U.S. patent application number 09/829264 was filed with the patent office on 2002-06-06 for tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases.
Invention is credited to Bishop, W. Robert, Doll, Ronald J., Mallams, Alan K., Njoroge, F. George, Petrin, Joanne M., Piwinski, John J., Remiszewski, Stacy W., Taveras, Arthur G., Wolin, Ronald L..
Application Number | 20020068742 09/829264 |
Document ID | / |
Family ID | 27487081 |
Filed Date | 2002-06-06 |
United States Patent
Application |
20020068742 |
Kind Code |
A1 |
Bishop, W. Robert ; et
al. |
June 6, 2002 |
Tricyclic amide and urea compounds useful for inhibition of
G-protein function and for treatment of proliferative diseases
Abstract
A method of inhibiting Ras function and therefore inhibiting the
abnormal growth of cells is disclosed. The method comprises the
administration of a compound of Formula 1.0: 1 to a biological
system. In particular, the method inhibits the abnormal growth of
cells in a mammal such as a human being. Novel compounds of the
formulas 2 are disclosed. Also disclosed are processes for making
3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3. Further
disclosed are novel compounds which are intermediates in the
process for making 3-substituted compounds of Formulas 5.0, 5.1,
5.2 and 5.3.
Inventors: |
Bishop, W. Robert; (Pompton
Plains, NJ) ; Doll, Ronald J.; (Maplewood, NJ)
; Mallams, Alan K.; (Long Valley, NJ) ; Njoroge,
F. George; (Union, NJ) ; Petrin, Joanne M.;
(Cedar Grove, NJ) ; Piwinski, John J.; (Clinton
Township, NJ) ; Wolin, Ronald L.; (Westfield, NJ)
; Taveras, Arthur G.; (Rockaway, NJ) ;
Remiszewski, Stacy W.; (Township of Washington, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
27487081 |
Appl. No.: |
09/829264 |
Filed: |
April 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09829264 |
Apr 9, 2001 |
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09400714 |
Sep 21, 1999 |
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6242458 |
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09400714 |
Sep 21, 1999 |
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09022137 |
Feb 11, 1998 |
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09022137 |
Feb 11, 1998 |
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08410187 |
Mar 24, 1995 |
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5719148 |
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08410187 |
Mar 24, 1995 |
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08312028 |
Sep 26, 1994 |
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08312028 |
Sep 26, 1994 |
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08137862 |
Oct 15, 1993 |
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Current U.S.
Class: |
514/253.03 ;
514/290 |
Current CPC
Class: |
A61K 31/444 20130101;
C07D 249/08 20130101; A61K 31/445 20130101; C07D 401/04 20130101;
C07D 401/14 20130101; C07D 401/12 20130101; A61P 35/00 20180101;
A61K 31/47 20130101; C07D 233/56 20130101; C07D 231/12 20130101;
A61K 31/505 20130101; A61K 31/50 20130101; A61K 31/496 20130101;
C07D 405/14 20130101; C07D 221/16 20130101; C07D 417/14 20130101;
A61K 31/495 20130101; C07D 409/14 20130101 |
Class at
Publication: |
514/253.03 ;
514/290 |
International
Class: |
A61K 031/495; A61K
031/473 |
Claims
What is claimed is:
1. A method for inhibiting the abnormal growth of cells comprising
administering an effective amount of a compound of Formula 1.0:
979or a pharmaceutically acceptable salt or solvate thereof,
wherein: one of a, b, c and d represents N or NR.sup.9 wherein
R.sup.9 is O.sup.-, --CH.sub.3 or --(CH.sub.2).sub.nCO.sub.2H
wherein n is 1 to 3, and the remaining a, b, c and d groups
represent CR.sup.1 or CR.sup.2; or each of a, b, c, and d are
independently selected from CR.sup.1 or CR.sup.2; each R.sup.1 and
each R.sup.2 is independently selected from H, halo, --CF.sub.3,
--OR.sup.10, --COR.sup.10, --SR.sup.10, --S(O).sub.tR.sup.11
(wherein t is 0, 1 or 2), --SCN, --N(R.sup.10).sub.2, --NO.sub.2,
--OC(O)R.sup.10, --CO.sub.2R.sup.10, --OCO.sub.2R.sup.11, --CN,
--NHC(O)R.sup.10, --NHSO.sub.2R.sup.10, --CONHR.sup.10,
--CONHCH.sub.2CH.sub.2OH, --NR.sup.10COOR.sup.11,
--SR.sup.11C(O)OR.sup.1- 1, 980--SR.sup.11N(R.sup.75 ).sub.2
(wherein each R.sup.75 is independently selected from H and
--C(O)OR.sup.11), benzotriazol-1-yloxy, tetrazol-5-ylthio, or
substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said
alkyl or alkenyl group optionally being substituted with halo,
--OR.sup.10 or --CO.sub.2R.sup.10; R.sup.3 and R.sup.4 are the same
or different and each independently represents H, any of the
substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 taken
together represent a saturated or unsaturated C.sub.5-C.sub.7 fused
ring to the benzene ring; R.sup.5, R.sup.6, R.sup.7 and R.sup.8
each independently represents H, --CF.sub.3, --COR.sup.10, alkyl or
aryl, said alkyl or aryl optionally being substituted with
--OR.sup.10, --SR.sup.10, --S(O).sub.tR.sup.11,
--NR.sup.10COOR.sup.11, --N(R.sup.10).sub.2, --NO.sub.2,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.11,
--CO.sub.2R.sup.10, OPO.sub.3R.sup.10 or one of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 can be taken in combination with R.sup.40 as
defined below to represent --(CH.sub.2).sub.r-- wherein r is 1 to 4
which can be substituted with lower alkyl, lower alkoxy, --CF.sub.3
or aryl, or R.sup.5 is combined with R.sup.6 to represent .dbd.O or
.dbd.S and/or R.sup.7 is combined with R.sup.8 to represent .dbd.O
or .dbd.S; R.sup.10 represents H, alkyl, aryl, or aralkyl; R.sup.11
represents alkyl or aryl; X represents N, CH or C, which C may
contain an optional double bond, represented by the dotted line, to
carbon atom 11; the dotted line between carbon atoms 5 and 6
represents an optional double bond, such that when a double bond is
present, A and B independently represent --R.sup.10, halo,
--OR.sup.11, --OCO.sub.2R.sup.11 or --OC(O)R.sup.10, and when no
double bond is present between carbon atoms 5 and 6, A and B each
independently represent H.sub.2, --(OR.sup.11).sub.2; H and halo,
dihalo, alkyl and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and
--OR.sup.10, .dbd.O, aryl and H, .dbd.NOR.sup.10 or
--O--(CH.sub.2).sub.p--O-- wherein p is 2, 3 or 4; R represents
R.sup.40, R.sup.42, R.sup.44, or R.sup.54, as defined below;
R.sup.40 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or
--D wherein --D represents 981wherein R.sup.3 and R.sup.4 are as
previously defined and W is O, S or NR.sup.10 wherein R.sup.10 is
as defined above; said R.sup.40 cycloalkyl, alkenyl and alkynyl
groups being optionally substituted with from 1-3 groups selected
from halo, --CON(R.sup.10).sub.2, aryl, --CO.sub.2R.sup.10,
--OR.sup.12, --SR.sup.12, --N(R.sup.10).sub.2,
--N(R.sup.10)CO.sub.2R.sup.11, --COR.sup.12, --NO.sub.2 or D,
wherein --D, R.sup.10and R.sup.11 are as defined above and R.sup.12
represents R.sup.10, --(CH.sub.2).sub.mOR.sup.- 10 or
--(CH.sub.2).sub.qCO.sub.2R.sup.10 wherein R.sup.10 is as
previously defined, m is 1 to 4 and q is 0 to 4; said alkenyl and
alkynyl R.sup.40 groups not containing --OH, --SH or
--N(R.sup.10).sub.2 on a carbon containing a double or triple bond
respectively; or R.sup.40 represents phenyl substituted with a
group selected from --SO.sub.2NH.sub.2, --NHSO.sub.2CH.sub.3,
--SO.sub.2NHCH.sub.3, --SO.sub.2CH.sub.3, --SOCH.sub.3,
--SCH.sub.3, or --NHSO.sub.2CF.sub.3, preferably, said group is
located in the para position of the phenyl ring; or R.sup.40
represents a group selected from 982wherein R.sup.20, R.sup.21 and
R.sup.46 are each independently selected from the group consisting
of: (1) H; (2) --(CH.sub.2).sub.qSC(O)CH.sub.3 wherein q is 1 to 3;
(3) --(CH.sub.2).sub.qOSO.sub.2CH.sub.3 wherein q is 1 to 3; (4)
--OH; (5) --CS(CH.sub.2).sub.w(substituted phenyl) wherein w is 1
to 3 and the substitutents on said substituted phenyl group are the
same substitutents as described below for said substituted phenyl;
(6) --NH.sub.2; (7) --NHCBZ; (8) --NHC(O)OR.sup.22 wherein R.sup.22
is an alkyl group having from 1 to 5 carbon atoms, or R.sup.22
represents phenyl substituted with 1 to 3 alkyl groups; (9) alkyl;
(10) --(CH.sub.2).sub.kphenyl wherein k is 1 to 6; (11) phenyl;
(12) substituted phenyl wherein the substituents are selected from
the group consisting of: halo, NO.sub.2, --OH, --OCH.sub.3,
--NH.sub.2, --NHR.sup.22, --N(R.sup.22).sub.2, alkyl,
--O(CH.sub.2).sub.tphenyl (wherein t is from 1 to 3), and
--O(CH.sub.2).sub.tsubstituted phenyl (wherein t is from 1 to 3);
(13) naphthyl; (14) substituted naphthyl, wherein the substituents
are as defined for substituted phenyl above; (15) bridged
polycyclic hydrocarbons having from 5 to 10 carbon atoms; (16)
cycloalkyl having from 5 to 7 carbon atoms; (17) heteroaryl; (18)
hydroxyalkyl; (19) substituted pyridyl or substituted pyridyl
N-oxide wherein the substituents are selected from methylpyridyl,
morpholinyl, imidazolyl, 1-piperidinyl, 1-(4-methylpiperazinyl),
--S(O).sub.tR.sup.11, or any of the substituents given above for
said substituted phenyl, and said substitutents are bound to a ring
carbon by replacement of the hydrogen bound to said carbon; 983(23)
--NHC(O)--(CH.sub.2).sub.k-phenyl or
--NH(O)--(CH.sub.2).sub.k-substituted phenyl, wherein said k is as
defined above; 984wherein R.sup.50 represents H, alkyl,
alkylcarbonyl, alkyloxycarbonyl, haloalkyl, or --C(O)NH(R.sup.10)
wherein R.sup.10 is H or alkyl; (25) --NHC(O)CH.sub.2C.sub.6H.sub.5
or --NHC(O)CH.sub.2-substit- uted--C.sub.6H.sub.5; (26)
--NHC(O)OC.sub.6H.sub.5; 985(31) --O-alkyl (e.g., --OCH.sub.3); and
(32) --CF.sub.3; (33) --CN; 986wherein R.sup.85 is H, alkyl, or
alkyl substituted by --OH or --SCH.sub.3; or R.sup.20 and R.sup.21
taken together form a .dbd.O group and the remaining R.sup.46 is as
defined above; or Two of R.sup.20, R.sup.21 and R.sup.46 taken
together form piperidine Ring V 987wherein R.sup.50 is as defined
above; with the proviso that R.sup.46, R.sup.20 and R.sup.21 are
selected such that the carbon atom to which they are bound does not
contain more than one heteroatom; R.sup.44 represents 988wherein
R.sup.25 represents heteroaryl, N-methylpiperdinyl or aryl; and
R.sup.48 represents H or alkyl; R.sup.54 represents an N-oxide
heterocyclic group of the formula (i), (ii), (iii) or (iv):
989wherein R.sup.56, R.sup.58, and R.sup.60 are the same or
different and each is independently selected from H, halo,
--CF.sub.3, --OR.sup.10, --C(O)R.sup.10, --SR.sup.10,
--S(O).sub.eR.sup.11 (wherein e is 1 or 2), --N(R.sup.10).sub.2,
--NO.sub.2, --CO.sub.2R.sup.10, --OCO.sub.2R.sup.11, --OCOR.sup.10,
alkyl, aryl, alkenyl or alkynyl, which alkyl may be substituted
with --OR.sup.10, --SR.sup.10 or --N(R.sup.10).sub.2 and which
alkenyl may be substituted with OR.sup.11 or SR.sup.11; or R.sup.54
represents an N-oxide heterocyclic group of the formula (ia),
(iia), (iiia) or (iva): 990wherein Y represents N.sup.+--O.sup.-
and E represents N; or R.sup.54 represents an alkyl group
substituted with one of said N-oxide heterocyclic groups (i), (ii),
(iii), (iv), (ia), (iia), (iiia) or (iva); Z represents O or S such
that R can be taken in combination with R.sup.5, R.sup.6, R.sup.7
or R.sup.8 as defined above, or R represents R.sup.40, R.sup.42,
R.sup.44 or R.sup.54.
2. The method of claim 1 wherein a is N and b, c, and d are carbon;
R.sup.1 and R.sup.2 are the same or different and each is
independently selected from H, halo, --CF.sub.3, lower alkyl, or
benzotriazol-1-yloxy, and R.sup.1 is at the C-4 position and
R.sup.2 is at the C-3 position; R.sup.3 and R.sup.4 are the same or
different and each is independently selected from H or halo, and
R.sup.3 is at the C-8 position and R.sup.4 is at the C-9 position;
when the double bond between carbon atoms 5 and 6 is present, A and
B independently represent H, lower alkyl or alkyloxy; and when the
double bond between carbon atoms 5 and 6 is absent, A and B
independently represent H.sub.2, (--H and --OH) or .dbd.O; R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are H; Z is O; and R represents
R.sup.42 and the R.sup.46 is selected from phenyl, substituted
phenyl, heteroaryl or piperidine Ring V.
3. The method of claim 2 wherein R.sup.20 and R.sup.21 are each
independently selected from H and alkyl; R.sup.3 is Cl; R.sup.4 is
H; R.sup.1 and R.sup.2 are individually selected from H,
benzotriazol-1-yloxy, C.sub.1 to C.sub.4 alkyl or halo; and
R.sup.46 represents 3-pyridyl, 3-pyridyl N-oxide, triazolyl,
4-pyridyl, 4-pyridyl N-oxide, 3-N-methylpiperidinyl,
4-N-methylpiperidinyl, 3-N-acetylpiperidinyl,
4-N-acetylpiperidinyl, 1-N-methylpiperazinyl, 1-piperazinyl, a
heterocycloalkyl of the formula 991
4. The method of claim 3 wherein both R.sup.20 and R.sup.21 are H,
or both R.sup.20 and R.sup.21 are methyl; R.sup.1 and R.sup.2 are
individually selected from H, Br, Cl, methyl or
benzotriazol-1-yloxy; and R.sup.46 represents 3-pyridyl, 3-pyridyl
N-oxide, triazolyl, 4-pyridyl, 4-pyridyl N-oxide,
3-N-methylpiperidinyl or 4-N-methylpiperidinyl,
1-N-methylpiperazinyl, 1-piperazinyl, a heterocycloalkyl of the
formula 992
5. The method of claim 1 wherein a is N and b, c, and d are carbon;
R.sup.1 and R.sup.2 are the same or different and each is
independently selected from H, halo, --CF.sub.3, lower alkyl, or
benzotriazol-1 -yloxy, and R.sup.1 is at the C-4 position and
R.sup.2 is at the C-3 position; R.sup.3 and R.sup.4 are the same or
different and each is independently selected from H or halo, and
R.sup.3 is at the C-8 position and R.sup.4 is at the C-9 position;
when the double bond between carbon atoms 5 and 6 is present, A and
B independently represent H, lower alkyl or alkyloxy; and when the
double bond between carbon atoms 5 and 6 is absent, A and B
independently represent H.sub.2, (--H and --OH) or .dbd.O; R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are H; Z is O; and R represents
R.sup.44 and the R.sup.25 represents pyridyl, pyridyl N-oxide,
phenyl, 3-N-methylpiperidinyl or 4-N-methylpiperidinyl.
6. The method of claim 5 wherein R.sup.25 represents 3-pyridyl or
phenyl; R.sup.3 is Cl; R.sup.4 is H; R.sup.48 represents are H or
methyl; and R.sup.1 and R.sup.2 are individually selected from H,
benzotriazol-1-yloxy, C.sub.1 to C.sub.4 alkyl or halo.
7. The method of claim 6 wherein R.sup.1 and R.sup.2 are
individually selected from H, Br, Cl, methyl or
benzotriazol-1-yloxy.
8. The method of claim 1 wherein the the cells inhibited are tumor
cells expressing an activated ras oncogene.
9. The method of claim 8 wherein the cells inhibited are pancreatic
tumor cells, lung cancer cells, myeloid leukemia tumor cells,
thyroid follicular tumor cells, myelodysplastic tumor cells,
epidermal carcinoma tumor cells, bladder carcinoma tumor cells or
colon tumors cells.
10. The method of claim 1 wherein the inhibition of the abnormal
growth of cells occurs by the inhibition of ras farnesyl protein
transferase.
11. The method of claim 1 wherein the inhibition is of tumor cells
wherein the Ras protein is activated as a result of oncogenic
mutation in genes other than the Ras gene.
12. The method of claim 1 wherein the compound is selected from the
compounds of Examples: 1, 2, 3, 4, 5, 6,19, 42, 43, 44, 45, 46, 47,
48, 49, 75, 76, 78, 82, 83, 84, 85, 89, 121, 180, 182, 183, 184,
187 structure 6.7, 187 structure 6.8, 192, 196, 197, 198, 200, 201,
206, 222, 223, 224, 225, 226, 227, 233, 234, 236, 239, 246, 247,
248, 249, 250, 251, 261, 262, 266, 267, 269, 273, 276, 283, 285,
286, 287, 288, 289, 291, 292, 293, 299, 300, 301, 303, 307, 309,
311, 312, 313, 314, 316, 350, 351, 352, 354, 356, 426, 400-G,
400-C, 400-F, 400-E, 425-H, 401, 400-B, 400, 400-L, 425-U, 413,
400-J, 417-B, 438, 411-W, 425-O, 400-D, 400-K, 410-G or 400-H.
13. A compound selected from a compound of the formula: 993or a
pharmaceutically acceptable salt or soIvate thereof, wherein all
the substituents are as defined in claim 1, and wherein for the
compounds of Formula 5.2 the substituents R.sup.20, R.sup.21, and
R.sup.46 are selected such that when one of said substituents
R.sup.20, R.sup.21, and R.sup.46 is selected from the group
consisting of: (1) H, (4) --OH, (6) --NH.sub.2, (8)
--NHC(O)OR.sup.22, (9) alkyl, (11) phenyl, (17) heteroaryl, (18)
hydroxyalkyl, (19) substituted pyridyl, (12) substituted phenyl and
(31) --O-alkyl, then the remaining two of said substituents
R.sup.20, R.sup.21 and R.sup.46 cannot both be H when: (a) R.sup.1
and R.sup.2 are both H, and (b) the double bond between C-5 and C-6
is absent, and (c) both A and B are H.sub.2, and (d) R.sup.4 is H,
and (e) R.sup.3 is H or Cl at C-8.
14. The compound of claim 13 wherein a is N and b, c, and d are
carbon; R.sup.1 and R.sup.2 are the same or different and each is
independently selected from H, halo, --CF.sub.3, lower alkyl, or
benzotriazol-1-yloxy, and R.sup.1 is at the C-4 position and
R.sup.2 is at the C-3 position; R.sup.3 and R.sup.4 are the same or
different and each is independently selected from H or halo, and
R.sup.3 is at the C-8 position and R.sup.4 is at the C-9 position;
when the double bond between carbon atoms 5 and 6 is present, A and
B independently represent H, lower alkyl or alkyloxy; and when the
double bond between carbon atoms 5 and 6 is absent, A and B
independently represent H.sub.2, (--H and --OH) or .dbd.O; R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are H; Z is O; and R.sup.46 is
selected from phenyl, substituted phenyl, heteroaryl, piperidine
Ring V, 1-N-methylpiperazinyl, 1-piperazinyl or a heterocycloalkyl
of the formula 994
15. The compound of claim 14 wherein R.sup.20 and R.sup.21 are each
independently selected from H and alkyl; R.sup.3 is Cl; R.sup.4 is
H; R.sup.1 and R.sup.2 are individually selected from H,
benzotriazol-1-yloxy, C.sub.1 to C.sub.4 alkyl or halo; and
R.sup.46 represents 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl,
4-pyridyl N-oxide, 3-N-methylpiperidinyl, 4-N-methylpiperidinyl,
3-N-acetylpiperidinyl, 4-N-acetylpiperidinyl,
1-N-methylpiperazinyl, 1-piperazinyl or a heterocycloalkyl of the
formula 995
16. The compound of claim 15 wherein both R.sup.20 and R.sup.21 are
H, or both R.sup.20 and R.sup.21 are methyl; R.sup.1 and R.sup.2
are individually selected from H, Br, Cl, methyl or
benzotriazol-1-yloxy; and R.sup.46 represents 3-pyridyl, 3-pyridyl
N-oxide, triazolyl, 4-pyridyl, 4-pyridyl N-oxide,
3-N-methylpiperidinyl, 4-N-methylpiperidinyl,
1-N-methylpiperazinyl, 1-piperazinyl or a heterocycloalkyl of the
formula 996
17. The compound of claim 13 wherein a is N and b, c, and d are
carbon; R.sup.1 and R.sup.2 are the same or different and each is
independently selected from H, halo, --CF.sub.3, lower alkyl, or
benzotriazol-1-yloxy, and R.sup.1 is at the C-4 position and
R.sup.2 is at the C-3 position; R.sup.3 and R.sup.4 are the same or
different and each is independently selected from H or halo, and
R.sup.3 is at the C-8 position and R.sup.4 is at the C-9 position;
when the double bond between carbon atoms 5 and 6 is present, A and
B independently represent H, lower alkyl or alkyloxy; and when the
double bond between carbon atoms 5 and 6 is absent, A and B
independently represent H.sub.2, (--H and --OH) or .dbd.O; R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are H; Z is O; and R.sup.25
represents phenyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl,
4-pyridyl N-oxide, 3-N-methylpiperidinyl, 4-N-methylpiperidinyl,
3-N-acetylpiperidinyl or 4-N-acetylpiperidinyl.
18. The compound of claim 17 wherein R.sup.25 represents phenyl,
3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, 4-pyridyl N-oxide,
3-N-methylpiperidinyl or 4-N-methylpiperidinyl; R.sup.3 is Cl;
R.sup.4 is H; R.sup.48 represents are H or methyl; and R.sup.1 and
R.sup.2 are individually selected from H, benzotriazol-1-yloxy,
C.sub.1 to C.sub.4 alkyl or halo.
19. The compound of claim 18 wherein R.sup.1 and R.sup.2 are
individually selected from H, Br, Cl, methyl or
benzotriazol-1-yloxy.
20. The compound of claim 13 selected from a compound having the
structure number: 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.60,
5.61, 5.62, 5.63, 5.64, 5.65, 5.66, 5.67, 5.68, 5.69, 5.70, 5.71,
5.72, 5.73, 5.74, 5.75, 5.76, 5.77, 5.78, 5.79, 5.81, 5.82, 5.83,
5.84, 5.85, 5.90, 5.91, 5.96, 5.97, 5.98, 5.99, 5.100, 5.101,
5.108, 5.109, 5.110, 5.111, 5.138, 5.139, 5.140, 5.141, 5.143, 5.4,
5.5, 5.6, 5.7, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16,
5.24, 5.26, 5.27, 5.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36,
5.37, 5.38, 5.40, 5.42, 5.44, 5.45, 5.46, 5.48, 5.92, 5.93, 5.94,
5.95, 5.102, 5.103, 5.104, 5.105, 5.107, 5.114, 5.115, 5.121,
5.122, 5.123, 5.124, 5.125, 5.126, 5.127, 5.128, 5.129, 5.132,
5.133, 5.134, 5.135, 5.136, 5.145, 5.146, 5.147, 5.149, 5.150,
5.151, 5.152, 5.153, 5.154, 5.200, 5.201, 5.202, 5.203, 5.204,
5.205, 5.206, 5.207, 5.208, 5.209, 5.210, 5.211, 5.212, 5.213,
5.214, 5.215, 5.216, 5.217, 5.218, 5.219, 5.220, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, 6.10, 6.11, 6.17, 6.19, 6.12, 6.13 or 6.14; or
selected from the compound of example number 82, 82A, 235, 316,
323, 310, 350, 352, 355, 89, 180, 181, 204, 234, 287, 288, 289,
290, 295, 296, 297, 298, 299, 300, 301, 303, 304, 305, 307, 309,
311, 356, 312, 313, 314, 354, 291, 292, 293 or 294.
