.sup.6 cells/ml with mouse media. Cells are
then plated 0.5 ml/well in 24-well plates coated with PEI, prepared
as described above. Cultures are fed twice per week by complete
exchange of media.
Preparation of Human Fetal Cortical Cultures
[2677] Human fetal brain tissue is obtained from Advanced
Bioscience Resources (Alameda, Calif.). Fetal brain tissue is used
promptly upon harvesting, and work is performed in a class II hood.
Tissue is processed by identifying the cerebral cortex, and
removing all traces of meninges with sterile forceps.
[2678] Cortical tissues are pooled by transferring to a 50 ml
conical tube. Pooled cortical tissues are then washed twice with 25
ml cold HBSS. Tissues are then rsuspended in 10 ml cold CMF HBSS
(Sigma H-9394) plus 1 ml DNase stock solution (Sigma D-4527) to
yield approximately 100 .mu.g/ml final concentration of DNase.
Tissue is triturated with a 10 ml pipette until the suspension
becomes homogeneous (approximately 20-30 times). The cell
suspension is centrifuged in a clinical centrifuge for three
minutes at approximately 600.times.g. The cell pellet is
resuspended in 10 ml trypsin-EDTA (1.times. trypsin EDTA, Sigman
T-3924), and incubated at 37.degree. C. for five minutes. Neuronal
media plus 10% FBS is added in an amount of 10 ml to 1 ml DNase
stock solution. The solution is mixed gently and incubated at room
temperature for three minutes.
[2679] The cell suspension is then filtered by passage through a
sterile, nylon screen (as described above). The filtrate is then
centrifuged as above. The cell pellet is resuspended in 5 ml human
media (prepared as described above). Cells are counted with a
hemacytometer by mixing 50 .mu.l cell suspension with 450 .mu.l
trypan blue solution. Cells are diluted to 1.2.times.10.sup.6
cells/ml with complete media (prepared as described above). The
cell suspension is then plated 2 ml/well in 6-well plates coated
with PEI, prepared as described above.
[2680] The cells are not disturbed for the first week. After that
time, cultures are fed twice per week by complete exchange of
media.
Neuronal Culture A.beta. Assays
[2681] Mature cultures are incubated with 300 .mu.l/well (mouse) or
750 .mu.l/well (human) fresh media for 24 hours to generate
baseline A.beta. values. Conditioned media are collected and stored
at -20.degree. C. until assayed.
[2682] Cultures are then treated with 300 .mu.l/well (mouse) or 750
.mu.l/well (human) fresh media containing compound at the desired
range of concentrations for 24 hours. Conditioned media are
collected and stored at -20.degree. C. until assayed.
[2683] For total A.beta. measurements and A.beta..sub.1-42
measurements, 100 .mu.l/well is analyzed by ELISA. Inhibition of
production for both total A.beta. and A.beta..sub.1-42 are
determined by the difference between the A.beta. values for the
compound treatment and baseline periods. Dose response curves are
plotted as percent inhibition versus compound concentration.
[2684] At the end of this treatment period, cell viability is
tested by MTT cytotoxicity assay. After conditioned media is
removed from cell plates for A.beta. measurement by ELIA, 25 .mu.l
of MTT stock (Sigma M-5655 at 5 mg/ml in 1.times.PBS, aliquoted and
stored at -20.degree. C.) are added to all wells. Cell plates are
incubated at 37.degree. C. in a CO.sub.2 incubator for 1 hour. MTT
lysis buffer is added in an amount of 125 .mu.l to each well, and
plates are placed on a titer plate shaker at low setting overnight.
Plates are read in a microplate reader at 562-650 nm. Cell
viability is calculated by percent of control cell optical density
(OD).
Example 75
Inhibition of .beta.-Secretase in Animal Models of AD
[2685] Various animal models can be used to screen for inhibition
of .beta.-secretase activity. Examples of animal models useful in
the invention include, but are not limited to, mouse, guinea pig,
and the like. The animals used can be wild type, transgenic, or
knockout models. Examples of transgenic non-human mammalian models
are described in U.S. Pat. Nos. 5,912,410 and 5,811,633. In
addition, mammalian models can express mutations in APP, such as
APP695-SW and the like described herein.
[2686] Aniamls are administered an amount of the compound inhibitor
formulated appropriately in PBS. Control animals are untreated, or
treated with an inactive compound. Administration is repeated daily
for a period of days. Beginning on day 0, brain tissue or fluid is
obtained from selected animals and analyzed for the presence of APP
cleavage peptides, including A.beta., using the specific antibodies
to A.beta.. At the end of the test period, animals are sacrificed
and brain tissue or fluid is analyzed for the presence of A.beta.
and/or beta amyloid plaques. The tissue is also analyzed for
necrosis.
[2687] Animals administered the compound inhibitors are expected to
demonstrate reduced A.beta. in brain tissues and fluids, and
reduced beta amyloid plaques in brain tissue, as compared with
non-treated controls.
Example 76
Inhibition of A.beta. Production in Human Patients
[2688] Patients suffering from Alzheimer's Disease (AD) demonstrate
an increased amount of A.beta. in the brain. AD patients are
administered an amount of the compound inhibitor diluted in PBS.
Administration is repeated daily for the duration of the test
period. Beginning on day 0, cognative and memory tests are
performed once per week.
[2689] Patients administered the compound inhibitors are expected
to demonstrate cognative and memory scores are expected to slow
and/or stabilize as compared with non-treated patients.
Example 77
Prevention of A.beta. Production in Patients at Risk for AD
[2690] Patients predisposed or at risk for developing AD are
identified either by recognition of a familial inheritance pattern,
for example, presence of the Swedish Muation, and/or by monitoring
diagnostic parameters. Patieints identified as predisposed or at
risk for developing AD patients are administered an amount of the
compound inhibitor diluted in PBS. Administration is repeated daily
for the duration of the test period. Beginning on day 0, cognative
and memory tests are performed once per month.
[2691] Patients administered the compound inhibitors are expected
to demonstrate cognative and memory scores are expected to remain
stable as compared with non-treated patients.
[2692] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereby and should only be
construed by interpretation of the scope of the appended
claims.
* * * * *