21. A pharmaceutical composition for inhibiting the abnormal growth
of cells comprising an effective amount of compound of claim 13 in
combination with a pharmaceutically acceptable carrier.
22. A process for producing 3-nitro substituted compounds of
Formula 1.0h: 997wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B,
a, b, d, and the dotted lines are as defined for Formula 1.0 in
claim 1, and R.sup.65 represents H or --OR.sup.66 wherein R.sup.66
represents alkyl, comprising: rea of a compound of Formula 1.0g:
998wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d, and
the dotted lines are as defined for Formula 1.0 in claim 1, and
R.sup.65 represents H or --OR.sup.66 wherein R.sup.66 represents
alkyl; with one molar equivalent of a nitrating reagent, said
nitrating reagent being preformed by mixing, at cold temperature,
equimolar amounts of tetrabutyl ammonium nitrate with TFAA; the
reaction of said nitrating reagent with said compound of Formula
1.0g taking place in a suitable aprotic solvent; and said reaction
with said nitrating reagent being conducted at a temperature and
for a period of time sufficient to allow the reaction to proceed at
a reasonable rate to produce the 3-nitro compound of Formula
1.0h.
23. A process for producing 3-nitro compounds of the formula:
999wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d, and
the dotted lines are as defined for Formula 1.0 in claim 1,
comprising: reacting one molar equivalent of a compound of Formula
1.0g: 1000wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b,
d, and the dotted lines are as defined for Formula 1.0 in claim 1,
and R.sup.65 represents H or --OR.sup.66 wherein R.sup.66
represents alkyl; with one molar equivalent of a nitrating reagent,
said nitrating reagent being preformed by mixing, at cold
temperature, equimolar amounts of tetrabutyl ammonium nitrate with
TFAA; the reaction of said nitrating reagent with said compound of
Formula 1.0g taking place in a suitable aprotic solvent; and said
reaction with said nitrating reagent being conducted at a
temperature and for a period of time sufficient to allow the
reaction to proceed at a reasonable rate to produce the 3-nitro
compound of Formula 1.0h: 1001hydrolyzing the compound of Formula
1.0h by dissolving the compound of Formula 1.0h in a sufficient
amount of concentrated acid, and heating the resulting mixture to a
temperature sufficient to remove the --C(O)R.sup.65 substituent to
produce the compound of Formula 1.0i.
24. A process for producing compounds of the formula: 1002wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d, and the dotted
lines are as defined for Formula 1.0 in claim 1, comprising:
reacting one molar equivalent a compound of formula: 1003with one
molar equivalent of a nitrating reagent; said nitrating reagent
being preformed, by mixing at a cold temperature, equimolar amounts
of tetrabutyl ammonium nitrate with TFAA; the reaction of said
nitrating reagent with the compound of Formula 1.0k taking place in
a suitable aprotic solvent; said reaction with said nitrating
reagent being conducted at a temperature and for a period of time
sufficient to allow the reaction to proceed at a reasonable rate to
produce the 3-nitro compound of Formula 1.0j.
25. A process for producing a compound of Formula 1.0m: 1004wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B. a, b, d, and the dotted
lines are as defined for Formula 1.0 in claim 1, and wherein
R.sup.68 is H or --COOR.sup.a wherein R.sup.a is a C.sub.1 to
C.sub.3 alkyl group, comprising: reacting one molar equivalent a
compound of formula: 1005with one molar equivalent of a nitrating
reagent; said nitrating reagent being preformed, by mixing at a
cold temperature, equimolar amounts of tetrabutyl ammonium nitrate
with TFAA; the reaction of said nitrating reagent with the compound
of Formula 1.0k taking place in a suitable aprotic solvent; said
reaction with said nitrating reagent being conducted at a
temperature and for a period of time sufficient to allow the
reaction to proceed at a reasonable rate to produce the 3-nitro
compound of Formula 1.0j: 1006reducing said compound of Formula
1.0j with a suitable reducing agent in a suitable solvent at a
suitable temperature to allow the reaction to proceed at a
reasonable rate; reacting the resulting hydroxy product with a
chlorinating agent in a suitable organic solvent at a suitable
temperature to allow the reaction to proceed at a reasonable rate
to produce a compound of Formula 1.0n: 1007reacting said compound
of Formula 1.0n with a compound of the formula: 1008wherein
R.sup.68 is as previously defined, in a suitable organic solvent
containing a suitable base at a suitable temperature to allow the
reaction to proceed at a reasonable rate to produce the compounds
of Formula 1.0m.
26. A compound selected from a compound of the formula: 1009wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d, and R.sup.65 are
as defined for Formula 1.0h in claim 22; 1010wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, A, B, a, b, and d are as defined for
Formula 1.0i in claim 23; 1011wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, A, B, a, b, and d are as defined for Formula 1.0j in claim
24; 1012wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d
and R.sup.68 are as defined for Formula 1.0m in claim 25;
1013wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, and d
are as defined for Formula 1.0j in claim 24; or 1014wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, and d are as
defined for Formula 1.0j in claim 24.
27. A compound selected from a compound of the formula: 1015
Description
BACKGROUND
[0001] International Publication Number WO92/11034, published Jul.
9, 1992, discloses a method of increasing the sensitivity of a
tumor to an antineoplastic agent, which tumor is resistant to the
antineoplastic agent, by the concurrent administration of the
antineoplastic agent and a potentiating agent of the formula: 3
[0002] wherein the dotted line represents an optional double bond,
X' is hydrogen or halo, and Y' is hydrogen, substituted carboxylate
or substituted sulfonyl. For example, Y' can be, amongst others,
--COOR' wherein R' is C1 to C6 alkyl or substituted alkyl, phenyl,
substituted phenyl, C7 to C12 aralkyl or substituted aralkyl or -2,
-3, or -4 piperidyl or N-substituted piperidyl. Y' can also be,
amongst others, SO.sub.2R' wherein R' is C1 to C6 alkyl, phenyl,
substituted phenyl, C7 to C12 aralkyl or substituted aralkyl.
Examples of such potentiating agents include
11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridi- nes
such as Loratadine.
[0003] Oncogenes frequently encode protein components of signal
transduction pathways which lead to stimulation of cell growth and
mitogenesis. Oncogene expression in cultured cells leads to
cellular transformation, characterized by the ability of cells to
grow in soft agar and the growth of cells as dense foci lacking the
contact inhibition exhibited by non-transformed cells. Mutation
and/or overexpression of certain oncogenes is frequently associated
with human cancer.
[0004] To acquire transforming potential, the precursor of the Ras
oncoprotein must undergo farnesylation of the cysteine residue
located in a carboxyl-terminal tetrapeptide. Inhibitors of the
enzyme that catalyzes this modification, farnesyl protein
transferase, have therefore been suggested as anticancer agents for
tumors in which Ras contributes to transformation. Mutated,
oncogenic forms of ras are frequently found in many human cancers,
most notably in more than 50% of colon and pancreatic carcinomas
(Kohl et al., Science, Vol. 260, 1834 to 1837, 1993).
[0005] In view of the current interest in inhibitors of farnesyl
protein transferase, a welcome contribution to the art would be
compounds useful for the inhibition of farnesyl protein
transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
[0006] Inhibition of farnesyl protein transferase by tricyclic
compounds of this invention has not been reported previously. Thus,
this invention provides a method for inhibiting farnesyl protein
transferase using tricyclic compounds of this invention which: (i)
potently inhibit farnesyl protein transferase, but not
geranylgeranyl protein transferase I, in vitro; (ii) block the
phenotypic change induced by a form of transforming Ras which is a
farnesyl acceptor but not by a form of transforming Ras engineered
to be a geranylgeranyl acceptor; (iii) block intracellular
processing of Ras which is a farnesyl acceptor but not of Ras
engineered to be a geranylgeranyl acceptor; and (iv) block abnormal
cell growth in culture induced by transforming Ras. Several
compounds of this invention have been demonstrated to have
anti-tumor activity in animal models.
[0007] This invention provides a method for inhibiting the abnormal
growth of cells, including transformed cells, by administering an
effective amount of a compound of this invention. Abnormal growth
of cells refers to cell growth independent of normal regulatory
mechanisms (e.g., loss of contact inhibition). This includes the
abnormal growth of: (1) tumor cells (tumors) expressing an
activated Ras oncogene; (2) tumor cells in which the Ras protein is
activated as a result of oncogenic mutation in another gene; and
(3) benign and malignant cells of other proliferative diseases in
which aberrant Ras activation occurs.
[0008] Compounds useful in the claimed methods are represented by
Formula 1.0: 4
[0009] or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0010] one of a, b, c and d represents N or NR.sup.9 wherein
R.sup.9 is O.sup.-, --CH.sub.3 or --(CH.sub.2).sub.nCO.sub.2H
wherein n is 1 to 3, and the remaining a, b, c and d groups
represent CR.sup.1 or CR.sup.2; or
[0011] each of a, b, c, and d are independently selected from
CR.sup.1 or CR.sup.2;
[0012] each R.sup.1 and each R.sup.2 is independently selected from
H, halo, --CF.sub.3, --OR.sup.10 (e.g., --OCH.sub.3), --COR.sup.10,
--SR.sup.10 (e.g., --SCH.sub.3 and --SCH.sub.2C.sub.6H.sub.5),
--S(O).sub.tR.sup.11 (wherein t is 0, 1 or 2, e.g., --SOCH.sub.3
and --SO.sub.2CH.sub.3), --SCN, --N(R.sup.10).sub.2,
--NR.sup.10R.sup.11, --NO.sub.2, --OC(O)R.sup.10,
--CO.sub.2R.sup.10, --OCO.sub.2R.sup.11, --CN, --NHC(O)R.sup.10,
--NHSO.sub.2R.sup.10, --CONHR.sup.10, --CONHCH.sub.2CH.sub.2OH,
--NR.sup.10COOR.sup.11, 5
[0013] --SR.sup.11C(O)OR.sup.11 (e.g.,
--SCH.sub.2CO.sub.2CH.sub.3), --SR.sup.11N (R.sup.75).sub.2 wherein
each R.sup.75 is independently selected from H and --C(O)OR.sup.11
(e.g., --S(CH.sub.2).sub.2NHC(O)O-t-b- utyl and
--S(CH.sub.2).sub.2NH.sub.2), benzotriazol-1-yloxy,
tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl
substituted tetrazol5-ylthio such as 1-methyl-tetrazol-5-ylthio),
alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally
being substituted with halo, --OR.sup.10 or --CO.sub.2R.sup.10;
[0014] R.sup.3 and R.sup.4 are the same or different and each
independently represents H, any of the substituents of R.sup.1 and
R.sup.2, or R.sup.3 and R.sup.4 taken together represent a
saturated or unsaturated C.sub.5-C.sub.7 fused ring to the benzene
ring (Ring III);
[0015] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently
represents H, --CF.sub.3, --COR.sup.10, alkyl or aryl, said alkyl
or aryl optionally being substituted with --OR.sup.10, --SR.sup.10,
--S(O).sub.tR.sup.11, --NR.sup.10COOR.sup.11, --N(R.sup.10).sub.2,
--NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.11,
--CO.sub.2R.sup.10, OPO.sub.3R.sup.10 or one of R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 can be taken in combination with R.sup.40 as
defined below to represent --(CH.sub.2).sub.r-- wherein r is 1 to 4
which can be substituted with lower alkyl, lower alkoxy, --CF.sub.3
or aryl, or R.sup.5 is combined with R.sup.6 to represent .dbd.O or
.dbd.S and/or R.sup.7 is combined with R.sup.8 to represent .dbd.O
or .dbd.S;
[0016] R.sup.10 represents H, alkyl, aryl, or aralkyl (e.g.,
benzyl);
[0017] R.sup.11 represents alkyl or aryl;
[0018] X represents N, CH or C, which C may contain an optional
double bond (represented by the dotted line) to carbon atom 11;
[0019] the dotted line between carbon atoms 5 and 6 represents an
optional double bond, such that when a double bond is present, A
and B independently represent --R.sup.10, halo, --OR.sup.11,
--OCO.sub.2R.sup.11 or --OC(O)R.sup.10, and when no double bond is
present between carbon atoms 5 and 6, A and B each independently
represent H.sub.2, --(OR.sup.11).sub.2; H and halo, dihalo, alkyl
and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and --OR.sup.10,
.dbd.O, aryl and H, .dbd.NOR.sup.10 or --O--(CH.sub.2).sub.p--O--
wherein p is 2, 3 or 4;
[0020] R represents R.sup.40, R.sup.42, R.sup.44, or R.sup.54, as
defined below;
[0021] R.sup.40 represents H, aryl, alkyl, cycloalkyl, alkenyl,
alkynyl or --D wherein --D represents 6
[0022] wherein R.sup.3 and R.sup.4 are as previously defined and W
is O, S or NR.sup.10 wherein R.sup.10 is as defined above; said
R.sup.40 cycloalkyl, alkenyl and alkynyl groups being optionally
substituted with from 1-3 groups selected from halo,
--CON(R.sup.10).sub.2, aryl, --CO.sub.2R.sup.10, --OR.sup.12,
--SR.sup.12, --N(R.sup.10).sub.2, --N(R.sup.10)CO.sub.2R.sup.11,
--COR.sup.12, --NO.sub.2 or D, wherein --D, R.sup.10 and R.sup.11
are as defined above and R.sup.12 represents R.sup.10,
--(CH.sub.2).sub.mOR.sup.10 or --(CH.sub.2).sub.qCO.sub.2R.sup.- 10
wherein R.sup.10 is as previously defined, m is 1 to 4 and q is 0
to 4; said alkenyl and alkynyl R.sup.40 groups not containing --OH,
--SH or --N(R.sup.10).sub.2 on a carbon containing a double or
triple bond respectively; or
[0023] R.sup.40 represents phenyl substituted with a group selected
from --SO.sub.2NH.sub.2, --NHSO.sub.2CH.sub.3,
--SO.sub.2NHCH.sub.3, --SO.sub.2CH.sub.3, --SOCH.sub.3,
--SCH.sub.3, or --NHSO.sub.2CF.sub.3, preferably, said group is
located in the para (p-) position of the phenyl ring; or
[0024] R.sup.40 represents a group selected from 7
[0025] wherein R.sup.20, R.sup.21 and R46 are each independently
selected from the group consisting of:
[0026] (1) H;
[0027] (2) --(CH.sub.2).sub.qSC(O)CH.sub.3 wherein q is 1 to 3
(e.g., --CH.sub.2SC(O)CH.sub.3);
[0028] (3) --(CH.sub.2).sub.qOSO.sub.2CH.sub.3 wherein q is 1 to 3
(e.g., --CH.sub.2OSO.sub.2CH.sub.3);
[0029] (4) --OH;
[0030] (5) --CS(CH.sub.2).sub.w(substituted phenyl) wherein w is 1
to 3 and the substitutents on said substituted phenyl group are the
same substitutents as described below for said substituted phenyl
(e.g., --C--S--CH.sub.2-4-methoxyphenyl);
[0031] (6) --NH.sub.2;
[0032] (7) --NHCBZ (wherein CBZ stands for carbonylbenzyloxy--i.e.,
CBZ represents --C(O)OCH.sub.2C.sub.6H.sub.5);
[0033] (8) --NHC(O)OR.sup.22 wherein R.sup.22 is an alkyl group
having from 1 to 5 carbon atoms (e.g., R.sup.22 is t-butyl thus
forming --NHBOC wherein BOC stands for tert-butyloxycarbonyl--i.e.,
BOC represents --C(O)OC(CH.sub.3).sub.3), or R.sup.22 represents
phenyl substituted with 1 to 3 alkyl groups (e.g.,
4-methylphenyl);
[0034] (9) alkyl (e.g., ethyl);
[0035] (10) --(CH.sub.2).sub.kphenyl wherein k is 1 to 6, usually 1
to 4 and preferably 1 (e.g., benzyl);
[0036] (11) phenyl;
[0037] (12) substituted phenyl (i.e., phenyl substituted with from
1 to 3 substituents, preferably one) wherein the substituents are
selected from the group consisting of: halo (e.g., Br, Cl, or I,
with Br being preferred); NO.sub.2; --OH; --OCH.sub.3; --NH.sub.2;
--NHR.sup.22; --N(R.sup.22).sub.2; alkyl (e.g., alkyl having from 1
to 3 carbons with methyl being preferred);
--O(CH.sub.2).sub.tphenyl (wherein t is from 1 to 3 with 1 being
preferred); and --O(CH.sub.2).sub.tsubstituted phenyl (wherein t is
from 1 to 3 with 1 being preferred); examples of substituted
phenyls include, but are not limited to, p-bromophenyl,
m-nitrophenyl, o-nitrophenyl, m-hydroxy-phenyl, o-hydroxyphenyl,
methoxyphenyl, p-methylphenyl, m-methyl-phenyl, and
--OCH.sub.2C.sub.6H.sub.5;
[0038] (13) naphthyl;
[0039] (14) substituted naphthyl, wherein the substituents are as
defined for substituted phenyl above;
[0040] (15) bridged polycyclic hydrocarbons having from 5 to 10
carbon atoms (e.g., adamantyl and norbornyl);
[0041] (16) cycloalkyl having from 5 to 7 carbon atoms (e.g.,
cyclopentyl, and cyclohexyl);
[0042] (17) heteroaryl (e.g., pyridyl, and pyridyl N-oxide);
[0043] (18) hydroxyalkyl (e.g., --(CH.sub.2).sub.vOH wherein v is 1
to 3, such as, for example, --CH.sub.2OH);
[0044] (19) substituted pyridyl or substituted pyridyl N-oxide
wherein the substituents are selected from methylpyridyl,
morpholinyl, imidazolyl, 1-piperidinyl, 1-(4-methylpiperazinyl),
--S(O).sub.tR.sup.11, or any of the substituents given above for
said substituted phenyl, and said substitutents are bound to a ring
carbon by replacement of the hydrogen bound to said carbon; 8
[0045] (23) --NHC(O)--(CH.sub.2).sub.k-phenyl or
--NH(O)--(CH.sub.2).sub.k- -substituted phenyl, wherein said k is
as defined above (i.e., 1-6, usually 1-4 and preferably 1);
[0046] (24) piperidine Ring V: 9
[0047] wherein R.sup.50 represents H, alkyl (e.g., methyl),
alkylcarbonyl (e.g., CH.sub.3C(O)--), alkyloxycarbonyl (e.g.,
--C(O)O-t--C.sub.4H.sub.9- , --C(O)OC.sub.2H.sub.5, and
--C(O)OCH.sub.3), haloalkyl (e.g., trifluromethyl), or
--C(O)NH(R.sup.10) wherein R.sup.10 is H or alkyl; Ring V includes
10
[0048] (25) --NHC(O)CH.sub.2C.sub.6H.sub.5 or
--NHC(O)CH.sub.2-substituted- -C.sub.6H.sub.5, for example
--NHC(O)CH.sub.2-p-hydroxyphenyl, --NHC(O)CH.sub.2-m-hydroxyphenyl,
and --NHC(O)CH.sub.2-o-hydroxyphenyl;
[0049] (26) --NHC(O)OC.sub.6H.sub.5; 11
[0050] (31) --O-alkyl (e.g., --OCH.sub.3);
[0051] (32) --CF.sub.3;
[0052] (33) --CN; 12
[0053] wherein R.sup.85 is H, alkyl, or alkyl substituted by --OH
or --SCH.sub.3; or
[0054] R.sup.20 and R.sup.21 taken together form a .dbd.O group and
the remaining R.sup.46 is as defined above; or
[0055] Two of R.sup.20, R.sup.21 and R.sup.46 taken together form
piperidine Ring V 13
[0056] wherein R.sup.50 represents H, alkyl (e.g., methyl),
alkylcarbonyl (e.g., CH.sub.3C(O)--), alkyloxycarbonyl (e.g.,
--C(O)O-t--C.sub.4H.sub.9- , --C(O)OC.sub.2H.sub.5, and
--C(O)OCH.sub.3), haloalkyl (e.g., trifluro-methyl), or
--C(O)NH(R.sup.10) wherein R.sup.10 is H or alkyl; Ring V includes
14
[0057] with the proviso R.sup.46, R.sup.20, and R.sup.21 are
selected such that the carbon atom to which they are bound does not
contain more than one heteroatom (i.e., R.sup.46, R.sup.20, and
R.sup.21 are selected such that the carbon atom to which they are
bound contains 0 or 1 heteroatom);
[0058] R44 represents 15
[0059] wherein R.sup.25 represents heteroaryl (e.g., pyridyl or
pyridyl N-oxide), N-methylpiperidinyl or aryl (e.g., phenyl and
substituted phenyl); and R.sup.48 represents H or alkyl (e.g.,
methyl);
[0060] R54 represents an N-oxide heterocyclic group of the formula
(i), (ii), (iii) or (iv): 16
[0061] wherein R.sup.56, R.sup.58, and R.sup.60 are the same or
different and each is independently selected from H, halo,
--CF.sub.3, --OR.sup.10, --C(O)R.sup.10, --SR.sup.10,
--S(O).sub.eR.sup.11 (wherein e is 1 or 2), --N(R.sup.10).sub.2,
--NO.sub.2, --CO.sub.2R.sup.10, --OCO.sub.2R.sup.11, --OCOR.sup.10,
alkyl, aryl, alkenyl or alkynyl, which alkyl may be substituted
with --OR.sup.10, --SR.sup.10 or --N(R.sup.10).sub.2 and which
alkenyl may be substituted with OR.sup.11 or SR.sup.11; or
[0062] R.sup.54 represents an N-oxide heterocyclic group of the
formula (ia), (iia), (iiia) or (iva): 17
[0063] wherein Y represents N.sup.+--O.sup.- and E represents N;
or
[0064] R.sup.54 represents an alkyl group substituted with one of
said N-oxide heterocyclic groups (i), (ii), (iii), (iv), (ia),
(iia), (iiia) or (iva);
[0065] Z represents O or S such that R can be taken in combination
with R.sup.5, R.sup.6, R.sup.7 or R.sup.8 as defined above, or R
represents R.sup.40, R.sup.42, R.sup.44 or R.sup.54.
[0066] Examples of R.sup.20, R.sup.21, and R.sup.46 for the above
formulas include: 18
[0067] wherein Y represents N or NO, R.sup.28 is selected from the
group consisting of: C.sub.1 to C.sub.4 alkyl, halo, hydroxy,
NO.sub.2, amino (--NH.sub.2), --NHR.sup.30, and --N(R.sup.30).sub.2
wherein R.sup.30 represents C.sub.1 to C.sub.6 alkyl.
[0068] Tricyclic compounds useful in the methods of this invention
are described in: (1) U.S. Pat. No. 5,151,423; (2) U.S. Pat. No.
4,826,853; (3) U.S. Pat. No. 5,089,496; (4) WO 88/03138 published
on May 5, 1988 (PCT/US87/02777); and (5) U.S. Pat. No. 5,104,876;
the disclosures of each being incorporated herein by reference
thereto. Those compounds within the scope of this invention which
are not described in these documents are described herein.
[0069] This invention also provides novel compounds of Formula 1.0
having the formula: 19
[0070] wherein all substituents are as defined for Formula 1.0
[0071] This invention further provides novel compounds of Formula
1.0 having the formula: 20
[0072] wherein all substituents are as defined for Formula 1.0
[0073] Additionally, this invention provides novel compounds of
Formula 1.0 having the formula: 21
[0074] wherein all substituents are as defined for Formula 1.0.
[0075] Compounds of Formula 5.2 include compounds wherein the
substituents R.sup.20, R.sup.21, and R.sup.46 are selected such
that when one of said substituents R.sup.20, R.sup.21, and R.sup.46
(e.g., R.sup.46) is selected from the group consisting of: (1) H,
(2) --OH, (3) --NH.sub.2, (4) --NHC(O)OR.sup.22, (5) alkyl, (6)
phenyl, (7) heteroaryl, (8) hydroxyalkyl, (9) substituted pyridyl,
(10) substituted phenyl and (11) --O-alkyl, then the remaining two
of said substituents R.sup.20, R.sup.21 and R.sup.46 (e.g.,
R.sup.20 and R.sup.21) cannot both be H when: (a) R.sup.1 and
R.sup.2 are both H, and (b) the double bond between C-5 and C-6 is
absent, and (c) both A and B are H.sub.2, and (d) R.sup.4 is H, and
(e) R.sup.3 is H or Cl at C-8. Compounds of Formula 5.2 also
include compounds wherein when R.sup.46 is a group (1) to (11)
defined above then R.sup.20 and R.sup.21 cannot both be H when:
R.sup.1 and R.sup.2 are both H, and both A and B are H or H.sub.2.
Compounds of Formula 5.2 further include compounds wherein when
R.sup.46 is a group (1) to (11) defined above then R.sup.20 and
R.sup.21 cannot both be H when R.sup.1 and R.sup.2 are both H.
Compounds of Formula 5.2 also include compounds wherein two of
R.sup.20, R.sup.21 and R.sup.46 are not H when R.sup.1 and R.sup.2
are both H.
[0076] This invention further provides novel compounds of Formula
1.0 having the formula: 22
[0077] wherein all the substituents are as defined for Formula 1.0.
Preferably R.sup.25 represents heteroaryl.
[0078] This invention also provides novel compounds of the formula
7.0 having the formula: 23
[0079] wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and R.sup.8 are as defined above for compounds of
the formula 1.0, which compounds are useful in the methods claimed
herein.
[0080] This invention also provides a method for inhibiting tumor
growth by administering an effective amount of the tricyclic
compounds, described herein, to a mammal (e.g., a human) in need of
such treatment. In particular, this invention provides a method for
inhibiting the growth of tumors expressing an activated Ras
oncogene by the administration of an effective amount of the above
described compounds. Examples of tumors which may be inhibited
include, but are not limited to, lung cancer (e.g., lung
adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma
such as, for example, exocrine pancreatic carcinoma), colon cancers
(e.g., colorectal carcinomas, such as, for example, colon
adenocarcinoma and colon adenoma), myeloid leukemias (for example,
acute myelogenous leukemia (AML)), thyroid follicular cancer,
myelodysplastic syndrome (MDS), bladder carcinoma and epidermal
carcinoma.
[0081] It is believed that this invention also provides a method
for inhibiting proliferative diseases, both benign and malignant,
wherein Ras proteins are aberrantly activated as a result of
oncogenic mutation in other genes--i.e., the Ras gene itself is not
activated by mutation to an oncogenic form--with said inhibition
being accomplished by the administration of an effective amount of
the tricyclic compounds described herein, to a mammal (e.g., a
human) in need of such treatment. For example, the benign
proliferative disorder neurofibromatosis, or tumors in which Ras is
activated due to mutation or overexpression of tyrosine kinase
oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited by
the tricyclic compounds described herein.
[0082] The compounds of this invention inhibit farnesyl protein
transferase and the farnesylation of the oncogene protein Ras. This
invention further provides a method of inhibiting ras farnesyl
protein transferase, in mammals, especially humans, by the
administration of an effective amount of the tricyclic compounds
described above. The administration of the compounds of this
invention to patients, to inhibit farnesyl protein transferase, is
useful in the treatment of the cancers described above.
[0083] The tricyclic compounds useful in the methods of this
invention inhibit the abnormal growth of cells. Without wishing to
be bound by theory, it is believed that these compounds may
function through the inhibition of G-protein function, such as ras
p21, by blocking G-protein isoprenylation, thus making them useful
in the treatment of proliferative diseases such as tumor growth and
cancer. Without wishing to be bound by theory, it is believed that
these compounds inhibit ras farnesyl protein transferase, and thus
show antiproliferative activity against ras transformed cells.
[0084] This invention also provides a process for producing 3-nitro
substituted compounds. The process comprises reacting one molar
equivalent of a compound: 24
[0085] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d,
and the dotted lines are as defined for Formula 1.0; and R.sup.65
represents H or --OR.sup.66 wherein R.sup.66 represents alkyl
(e.g., C.sub.1 to C.sub.4 alkyl, preferably ethyl); with one molar
equivalent of a nitrating reagent, said nitrating reagent being
preformed (i.e., prepared first) by mixing, at cold temperature
(e.g., at 0.degree. C.) equimolar amounts of tetrabutyl ammonium
nitrate with TFAA; the reaction of the nitrating reagent with the
compound of Formula 1.0 g taking place in a suitable aprotic
solvent (e.g., CH.sub.2Cl.sub.2, CHCl.sub.3, toluene or THF); said
reaction with said nitrating reagent being conducted at a
temperature and for a period of time sufficient to allow the
reaction to proceed at a reasonable rate to produce the desired
final 3-nitro compound of Formula 1.0h (described below)--i.e., the
reaction of the compound of Formula 1.0g with said nitrating
reagent is conducted at an initial temperature of 0.degree. C., and
said reaction temperature is thereafter allowed to rise to about
25.degree. C. during the reaction time period. The reaction usually
proceeds overnight to completion, i.e., the reaction usually
proceeds for about 16 hours. The reaction can be conducted within a
temperature of 0.degree. C. to about 25.degree. C. during a time
period of about 10 to about 24 hours. Preferably the reaction is
initially conducted at 0.degree. C. and the temperature is allowed
to warm up to 25.degree. C. The reaction produces the 3-nitro
compound (1.0h): 25
[0086] The compound of Formula 1.0h can then be converted to other
3-substituted products by methods well known to those skilled in
the art. For example, the 3-nitro compounds can be converted to
3-amino, 3-halo, 3-cyano, 3-alkyl, 3-aryl, 3-thio, 3-arylalkyl,
3-hydroxyl, and 3--OR.sup.67 wherein R.sup.67 is alkyl or aryl. The
3-substituted compounds can then be converted to final products
(wherein R.sup.65 is R.sup.42 or R.sup.44) by the procedures
described herein.
[0087] This invention also provides a process for producing 3-nitro
compounds of the formula (1.0i): 26
[0088] by producing a compound of Formula 1.0h from 1.0 g as
described above; and then hydrolyzing the compound of Formula 1.0h
by dissolving the compound of Formula 1.0h in a sufficient amount
of concentrated acid (e.g., concentrated HCl or aqueous sulfuric
acid), and heating the resulting mixture to a temperature
sufficient to remove (hydrolyze) the --C(O)R.sup.65 substituent,
for example, heating to reflux or to a temperature of about
100.degree. C. This hydrolysis process is exemplified in
Preparative Example 28.
[0089] The compound of Formula 1.0i can then be converted to other
3-substituted compounds as discussed above for the compounds of
Formula 1.0h. The compounds of Formula 1.0i can then be converted
to compounds of this invention by the methods described herein.
[0090] This invention also provides a process for producing
compounds of the formula (1.0j): 27
[0091] by reacting one molar equivalent a compound of formula
(1.0k): 28
[0092] with one molar equivalent of a nitrating reagent, said
nitrating reagent being preformed (i.e., prepared first) by mixing,
at cold temperature (e.g., at 0.degree. C.) equimolar amounts of
tetrabutyl ammonium nitrate with TFAA; the reaction of the
nitrating reagent with the compound of Formula 1.0k taking place in
a suitable aprotic solvent (e.g., CH.sub.2Cl.sub.2, CHCl.sub.3,
toluene or THF); said reaction with said nitrating reagent being
conducted at a temperature and for a period of time sufficient to
allow the reaction to proceed at a reasonable rate to produce the
desired final 3-nitro compound of Formula 1.0j--i.e., the reaction
of the compound of Formula 1.0k with said nitrating reagent is
conducted at an initial temperature of 0.degree. C., and said
reaction temperature is thereafter allowed to rise to about
25.degree. C. during the reaction time period. The reaction usually
proceeds overnight to completion, i.e., the reaction usually
proceeds for about 16 hours. The reaction can be conducted within a
temperature of 0.degree. C. to about 25.degree. C. during a time
period of about 10 to about 24 hours. Preferably the reaction is
initially conducted at 0.degree. C. and the temperature is allowed
to warm up to 25.degree. C. In Formulas 1.0j and 1.0k, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, A, B, a, b, d, and the dotted lines are
as defined for Formula 1.0
[0093] The compounds of Formula 1.0j can be converted to compounds
of Formula 1.0h by methods described below. Also, as discussed
above for the compounds of Formula 1.0h, the compounds of Formula
1.0j can be converted to other 3-substituted compounds wherein the
substituents are those discussed above for Formula 1.0h.
[0094] The compounds of Formula 1.0j can be converted to compounds
of Formula 1.0m: 29
[0095] wherein R.sup.68 is H or --COOR.sup.a wherein R.sup.a is a
C.sub.1 to C.sub.3 alkyl group (preferably R.sup.68 is H), by
reducing a compound of Formula 1.0j with a suitable reducing agent
(such as sodium borohydride) in a suitable solvent (such as EtOH or
MeOH) at a suitable temperature to allow the reaction to proceed at
a reasonable rate (e.g., 0 to about 25.degree. C.); reacting the
resulting product (Formula 1.0j wherein the .dbd.O has been reduced
to a --OH) with a chlorinating agent (e.g., thionyl chloride) in an
suitable organic solvent (e.g., benzene, toluene or pyridine) at a
suitable temperature to allow the reaction to proceed at a
reasonable rate (e.g., about -20 to about 20.degree. C., preferably
at -15.degree. C., see, for example Preparative Example 7) to
produce a compound of Formula 1.0n: 30
[0096] and reacting a compound of Formula 1.0n with a compound of
the formula: 31
[0097] wherein R.sup.68 is as previously defined, and is preferably
H, in a suitable organic solvent (such as THF or toluene)
containing a suitable base (such as Et.sub.3N or
N-methylmorpholine) at a suitable temperature to allow the reaction
to proceed at a reasonable rate (e.g., 25 to about 120.degree.
C.).
[0098] Compounds of Formula 1.0m can be converted to compounds of
this invention by the methods disclosed herein. Also, as discussed
above for the compounds of Formula 1.0h, the compounds of Formula
1.0m can be converted to other 3-substituted compounds wherein the
substituents are those discussed above for Formula 1.0h.
[0099] This invention also provides novel compounds (produced in
the above described processes as intermediates to the compounds of
this invention) having the formulas: 32
[0100] wherein all substituents are as defined herein.
[0101] Preferably, for the intermediate compounds of the processes
of this invention, R.sup.1 and R.sup.2 are H; R.sup.3 is halo, most
preferably Cl, in the C-8 position; R.sup.4 is H; and A and B are H
when the double between C-5 and C-6 is present, and A and B are
H.sub.2 when the bond between C-5 and C-6 is a single bond (most
preferably the bond between C-5 and C-6 is a single bond). Those
skilled in the art will appreciate that Rings I, II, and/or III can
be further substituted, as described herein, to produce the desired
compounds of the invention.
[0102] Examples of such novel intermediate compounds include:
33
DETAILED DESCRIPTION OF THE INVENTION
[0103] As used herein, the following terms are used as defined
below unless otherwise indicated:
[0104] M.sup.+-represents the molecular ion of the molecule in the
mass spectrum;
[0105] MH.sup.+-represents the molecular ion plus hydrogen of the
molecule in the mass spectrum;
[0106] Bu-represents butyl;
[0107] Et-represents ethyl;
[0108] Me-represents methyl;
[0109] Ph-represents phenyl;
[0110] benzotriazol-1-yloxy represents 34
[0111] 1-methyl-tetrazol-5-ylthio represents 35
[0112] alkyl-(including the alkyl portions of alkoxy, alkylamino
and dialkylamino)-represents straight and branched carbon chains
and contains from one to twenty carbon atoms, preferably one to six
carbon atoms;
[0113] alkanediyl-represents a divalent, straight or branched
hydrocarbon chain having from 1 to 20 carbon atoms, preferably 1 to
6 carbon atoms, the two available bonds being from the same or
different carbon atoms thereof, e.g., methylene, ethylene,
ethylidene, --CH.sub.2CH.sub.2CH.sub.- 2--, --CH.sub.2CHCH.sub.3,
--CHCH.sub.2CH.sub.3, etc.
[0114] cycloalkyl-represents saturated carbocyclic rings branched
or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7
carbon atoms;
[0115] heterocycloalkyl-represents a saturated, branched or
unbranched carbocylic ring containing from 3 to 15 carbon atoms,
preferably from 4 to 6 carbon atoms, which carbocyclic ring is
interrupted by 1 to 3 hetero groups selected from --O--, --S-- or
--NR.sup.10-(suitable heterocycloalkyl groups including 2- or
3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or
4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or
4-dioxanyl, etc.);
[0116] alkenyl-represents straight and branched carbon chains
having at least one carbon to carbon double bond and containing
from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and
most preferably from 3 to 6 carbon atoms;
[0117] alkynyl-represents straight and branched carbon chains
having at least one carbon to carbon triple bond and containing
from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
[0118] aryl (including the aryl portion of aryloxy and
aralkyl)-represents a carbocyclic group containing from 6 to 15
carbon atoms and having at least one aromatic ring (e.g., aryl is a
phenyl ring), with all available substitutable carbon atoms of the
carbocyclic group being intended as possible points of attachment,
said carbocyclic group being optionally substituted (e.g., 1 to 3)
with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy,
CF.sub.3, amino, alkylamino, dialkylamino, --COOR.sup.10 or
--NO.sub.2; and
[0119] halo-represents fluoro, chloro, bromo and iodo; and
[0120] heteroaryl-represents cyclic groups, optionally substituted
with R.sup.3 and R.sup.4, having at least one heteroatom selected
from O, S or N, said heteroatom interrupting a carbocyclic ring
structure and having a sufficient number of delocalized pi
electrons to provide aromatic character, with the aromatic
heterocyclic groups preferably containing from 2 to 14 carbon
atoms, e.g., triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide
(optionally substituted with R.sup.3 and R.sup.4), wherein pyridyl
N-oxide can be represented as: 36
[0121] The following solvents and reagents are referred to herein
by the abbreviations indicated: tetrahydrofuran (THF); ethanol
(EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate
(EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA);
trifluoroacetic anhydride (TFM); 1-hydroxybenzotriazole (HOBT);
m-chloroperbenzoic acid (MCPBA); triethylamine (Et.sub.3N); diethyl
ether (Et.sub.2O); ethyl chloroformate (ClCO.sub.2Et);
1-(3-dimethylaminopropyl)-3-ethyl carbodiimde hydrochloride
(DEC)
[0122] Reference to the position of the substituents R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is based on the numbered ring
structure: 37
[0123] For example, R.sup.1 can be at the C-4 position and R.sup.2
can be at the C-2 or C-3 position. Also, for example, R.sup.3 can
be at the C-8 position and R.sup.4 can be at the C-9 position.
[0124] Representative structures of Formula 1.0 include but are not
limited to: 38
[0125] Preferably, for the compounds of Formula 1.0 (including 1.0a
to 1.0d):
[0126] each of a, b, c, and d are C (carbon); or
[0127] one of a, b, c and d (most preferably a) represents N or NO,
most preferably N, and the remaining a, b, c and d groups represent
CR.sup.1 or CR.sup.2;
[0128] each R.sup.1 and each R.sup.2 is independently selected from
H, halo (e.g., Cl, Br and F), --CF.sub.3, --OR.sup.10 (e.g.,
hydroxy and alkoxy (e.g., --OCH.sub.3)), alkyl (e.g., methyl and
t-butyl, said alkyl group being optionally substituted with halo),
benzotriazol-1 -yloxy, --S(O).sub.tR.sup.11 (e.g.,
--SCH.sub.2CH.sub.3), --SR.sup.11C(O)OR.sup.1- 1 (e.g.,
--SCH.sub.2CO.sub.2CH.sub.3), --SR.sup.10 (e.g., R.sup.10
represents --CH.sub.2C.sub.6H.sub.5) and
1-methyl-tetrazol-5-ylthio; most preferably R.sup.1 and R.sup.2 are
independently H, halo, --CF.sub.3, lower alkyl (e.g., C.sub.1 to
C.sub.4, more preferably methyl) or benzotriazol-1-yloxy; more
preferably R.sup.1 is Cl or H, and R.sup.2 is H, Cl or Br; still
more preferably R.sup.1 is at the C-4 position, and R.sup.2 is at
the C-3 position; even more preferably R.sup.2 is Br, Cl or I;
[0129] R.sup.3 and R.sup.4 are the same or different and each
independently represents H, halo, --CF.sub.3, --OR.sup.10,
--COR.sup.10, --SR.sup.10, --S(O).sub.tR.sup.11 (wherein t is 0, 1
or 2), --N(R.sup.10).sub.2, --NO.sub.2, --OC(O)R.sup.10,
--CO.sub.2R.sup.10, --OCO.sub.2R.sup.11, --C(O)NHR.sup.10, --CN,
--NR.sup.10COOR.sup.11, alkynyl, alkenyl or alkyl, said alkyl or
alkenyl group optionally being substituted with halo, --OR.sup.10
or --CO.sub.2R.sup.10; most preferably R.sup.3 and R.sup.4
independently represent H, halo, --CF.sub.3, --OR.sup.10 or alkyl
(said alkyl group being optionally substituted with halo); more
preferably R.sup.3 and R.sup.4 independently represent H or halo
(e.g., Cl, Br, or F); even more preferably R.sup.3 is at the C-8
position and R.sup.4 is at the C-9 position; still more preferably
R.sup.3 is Cl at the C-8 position and R.sup.4 is H at the C-9
position;
[0130] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently
represents H, --CF.sub.3 or alkyl (said alkyl optionally being
substituted with --OR.sup.10); most preferably R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 independently represent H and alkyl, and more
preferably H;
[0131] when the optional double bond between carbon atoms 5 and 6
is present, A and B independently represent H, --R.sup.10 or
--OR.sup.10, most preferably H, lower alkyl (C.sub.1 to C.sub.4)
and alkyloxy (i.e., R.sup.10 represents alkyl), more preferably H
and --OH, and still more preferably H; and when no double bond is
present between carbon atoms 5 and 6, A and B each independently
represent H.sub.2, --(OR.sup.10).sub.2, alkyl and H, (alkyl).sub.2,
--H and --OR.sup.10 or .dbd.O, most preferably H.sub.2, --H and
--OH, or .dbd.O, and more preferably A represents H.sub.2 and B
represents H.sub.2 or .dbd.O;
[0132] R represents R.sup.42 or R.sup.44; and
[0133] Z represents O or S, and most preferably O.
[0134] Compounds of Formula 5.0 include: 39
[0135] For the compounds of Formulas 5.0, 5.0a-5.0g, 5.1,
5.1a-5.1g, 5.2, 5.2a-5.2b, 5.3, 5.3a-5.3g, 5.3A, 5.3Aa-5.3Ag, and
5.3B, the definitions of the substituents are as defined for
Formula 1.0.
[0136] Preferably, for compounds of Formulas 5.0, 5.0a-5.0g, 5.1,
5.1a-5.1g, 5.2, and 5.2a-5.2b, R.sup.46 is selected from piperidine
Ring V, heteroaryl, phenyl, substituted phenyl, substituted pyridyl
or substituted pyridyl N-oxide, and R.sup.20 and R.sup.21 are
independently selected from H or alkyl. Most preferably, R.sup.46
is pyridyl, pyridyl N-oxide or piperidine Ring V. More preferably,
R.sup.46 is pyridyl, pyridyl N-oxide or piperidine Ring V and both
R.sup.20 and R.sup.21 are hydrogen or both R.sup.20 and R.sup.21
are alkyl (still more preferably methyl).
[0137] Even more preferably, R.sup.46 is selected from 3-pyridyl,
4-pyridyl, 3-pyridyl N-oxide, 4-pyridyl N-oxide,
4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 4-N-acetylpiperidinyl
or 3-N-acetylpiperidinyl, and both R.sup.20 and R.sup.21 are
hydrogen or both R.sup.20 and R.sup.21 are alkyl (still even more
preferably methyl). Even still more preferably, R.sup.46 is
selected from 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, and
4-pyridyl N-oxide, and both R.sup.20 and R.sup.21 are hydrogen or
both R.sup.20 and R.sup.21 are methyl.
[0138] Examples of the R.sup.42 groups include: 40
[0139] Preferably for the compounds of Formulas 5.3, 5.3a-5.3g,
5.3A, 5.3Aa-5.3Ag, and 5.3B, R.sup.25 represents phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, or 2-, 3- or 4-pyridyl N-oxide, and most
preferably 4-pyridyl or 4-pyridyl N-oxide. More preferably,
R.sup.48 represents H or methyl and still more preferably H.
[0140] Compounds of the formula 7.0c include compounds of the
formula: 41
[0141] wherein R.sup.21, R.sup.20, R.sup.46, R.sup.25 and R.sup.48
are as defined above for compounds of the formula 1.0.
[0142] Compounds of the formula 7.0b include compounds of the
formula: 42
[0143] wherein R.sup.21, R.sup.20, R.sup.46, R.sup.25 and R.sup.48
are as defined above for compounds of the formula 1.0.
[0144] Compounds of the formula 7.0a include compounds of the
formula: 43
[0145] wherein R.sup.21, R.sup.20, R.sup.46, R.sup.25 and R.sup.48
are as defined above for compounds of the formula 1.0.
[0146] Preferably for compounds of the formula 7.0e, 7.0g and 7.0j
the group R.sup.46 is selected from piperidine ring V, heteroaryl,
phenyl, substituted phenyl, substituted pyridyl or substituted
pyridyl N-oxide, and R.sup.20 and R.sup.21 are independently
selected from H or alkyl. Most preferably R is pyridyl, pyridyl
N-oxide or piperidine ring V. It is also preferred that R.sup.20
and R.sup.21 are both H or are both alkyl, preferably methyl.
[0147] Preferably for compounds of the formula 7.0f, 7.0h and 7.0k,
the group R.sup.25 is phenyl, 3-pyridyl, 4-pyridyl, 3-pyridyl
N-oxide, 4-pyridyl N-oxide or piperidine ring V. More preferably
R.sup.48 is H or methyl, with H being most preferred.
[0148] Preferably for the compounds of formula 7.0a, 7.0b, 7.0c,
7.0e, 7.0f, 7.0g, 7.0h, 7.0j and 7.0k the groups R.sup.5, R.sup.6,
R.sup.7 and R.sup.8 are H, and R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently selected from H, halo, --NO.sub.2,
--N(R.sup.10).sub.2, alkyl, alkenyl, alkynyl, --COR.sup.10,
--CO.sub.2R.sup.10, --CF.sub.3, --OR.sup.10, and --CN, wherein
R.sup.10 is as defined above for compounds of the formula 1.0.
[0149] Representative compounds of the invention include: 44
[0150] Preferred compounds of this invention are selected from the
group consisting of compounds of Examples: 1, 2, 3, 4, 5, 6, 19,
42, 43, 44, 45, 46, 47, 48, 49, 75, 76, 78, 82, 83, 84, 85, 89,
121, 180, 182, 183, 184, 187 (6.7 and 6.8), 192, 196, 197, 198,
200, 201, 206, 222, 223, 224, 225, 226, 227, 233, 234, 236, 239,
246, 247, 248, 249, 250, 251, 261, 262, 266, 267, 269, 273, 276,
283, 285, 286, 287, 288, 289, 291, 292, 293, 299, 300, 301, 303,
307, 309, 311, 312, 313, 314, 316, 350, 351, 352, 354 and 356.
[0151] More preferred compounds of this invention are selected from
the group consisting of compounds of Examples: 1, 2, 42, 43, 75,
78, 82, 180, 183, 187 (6.7 and 6.8), 196, 197, 198, 200, 222, 223,
224, 227, 233, 234, 246, 247, 248, 249, 250, 251, 266, 269, 273,
283, 285, 286, 291, 292, 300, 301, 303, 307, 311, 312, 313, 314,
350, 351, 352, 354 and 356.
[0152] Even more preferred compounds of this invention are selected
from the group consisting of compounds of Examples: 82, 197, 233,
246, 266, 312, 351, 352, 354 and 356.
[0153] Also more preferred are the compounds of Examples: 426,
400-G, 400-C, 400-F, 400-E, 425-H, 401, 400-B, 400, 400-L, 425-U,
413, 400-J, 417-B, 438, 411-W, 425-O, 400-D, 400-K, 410-G and
400-H.
[0154] Lines drawn into the ring systems indicate that the
indicated bond may be attached to any of the substitutable ring
carbon atoms.
[0155] Certain compounds of the invention may exist in different
isomeric (e.g., enantiomers and diastereoisomers) forms. The
invention contemplates all such isomers both in pure form and in
admixture, including racemic mixtures. Enol forms are also
included.
[0156] Certain tricyclic compounds will be acidic in nature, e.g.
those compounds which possess a carboxyl or phenolic hydroxyl
group. These compounds may form pharmaceutically acceptable salts.
Examples of such salts may include sodium, potassium, calcium,
aluminum, gold and silver salts. Also contemplated are salts formed
with pharmaceutically acceptable amines such as ammonia, alkyl
amines, hydroxyalkylamines, N-methylglucamine and the like.
[0157] Certain basic tricyclic compounds also form pharmaceutically
acceptable salts, e.g., acid addition salts. For example, the
pyridonitrogen atoms may form salts with strong acid, while
compounds having basic substituents such as amino groups also form
salts with weaker acids. Examples of suitable acids for salt
formation are hydrochloric, sulfuric, phosphoric, acetic, citric,
oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,
maleic, methanesulfonic and other mineral and carboxylic acids well
known to those in the art. The salts are prepared by contacting the
free base form with a sufficient amount of the desired acid to
produce a salt in the conventional manner. The free base forms may
be regenerated by treating the salt with a suitable dilute aqueous
base solution such as dilute aqueous NaOH, potassium carbonate,
ammonia and sodium bicarbonate. The free base forms differ from
their respective salt forms somewhat in certain physical
properties, such as solubility in polar solvents, but the acid and
base salts are otherwise equivalent to their respective free base
forms for purposes of the invention.
[0158] All such acid and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0159] Compounds of Formula 1.0 wherein R is --N(R.sup.10).sub.2,
and compounds of Formulas 5.3, 5.3A and 5.3B can be prepared by
reacting compound 405.00 (described below) with an isocyanate
(R.sup.10--N.dbd.C.dbd.O) in a solvent such as DMF,
CH.sub.2Cl.sub.2 or THF in accordance with methods known in the
art.
[0160] The following processes may be employed to produce compounds
of the invention--i.e., compounds of Formula 1.0 represented by
compounds of Formulas 5.0, 5.1, 5.2 and 5.3. For purposes of
describing the processes, the compounds are represented by Formula
400.00: 45
[0161] wherein R represents R.sup.42 or R.sup.44, and all other
substitutents are as described herein.
[0162] A. A compound of Formula 405.00 may be coupled with a
compound of the formula RCOOH in the presence of coupling agent
such as DEC, N,N'-dicyclohexylcarbodiimide (DCC) or
N,N'-carbonyldiimidazole (CDl) to produce compounds of Formula
400.00: 46
[0163] The reaction is usually conducted in an inert solvent such
as THF, DMF or CH.sub.2Cl.sub.2 at a temperature between about
0.degree. C. and reflux, preferably at about room temperature. When
the coupling agent is DCC or DEC, the reaction is preferably run in
the presence of HOBT. Method A is the method of choice for
preparing compounds of this invention.
[0164] B. A compound of Formula 405.00 may also be reacted with a
compound of Formula 410.00 in the presence of base to produce
compounds of Formula 400.00: 1 405.00 + RC ( O ) L ( 410.00 )
400.00 .
[0165] Representative examples of appropriate bases are pyridine
and Et.sub.3N. L designates a suitable leaving group. For example,
a compound of compound 410.00 may be an acyl halide (e.g., L
represents halo) or an acyl anhydride, (e.g., L is --O--C(O)--R).
The leaving group may also be alkoxy, in which case the compounds
of Formula 400.00 may be produced by refluxing a compound of
Formula 405.00 with an excess of a compound of Formula 410.00.
[0166] Compounds of Formula 405.00 may be prepared by cleaving the
group COOR.sup.a from the corresponding carbamates 415.00, for
example, via acid hydrolysis (e.g., HCl) or base hydrolysis (e.g.,
KOH): 47
[0167] wherein R.sup.a is a group which does not prevent the
cleavage reaction, e.g., R.sup.a is an optionally substituted alkyl
such as ethyl.
[0168] Alternatively, depending upon the nature of R.sup.a, as
determined by one skilled in the art, Compound 415.00 may be
treated with an organometallic reagent (e.g., CH.sub.3Li), a
reductive reagent (e.g., Zn in acid), etc., to form compounds of
Formula 405.00.
[0169] Compound 415.00 may be prepared from the N-alkyl compound
shown as Formula 420.00 below, in the manner disclosed in U.S. Pat.
Nos. 4,282,233 and 4,335,036. 48
[0170] It also will be apparent to one skilled in the art that
there are other methods for converting Compound 420.00 to Compound
405.00. For example, treatment of Compound 420.00 with BrCN via von
Braun reaction conditions would provide nitrile 420.00a. Subsequent
hydrolysis of the nitrile under either aqueous basic or acidic
conditions would produce Compound 405.00. This method is preferable
when there is substitution on the piperidine or piperazine ring.
49
[0171] C. The compounds of Formula 400.00 wherein Z is O or S may
be made by an alternative process using direct conversion of the
N-alkyl compound 420.00 with an appropriate compound of Formula
410.00 such as an acyl halide or acyl anhydride. Preferably the
reaction is run in the presence of an appropriate nucleophile (e.g.
LiI, etc.) and solvent (e.g., toluene, dioxane or xylenes). An
appropriate base, may be added, and heating may be required.
Typically, a temperature ranging from 50-150.degree. C. (preferably
100-120.degree. C.) is utilized. 50
[0172] Compound 420.00 is prepared as described in part B
above.
Preparation of Single Bond Compounds
[0173] Compounds of Formula 400.00, wherein X is carbon and the
bond to carbon 11 (C-11) is a single bond, can be prepared by
reducing compounds of Formula 405.00, wherein X is carbon and the
bond to C-11 is a double bond, with lithium aluminum hydride in
THF. Conversion to final products can be done following the process
described above for conversion of compounds of Formula 405.00 to
compounds of Formula 400.00.
Preparation of Double Bond Compounds
[0174] Compounds of Formula 400.00, wherein X is a carbon atom
having an exocyclic double bond to carbon 11, may be prepared from
compound 420.00 as described above. Compounds of Formula 420.00 may
be produced by the methods disclosed generally in U.S. Pat. No.
3,326,924 or alternatively may be prepared by a ring closure
reaction, wherein the desired cycloheptene ring is formed by
treating compound 425.00 with a super acid. Suitable super acids
for this purpose include, for example, HF/BF.sub.3,
CF.sub.3SO.sub.3H (triflic acid), CH.sub.3SO.sub.3H/BF.sub.3- ,
etc. The reaction can be performed in the absence of, or with, an
inert co-solvent such as CH.sub.2Cl.sub.2. The temperature and time
of the reaction vary with the acid employed. For example, with
HF/BF.sub.3 as the super acid system the temperature may be
controlled so as to minimize side reactions, such as HF addition to
the exocyclic double bond. For this purpose, the temperature is
generally in the range of from about +5.degree. C. to -50.degree.
C. With CF.sub.3SO.sub.3H as the super acid system, the reaction
may be run at elevated temperatures, e.g., from about 25.degree. C.
to about 150.degree. C. and at lower temperatures but the reaction
then takes longer to complete.
[0175] Generally the super acid is employed in excess, preferably
in amounts of from about 1.5 to about 30 equivalents. 51
[0176] A ketone compound of Formula 425.00 may be formed by
hydrolysis of 430.00, e.g., such as by reacting a Grignard
intermediate of Formula 430.00 with an aqueous acid (e.g., aqueous
HCl). I.sup.a in Formula 430.00 represents chloro, bromo or iodo.
52
[0177] The Grignard intermediate 430.00 is formed by the reaction
of the cyano compound 435.00 with an appropriate Grignard reagent
440.00 prepared from 1-alkyl-4halopiperidine. The reaction is
generally performed in an inert solvent, such as ether, toluene, or
THF, under general Grignard conditions e.g., temperature of from
about 0.degree. C. to about 75.degree. C. Alternatively, other
organometallic derivatives of the 1alkyl-4-halo piperidine can be
employed. 53
[0178] The cyano compound of Formula 435.00 is produced by
converting the tertiary butyl amide of Formula 445.00 with a
suitable dehydrating agent, such as POCl.sub.3, SOCl.sub.2,
P.sub.2O.sub.5, toluene sulfonyl chloride in pyridine, oxalyl
chloride in pyridine, etc. This reaction can be performed in the
absence of or with a co-solvent, such as xylene.
[0179] The dehydrating agent such as POCl.sub.3 is employed in
equivalent amounts or greater and preferably in amounts of from
about 2 to about 15 equivalents. Any suitable temperature and time
can be employed for performing the reaction, but generally heat is
added to accelerate the reaction. Preferably the reaction is
performed at or near reflux. 54
[0180] The tert-butylamide of Formula 445.00 may be produced by
reaction of a compound of Formula 450.00a and 450.00b, in the
presence of base, wherein G is chloro, bromo or iodo. 55
[0181] The compound of Formula 450.00a may be formed by hydrolysis
of the corresponding nitrile wherein the appropriate cyanomethyl
pyridine, such as 2-cyano-3-methylpyridine, is reacted with a
tertiary butyl compound in acid, such as concentrated sulfuric acid
or concentrated sulfuric acid in glacial acetic acid. Suitable
tertiary butyl compounds include, but are not limited to, t-butyl
alcohol, t-butyl chloride, t-butyl bromide, t-butyl iodide,
isobutylene or any other compound which under hydrolytic conditions
forms t-butyl carboxamides with cyano compounds. The temperature of
the reaction will vary depending upon the reactants, but generally
the reaction is conducted in the range of from about 50.degree. C.
to about 100.degree. C. with t-butyl alcohol. The reaction may be
performed with inert solvents, but is usually run neat.
[0182] An alternative process for the formation of compounds of
Formula 400.00a may involve direct cyclization of Compound 455.00
as shown below. 56
[0183] Cyclization to form the cycloheptene ring may be
accomplished with a strong acid (e.g., triflic, polyphosphoric,
HF/BF.sub.3), and may be performed in an inert solvent, such as
ether, toluene or THF. The temperature and time may vary with the
acid employed, as described in process A above.
[0184] Compounds of Formula 455.00 wherein Z.dbd.O or S may be
prepared by treating a compound of Formula 425.00 with an
appropriate acyl halide or acyl anhydride of formula 410.00. Most
preferably this reaction is run in the presence of a good
nucleophile, such as LiI, in the appropriate solvent, such as
toluene, dioxane or xylene, and at a temperature ranging from
50-150.degree. C., preferably 100-120.degree. C. 57
[0185] A second method of preparing compounds of Formula 455.00
involves reacting an unsubstituted piperidylidene compound of
Formula 460.00 with the appropriate acyl halide or acyl anhydride
of Formula 410.00 in the presence of base, such as pyridine or
Et.sub.3N. Alternatively, if L.dbd.OH in compound 410.00, then
coupling of compound 460.00 with compound 410.00 may require use of
a conventional coupling reagent, such as DCC or CDI. 58
[0186] Compounds of Formula 460.00 may be produced from the
corresponding carbamates of Formula 465.00, via acid hydrolysis,
using for example, aqueous HCl, or base hydrolysis using for
example, KOH. Alternatively, some compounds can be prepared by
treating the carbamate, Formula 465.00, with an organometallic
reagent, such as methyl lithium or a reductive reagent, such as
zinc in acid, etc., depending upon the nature of the R.sup.a group.
For example, if R.sup.a is a simple alkyl group, CO.sub.2R.sup.a
may be cleaved by alkaline hydrolysis at 100.degree. C. 59
[0187] The carbamate compounds of Formula 465.00 may be prepared
from the appropriate alkyl compound of Formula 425.00 by treatment
with a chloroformate, preferably in an inert solvent, such as
toluene, with warming to approximately 80.degree. C. Other
alternative methods are available for the conversion of 425.00 to
455.00 as previously described (e.g. Von Braun reaction
conditions). Compounds of Formula 425.00 may be prepared as
described above.
Substitution on the Pyridine Ring
[0188] Various methods can be used as described in WO 88/03138 to
provide compounds which are substituted on the pyridine ring, i.e.,
in positions 2-, 3- and or 4- positions of the tricyclic ring
system. For example, the cyclization methods described on pages
20-30 of WO 88/03138 can already have the appropriate substituents
on the pyridine ring in place. A variety of substituted pyridines
are known in the literature and can be employed in these syntheses.
Alternatively, the azaketone of Formula XIX (from page 27 of WO
88/03138) 60
[0189] wherein R.sup.1 and R.sup.2 are both H can be converted to
the appropriately substituted azaketone wherein R.sup.1 and R.sup.2
are non-H substitutents. If both R.sup.1 and R.sup.2 are desired to
be non-H substitutents the procedure would be repeated.
[0190] The azaketone is thus reacted with an oxidizing agent such
as meta-chloroperoxybenzoic acid (MCPBA) or hydrogen peroxide to
produce the corresponding compound in which the nitrogen of the
pyridine ring is as an N-oxide: 61
[0191] wherein one of a', b', c' or d' is N.fwdarw.O and the others
are CH or CR.sup.1 or CR.sup.2. This reaction is normally run at
temperatures from -15.degree. C. to reflux, more typically at about
0.degree. C. The reaction is preferably conducted in an inert
solvent such as CH.sub.2Cl.sub.2 for MCPBA or acetic acid for
hydrogen peroxide.
[0192] The azaketone N-oxide of Formula 470.00a can then be reacted
with a chlorinating agent such as SO.sub.2Cl.sub.2 or SOCl.sub.2 to
form a compound of Formula 470.00b. Typically, this reaction
results in monosubstitution of Cl in the ortho or para-position
relative to the N atom of the ring. 62
[0193] To provide the disubstituted products, steps 1 and 2 above
are repeated. 63
[0194] Typically, the resulting disubstituted compounds have Cl
ortho and para relative to the N atom of the pyridine ring.
[0195] The mono or disubstituted compounds of Formulas 470.00b and
470.00c above can be reacted with various nucleophiles such as
alkoxides, amines, thiols, etc. This will result in compounds where
one or both of the Cl substituents are replaced by the nucleophile
to provide a compound of Formula 470.00d or a compound easily
converted to Formula 470.00d. 64
[0196] The substituted ketone of Formula 470.00 can then be
converted to the desired compound by the methods described above
and in WO 88/03138 and in U.S. Pat. No. 3,326,924.
[0197] Formula 405.00, wherein R.sup.1 or R.sup.2 are chlorine, can
be made by the following alternate process. 65
[0198] The N-oxide of Formula 415.00 can be treated with POCl.sub.3
to form a compound of Formula 415.01. Typically, this reaction
results in mono-substitution of Cl in the ortho or para position
relative to the N atom of the ring.
[0199] Alternatively, the Cl substituted azaketones of Formula
470.00b or 470.00c above can be converted t o the corresponding
derivatives of Formula 405.00 above wherein R.sup.1 and/or R.sup.2
is Cl by methods analogous to those described above. At this point
the Cl substituent(s) can be displaced by an appropriate
nucleophile to provide the desired substituent. Suitable
nucleophiles include alkoxide, amines, thiols, etc. This reaction
usually requires higher temperatures (e.g., from about 100.degree.
to about 200.degree. C.) than the displacement reaction to produce
ketone 470.00d above. It is also usually conducted in a sealed
vessel in an inert solvent. The compound of Formula 405.00 is then
converted to a compound of Formula 400.00 as described above.
[0200] Various electrophilic species can also be added to the
pyridine ring from the corresponding halo-substituted pyridine
(Formula 405.00 wherein R.sup.1 is halo, preferably bromo or iodo).
Transmetallation of the halo derivative using an alkyl lithium
(e.g. n-BuLi) provides the lithio derivative, which can then be
quenched with the appropriate electrophile (e.g. R.sup.1L,
etc.).
[0201] An alternative process for introducing substituents at the
C-3 position of pyridine Ring I of Formula 1.0, involves nitrating
a compound of Formula 415.00 (except wherein X is nitrogen) or a
compound of Formula 470.00d with tetrbutylammonium nitrate--TFAA in
CH.sub.2Cl.sub.2 at a temperature of 0.degree. C. to room
temperature (about 25.degree. C.). The nitro group may then be
reduced to the corresponding amine using iron filings in EtOH, or
powdered zinc--acetic acid in aqueous THF, or powdered Zn and
either CuCl.sub.2 or CuBr.sub.2 in aqueous EtOH. By methods know to
those skilled in the art, the amine group can be converted to a
variety of substituents, such as, halo, cyano, thio, hydroxyl,
alkyl, alkenyl, alkynyl and haloalkyl.
[0202] Wherein Z represents sulfur, a compound of Formula 400.00
wherein Z is oxygen is reacted with P.sub.2S.sub.5, Lawesson's
reagent, or another reagent capable of introducing sulfur in place
of oxygen. The reaction may take place at elevated temperature in
pyridine, toluene or other suitable solvents. In this and other
reactions, numerous conversions of a compound of Formula 400.00
(Z=0) to another compound of Formula 400.00 (Z.dbd.S) are
possible.
Preparation of C5-C6-Ene Derivatives
[0203] Compounds of formula 400.00 with a double bond between C-5
and C-6 can be prepared by heating a compound of Formula 470.00h in
acetic acid with SeO.sub.2 to produce a compound of Formula
470.00i. Compounds of Formula 470.00i can be converted to final
products according to methods already described. 66
Preparation of Piperazine Analogs
[0204] Compounds having a piperazine ring bound to the C-11 of the
tricyclic nucleus, i.e., Formula 1.0 wherein X is N, are best
prepared via alkylation of the appropriately substituted piperazine
compound of Formula 700.00 with a compound of Formula 705.00.
Compounds of Formula 705.00 contain the appropriately substituted
halide (such as Cl, Br, or I) or other similar leaving group (e.g.,
tosyloxy or mesyloxy). The reaction is usually conducted in an
inert solvent, such as THF or toluene, optionally with a base such
as Et.sub.3N or potassium carbonate, and typically at a temperature
range of ambient to reflux to produce a compound of Formula 710.00.
67
[0205] In this reaction R.sup.g is H, CO.sub.2R.sup.a (wherein
R.sup.a is a C.sub.1 to C.sub.4 alkyl group) or C(Z)R. The
preparation of compound 705.00 wherein L is Cl is analogous to the
procedure described in U.S. Pat. No. 3,409,621. One skilled in the
art can prepare other derivatives of 705.00 (e.g., L is Br, I,
mesyloxy, or tosyloxy). When R.sup.g is H, C(Z)R or
CO.sub.2R.sup.a, these are converted to compounds of the invention
by processes known in the art.
[0206] An alternate route for generating the compound of Formula
710.00 is by reductive amination of the aza ketone 715.00 with the
piperazine 700.00 68
[0207] The reaction is typically carried out in a polar solvent,
such as MeOH or EtOH, optionally in the presence of a dehydrating
agent, such as 3 .ANG. molecular sieves. The intermediate Schiff
base can be reduced to the compound of Formula 710.00 by employing
a variety of reducing agents, such as NaCNBH.sub.3, or catalytic
hydrogenation, for example, hydrogen over Pd/C.
[0208] When R.sup.g is C(Z)R, these are the compounds of the
invention. When R.sup.g is H or CO.sub.2R.sup.a, these are
converted to compounds of the invention as described herein.
[0209] Compounds of Formulas 5.3A and 5.3B, wherein R.sup.25
represents a pyridyl N-oxide, can be produced by reacting compounds
of Formulas 5.3A and 5.3B, wherein R.sup.25 is pyridyl, with a one
molar equivalent of an oxidizing agent (such as oxone).
[0210] Compounds of Formulas 5.3, 5.3A and 5.3B, wherein R.sup.25
represents a pyridyl N-oxide, can be produced by reacting the
product of Preparative Example 12 with a peroxyacid (such as MCPBA)
to give the corresponding N-oxide intermediate. The desired N-oxide
product may be obtained from the N-oxide intermediate by following
the procedure of Example 183.
[0211] Compounds of the formula 7.0a, 7.0b and 7.0c can be prepared
from amines of the formula 7.1a, 7.1b and 7.1c, respectively, by
coupling a compound of the formula 7.0a, 7.0b or 7.0c with a
carboxylic acid of the formula RCOOH via the method described above
for reacting compounds of the formula 405.00. 69
[0212] Alternatively, a compound of the formula 7.0a, 7.0b or 7.0c
is treated with a compound of the formula RC(O)L, where L is a
suitable leaving group, via the procedure described above for
compounds of the formula 405.00.
[0213] Compounds of the formula 7.1a can be prepared from a
compound of the formula 420.50, (i.e., a compound of the formula
420.00 wherein A and B are both H, no double bond is present
between carbons 5 and 6, or between carbon 11 and X, X is CH, and
the N-alkyl group is a methyl group) as shown in Reaction Scheme 1.
70
[0214] In Step A of Reaction Scheme 1, a compound of the formula
420.50 is reacted with a strong base, such as an lithium
diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium),
at -100.degree. to -10.degree. C., preferably at -80.degree. to
-20.degree. C., then treated with methyl iodide to form a compound
of formula 7.2a.
[0215] In Step B of Reaction Scheme 1, a compound of the formula
7.2a is converted to a compound of the formula 7.3a via
substantially the same procedure as described above for formation
of compounds of the formula 415.00.
[0216] In Step C of Reaction Scheme 1, a compound of the formula
7.3a is hydrolyzed via essentially the same procedure as described
above for formation of compounds of formula 405.00, to form a
compound of the formula 7.1a.
[0217] Compounds of the formula 7.1b can be prepared from a
compound of the 420.51 (i.e., a compound of the formula 420.00
wherein A and B are both H, no double bond is present between
carbons 5 and 6, a double bond is present between carbon 11 and X,
X is C, and the N-alkyl group is a methyl group) via the process
shown in Reaction Scheme 2. 71
[0218] In Step A of Reaction Scheme 2, a compound of the formula
420.51 is reacted with a strong base, such as an lithium
diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium),
at -100.degree. to -10.degree. C., preferably at -80.degree. to
-20.degree. C., then treated with a protic solvent, such as an
alcohol, preferably MeOH, to form a compound of formula 7.2b.
[0219] In Step B of Reaction Scheme 2, a compound of the formula
7.2b is converted to a compound of the formula 7.3b via
substantially the same procedure as described above for formation
of compounds of the formula 415.00.
[0220] In Step C of Reaction Scheme 2, a compound of the formula
7.3b is hydrolyzed via essentially the same procedure as described
above for formation of compounds of formula 405.00, to form a
compound of the formula 7.1b.
[0221] Compounds of the formula 7.1c can be prepared from a
compound of the 420.51 via the process shown in Reaction Scheme 3.
72
[0222] In Step A of Reaction Scheme 3, a compound of the formula
420.51 is reacted with a strong base, such as an lithium
diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium),
at -100.degree. to -10.degree. C., preferably at -80.degree. to
-20.degree. C., then treated with methyl iodide to form a compound
of formula 7.2c.
[0223] In Step B of Reaction Scheme 3, a compound of the formula
7.2c is converted to a compound of the formula 7.3c via
substantially the same procedure as described above for formation
of compounds of the formula 415.00.
[0224] In Step C of Reaction Scheme 1, a compound of the formula
7.3c is hydrolyzed via essentially the same procedure as described
above for formation of compounds of formula 405.00, to form a
compound of the formula 7.1c.
[0225] In the above processes, it is sometimes desirable and/or
necessary to protect certain R.sup.1, R.sup.2, R.sup.3 and R.sup.4
etc., groups during the reactions. Conventional protecting groups
are operable as described in Greene, T. W., "Protective Groups In
Organic Synthesis," John Wiley & Sons, New York, 1981. For
example, the groups listed in column 1 of Table 1 may be protected
as indicated in column 2 of the table:
1TABLE 1 PROTECTED GROUPS 1. GROUP TO BE PROTECTED 2. PROTECTED
GROUP --COOH --COOalkyl, --COObenzyl, --COOphenyl, 73 74 75 76 77
78 79 80 --OH 81 --OCH.sub.2phenyl, --OCH.sub.3,
OSi(CH.sub.3).sub.2(t-Bu), --NHR, wherein R is any substituent on
an amino group within the scope of the claims 82
--NR--CO--CF.sub.3, --NRCOCH.sub.3, 83 --NH.sub.2 84
--NH--C(O)--O(t-Bu)
[0226] Other protecting groups well known in the art also may be
used. After the reaction or reactions, the protecting groups may be
removed by standard procedures.
[0227] Compounds useful in this invention are exemplified by the
following preparative examples, which should not be construed to
limit the scope of the disclosure. Alternative mechanistic pathways
and analogous structures within the scope of the invention may be
apparent to those skilled in the art.
PREPARATIVE EXAMPLE 1
[0228] A. N-(1.1-Dimethylethyl)-3-Methyl-2-Pyridine Carboxamide
85
[0229] Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800
mL) and heat to 70.degree. C. Add concentrated sulphuric acid (400
mL) dropwise over 45 minutes. Maintain the temperature at
75.degree. C., until the reaction is complete, and for an
additional 30 minutes. Dilute the mixture with water (400 mL),
charge with toluene (600 mL) and bring to pH 10 with concentrated
aqueous ammonia. Maintain the temperature at 50-55.degree. C.
during the work up. Separate the toluene phase, and reextract the
aqueous layer. Combine toluene phases and wash with water. Remove
the toluene to yield the title compound N-(1,1
-dimethylethyl)-3-methyl-2-pyridine carboxamide, as an oil, from
which solid product is crystallized. (Yield 97%, as determined by
an internal standard assay with gas chromatography).
[0230] B.
3-[2-(3-Chlorophenyl)Ethyl]-N-(1,1-Dimethyl-Ethyl)2-Pyridine
Carboxamide 86
[0231] Dissolve the title compound of Preparative Example 1 A,
N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (31.5 g.) in
THF (600 mL) and cool the resulting solution to -40.degree. C. Add
n-butyllithium (2 eq.) in hexane while maintaining the temperature
at -40.degree. C. The solution turns deep purple-red. Add sodium
bromide (1.6 g) and stir the mixture. Add solution of
m-chlorobenzylchloride (26.5 g., 0.174 mole) in THF (125 mL) while
maintaining the temperature at -40.degree. C. Stir the reaction
mixture until the reaction is complete as determined by thin layer
chromatography. Add water to the reaction until the color is
dissipated. Extract the reaction mixture with EtOAc, wash with
water, and concentrate to a residue which is the title compound.
(Yield 92% as shown by chromatography).
[0232] C. 3-[2-(3-Chlorophenyl)Ethyl]-2-Pyridine-Carbonitrile
87
[0233] Heat a solution of the title compound of Preparative Example
1B, 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine
carboxamide (175 g, 0.554 mole) in phosphorous oxychloride (525 mL,
863 g, 5.63 mole) and reflux for 3 hours. Determine completion of
the reaction by thin layer chromatography. Remove any excess
phosphorous oxychloride by distillation at reduced pressure and
quench the reaction in a mixture of water and isopropanol. Bring to
pH 5-7 by adding 50% aqueous NaOH solution while maintaining the
temperature below 30.degree. C. Filter the crystalline slurry of
crude product and wash with water. Purify the crude product by
slurrying the wet cake in hot isopropanol, and cool to 0-5.degree.
C. Filter the product, wash with hexane and dry at a temperature
below 50.degree. C. to yield the title compound. (Yield: 118 g
(HPLC purity 95.7%), m.p. 72.degree. C.-73.degree. C., 89.4% of
theory).
[0234] D.
1-(Methyl-4-Piperidinyl)[3-(2-(3-Chlorophenyl)Ethyl)2-Pyridinyl]-
Methanone Hydrochloride 88
[0235] Dissolve the title compound of Preparative Example 1C, (118
g, 0.487 mole) in dry THF (1.2L) and add N-methyl-piperidyl
magnesium chloride (395 mL, 2.48 mole/liter, 0.585 mole, 1.2 eq.)
over 15 minutes. Maintain the temperature at 40.degree.
C.-50.degree. C. by cooling with water as necessary, for 30
minutes. Determine completion of the reaction by thin layer
chromatography. Quench the reaction by reducing the pH to below 2
with 2N HCl and stir the resulting solution at 25.degree. C. for 1
hour. Remove the bulk of the THF by distillation and adjust the
resulting solution to pH 3.5 by addition of aqueous NaOH. Cool to 0
to 5.degree. C. and filter off the crystalline hydrochloride salt
product. Wash with ice cold water and dry to constant weight at
60.degree. C. to yield the title compound. (Yield: 168.2 g (HPLC
purity 94%), m.p. 183.degree.-185.degree. C., 89% of theory).
[0236] E.
8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-BENZO[5,-
6]Cyclohepta[1,2-b]Pyridine 89
[0237] Dissolve the title compound of Preparative Example 1D above
(59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at
-35.degree. C. and add boron trifluoride (44.3 g, 0.66 mole) over 1
hour. Determine completeness of the reaction by thin layer
chromatography. Quench the reaction using ice, water and KOH
bringing the solution to a final pH of 10. Extract the product with
toluene and wash with water and brine. Concentrate the toluene
solution to a residue, and dissolve in hot hexane. Remove the
insolubles by filtration and concentrate the filtrate to yield the
title compound as an off-white powder. (Yield: 45.7 g (HPLC purity:
95%), 92% of theory).
[0238] Alternative Step E:
8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Di-
hydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine
[0239] React the title compound of Preparative Example 1D above
(177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1
g, 5.31 mole) at 90-95.degree. C. for 18 hours under nitrogen.
Determine the completeness of the reaction by thin layer
chromatography. Cool the reaction and quench the reaction with
ice-water and adjust the pH to 6 with barium carbonate. Extract the
product with CH.sub.2Cl.sub.2, and concentrate under reduced
pressure to about 1 liter. Wash with water, and extract the product
into 1 N HCl which is treated with 30 g of activated charcoal, and
filter through celite. Adjust the pH of the filtrate to 10 with
aqueous NaOH (50%), extract the product into CH.sub.2Cl.sub.2, and
remove under reduced pressure to form a residue. Dissolve the
residue in hot hexane, and filter to remove insolubles. Concentrate
the filtrate to yield the title compound as a beige powder. (Yield:
126 g (HPLC purity 80%), 65% of theory).
[0240] F.
8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)-6,11-Dihydro-5H--
Benzo[5,6]Cyclohepta[1,2-b]Pyridine 90
[0241] Dissolve the title compound of Preparative Example 1E above
(45.6 g, 0.141 mole) in toluene (320 mL) at 80.degree. C. and to it
gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole).
Following complete addition, maintain the temperature at 80.degree.
C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g,
0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g,
0.0429 mole). Monitor completeness of the reaction by thin layer
chromatography. Upon completion, cool the reaction mixture to
ambient temperature, and wash the toluene solution with water.
Concentrate the organic layer to a residue and dissolve in hot
acetonitrile (320 mL). Decolorize the solution with 14 g of
activated charcoal. Remove the activated charcoal by filtration and
concentrate the filtrate to a crystalline slurry. Cool the mixture
to 0-5.degree. C., and isolate the product by filtration. Wash with
cold acetonitrile and dry the product at below 70.degree. C. to
yield the title compound. (Yield: 42.4 g (HPLC purity 97.4%), 80%
of theory).
[0242] G.
8-Chloro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5.6]Cyclohe-
pta[1,2-b]Pyridine 91
[0243] Hydrolize the title compound of Preparative Example 1F,
8chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]-
cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in
EtOH (305 mL) and water (270 mL) at reflux under an argon
atmosphere for 64 hours. Partially distill off the EtOH and dilute
the residue with brine, and extract with EtOAc (3.times.). Wash the
combined organic phases with water and dry with Na.sub.2SO.sub.4.
Remove the solvent to give a solid which can be recrystallized from
toluene to give the title compound as a white solid. (Yield: 24.5
g, 77%, melting point 154-155.degree. C.).
[0244] H. By substituting in step 1B above, the benzylic halide:
92
[0245] for meta-chlorobenzylchloride, and employing basically the
same methods as steps C through G, the compound 93
[0246] is prepared. Dichloro compound (I) is recrystallized from
toluene and has a melting point of 150-152.degree. C. Reaction
times are determined by TLC or HPLC. In some instances purification
of the product by chromatography is necessary.
PREPARATIVE EXAMPLE 2
[0247] A.
N-(1,1-Dimethylethyl)-3-[2-(4-Fluorophenyl)-Ethyl]-2-Pyridine
Carboxamide 94
[0248] Cool a solution of
N-(1,1-dimethylethyl)-3-methyl-2-pyridine-carbox- amide (38.4 g,
0.2 mole) in dry THF (250 mL) to -40.degree. C. and add n-butyl
lithium (185 mL, 0.44 mole). Add sodium bromide (1.9 g, 18 mmol.)
and stir for 15 minutes. Add 4-fluorobenzylchloride (31.8 g, 0.22
mole) and stir for 2.5 hours while warming to -5.degree. C. Quench
the reaction with water and extract the product twice with EtOAc,
then wash with brine (2.times.). Dry the organic phase over
Na.sub.2SO.sub.4, filter and remove the solvent to give the title
compound. (60.0 g, Yield 99%, m.p. 59-61.degree. C.)
[0249] B. 3-[2-(4-Fluorophenyl)Ethyl]-2-Pyridine Carbonitrile
95
[0250] Heat the title compound of Preparative Example 2A above
(60.0 g, 0.2 mole) in POCl.sub.3 (200 mL) to 110.degree. C. under
an argon atmosphere for 3.5 hours. Pour the reaction mixture onto
ice and basify with NaOH (50%) solution. Extract the mixture with
EtOAc (3.times.) and wash with water. Wash with brine and dry over
Na.sub.2SO.sub.4. Remove the solvent and pass the residue through a
coarse SiO.sub.2 (60-200 mesh) column to give the title compound as
a white solid (40 g, Yield 88%, m.p. 48-49.degree. C.).
[0251] C.
9-Fluoro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-11--
One 96
[0252] Cyclize the title compound of Preparative Example 2B above
(31.5 g, 139 mmol) in polyphosphoric acid (1.24 kg) at 200.degree.
C. for 5.5 hours. Pour onto ice and basify with NaOH solution
(50%). Extract the product with chloroform (3.times.) and wash with
brine. Dry the organic phase with Na.sub.2SO.sub.4, filter and
remove the solvent to give the title compound (20.4 g, yield 64%,
m.p. 78-81.degree. C. after recrystallization from diisopropyl
ether).
[0253] D.
9-Fluoro-11-(1-Methyl-4-Piperidinyl)-6,11-Dihydro-5H-Benzo[5,6]C-
yclophepta[1,2-b]Pyridin-11-Ol 97
[0254] Dissolve the title compound of Preparative Example 2C above
(10.0 g, 44 mmol) in THF (100 mL) and add slowly to a cooled
(-40.degree. C.) solution of the Grignard reagent prepared from
N-methyl-4-chloro-piperidi- ne (57.9 mL, 88 mmol) and magnesium in
THF (70 mL). Stir the mixture for about 1 hour while warming up to
0.degree. C. Quench the reaction with NH.sub.4Cl solution and
extract with EtOAc (2.times.). Wash the organic phase with brine
and dry over Na.sub.2SO.sub.4, filter and remove the solvent.
Purify the residue with flash chromatography and elute with MeOH
(5%) in CHCl.sub.3 to give the title compound as white granular
crystals. (10.1 g, Yield 70%, m.p. 126-127.degree. C. after
recrystallization from diisopropyl ether.)
[0255] E.
9-Fluoro-11-(1-Methyl-4-Piperidylene)-6,11-Dihydro-5H-Benzo[5,6]-
Cyclohepta[1,2-b]Pyridine 98
[0256] Add the title compound of Preparative Example 2D above (7.3
g, 22.3 mmol) to a mixture of cooled H.sub.2SO.sub.4 and
CF.sub.3SO.sub.3H (1:1), (146 mL). Stir the reaction mixture for
0.5 hours at ice bath temperature and then at room temperature for
1.5 hours. Pour the reaction mixture onto ice and basify with NaOH
(50%) solution. Extract the product with EtOAc (3.times.) and wash
with brine. Dry the organic phase over Na.sub.2SO.sub.4, filter and
remove the solvent to give a crude oil. Charcoal the oil and
recrystallize from EtOAc and isopropyl ether to give the title
compound. (5.6 g, Yield 82%, m.p. 134.5-135.5.degree. C.).
[0257] F.
9-Fluoro-11-(1-Ethoxycarbonyl-4-Piperidylidene)-6,11-Dihydro-5H--
Benzo[5,6]cyclohepta[1,2-b]Pyridine 99
[0258] Stir a solution of the title compound of Preparative Example
2E above (5.0 g, 16.2 mmol) and Et.sub.3N (2.6 g, 26 mmol) in dry
toluene (60 mL) at 80.degree. C. under an argon atmosphere, and add
ethyl chloroformate (9.8 g, 90 mmol) via a syringe. Stir the
reaction at this temperature for 30 minutes and at room temperature
for one hour. Filter the reaction and remove the solvent. Pass the
residue through a coarse SiO.sub.2 column (60-200 mesh), and elute
with CHCl.sub.3 to yield the title compound as a white solid. (4.5
g, Yield 76%, m.p. 112-114.degree. C. after trituration with
pentane).
[0259] G.
9-Fluoro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohe-
pta[1,2-b]Pyridine 100
[0260] Reflux the title compound of Preparative Example 2F above
(3.83 g, 10.4 mmol) with KOH (4.6 9) in 50 mL of EtOH/H.sub.2O
(1:1) for 4 hours under an argon atmosphere. Pour the reaction
mixture into a brine solution and extract with EtOAc (2.times.),
dry over Na.sub.2SO.sub.4 and filter. Remove the solvent to give
the title compound (2.86 g, Yield 90%, m.p. 138-140.degree.
C.).
[0261] H. By employing the benzyl halide 101
[0262] in place of 4-fluorobenzyl chloride in step 2A above, the
product 102
[0263] is prepared (m.p. 138-140.degree. C., triturated with
pentane) by employing basically the same process as described in
steps 2A-2G. Workup time is determined by either TLC or HPLC. In
some instances purification of the product by chromatography is
necessary.
PREPARATIVE EXAMPLE 3
[0264] A 3.5-Dimethylpyridinium N-Oxide 103
[0265] A solution of 285 mL (1.31 mol) of 35% peracetic acid was
slowly added to a stirred solution of 149 g (1.39 mol) of
3,5-dimethylpyridine during which the temperature rose to
85.degree. C. and was maintained at this temperature during
addition. After the temperature of the mixture dropped to about
35.degree. C. the reaction was stored at 5.degree. C.
overnight.
[0266] After partial removal of 185 ml of acetic acid via
distillation under vacuum, the reaction was washed with NaHSO.sub.4
solution and then neutralized with 10% NaOH solution to pH of about
7. The product was extracted with CH.sub.2Cl.sub.2 to give the
title compound as a white solid (yield 142 g, 83%).
[0267] B. 1-Methoxy-3,5-Dimethylpyridinium Methyl Sulfate 104
[0268] Dimethylsulfate (42.0 g, 0.33 mol) was slowly added to 41.0
g (0.33 mol) of 3,5-dimethylpyridinium N-oxide with mechanical
stirring. The mixture was then heated on a steam bath for 1 hr.
Then vacuum was applied while cooling to give a brownish solid of
the title compound in quantitative yield.
[0269] C. 2-Cyano-3,5-Dimethylpyridine 105
[0270] To a cooled (0.degree. C.) solution of sodium cyanide (49.0
g, 0.999 mol, 3.0 eq.) in 135 mL of water (air free) was dripped
1-methoxy-3,5-dimethyl pyridinium methyl sulfate (83.0 g, 0.33 mol)
in 100 mL water (air free) in 1.25 hr., keeping the temperature
below 3.degree. C. The reaction mixture was stored at about
3.degree. C. overnight. The mixture was filtered and washed with
water to give 40 g of the title compound. An analytical sample was
recrystallized from isopropyl ether and pentane (4:1) (m.p.:
61-62.degree. C.).
[0271] D. N-(1,1-Dimethylethyl)-3,5-Dimethyl-2-Pyridine Carboxamide
106
[0272] To a stirred solution of 20.3 g (0.153 mol) of
2-cyano-3,5-dimethylpyridine in 100 mL of 20 mL of conc. sulfuric
acid within 10 minutes, followed by 20 mL of t-butanol over an
additional 15 minutes. The solution was warmed at 75.degree. C. for
30 minutes after which it was cooled to room temperature and
basified with 25% NaOH. The product was extracted 3.times. with
EtOAc (600 mL), which was combined and washed 1.times. with brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
give the title compound (31.26 g) as a yellowish oil.
[0273] E.
8-Chloro-3-Methyl-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,-
6]Cyclohepta[1,2-b]Pyridine 107
[0274] By substituting in step 1B above
N-(1,1-dimethylethyl)-3,5-dimethyl- -2-pyridine carboxamide for
N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide and employing
basically the same methods as steps B through G of Preparative
Example 1, one obtains 8-chloro-3-methyl-11-(4-piperidylid-
ene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. Reaction
times are determined by TLC or HPLC.
PREPARATIVE EXAMPLE 4
[0275] By substituting 108
[0276] for 3,5-dimethylpyridine in Preparative Example 3 above and
following basically the same procedure (steps A-E), the compounds
109
[0277] respectively, can be prepared. Note that the addition of the
nitrile group to the pyridine in Step C of Preparative Example 3
can result in the formation of other undesirable isomers which can
be removed via flash chromatography.
PREPARATIVE EXAMPLE 5
[0278] A
8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-11-O-
ne N-Oxide 110
[0279] To a mixture of 25.1 grams (0.103 mole) of
8-chloro-5,6-dihydro-11H-
-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 175 ml of dry
CH.sub.2Cl.sub.2 at 0.degree. C. under an argon atmosphere was
added dropwise over 70 minutes a solution of 24.12 grams of
3-chloroperoxy-benzoic acid in 150 ml of CH.sub.2Cl.sub.2. After
the addition the solution was stirred for 1/2 hour after which the
ice bath was removed. After two days the reaction was poured into
1.0 N aqueous NaOH and extracted with CH.sub.2Cl.sub.2. The organic
portions were combined, washed once with water, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The resultant
product was triturated with isopropyl ether and filtered to provide
25.8 grams (96%) yield of the title compound.
[0280] B.
2,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyridin-
-11-One and
4,8-Dichloro-5.6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridi-
n-11-One 111
[0281] To a mixture of 29.13 grams (112.2 mmol) of the title
compound from Preparative Example 5A above, in 40 ml of dry
CH.sub.2Cl.sub.2 at 0.degree. C. and under argon atmosphere was
added 500 ml of 1.0 M SO.sub.2Cl.sub.2 dropwise over 1 hour. The
ice bath was then removed and the reaction stirred at room
temperature for 1 hr and then refluxed for seven hours. The mixture
was poured into 1.0 N aqueous NaOH and extracted three times with
CH.sub.2Cl.sub.2. The organic portions were combined, dried over
MgSO.sub.4, filtered and concentrated in vacuo to yield a product
which was purified and separated via flash chromatography to yield
the two title compounds.
[0282] C.
4-(2,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyri-
din-11-Ylidene)Piperidine and
4-(4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cy-
clohepta-[1,2]-Pyridin-11-Ylidene)Piperidine 112
[0283] By following essentially the same procedure as that
described in parts D-G of Preparative Example 2 above, the
2,8-dichloro and 4,8-dichloro products of Preparative Example 5B
above were converted to the corresponding title compounds.
PREPARATIVE EXAMPLE 6
[0284] A.
3-(1,1-Dimethyl-1-Ethyl)-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cycl-
ohepta[1,2-b]Pyridin-11-One 113
[0285] To a mixture of 20.05 grams (82.28 mmol) of
8-chloro-5,6-dihydro-11-
H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at
-72.degree. C. and under an atmosphere of nitrogen was added
dropwise over 40 minutes 66.0 ml of 2.7 M t-butyl magnesium
chloride in THF. The reaction mixture was slowly warmed to room
temperature and stirred overnight. The mixture was then poured into
10% aqueous ammonium chloride and extracted four times with
CH.sub.2Cl.sub.2. The combined organic portions were dried over
MgSO.sub.4, filtered, and concentrated in vacuo to give the title
compound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-
-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These
compounds were separated via flash chromatography to give the title
compound, which was recrystallized from isopropyl ether to give
4.37 grams (18%) of the title compound as a white solid.
[0286] B.
4-[3-(1,1-Dimethyl-1-Ethyl)-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]C-
yclohepta[1,2-b]Pyridin-11-Ylidene]Piperidine 114
[0287] By using the title compound of Part A above and applying
essentially the same procedure described in parts D-G of
Preparative Example 2 above, one can obtain the title compound.
PREPARATIVE EXAMPLE 7
[0288] A.
8-Chloro-6,11-Dihydro-11-Hydroxy-5H-Benzo[5,6]-Cyclohepta[1,2-b]-
Pyridine 115
[0289] To a mixture of 25.03 g (103 mmol) of
8-chloro-5,6-dihydro-11H-benz-
o[5,6]cyclohepta[1,2-b]pyridin-11-one in 200 mL of MeOH at room
temperature and under a nitrogen atmosphere was added portionwise
over a period of about 1 hour 4.82 g (124 mmol) of sodium
borohydride. Occasional cooling with an ice bath was necessary at
times during the addition in order to avoid excessive reflux. After
1.6 hours the mixture was poured into ice cold water and then
extracted with EtOAc (3.times.). The combined organic portions were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was recrystallized from hot
isopropyl ether. The remaining filtrate was purified via flash
chromatography (20% EtOAc in hexanes) to yield more product which
solidified on standing. Both batches were combined to yield 20.41 g
of the title compound as a white solid.
[0290] B. 8,11
-Dichloro-6,11-Dihydro-5H-BENZO[5,6]Cyclohepta[1,2-b]Pyridi- ne
116
[0291] To a mixture of 13.3 g (54 mmol) of
8-chloro-6,11-dihydro-11-hydrox-
y-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 290 mL of toluene at
-15.degree. C. and under an atmosphere of nitrogen was added via
syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) of thionyl
chloride. The extent of reaction was monitored by TLC (50% EtOAc in
hexanes). When completed the mixture was poured into 300 mL of 1.0
N aqueous NaOH and extracted with EtOAc (5.times.). The combined
organic portions were washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was taken up in
EtOAc, quickly filtered through basic alumina, and concentrated
again to yield a product which was triturated with pentane to yield
10.22 g of the title compound as a tan solid.
[0292] C.
8-Chloro-11-(1-Piperazinyl)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta-
[1,2-b]Pyridine 117
[0293] To a mixture of 10.0 g (37.9 mmol) of
8,11-dichloro-6,11-dihydro-5H- -benzo[5,6]cyclohepta[1,2-b]pyridine
and 1.0 mL of Et.sub.3N in 200 mL of dry THF at room temperature
and under a nitrogen atmosphere was added 33.0 g of piperazine. The
mixture was stirred at room temperature for 22.5 hours and then
refluxed for 5.5 hours. It was then cooled to room temperature,
poured into 250 mL of 5% aqueous NaOH, and extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic portions were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was purified via flash
chromatography (2.fwdarw.5% MeOH saturated with ammonia in
CH.sub.2Cl.sub.2) to yield the title compound as a glass.
PREPARATIVE EXAMPLE 8
[0294] A. Ethyl 3-Pyridylacetic Acid 1-N-Oxide 118
[0295] Ethyl 3-pyridylacetic acid (10 grams) (60.6 mmoles) was
dissolved in dry CH.sub.2Cl.sub.2 (120ml) and the solution was
stirred at -18.degree. C. for 30 minutes. MCPBA (31.34 grams)
(181.6 mmoles) was added and the mixture was stirred at -18.degree.
C. for 1 hour and then at 25.degree. C. for 87 hours. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and washed with saturated
aqueous sodium bicarbonate and then water. The CH.sub.2Cl.sub.2 was
then dried (magnesium sulphate), filtered and evaporated to
dryness. The residue was chromatographed on silica gel using 3%
(10% concentrated ammonium hydroxide in MeOH)--CH.sub.2Cl.sub.2 as
the eluant to give the title compound (Yield: 8.45 grams, 77%,
MH.sup.+182).
[0296] B. 3-Pyridylacetic Acid 1-N-Oxide 119
[0297] 3-Pyridylacetic acid (0.2747 grams) (1.5 mmoles) was
dissolved in EtOH (200 proof) (1.22 ml.) and a 1M solution of LiOH
in water (3.64 ml.) (3.0 mmoles) was added and the mixture was
stirred at 25.degree. C. for 4 hours. 1N HCl (4.28 ml.) was added
and the mixture was pumped down to dryness on a rotary evaporator
to give the title compound (Yield: 0.2931 grams, 100%).
PREPARATIVE EXAMPLE 9
[0298] A. Ethyl .alpha.-Methyl-3-Pyridylacetic Acid. 120
[0299] To ethyl 3-pyridylacetic acid (10.86 grams) (65.7 mmoles)
was added a 2.0M solution of lithium diisopropylamide in
THF/heptane/ethyl benzene (32.87 ml.) (65.8 mmoles) at -30.degree.
C. The semi-solid mixture was agitated and sonicated for 1 hour.
The mixture was allowed to remain at 25.degree. C. for 1 hour,
whereupon methyl iodide (4.09 ml.) (65.7 mmoles) was added. After 1
hour at 25.degree. C. the mixture was taken up in CH.sub.2Cl.sub.2
and washed with saturated aqueous sodium bicarbonate and water. The
CH.sub.2Cl.sub.2 was dried (magnesium sulphate), filtered and
evaporated to dryness. The residue was chromatographed on silica
gel using 10% EtOAc in hexane as the eluant to give the title
compound (Yield: 3.48 grams, 30%, MH.sup.+180).
[0300] B. .alpha.-Methyl-3-Pyridylacetic Acid 121
[0301] The title compound from Preparative Example 9A above (2.16
grams) (12.05 mmoles) was dissolved in EtOH (10 ml.) and 1.0M LiOH
in water (29.15 ml.) (29.2 mmoles) was added. The mixture was
stirred at 25.degree. C. for 4 hours, whereupon 1N HCl (34.27 ml.)
(34.2 mmoles) was added and the solution was evaporated to dryness
to give the title compound (Yield 2.33 grams, 100%).
PREPARATIVE EXAMPLE 10
[0302] .alpha.,.alpha.-Dimethyl-3-Pyridylacetic Acid. 122
[0303] Ethyl .alpha.,.alpha.-dimethyl -3-pyridylacetate (disclosed
in EP Application 0 288 279, published Oct. 26, 1988) (2.67 grams,
13.8 mmoles) was dissolved in EtOH (11.1 ml.) and a 1.0M LiOH in
water (33.3 ml.) (33.4 mmoles) was added. The mixture was stirred
at 25.degree. C. for 4 hours. 1N HCl (38.73 ml.) was added and
after 5 minutes the mixture was evaporated to dryness to give the
titlle compound (Yield: 100%).
PREPARATIVE EXAMPLE 11
[0304] A.
8-Chloro-6.11-Dihydro-11-(1-Piperazinyl)-5H-Benzo[5,6]Cyclohepta-
[1,2-b]Pyridine 1-N-Oxide 123
[0305] To a mixture of 8-chloro-5,6-dihydro-11
H-benzo[5,6]cyclohepta-[1,2- -b]pyridin-11-one (5 grams) (20.6
mmoles) in dry CH.sub.2Cl.sub.2 (35 ml) was added dropwise MCPBA
(4.7 grams) (27.3 mmoles) in dry CH.sub.2Cl.sub.2 (75 ml) at
0-25.degree. C. over 1 hour. The mixture was diluted with
CH.sub.2Cl.sub.2 and washed with saturated aqueous sodium
bicarbonate and water. The CH.sub.2Cl.sub.2 was dried (magnesium
sulphate), filtered and evaporated to dryness. The residue was
chromatographed on silica gel using 1% (10% saturated ammonium
hydroxide in MeOH)--CH.sub.2Cl.sub.2 as the eluant to give the
title compound (Yield: 2.81 grams, 53%, MH.sup.+260).
[0306] B.
8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-11--
Ol 1-N-Oxide 124
[0307] By using the title compound (8.6 grams) from Preparative
Example 11A and reducing it by the procedure described in
Preparative Example 7A above the title alcohol was obtained (Yield:
7.03 grams, 81%, MH.sup.+262).
[0308] C.
8,11-Dichloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin- e
1-N-Oxide 125
[0309] The title compound from Preparative Example 11B (6.2 grams)
(23.7 mmoles) was reacted with thionyl chloride as described in
Preparative Example 7B to give the title compound.
[0310] D.
8-Chloro-6,11-Dihydro-11-(1-Piperazinyl)-5H-Benzo[5,6]Cyclohepta-
[1,2-b]Pyridine 1-N-Oxide 126
[0311] The title compound from Preparative Example 11C above was
reacted with piperazine (9.9 grams) (115.0 mmoles) as described in
Preparative Example 7C to give the title compound (Yield: 6.78
grams, 87%, MH.sup.+330).
PREPARATIVE EXAMPLE 12
[0312] 4-Ethoxycarbonylaminopyridine 127
[0313] 4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry
pyridine (217 ml.) and cooled to 0.degree. C. over 30 minutes.
Ethyl chloroformate (17.2 ml.) (180.7 mmoles) was addedand the
solution was stirred at 0.degree. C. for 1 hour and then at
25.degree. C. for 40 hours. The mixture was diluted with
CH.sub.2Cl.sub.2 and washed with saturated aqueous NaHCO.sub.3 and
water. The CH.sub.2Cl.sub.2 was dried (MgSO.sub.4), filtered and
evaporated to dryness. The residue was chromatographed on silica
gel using 2%(10% saturated NH.sub.4OH in MeOH)--CH.sub.2Cl.sub.2 to
give the title compound (Yield: 10 grams, 33%, M.sup.+166).
[0314] By using essentially the same procedure, with the exception
that 128
[0315] was used instead of 4-aminopyridine, the compound 129
[0316] was obtained, respectively.
PREPARATIVE EXAMPLE 13
[0317] A. N-Acetylisonipecotic Acid 130
[0318] Isonipecotic acid (10 grams) (77.5 mmoles) and acetic
anhydride (23.7 grams) (232.5 mmoles) were dissolved in MeOH (100
ml.) and the mixture was stirred at 25.degree. C. for 24 hours. The
mixture was evaporated to dryness and the residue was azeotroped
with toluene to give the title compound (Yield: 12.8 grams, 97%,
MH.sup.+172).
[0319] B. 1-N-tert-Butoxycarbonylisonipecotic Acid 131
[0320] Isonipecotic acid (20 grams) (155.0 mmoles) was dissolved in
THF-water (1:1) (400 ml) and NaOH (6.2 grams) (155.0 mmoles) and
di-tert-butyldicarbonate (37.2 grams) (170.5 mmoles) were added.
The mixture was stirred at 25.degree. C. for 72 hours. The solution
was then eluted through a bed of washed BioRad 50WX4 (RSO3H resin)
(150 ml bed) and the resin was eluted with a 1:1 mixture of THF and
water. The eluate was evaporated to dryness to give the title
compound (Yield: 33.78 grams, 90%).
PREPARATIVE EXAMPLE 14
[0321] 1-N-Acetylnipecotic Acid 132
[0322] Nipecotic acid (3.87 grams) (30.0 mmoles) was reacted with
acetic anhydride (9.17 grams) (90 mmoles) as described in
Preparative Example 13A to give the title compound (Yield: 5.0
grams, 97%, MH.sup.+172).
PREPARATIVE EXAMPLE 15
[0323] 1-N-Methylnipecotic Acid 133
[0324] Arecaidine hydrochloride (4 grams) (22.6 mmoles) was
hydrogenated in water (100 ml) using 10% Pd-C at 40 psi at
25.degree. C. for 24 hours. The catalyst was filtered off and
washed with water. The aqueous solution was shaken with BioRad
AG1X8 resin (OH.sup.- form) (23 ml bed) and after 5 minutes the
resin was filtered off and washed with water. The aqueous solution
was evaporated to give the title compound (Yield: 2.95 grams,
92%).
PREPARATIVE EXAMPLE 16
[0325] 1-N-Acetyl D,L-Pipecolinic Acid 134
[0326] D,L-Pipecolinic acid (10 grams) (77.5 mmoles) and acetic
anhydride (23.7 grams) (232.5 mmoles) were reacted as described in
Preparative Example 13A above to give the title compound (Yield:
12.94 grams, 98%, MH.sup.+172).
PREPARATIVE EXAMPLE 17
[0327] A. Piperidine-4-Acetic Acid 135
[0328] 4-Pyridylacetic acid (7 grams) (40.4 mmoles) was
hydrogenated as described in Preparative Example 15 to give the
title compound (Yield: 5.2 grams, 90%, MH.sup.+144).
[0329] B. 1-N-Acetyl-4-Piperidinylacetic Acid 136
[0330] 4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted
with acetic anhydride (10.7 grams) (105.0 mmoles) as described in
Preparative Example 13A to give the title compound (Yield: 6.4
grams, 99%, MH.sup.+185).
[0331] C. 1-N-Methyl-4-Piperidinylacetic Acid 137
[0332] 4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from
Preparative Example 17A was dissolved in water (50 ml) and 37%
formalin (2.72 ml) (33.6 mmoles) was added. The mixture was
hydrogenated over 10% Pd-C at 55psi at 25.degree. C. for 68 hours.
The catalyst was filtered off and washed with water. The combined
filtrates were evaporated to dryness to give the title compound (
MH.sup.+158).
[0333] D. 1-N-tert-Butoxycarbonylpiperidinyl-4-Acetic Acid 138
[0334] 4-Piperidinylacetic acid (41.24 grams) (288.4 mmoles) from
Preparative Example 17A was reacted with di-tert-butyldicarbonate
(69.14 grams) (317.3 mmoles) and NaOH (11.52 grams) (288.4 mmoles)
as described in Preparative Example 13B above to give the title
compound (Yield: 53.0 grams, 76%).
PREPARATIVE EXAMPLE 18
[0335] A. 3-Piperidinylacetic Acid 139
[0336] 3-Pyridylacetic acid hydrochloride (13 grams) (74.9 mmoles)
was hydrogenated as described in Preparative Example 15 to give a
mixture of unreacted 3-pyridylacetic acid and the title compound
(76:24) (8.63 grams, MH.sup.+144).
[0337] B. 1-N-ACETYL-3-Piperidinylacetic Acid 140
[0338] The mixture of compounds from Preparative Example 18A (8.56
grams) were reacted with acetic anhydride (8.56 grams) as described
in Preparative Example 13A and the crude mixture of products was
taken up in MEOH (60 ml) and passed over a bed of BioRad AG50WX4
resin (RSO.sub.3H) and the latter was eluted with MeOH. The eluates
were evaporated to dryness to give the title compound (Yield: 1.23
grams, MH.sup.+186).
[0339] C. 1-N-Methyl-3-Piperidinylacetic Acid 141
[0340] The mixture of compounds from Preparative Example 18A (4
grams) and 37% formalin (2.72 ml.) were hydrogenated as described
in Preparative Example 17C to give the title compound
(MH.sup.+158).
PREPARATIVE EXAMPLE 19
[0341] Preparation of the R(+) and S(-) Diastereoisomers
[0342] The racemic 8-chloro-11-(1
-piperazinyl)-6,11-dihydro-5H-benzo-[5,6-
]cyclohepta[1,2-b]pyridine prepared in Preparative Example 7C above
was resolved by the method described in Preparative Example 15 A-C,
pages 116-118, of WO 92/00293, published Jan. 9, 1992, to give the
R(+) and S(-) diastereoisomers: 142
PREPARATIVE EXAMPLE 20
[0343] A.
3-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyr-
idin-11-One 143
[0344] Cyclize 3-[2-(3-chlorophenyl)ethyl]-4-bromo-2-pyridine
carbonitrile (10.7 g, 32.8 mmol) in triflic acid (82 mL) at
60.degree. C. for 2 hours and then at room temperature for 2 hours.
Add 80 mL of 5N HCl carefully, then reflux in an oil bath
(120.degree. C.) for 30 minutes. Cool the solution and pour into
ice and basify with 25% NaOH solution. Extract the product with
CH.sub.2Cl.sub.2 and wash with brine. Dry the organic layer with
Na.sub.2SO.sub.4, filter and remove the solvent to give crude
product (10.4 g). Purify the crude product with flash
chromatography on silica gel and elute with 15% EtOAc-hexane to
give the title compound as a white solid (9 g , 27.95 mmol, Yield
85.2% MH.sup.+322).
[0345] B.
8-Chloro-3-Methoxy-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]P-
yridin-11-One 144
[0346] Dissolve the title compound of Preparative Example 20A (2.37
g, 7.4 mmol) in dry MeOH and add Na metal (3.37 g, 180 mmol). the
reaction is stirred overnight at room temperature. Reflux the
reaction for 3 hours, cool to room temperature and extract with
CH.sub.2Cl.sub.2-water. Dry the CH.sub.2Cl.sub.2 fraction and
chromatograph on silica gel eluting with 50% EtOAc-hexanes to give
the title compound as a light yellow solid(1.5 g, Yield 72%
MH.sup.+274).
[0347] C.
8-Chloro-3-Methoxy-11-(-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[-
5,6]-Cyclohepta[1,2-b]Pyridine 145
[0348] By substituting in Preparative Example 2 step D,
8-chloro-3-methoxy-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-
-one for
9-fluoro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-o-
ne and employing basically the same methods as steps D through H of
Preparative Example 2, one obtains 8-chloro-3-methoxy-
11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-
e as a white solid (MH.sup.+340).
PREPARATIVE EXAMPLE 25
[0349] A. Ethyl .alpha.-Methyl-4-Pyridyl Acetic Acid 146
[0350] To dry THF at -78.degree. C. was added diisopropylamine(5.05
g 48 mmol, 7 mL) and then n-butyl lithium. The reaction mixture was
stirred for 0.5 h and then ethyl 4-pyridyl acetic acid (7.85 g, 46
mmol) was added, and after sirring for 0.5 h at that -78.degree. C.
the reaction temperature was raised to room temperature. DMF (20 mL
was added and the reaction mixture cooled to -78.degree. C. again.
Methyl iodide(7.07 g, 50.2 mmol, 3.15 mL) was added and the
reaction mixture stirred at that temperature for 1 h and then at
room temperature overnight. All the volatiles were then stripped
off and the reaction mixture was partitioned between
water--CH.sub.2Cl.sub.2. The aqueous phase was washed twice with
CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 phases were dried
and evaporated. The crude product was chromatographed on silica gel
eluting with 80% EtOAc hexane to give the title compound (7.88 g,
MH.sup.+179).
[0351] B. .alpha.-Methyl-4-Pyridyl Acetic Acid 147
[0352] The compound from Preparative Example 25A was hydrolysed in
a similar manner to Preparative Example 9B to give the title
compound (MH.sup.+152).
PREPARATIVE EXAMPLE 26
[0353] A.-B. .alpha.,.alpha.-Dimethyl-4-Pyridyl Acetic Acid 148
[0354] By essentialy the same procedure as set forth in Preparative
Example 10A-B, but using ethyl .alpha.--methyl-4-pyridylacetic acid
(from Preparative Example 25) instead of ethyl pyridyl acetic acid
the title compound was obtained as an oil (MH.sup.+166).
PREPARATIVE EXAMPLE 27
[0355] Ethyl
4-[4.8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Py-
ridin-11-Ylidene]-1 -Piperidinecarboxylate and
[0356] Ethyl
4-[2,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Py-
ridin-11-Ylidene]-1-Piperidine-Carboxylate 149
[0357] To phosphorous oxychloride (256 mL) stirring at reflux was
added dropwise a solution of the title compound (109 grams) from
Example 231A dissolved in CHCl.sub.3 (850 mL). After stirring the
resulting solution for an additional 20 minutes at reflux, the
reaction mixture was cooled to room temperature and the chloroform
removed in vacuo. The resulting solution was cooled in an ice-water
bath and to it was slowly added 1N aqueous NaOH (850 mL) followed
by 50% aqueous NaOH until the resulting mixture was slightly basic.
Extraction with EtOAc, drying of the organic phase over anhydrous
MgSO.sub.4, concentration in vacua, and purification by flash
column chromatography provided the 4,8-dichloro product (27 grams,
23% yield, mp 141.6-145.6.degree. C.) and the 2,8-dichloro product
(9 grams, 8% yield, 176.5-177.9.degree. C.).
PREPARATIVE EXAMPLE 28
[0358]
4.8-Dichloro-11-(4-Piperidylidene)-6,11-5H-Benzo[5,6]-Cyclohepta[1,-
2-b]Pyridine 150
[0359] A solution of the 4,8-dichloro compound from Preparative
Example 27 (2.6 grams) dissolved in absolute EtOH (50 mL) and
concentrated HCl (100 mL) was stirred at reflux for 48 hours. The
reaction mixture was cooled in an ice-water bath and was made basic
by addition of solid KOH. Concentration in vacuo afforded a solid
which was diluted with CH.sub.2Cl.sub.2 and water. The organic
phase was dried over anhydrous MgSO.sub.4 and concentrated in vacuo
to provide the title compound (2.0 grams, 93% yield,
mp=181.1-183.2.degree. C.).
PREPARATIVE EXAMPLE 29
[0360] Ethyl
4-[4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Py-
ridin-11-Ylidene]-1-Piperidine Carboxylate, N-Oxide 151
[0361] To a cooled (0.degree. C.) solution of the 4,8-dichloro
compound from Preparative Example 27 (9.5 grams) dissolved in
CH.sub.2Cl.sub.2 (300 mL) under N.sub.2 was added dropwise a
solution of MCPBA (6.8 grams) dissolved in EtOAc (200 mL). The
resulting mixture was washed with 1N aqueous NaOH, dried over
anhydrous MgSO.sub.4 and concentrated in vacua. The residue was
purified by flash column chromatography (silica gel) using 100%
EtOAc then 10% MeOH--CH.sub.2Cl.sub.2 to afford the title compound
(4.9 grams, 50%, MH.sup.+433).
PREPARATIVE EXAMPLE 30
[0362] Ethyl
4-[4-(2-Aminoethylthio)-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cy-
clohepta[1,2-b]Pyridin-11-Ylidene]-1-Piperidine Carboxylate 152
[0363] A mixture of the title compound from Preparative Example 29
(0.53 grams), 2-aminoethanethiol hydrochloride (0.74 grams) and
absolute EtOH(15 mL) was stirred at reflux for 48 hours. The
mixture was cooled to 25.degree. C., diluted with CH.sub.2CI.sub.2
and washed with 1N aqueous NaOH. The organic phase was dried over
anhydrous MgSO.sub.4 and concentrated in vacuo to provide the title
compound (0.5 grams, 88%, MH.sup.+458).
PREPARATIVE EXAMPLE 31
[0364] 1.1-Dimethylethyl
[2-[[8-Chloro-6,11-Dihydro-11-(1-Ethoxycarbonyl)--
4-Piperidinylidene]-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-4-Yl]thio]ethyl]-
Carbamate 153
[0365] To the title compound from Preparative Example 30 (0.33
grams) dissolved in CH.sub.2Cl.sub.2 (60 mL) was added
di-tert-butyldicarbonate (0.17 grams). The solution was stirred at
25.degree. C. under N.sub.2 overnight. An additional 0.1 grams of
di-tert-butyldicarbonate was added and after 4 hours the reaction
mixture was diluted with CH.sub.2Cl.sub.2, washed with 1N aqueous
NaOH and concentrated in vacuo to afford the title compound (0.5
grams, 100%, MH.sup.+558).
PREPARATIVE EXAMPLE 32
[0366] 1.1-Dimethylethyl
[2-[[8-Chloro-6,11-Dihydro-11-[4-Piperidinylidene-
]-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-4-Yl]thio]Ethyl]Carbamate
154
[0367] To the title compound from Preparative Example 31 (0.22
grams) dissolved in absolute EtOH (5 mL) was added water (5 mL) and
solid KOH (0.33 grams). The solution was stirred at reflux for 4
days, then cooled to 25.degree. C., diluted with CH.sub.2Cl.sub.2
and washed with water. The organic phase was concentrated in vacuo
and the residue purified by flash column chromatography (silica
gel) using 5% MeOH--CH.sub.2Cl.sub.2 saturated with NH.sub.4OH to
afford the title compound (0.04 grams, 19%, MH.sup.+486).
PREPARATIVE EXAMPLE 33
[0368] 3-Pyridylisocyanate, Hydrochloride 155
[0369] A 1.93 solution of phosgene in toluene (20%) (584 mL) was
diluted with dry CH.sub.2Cl.sub.2 (1 L) and the mixture was stirred
at 0.degree. C.. under nitrogen atmosphere. A solution of
3-aminopyridine (21.1 grams) and dry pyridine (19 mL) dissolved in
dry CH.sub.2Cl.sub.2 (600 mL) was added dropwise to the stirred
solution at 0.degree. C. over a period of 5.5 hours. The mixture
was stirred at 0-25.degree. C. for an additional 48 hours. A stream
of nitrogen was passed through the solution to remove most of the
phosgene and the solution was then evaporated until almost all of
the solvent was removed to give the title compound which was then
taken up in dry pyridine (850 mL) to give a stock solution of the
title compound.
PREPARATIVE EXAMPLE 34
[0370] A.
8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidinyl)-11H-Benzo[5,6]Cyclo-
hepta(1,2-b)Pyridine
[0371] B.
8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidinyl)-9-Ethyl-11H-Benzo[5-
,6]Cyclohepta(1,2-b)Pyridine 156
[0372] The title compound of Preparative Example 1F above (51.15
grams, 0.1336 mole) was dissolved in trifluoromethanesulfonic acid
(170 mL). The dark mixture was heated to reflux for 70 h. The
solution was cooled to room temperature and was then poured into
800 mL of an ice/water slurry and the resulting mixture stirred.
Concentrated NH.sub.4OH solution (175 mL) was added to the mixture
in small portions so that the temperature of the mixture was below
20.degree. C. The resulting basic mixture was extracted with
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 extract was washed with
brine and was then evaporated to give a brown residue. This residue
was dissolved in CH.sub.2Cl.sub.2 (750 mL) and the solution cooled
to 0.degree. C. Ethyl chloroformate (14.8 grams, 0.136 mole) was
added over 5 minutes and the resulting mixture stirred at 0.degree.
C. for 15 minutes. Saturated NaHCO.sub.3 solution (150 mL) was
added and the cooling bath was removed. The resulting biphasic
mixture was stirred rapidly for 3h. The layers were separated and
the CH.sub.2Cl.sub.2 layer was filtered through silica gel. The
filtrate was evaporated to dryness and the residue chromatographed
on silica gel using a gradient of hexane--CH.sub.2Cl.sub.2-acetone
16:2.5:1.5 to hexane--CH.sub.2Cl.sub.2-a- cetone 28:7.5:4.5 as
eluent to give title compound A (25.02 g 49% MH.sup.+383) and title
compound B (4.85 g, 9%, MH.sup.+411).
[0373] C.
8-Chloro-11-(4-Piperdinyl)-11H-Benzo[5,6]Cyclohepta(1,2-b)Pyridi-
ne 157
[0374] Hydrolyze the title compound of Preparative Example 34A by
dissolving in 50% aqueous H.sub.2SO.sub.4 (v/v) and heating to
90.degree. to 100.degree. C. for 16 h. The cooled acidic mixture
was neutralized with 25% NaOH solution (w/v). The resulting mixture
was extracted with EtOAc and the EtOAc extract was dried with
Na.sub.2SO.sub.4. Filtration and evaporation of the EtOAc afforded
the title compound(MH.sup.+311).
PREPARATIVE EXAMPLE 35
[0375]
8-Chloro-9-Ethyl-11-(4-Piperidinyl)-11H-Benzo-[5,6]Cyclohepta[1,2-b-
]Pyridine 158
[0376] Hydrolyze the title compound of Preparative Example 34B
following the procedure described in Preparative Example 34C to
provide the title compound. Decomposes between 205.7-215.4.degree.
C., heating 2-3.degree. C. per minute.
PREPARATIVE EXAMPLE 36
[0377] A.
8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidinyl)-11H-Benzo[5,6]Cyclo-
hepta[1,2]Pyridine-1-Oxide 159
[0378] The title compound from Preparative Example 34A above (20.23
grams, 52.84 mmoles) was dissolved in CH.sub.2Cl.sub.2 (250 mL).
MCPBA (1.25 equivalents) was added in one portion and this solution
was stirred for 45 minutes. Sodium bisulfite solution (20% w/v) was
added and the biphasic mixture rapidly stirred for 30 minutes. The
layers were separated and the organic layer was washed with
saturated Na.sub.2CO.sub.3 solution and dried with
Na.sub.2SO.sub.4. Filtration and evaporation afforded the title
compound (21 g, 99%, mp 78.6-89.4.degree. C., MH+399).
[0379] B. 4.8Dichloro-11-(1
-Ethoxycarbonyl-4-Piperidin-Yl)-11H-Benzo[5,6]-
Cyclohepta[1,2-b]Pyridine (A) and
[0380]
2.8-Dichloro-11-(1-Ethoxycarbonyl-4-Piperidin-Yl)-11H-Benzo[5,6]Cyc-
lohepta[1,2-B]pyridine (B) 160
[0381] The title compound from Preparative Example 36A (21 grams,
53 mmoles) above was dissolved in anhydrous dichloroethane (250 mL)
and the solution cooled to 0.degree. C. POCl.sub.3 (49.4 grams,
0.322 mole) was added dropwise to the dichloroethane solution over
15 minutes. After the POCl.sub.3 was added the reaction mixture was
warmed to 45-50.degree. C. and stirred for 18h. Additional
POCl.sub.3 (8.2 grams) was added and the mixture heated to reflux
for 9 h. The mixture was cooled and added to an ice cooled, stirred
solution of NaOH (15% w/v). The resulting biphasic mixture was
stirred rapidly for 18 h. The layers were separated and the aqueous
layer was extracted with CH.sub.2Cl.sub.2. The combined organic
layers were washed with water followed by brine and dried
(Na.sub.2SO.sub.4). The mixture was filtered and evaporated, and
the residue chromatographed on silica gel using a gradient of 25%
EtOAc in hexane to 45% EtOAc in hexane as eluent. The title
compound A was obtained as a yellow solid (5.98 g M+417), and title
compound B was obtained as a yellow solid (1.0 g, mp
84.4-90.6.degree. C.).
[0382] C.
4.8-Dichloro-11-(4-Piperidinyl)-11H-Benzo[5,6]-Cyclohepta[1,2-b]-
Pyridine 161
[0383] The title compound A from Preparative Example 36B was
hydrolyzed under the conditions described in Preparative Example
34C to give the title compound (M.sup.+345).
PREPARATIVE EXAMPLE 37
[0384] A.
4-(8-Chloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene)-1-
-(Ethoxycarbonyl)-Piperidine 162
[0385] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, et al. By substituting in Preparative
Example 2,8-chloro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-one
for
9-fluoro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-one
and employing basically the same methods as steps D through F of
Preparative Example 2, one obtains the title compound (mp
154.7-155.5.degree. C.).
[0386] B.
8-Chloro-11-(4-Piperidinyl)-Benzo[5.6]Cyclohepta[1,2-b]Pyridine
163
[0387] Hydrolyze the title compound of Preparative Example 37A
following the procedure described in Preparative Example 334C (mp
168.5-171.2.degree. C., decomposition).
PREPARATIVE EXAMPLE 38
[0388]
8-Chloro-11-(1-Piperazinyl)-11H-Benzo[5.6]Cyclohepta[1,2b]Pyridine
164
[0389] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, J. J., et al. By substituting in Preparative
Example 7A, 8-chloro-11H-benzo[5,6]cyclo-hepta[1,2-b]pyridin-11-one
(11.53 g) (47.71 mmoles) for
8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-1-
1-one and employing basically the same methods as steps A through C
of Preparative Example 7, one obtains 11.53 g (36%) of the title
compound (MH.sup.+312).
PREPARATIVE EXAMPLE 39
[0390] A. Ethyl .alpha.,.alpha.-Dimethyl-3-Pyridylacetic Acid
N-Oxide 165
[0391] By substituting in Preparative Example 8A, ethyl
.alpha.,.alpha.-dimethyl-3-pyridylacetic acid (4.0 g, 20.7 mmoles)
for ethyl 3-pyridylacetic acid and using the same method as
described in Preparative Example 8A, one obtains the title compound
(3.2 g, 74%, MH.sup.+210).
[0392] B. .alpha.,.alpha.-Dimethyl-3-Pyridylacetic Acid N-Oxide
166
[0393] By substituting in Preparative Example 8B, ethyl
.alpha.,.alpha.-dimethyl-3-pyridylacetic acid N-oxide (0.142 g,
0.68 mmoles) (Preparative Example 39A) for ethyl 3-pyridylacetic
acid N-oxide and using the same method as described in Preparative
Example 8B, one obtains the title compound.
PREPARATIVE EXAMPLE 40
[0394]
4-Bromo-8-Chloro-11-(1-Piperazinyl)-6,11-Dihydro-5H-Benzo[5,6]Cyclo-
hepta[1,2-b]Pyridine 167
[0395] By substituting in Preparative Example 7A,
4-bromo-8-chloro-11-(1-p-
iperazinyl)-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one
(1.5 g, 4.65 mmoles) (Preparative Example 20A) for
8-chloro-5,6-dihydro-11H-be-
nzo[5,6]cyclohepta[1,2-b]pyridin-11-one and using the same methods
as described in steps A through C of Preparative Example 7, one
obtains the title compound (1.31 g, 72%, MH.sup.+392).
PREPARATIVE EXAMPLE 41
[0396] 4.8-Dichloro-11-(1-Piperazinyl)-6,11
-Dihydro-5H-Benzo[5,6]Cyclohep- ta[1,2-b]Pyridine 168
[0397] By substituting in Preparative Example 7A
4,8-Dichloro-5,6-dihydro--
11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (6.64 g, 28.37
mmoles) (Preparative Example 5B) for
8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta
[1,2-b]pyridin-11-one and using the same methods as described in
steps A through C of Preparative Example 7, one obtains the title
compound (2.59 g, 26%, MH.sup.+348).
PREPARATIVE EXAMPLE 42
[0398] Ethyl
4-[4-[(1H-Benzotriazol-1-Yl)Oxy]-8-Chloro-5,6-Dihydro-11H-Ben-
zo[5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-1-Piperidine
Carboxylate 169
[0399] To a solution of the 4,8-dichloro compound from Preparative
Example 27 (1.5 grams) in dry DMF (20 mL) was added HOBT (1.5
grams). After stirring for 14 days at 25.degree. C., NaH (0.84
grams, 60% in mineral oil) was added and after an additional 24
hours, the mixture was poured into water. Filtration provided the
title compound (Yield: 1.7 grams, 89%, mp=181.5-183.9.degree. C.,
MH.sup.+516).
PREPARATIVE EXAMPLE 43
[0400] ETHYL
4-[4-Hydroxy-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,-
2-b]Pyridin-11-Ylidene]-1-Piperidine Carboxylate 170
[0401] To a solution of the title compound from Preparative Example
42 (0.15 grams) and glacial HOAc (5 mL) was added Zn dust (0.2
grams). After stirring at 25.degree. C. for 1 hour, the mixture was
filtered through celite and the filtrate concentrated in vacuo. The
residue was diluted with EtOAc, washed with saturated aqueous
NaHCO.sub.3 and brine. The organic layer was separated, dried over
MgSO.sub.4 and concentrated in vacuo to give the title compound
(Yield: 0.11 grams, 95%, MH+399).
PREPARATIVE EXAMPLE 44
[0402] Ethyl
4-[3-Bromo4-Hydroxy-8-Chloro-5.6-Dihydro-11H-Benzo[5,6]Cycloh-
epta[1,2-b]Pyridin-11-Ylidene]-1-Piperdine Carboxylate 171
[0403] To a solution of the title compound from Preparative Example
43 (1.3 grams) and glacial HOAc (5 mL) was added a 0.7 M
bromine-HOAc solution (4 mL) at 25.degree. C. under N.sub.2. The
solution was poured into 200 mL of water and the resulting solid
was filtered, then washed with water. The solid was dried under
vacuum overnight to provide the title compound (Yield: 1.2 grams,
81%, MH.sup.+477).
PREPARATIVE EXAMPLE 45
[0404] Ethyl
4-[3-Bromo-4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[-
1,2-b]Pyridin-11-Ylidene]-1-Piperidine Carboxylate 172
[0405] A mixture of the title compound from Preparative Example 44
(5.1 grams), phosphorous oxychloride (20 mL) and CHCl.sub.3 (40 mL)
was stirred at reflux over night. The reaction mixture was made
basic by the slow addition of 1N aqueous NaOH, and the resultant
mixture was diluted with CH.sub.2Cl.sub.2. The mixture was shaken
well and after separation of the phases, the organic phase was
washed with 1 N aqueous NaOH. The organic phase was dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo to provide
a solid which was mixed with MeOH and filtered. Concentration of
the filtrate provided the title compound as a solid (Yield: 5.7
grams,MH.sup.+497).
PREPARATIVE EXAMPLE 46
[0406]
3-Bromo-4,8-Dichloro-11-(4-Piperidylidene)-6,11-5H-Benzo[5,6]Cycloh-
epta[1,2-b]Pyridine 173
[0407] A solution of the title compound from Preparative Example 45
(5.7 grams) dissolved in absolute EtOH (100 mL) and concentrated
HCl (200 mL) was stirred at reflux for 24 hours. The reaction
mixture was cooled in an ice-water bath and was made basic by the
addition of solid KOH. Extraction with CH.sub.2Cl.sub.2 and
concentration of the organic phase in vacuo afforded the title
compound as a solid (1.7 grams, 35% yield, MH.sup.+425).
PREPARATIVE EXAMPLE 47
[0408] A.
4-(8-Chloro-3Nitro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]P-
yridin-11-Ylidene)-1-Piperidine-1-Carboxylic Acid Ethyl Ester
174
[0409] Tetrabutyl ammonium nitrate(4.98 g, 16.3 mmol) was dissolved
in CH.sub.2Cl.sub.2(20 mL) and TFAA(3.12 g,14.9 mmol, 2.1 mL) was
then added. The solution was cooled to 0.degree. C. and then added
(by cannulation) to a solution of
4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cycl-
ohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylic aid
ethyl ester (5.69 g, 14.9 mmol) in CH.sub.2Cl.sub.2 (35 mL) also
cooled to 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 3h and then allowed to go to room temperature
(25.degree. C.) overnight. The reaction mixture was then extracted
with saturated NaHCO.sub.3 (60 mL) dried over MgSO.sub.4 and
concentrated to give a semi-solid material that was chromatographed
on silica gel eluting first with 10% and then 20% EtOAc-hexane.
Removal of the organic solvents gave the title compound in 44%
yield as a light yellow solid. MP=90.4-91.0.degree. C.,
MH.sup.+428.
[0410] B.
4-(8-Chloro-3-Amino-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]-
Pyridin-11-Ylidene)-1-Piperidine-1-Carboxylic Acid Ethyl Ester
175
[0411] The title compound from Preparative Example 47A (5.99 g, 14
mmol) was dissolved in 85% aqueous EtOH. To this solution was added
iron filings (7.01 g, 125.57 mmol) and CaCl.sub.2 (0.69 g, 6.29
mmol) and the reaction mixture was refluxed for 16 h. The reaction
mixture was filtered through a bed of celite while hot and the
celite was washed with hot EtOH (700 mL). The EtOH solution was
then decolorized with activated charcoal (2.4 g) and then filtered
through celite. EtOH was then rotary eavaporated to give the title
compound in 100% yield as an off-white solid.
MP=102.4-103.1.degree. C., MH.sup.+398.
[0412] C.
4-(8-Chloro-3-Bromo-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]-
Pyridin-11-Ylidene)-1-Piperidine-1-Carboxylic Acid Ethyl Ester
176
[0413] The title compound from Preparative Example 47B (3.00 g,
7.60 mmol) was dissolved in HBr (48%, 30 mL). The reaction mixture
was cooled to -5.degree. C. (ice-ethylene glycol bath) and
bromine(2 mL) was added dropwise. The reaction mixture was stirred
at -5.degree. C. for 15 minutes. Sodium nitrite (1.57 g, 22.8 mmol)
dissolved in water (15 mL) was slowly added to the reaction
mixture. The reaction mixture was then stirred for 45 minutes and
then quenched with 40% NaOH to pH .about.10. The aqueous phase was
then extracted with EtOAc(3.times.100 mL). Combined EtOAc fractions
were dried over Na.sub.2SO.sub.4 and then concentrated to give the
title compound in 83% yield as a light brown solid.
Mp=146-148.degree. C., MH+463.
PREPARATIVE EXAMPLE 48
[0414] Step A: 177
[0415] Combine 6 g (15.11 mmol) of the title compound of
Preparative Example 47B and benzene, and add 2.3 g (9.06 mmol) of
iodine. Heat the mixture at reflux for 3 hours, cool, then dilute
with 50 mL of CH.sub.2Cl.sub.2. Wash the organic phase with 5%
NaHSO.sub.3(aqeuous) (3.times.80 mL), then with 1M NaOH (aqueous)
(2.times.80 mL), and dry over MgSO.sub.4. Concentrate to a residue
chromatograph (silica gel, 30% EtOAc/hexanes), to give 3.2 g (42%
yield) of the product iodo compound. Mass Spec., MH+=509
[0416] Step B: 178
[0417] The product of Step A is hydrolyzed via substantially the
same procedure as described in Example 358, Step A, to give the
iodoamine product in 89% yield.
PREPARATIVE EXAMPLE 49
[0418] 179
[0419] The product of Preparative Example 47, Step C, (2.42 g) is
hydrolyzed via substantially the same procedure as described in
Example 358, Step A, to give 1.39 g (69% yield) of the bromoamine
product.
[0420] Using the starting compound indicated and following
essentially the same procedure as for Preparative Example 49, the
following compounds were prepared:
2 Starting Analytical Compound Compound Data Preparative Example
51, Step C 180 Mass Spec.: MH.sup.+ = 407 Preparative Example
49A
PREPARATIVE EXAMPLE 50
[0421] 181
[0422] Combine 82.0 g (0.26 mole) of the product of Preparative
Example 1, Step G, and 1 L of toluene, then add 20.06 g (0.53 mole)
of LiAlH.sub.4 and heat the reaction mixture at reflux overnight.
Cool the mixture to room temperature and add .about.1 L of
Et.sub.2O, followed by dropwise addition of saturated
Na.sub.2SO.sub.4 (aqueous) until a precipitate forms. Filter and
stir the filtrate over MgSO.sub.4 for 30 minutes, then concentrate
in vacuo to give the product compound in 83% yield. Mass Spec.:
MH.sup.+=313 182
[0423] Combine 74 g (0.24 mol) of the Product from Step A and 95 g
(6.84 equiv.) of HCO.sub.2H, then add 129 g of 7% formadehyde and
heat the mixture to .about.80.degree. C. for 2 hours. Cool the
mixture to room temperature and basify with 25% NaOH (aqueous).
Extract with EtOAc (3.times.1.3 L), dry the extracts over
Na.sub.2SO.sub.4 and concentrate to a residue. Recystallize the
residue from iPr.sub.2O and Et.sub.2O to give the product compound.
Mass Spec.: MH.sup.+=326. 183
[0424] Combine 28 g of the Product of Step B and 800 mL of THF and
cool to -65.degree. C. Add a solution of 41.2 mL (1.2 equiv.) of
2.5 M n-BuLi in hexanes, stir for 1 hour at -65.degree. C., then
warm to -30.degree. C. and stirred at that tepmerature for 1 hour.
Cool to -65.degree. C. and add 10.5 mL of CH.sub.3I, then warm to
-10.degree. C. and quench with 1.5 mL of Et.sub.2O followed by 10
mL of NH.sub.4OH (aqueous). Dry the organic phase over
K.sub.2CO.sub.3 and concentrate in vacuo to a residue. Dissolve the
residue in CH.sub.2Cl.sub.2, wash with H2O, dry over
Na.sub.2SO.sub.4 and concentrate in vacuo to give a residue.
Chromatograph (silica gel, 5% MeOH/EtOAc+NH.sub.4OH) to give 26 g
of the product compound. 184
[0425] Combine 26 g of the Product of Step C, toluene, and 33 mL (3
equiv.) of Et.sub.3N, then heat to 70.degree. C. Slowly add 45 mL
(6 equiv.) of ClCO.sub.2Et over a period of 45 min. Stir for 15
min. then pour the mixture into ice and add 100 mL of 1 N NaOH
(aqueous). Extract with EtOAc, dry the extract and concentrate in
vacuo to give 37 g of the product compound. 185
[0426] Hydrolyze 3.5 g (8.8 mmol) of the Product of Step D, by
substantially the same procedure as described for Example 358, Step
A, to give 2.26 g (79% yield) of the product compound. Mass Spec.:
MH.sup.+=327
PREPARATIVE EXAMPLE 51
[0427] 186
[0428] Dissolve 8.66 g (28.6 mmol) of tetra-n-butylammonium nitrate
in 50 mL of CH.sub.2Cl.sub.2 and add 5.99 g (28.57 mmol, 2.1 mL) of
TFAA. Cool to 0.degree. C. and add the mixture (via cannula) to a
solution of 10.36 g (14.9 mmol) of the product of Preparative
Example 50, Step D in 150 mL of CH.sub.2Cl.sub.2 at 0.degree. C.,
then stir at 0.degree. C. for 3 hours. Allow the mixture to warm to
25.degree. C. while stirring overnight, then extract with 150 mL of
saturated NaHCO.sub.3 (aqueous) and dry over MgSO.sub.4.
Concentrate in vacuo to a residue and chromatograph the residue
(silica gel, 10% EtOc/hexane, then 20% EtOAc/hexane) to give a 57%
yield of the product compound. Mass Spec.: MH.sup.+=442. 187
[0429] Combine 5.9 g (13.29 mmol) of the Product of Step A and 400
mL of 85% EtOH (aqueous), add 6.6 g (119 mmol) of Fe filings and
0.66 g (5.98 mmol) of CaCl.sub.2, and heat at reflux for 16 hours.
Filter the hot mixture through a bed of celite.RTM., wash the
celite.RTM. with 700 mL of hot EtOH. Concentrate the filtrate in
vacuo to give a 100% yield of the product compound. Mass Spec.:
MH.sup.+=414. 188
[0430] Combine 6.5 g (15.7 mmol) of the Product of Step B and 63 mL
of 48% HBr, cool the mixture to -5.degree. C. and slowly (dropwise)
add 4.4 mL of Br.sub.2 bromine(4.4 mL). Stir the mixture at
-5.degree. C. for 15 minutes and slowly add a solution of 3.25 g
(47.1 mmol) of NaNO.sub.2 in 30 mL of water. Stir for 45 minutes,
then quench with 50% NaOH (aqueous) to pH .about.10. Extract with
EtOAc (3.times.200 mL), dry the combined extracts over
Na.sub.2SO.sub.4 and concentrate in vacuo to give 6.32 g (81%
yield) of the product compound. Mass Spec.: MH.sup.+=479
PREPARATIVE EXAMPLE 51A
[0431] 189
[0432] Combine 24.32 g (74.9 mmol) of the Product from Preparative
Example 50, Step A, 500 mL of toulene, 83 mL of Et.sub.3N and 65.9
mL of ethyl chloroformate and heat the mixture at reflux overnight.
Cool to 25.degree. C., pour into 200 mL of water and extract with
EtOAc. Dry the extract over MgSO.sub.4, concentrate in vacuo to a
residue and chromatograph (silica gel, 50% EtOAc/hexane) to give 15
g of the product compound. Mass Spec.: MH.sup.+=385. 190
[0433] Dissolve 3.2 g (10.51 mmol) of tetra-n-butylammonium nitrate
in 25 mL of CH.sub.2Cl.sub.2 and add 2.2 g (10.51 mmol, 1.5 mL) of
TFAA. Cool to 0.degree. C. and add the mixture (via cannula) to a
solution of 3.68 g (9.56 mmol) of the product of Step A in 50 mL of
CH.sub.2Cl.sub.2 at 0.degree. C., then stir at 0.degree. C. for 3
hours. Allow the mixture to warm to 25.degree. C. while stirring
overnight, then extract with saturated NaHCO3 (aqueous) and dry
over MgSO.sub.4. Concentrate in vacuo to a residue and
chromatograph (silica gel, 30% EtOc/hexane) to give a 1.2 g of the
product compound. Mass Spec.: MH.sup.+=430. 191
[0434] Combine 2.0 g (4.7 mmol) of the Product of Step B and 150 mL
of 85% EtOH (aqueous), add 2.4 g (42 mmol) of Fe filings and 0.24 g
(2.1 mmol) of CaCl.sub.2, and heat at reflux for 16 hours. Filter
the hot mixture through a bed of celite.RTM., wash the celite.RTM.
with hot EtOH. Concentrate the filtrate in vacuo to give a 100%
yield of the product compound. Mass Spec.: MH.sup.+=400. 192
[0435] Combine 2.0 g (5.2 mmol) of the Product of Step C and 20 mL
of 48% HBr, cool the mixture to -5.degree. C. Stir the mixture at
-5.degree. C. for 15 minutes and slowly add a solution of 1.07 g
(15.5 mmol) of NaNO.sub.2 in 10 mL of water. Stir for 45 minutes,
then quench with 50% NaOH (aqueous) to pH .about.10. Extract with
EtOAc, dry the combined extracts over MgSO.sub.4 and concentrate in
vacuo to give the product compound. Mass Spec.: MH.sup.+=465
193
[0436] Hydroyze 4.0 g of the Product of Step D via substantially
the same process as described for Example 358, Step A, to give 1.39
g of the product compound. Mass Spec.: MH.sup.+=392
PREPARATIVE EXAMPLE 52
[0437] 194
[0438] Dissolve 9.8 g (30.2 mmol) of the Product of Preparative
Example 1, Step E, in THF under nitrogen, cool the mixture to
-15.degree. C., then add 17.76 mL (30.3 mmol) of 2.5 M
n-butyllithium in hexanes and stir for 1.5 hours. Cool the reaction
mixture to -70.degree. C. and add 2.45 mL (60 mmol) of MeOH and
warm to room temperature overnight. Add 300 mL of (Et.sub.2O) and
extract with water (3.times.100 mL). Dry the extracts, concentrate
in vacuo to a residue and chromatograph the residue (silica gel, 5%
Et.sub.3N/EtOAc) to give 6.59 g (68% yeild) of the product
compound.
[0439] Via substantially the same procedure as described in
Preparative Example 52, Step A, except that methyl iodide is used
in place of MeOH, the following product compound is prepared:
3 Starting Analytical Compound Compound Data Preparative Example 1,
Step E 195 Mass Spec.: MH.sup.+ = 339 Preparative Example 52A
[0440] 196
[0441] Treat 3 g (9.23 mmol) of the Product of Step A with 10 mL of
ClCO.sub.2Et and 10 mL of Et.sub.3N via substantially the same
procedure as described in Preparative Example 50, Step D, to give
2.2 g (64% yield) of the product compound. Mass Spec.:
MH.sup.+=383
[0442] Using the starting compound indicated and substantially the
same procedure as described in Preparative Example 52, Step B, the
following product compound is prepared:
4 Starting Analytical Compound Compound Data Preparative Example
52A, Step A 197 Mass Spec.: MH.sup.+ = 397 Preparative Example
52A
[0443] 198
[0444] Treat the Product of Step B via substantially the same
procedure as described in Preparative Example 1, Step F, to give
the product compound. Mass Spec.: MH.sup.+=310
[0445] Using the starting compound indicated and substantially the
same procedure as described in Preparative Example 52, Step C, the
following product compound is prepared:
5 Starting Analytical Compound Compound Data Preparative Example
52A, Step B 199 Mass Spec.: MH.sup.+ = 325 Preparative Example
52A
PREPARATIVE EXAMPLE 53
[0446] 200
[0447] Combine 14.95 g (39 mmol) of the Product of Preparative
Example 34A and 150 mL of CH.sub.2Cl.sub.2, then add 13.07 g (42.9
mmol) of (nBu).sub.4NNO.sub.3 and cool the mixture to 0.degree. C.
Slowly add (dropwise) a solution of 6.09 mL (42.9 mmol) of TFAA in
20 mL of CH.sub.2Cl.sub.2 over 1.5 hours. Keep the mixture at
0.degree. C. overnight, then wash successively with saturated
NaHCO.sub.3 (aqueous), water and brine. Dry the organic solution
over Na.sub.2SO.sub.4, concentrate in vacua to a residue and
chromatograph the residue (silica gel, EtOAc/hexane gradient) to
give 4.32 g and 1.90 g of the two product compounds 53(i) and
53(ii), respectively.
[0448] Mass Spec. for compound 53(i): MH.sup.+=428.2;
[0449] Mass Spec. for compound 53(ii): MH.sup.+=428.3 201
[0450] The compound 53(ii) from Step A (0.20 g) is hydrolyzed via
substantially the same procedure as described for Example 358, Step
A, to give 0.16 g of the product compound.
[0451] Using the starting compound indicated and substantially the
same procedure as described in Preparative Example 53, Step B, the
following product compound is prepared:
6 Starting Analytical Compound Compound Data Preparative Example
53, Step A, compound 53(i) 202 -- Preparative Example 53A
Preparative Example 54, Step B, compound 54(ii) 203 Mass Spec.:
MH.sup.+ =466.9 Preparative Example 53B Preparative Example 54,
Step B, compound 54(i) 204 Mass Spec.: MH.sup.+ =466.9 Preparative
Example 53C
PREPARATIVE EXAMPLE 54
[0452] 205
[0453] Combine 22.0 g (51.4 mmol) of the product 53(i) from
Preparation 53, Step A, 150 mL of 85% EtOH (aqueous), 25.85 g
(0.463 mole) of Fe powder and 2.42 g (21.8 mmol) of CaCl.sub.2, and
heat at reflux overnight. Add 12.4 g (0.222 mole) of Fe powder and
1.2 g (10.8 mmol) of CaCl.sub.2 and heat at reflux for 2 hours. Add
another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of
CaCl.sub.2 and heat at reflux for 2 hours more. Filter the hot
mixture through celite.RTM., wash the celite.RTM. with 50 mL of hot
EtOH and concentrate the filrtrate in vacuo to a residue. Add 100
mL of anhydrous EtOH, concentrate to a residue and chromatograph
the residue (silica gel, MeOH/CH.sub.2Cl.sub.2 gradient) to give
16.47 g of the product compound. 206
[0454] Combine 16.47 g (41.4 mmol) of the product compound from
Preparative Example 54, Step A, and 150 mL of 48% HBr (aqueous) and
cool to -3.degree. C. Slowly add (dropwise) 18 mL of bromine, then
slowly add (dropwise) a solution of 8.55 g (0.124 mole) of
NaNO.sub.3 in 85 mL of water. Stir for 45 minutes at -3.degree. to
0.degree. C., then adjust to pH=10 by adding 50% NaOH (aqueous).
Extract with EtOAc, wash the extracts with brine and dry the
extracts over Na.sub.2SO.sub.4. Concentrate to a residue and
chromatograph (silica gel, EtOAc/hexane gradient) to give 10.6 g
and 3.28 g of the two product compounds 54(i) and 54(ii),
respectively.
[0455] Mass Spec. for compound 54(i): MH.sup.+=461.2;
[0456] Mass Spec. for compound 54(ii): MH.sup.+=539
PREPARATIVE EXAMPLE 55
[0457] 207
[0458] The title compound is known and is prepared by the procedure
described in Bioorg. & Med. Chem. Lett., 3, (No. 6) 1073-1078
(1993).
PREPARATIVE EXAMPLE 56
[0459] 208
[0460] Combine 2.04 g of the product of Preparative Example 44, 1.3
mL of PBr.sub.3, 1.0 mL of Et.sub.3N and 20 mL of CH.sub.2Br.sub.2,
and heat the mixture at reflux overnight. Cool the mixture, dilute
with CH.sub.2Cl.sub.2 and wash with 1 N NaOH (aqueous). Dry over
MgSO.sub.4 and concentrate in vacuo to give 1.22 g (53% yield) of
the product compound. Mass Spec.: MH.sup.+=541 209
[0461] Combine 0.3 g of the product compound from Preparative
Example 56, Step A, and 8 mL of n-butylamine and stir at
120.degree. C. in a sealed tube for 48 hours. Concentrate in vacuo
to a residue and purify by preparative plate chromatography (silica
gel, 1.5-2.5% MeOH/CH.sub.2Cl.sub.2) to give 80 mg (27%) yield of
the product compound. Mass Spec.: MH.sup.+=534 210
[0462] Combine 66 mg of the product compound from Preparative
Example 56, Step B, 4 mL of anhydrous EtOH, and 15 mL of
concentrated HCl stir at reflux for 60 hours. Cool the reaction
mixture to about 0.degree. C. and basify by the adding KOH. Extract
with CH.sub.2Cl.sub.2, dry the extract over MgSO.sub.4, and
concentrate in vacuo to give 46 mg (81% yield) of the product
compound. Mass Spec.: MH.sup.+=462
PREPARATIVE EXAMPLE 57
[0463] 211
[0464] Combine 1.19 g of the product of Preparative Example 44, 10
mL of anhydrous DMF, 0.2 g of NaH (60% in mineral oil) and 0.19 mL
of methyl iodide, and stirr at room temperature overnight.
Concentrate in vacua to a residue, dilute the residue with
CH.sub.2Cl.sub.2, wash with saturated NaHCO.sub.3 (aqueous), and
dry over MgSO.sub.4. Concentrate in vacua to give 1.13 g (92%
yield) of the product compound. Mass Spec.: MH.sup.+=493. 212
[0465] Hydrolyze 1.13 g of the product of Step A via substantially
the same procedure as describe for Preparative Example 56, Step C,
to give 0.61 g (63% yield) of the product compound.
PREPARATIVE EXAMPLE 58
[0466] 213
[0467] Combine 1.07 g (3.52 mmol) of tetrabutylammonium nitrate, 4
mL of anhydrous CH.sub.2Cl.sub.2 and 0.743 g (3.52 mmol) of TFAA,
and add the resulting mixture to a solution of 1.22 g (3.20 mmol)
of the title compound of Preparative Example 37 in 8 mL of
anhydrous CH.sub.2Cl.sub.2 at room temperature. Stir at room
temperature overnight, then wash with 20 mL of saturated
NaHCO.sub.3 (aqueous) and 20 mL of brine, and dry over MgSO.sub.4.
Concentrate in vacuo and chromatograph the resulting residue
(silica gel, EtOAc/hexane) to give 0.216 g of the product compound
58(i) and 0.27 g of the product compound 58(ii).
[0468] Analytical data for Compound 58(i): Mass Spec.
MH.sup.+=426.
[0469] Analytical data for Compound 58(i): m.p.
97.5.degree.-99.2.degree. C. 214
[0470] Reduce the product 58(i) from Step A via essentially the
same procedure as described in Preparative Example 47, Step B, to
give the product compound. Mass Spec.: MH.sup.+=396 215
[0471] React the product from Step B with HBr and bromine via
essentially the same procedure as described in Preparative Example
47, Step C, to give the product compound. Mass Spec.: MH.sup.+=459
216
[0472] Hydrolyze 0.83 g of the product from Step C via essentially
the same procedure as described in Preparative Example 56, Step C,
to give 0.56 g of the product compound. Mass Spec.:
MH.sup.+=387
PREPARATIVE EXAMPLE 59
[0473] 217
[0474] Combine 7.3 g (26.4 mmol) of the starting ketone (see J.
Med. Chem., 4238 (1992)) and 230 mL of THF and cool to 0.degree. C.
Add a solution of 32.2 mmol) of N-methyl-piperidine-4-magnesium
bromide in 26 mL of THF and stir at 0.degree.-5.degree. C. for 4
hours. Add 400 mL of EtOAc, wash with saturated NH.sub.4Cl
(aqueous), and dry over MgSO.sub.4. Concentrate in vacuo to a
residue, add -200 mL of CH.sub.2Cl.sub.2 and stir for 0.5 hours.
Filter to collect the resulting solid and concentrate the filtrate
to a volume of .about.100 mL and let sit at 5.degree. C. for 18
hours. Filter and combine the solids to obtain a total of 7 g (19.4
mmol) of the product compound. m.p.=153.7.degree.-158.degree. C.;
Mass Spec.: (Cl) MH.sup.+=376 218
[0475] Combine 5 g of the product from Step A and 30 mL of TFA at
ambient temperature and stir for 1 hour. Concentrate in vacuo to a
residue, dissolve the residue in CH.sub.2Cl.sub.2 and wash with a
saturated NaHCO.sub.3 (aqueous). Concentrate in vacua to give 4.64
g of the product compound. m.p.=136.7.degree.-138.degree. C.; Mass
Spec.: (FAB) MH.sup.+=358.1 219
[0476] Combine 0.6 g (1.75 mmol) of the product of Step B and 25 mL
of toluene, add 0.73 mL (5.27 mmol) of Et.sub.3N and 1.34 mL (14
mmol) of ClCO.sub.2Et, and heat to 80.degree. C. for 2 hours. Add
0.7 mL more of ClCO.sub.2Et, heat for 1 more hour, then cool to
25.degree. C. and concentrate in vacua to a residue. Dissolve the
residue in EtOAc and wash with 1N NaOH (aqueous) followed by brine.
Dry over MgSO.sub.4, concentrate in vacuo to a residue and
chromatograph (silica gel, 10% EtOAc/hexanes) to give 0.55 g of the
product compound. Mass Spec.: (FAB) MH.sup.+=416.2 220
[0477] Dissolve 5 g (12.5 mmol) of the product of Step C in 30% HBr
in HOAc and heat at 40.degree. C. for 24 hours, then cautiously add
the mixture to cold 25% NaOH (aqueous). Extract with
CH.sub.2Cl.sub.2 (3.times.100 mL), concentrate the extracts to a
residue and chromatograph (silica gel, 5% to 30%
MeOH/CH.sub.2Cl.sub.2) to give 2.18 g of the product compound.
m.p.=159.5.degree.-160.8.degree. C.; Mass Spec.: (FAB)
MH.sup.+=344.1
PREPARATIVE EXAMPLE 60
[0478] 221
[0479] Combine 16.25 g (40.83 mmol) of the product of Preparative
Example 47, Step B. and a slurry of 7.14 g (61.11 mmol) of
NOBF.sub.4 in 100 mL of CH.sub.2Cl.sub.2 and stir the mixture for 3
hours. Add 100 mL of o-dichlorobenzene and heat for 5 hours,
distilling the CH.sub.2Cl.sub.2 from the mixture. Concentrate in
vacuo to a residue, add 200 mL of CH.sub.2Cl.sub.2 and wash with
water (2.times.200 mL). Dry over MgSO.sub.4, concentrate in vacuo
to a residue, and chromatograph (silica gel, 20% EtOAc/hexane) to
give 4.1 g of product compound 60(i) and 4.01 g of Product compound
60(ii). Analytical data for compound 60 (i): Mass Spec.:
MH.sup.+=418 Analytical data for compound 60 (ii): Mass Spec.:
MH.sup.+=401 222
[0480] Hydrolyze 3.4 g of the product 60 (ii) from Step A via
essentially the same process as described for Example 358, Step A,
to give 3.01 g of product compound. Mass Spec.: MH.sup.+=329
[0481] Using the starting compound indicated and substantially the
same procedure as described in Preparative Example 60, Step B, the
following product compound is prepared:
7 Starting Analytical Compound Compound Data Preparative Example
60, Step A, compound 60(i) 223 Mass Spec.: MH.sup.+ =346
Preparative Example 60A
PREPARATIVE EXAMPLE 61
[0482] 224
[0483] Combine 10 g (60.5 mmol) of ethyl 4-pyridylacetate and 120
mL of dry CH.sub.2Cl.sub.2 at -20.degree. C., add 10.45 g (60.5
mmol) of MCPBA and stir at -20.degree. C. for 1 hour and then at
25.degree. C. for 67 hours. Add an additional 3.48 g (20.2 mmoles)
of MCPBA and stir at 25.degree. C. for 24 hours. Dilute with
CH.sub.2Cl.sub.2 and wash with saturated NaHCO.sub.3 (aqueous) and
then water. Dry over MgSO.sub.4, concentrate in vacuo to a residue,
and chromatograph (silica gel, 2%-5.5% (10% NH.sub.4OH in
MeOH)/CH.sub.2Cl.sub.2)to give 8.12 g of the product compound. Mass
Spec.: MH.sup.+=182.15 225
[0484] Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL
of EtOH and 96.6 mL of 10% NaOH (aqueous) and heat the mixture at
67.degree. C. for 2 hours. Add 2 N HCl (aqueous) to adjust to pH
=2.37 and concentrate in vacuo to a residue. Add 200 mL of dry
EtOH, filter through celite.RTM. and wash the filter cake with dry
EtOH (2.times.50 ml). Concentrate the combined filtrates in vacuo
to give 2.43 g of the title compound.
[0485] Using the product of Preparative Example 26 and
substantially the same procedure as described for Preparative
Example 61, Steps A and B, the following compound was prepared:
226
PREPARATIVE EXAMPLE 62
[0486] 227
[0487] Combine 10 g (65.7 mmol) of 3-methoxycarbonylaminopyridine
and 150 mL of CH.sub.2Cl.sub.2, cool to 0.degree. C. and slowly add
(dropwise) a solution of 13.61 g (78.84 mmol) of MCPBA in 120 mL of
CH.sub.2Cl.sub.2 at 0.degree. C. over a period of 1 hour. Stir the
mixture at 25.degree. C. for 5 days, then wash with saturated
NaHCO.sub.3 (aqueous), then water and dry over MgSO4. Concentrate
in vacuo to a residue and chromatograph (silica gel, 2%-5% (10%
NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give the product compound.
Mass Spec.: MH.sup.+=169
PREPARATIVE EXAMPLE 63
[0488] 228
[0489] Combine 5 g (36.0 mmol) of isonicotinic acid 1-N-oxide and
150 mL of anhydrous DMF, add 5.5 mL (39.6 mmol) of Et.sub.3N and
stir at 0.degree. C. for 0.5 hours. Slowly add (dropwise) 8.5 mL
(39.6 mmol) of diphenylphosphoryl azide at 0.degree. C. over 10
minutes, stir at 0.degree. C. for 1 hour and then at 25.degree. C.
for 24 hours (as generally described in Pavia, et al, Journal of
Medicinal Chemistry, 33, 854-861 (1990). Concentrate in vacuo to a
residue and chromatograph (silica gel, 0.5%-1%
MeOH/CH.sub.2Cl.sub.2) to give 5.9 g of the product compound.
[0490] Using nicotinic acid 1-N-oxide and substantially the same
procedure as described for Preparative Example 63 the following
compound was prepared: 229
PREPARATIVE EXAMPLE 64
[0491] 230
[0492] Hydrogenate 25 g (144 mmol) of 3-pyridylacetic acid
hydrochloride for 144 hours using the procedure described in
Preparative Example 15 to give 20 g of the product compound. Mass
Spec.: MH.sup.+=144. 231
[0493] React 12 g (83.8 mmol) of the product of Step B for 148
hours using the procedure described in Preparative Example 13, Step
B, to give 17.5 g of the product compound. Mass Spec.:
MH.sup.+=244.25
PREPARATIVE EXAMPLE 65
[0494] 232
[0495] Combine 25 g (164.4 mmol) of methyl 3-pyridylcarbamate and
163.3 mL of 1N HCl (aqueous), stir until all of the solid
dissolves, then hydrogenate over 10% Pd/C at 25.degree. C. at 55
psi for 220 hours. Filter, wash the solids with water and treat the
combined filtrates with 150 mL of BioRad AG1X8 ion exchange resin
(OH.sup.-). Filter, wash the resin with water and concentrate the
filtrate to a volume of 100 mL. Add 16.43 mL (197.3 mmol) of 37%
formalin and hydrogenate over 10% Pd/C at 25.degree. C. at 55 psi
for 89 hours. Filter, wash the solids with water and concentrate in
vacuo to give 24.3 g of the title compound. Mass Spec.:
MH.sup.+=173.2
PREPARATIVE EXAMPLE 66
[0496] 233
[0497] Cool 50.0 g (20.5 mmol) of 8-chloro-5,6-dihydro-11
H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one to 0.degree. C., slowly
add 75 mL (93.69 mmol) of sulfur monochloride over 20 minutes, then
slowly add 25 mL (48.59 mmol) of Br.sub.2 over 15. Heat at
95.degree. C. for 20 hour, add 12.5 mL (24.3 mmol) of Br.sub.2 and
heat for a another 24 hours. Cool the mixture, and slowly add to a
mixture of CH.sub.2Cl.sub.2 and 1N NaOH (aqueous) at 0.degree. C.
Wash the organic phase with water, dry over MgSO.sub.4 and
concentrate in vacuo to a residue. Chromatograph the residue
(silica gel, 500 mL CH.sub.2Cl.sub.2 then 0.2%-5% (10% NH.sub.4OH
in MeOH)/CH.sub.2Cl.sub.2), then chromatograph again (silica gel,
3%-8.5% EtOAc/hexane) to give 8.66 g of the product compound. Mass
Spec.: MH.sup.+=322
PREPARATIVE EXAMPLE 67
[0498] 234
[0499] Dissolve 0.16 g (0.46 mmol) of
4-(8-methyl-5,6-dihydro-11H-benzo[5,-
6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-ethoxycarbonyl-piperidine,
in 2 mL EtOH and add 4 mL of 12 N HCl. Heat the solution for 3
hours at 85.degree. C., then cool to 25.degree. C. Adjust to pH=10
with 50% NaOH (aqueous) and extract several times with 50 mL of
EtOAc. Combine the organic layers, dry them over MgSO.sub.4, and
concentrate in vacuo to give the product compound.
PREPARATIVE EXAMPLE 68
[0500] 235
[0501] Disolve 2 g (5.22 mmol) of the title compound of Preparative
Example 1F in 2.6 mL of dry N-methyl-2-pyridone. Add 0.87 g (9.4
mmol) of CuCN and 0.139 g (0.93 mmol) of sodium iodide. Heat the
mixture at 200.degree. C. under nitrogen for 20 hours, cool to
25.degree. C. and repeatedly grind and mix with five 50 mL portions
of CH.sub.2Cl.sub.2 and 7 M NH.sub.4OH (aqueous). Wash the organic
layer with 7 M NH.sub.4OH until the organic layer is no longer blue
or green. Dry the combined organic layers over MgSO.sub.4 and
concentrate in vacuo to a residue. Chromatograph (silica gel 70%
EtOAc/hexane), then recrystallize from EtOAc/hexane to give the
product compound. m.p.=152.4.degree.-153.5.degre- e. C.; Mass
Spec.: MH.sup.+=374 236
[0502] Dissolve 4.08 g (10.93 mmol) of the product of Step A in 12
M HCl and heat at 85.degree. C. for 18 hours. Concentrate in vacuo
to a residue. Dissolve the residue in 175 mL of MeOH, saturate with
HCl gas, and heat at reflux for 18 hours. Concentrate in vacuo to
give the product compound as its HCl salt. Mass Spec.:
MH.sup.+=335
PREPARATIVE EXAMPLE 68
[0503] 237
[0504] Combine 75 g (0.196 mole) of the Product of Example 1, Step
F. and 300 mL of CH.sub.2Cl.sub.2 at 0.degree. C., and slowly add
(dropwise) a solution of 72 g (0.236 mole) of tetrabutylammonium
nitrate and 35 mL (0.247 mole) of TFAA in 500 mL of
CH.sub.2Cl.sub.2. Stir at 25.degree. C. overnight, slowly add
(dropwise) 1 L of saturated NaHCO.sub.3 (aqueous). Separate the
layers, wash the organic phase with brine and dry over MgSO.sub.4.
Concentrate in vacuo to a residue, chromatograph twice (1 kg silica
gel, gradient of EtOAc/CH.sub.2Cl.sub.2) to give 8.63 g of product
compound 69(i), and 34 g of product compound (ii). Recrystallize
compound 69(i) from CH.sub.2Cl.sub.2/hexane to give the purified
product compound 69(i). m.p.=186.degree.-187.degree. C.; Mass
Spec.: (FAB) MH.sup.+=401
PREPARATIVE EXAMPLE 69
[0505] 238
[0506] Combine 0.4 g (1 mmol) of the Product of Example 47, Step B,
and 0.2 mL (1.2 mmoles) of 2, 5-diethoxytetrahydrofuran in 3 mL of
glacial HOAc, and heat at reflux for 1.5 hours. Cool the mixture,
wash with saturated NaHCO.sub.3 (aqueous), then with brine, dry
over MgSO.sub.4, and concentrate in vacuo to a residue.
Chromatograph (silica gel, 5%-15% EtOAc/CH.sub.2Cl.sub.2) to give
0.34 g of the product compound. Mass Spec.: (FAB) MH.sup.+=448
PREPARATIVE EXAMPLE 70
[0507] 239
[0508] Combine 13.8 g (34.7 mmol) of the Product of Example 47,
Step B, and 90 mL of water at 0.degree. C., add a solution of 6.9
mL of concentrated H.sub.2SO.sub.4 in 45 mL of water and stir the
mixture. Slowly add (dropwise) a solution of 2.55 g (40 mmol) of
NaNO.sub.2 in 75 mL of water and stir at 0.degree.-5.degree. C. for
0.5 hours. Add a boiling solution of 35.1 g CuSO.sub.4 in 135 mL of
water and heat at 100.degree. C. for 15 min. Cool the mixture,
extract with CH.sub.2Cl.sub.2 (2.times.200 mL), wash the extracts
with brine, dry over MgSO.sub.4, and concentrate in vacua to a
residue. Chromatograph (silica gel, 1.5%-10% MeOH/
CH.sub.2Cl.sub.2) to give 11.36 g of the product compound. 240
[0509] Combine 11.36 g (28.5 mmol) of the Product of Step A and
12.4 g (34.7 mmol) of N-phenyltriflimide in 120 mL of dry
CH.sub.2Cl.sub.2 at 0.degree. C., add 4.6 mL (33 mmol) of Et.sub.3N
and stir at 25.degree. C. overnight. Concentrate in vacuo to a
residue and chromatograph (silica gel, 2%-5%
EtOAc/CH.sub.2Cl.sub.2) to give 10.95 g of the product compound.
Recrystallize from hot MeOH. m.p.=154.5.degree.-156.degree. C.;
Mass Spec.: (FAB) MH.sup.+=531 241
[0510] Combine 12.2 g (23 mmol) of the Product of Step B and 85 mL
of 1-methyl-2-pyrrolidinone at 25.degree. C., then add 2.84 g LiCl,
0.212 g of tris-furylphosphine and 0.585 g of
dipalladiumtribenzylideneacetone and stir for 15 min. Slowly add
(dropwise) 7.5 mL (25.77 mmol) of tributylvinyltin and stir at
25.degree. C. for 2.5 hours. Dilute with 500 mL of water at
0.degree. C. and extract with 6700 mL of EtOAc. Filter the organic
phase through celite.RTM., wash the celite with EtOAc, then wash
the filtrate twice with 30% NaF (aqueous). Filter the organic
solutionwash with brine and dry over MgSO.sub.4. Concentrate in
vacuo to a residue and chromatograph (silica gel, 15%-40%
EtOAc/hexane) to give 8.58 g of the product compound. Mass Spec.:
(FAB) MH.sup.+=409
[0511] Using the stannane indicated, the following compounds were
prepared via substantially the same procedure as described for
Preparative Example 70, Step C:
8 Starting Analytical Compound Product Compound Data 2-(tributyl-
stannyl)- thiophene and Preparative Example 70 Step B 242 m.p.
=155.degree..about.157.degree. C. Mass Spec.: MH.sup.+ = 465
Preparative Example 70-A
[0512] 243
[0513] Hydrolyze 1.18 g (2.89 mmol) of the product of Step C via
substantially the same procedure as described in Example 358, Step
A, to give 0.95 g of the product compound. Mass Spec.: (FAB)
MH.sup.+=337
PREPARATIVE EXAMPLE 71
[0514] 244
[0515] Combine 1.01 g (19.9 mmol) of the Product of Example 48,
Step A, 30 mL of DMF, 1.33 g (6.96 mmol) of methyl
2,2-difluoro-2-(fluorosulfonyl)-a- cetate and 0.75 g (3.97 g) of
CuI. Heat the mixture at 60.degree.-80.degree. C. for 3 hours, then
concentrate to a residue. Dilute the residue with water, extract
with CH.sub.2Cl.sub.2, and concentrate in vacuo to a residue.
Chromatograph (silica gel, 30% EtOAc/hexane, then 10%
MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to give 0.15 g of the product
compound. Mass Spec.: MH.sup.+=451.1 245
[0516] Hydrolyze the product of Step A using essentially the same
procedure as described in Preparative Example 1, Step G, to give
the product compound. Mass Spec.: MH.sup.+=379
PREPARATIVE EXAMPLE 72
[0517] 246
[0518] Dissolve 20 g (50 mmol) of the Product of Example 1, Step F,
in 400 mL of concentrated H.sub.2SO.sub.4, cool to -5.degree. C.
and add 5.1 g (50 mmol) of KNO.sub.3 in small portions. Stir for 3
hours, cool the mixture and slowly basify with 50% NaOH (aqueous).
Extract with CH.sub.2Cl.sub.2 (3.times.500 mL), dry the combined
extracts over MgSO.sub.4, and concentrate in vacuo to a residue.
Chromatograph (silica gel, 50% EtOAc/hexane) to give 16.33 g of the
product compound (72i) and 2.6 g of the product compound (72ii).
For product compound (72i), Mass Spec.: MH.sup.+=428. For product
compound (72ii), Mass Spec.: MH.sup.+=428. 247
[0519] Hydrolyze 5.46 g (12.76 mmol) of the Product of (72i) from
Step A, via substantially the same procdure as described for
Example 358, Step A, to give 4.34 g of the product compound. Mass
Spec.: MH.sup.+=356
PREPARATIVE EXAMPLE 73
[0520] 248
[0521] Combine 1.6 g of the Product (54i) of Preparative Example
54, Step B, 12 mL of CH.sub.2Cl.sub.2, and 1.16 g of
tetrabutylammonium nitrate, cool to 0.degree. C. and slowly add
(dropwise) a solution of 0.8 g of TFAA in 2 mL of CH.sub.2Cl.sub.2.
Stir for 6 hours at 0.degree. C., let the mixture stand at
0.degree. C. overnight, then wash successively with saturated
NaHCO.sub.3 (aqueous), water and brine, and dry over
Na.sub.2SO.sub.4. Concentrate in vacuo to a residue, then
chromatograph (silica gel, 30% EtOAc/hexane) to give 0.38 g of the
product compound. 249
[0522] Hydrolyze 0.38 g of the Product of Step A via substantially
the same procedure as described for Example 358, Step A, to give
0.235 g of the product compound.
EXAMPLE 1
[0523]
1-(4-Pyridylacetyl)-4-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohept-
a[1,.2-b]Pyridin-11-Ylidene)Piperidine 250
[0524] To a mixture of 528 mg (1.7 mmol) of
4-(8-chloro-5,6-dihydro-11H-be-
nzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine (product
from Preparative Example 1, Step G), 274 mg (1.7 mmol) of
4-pyridylacetic acid hydrochloride, and 242 mg (1.8 mmol) of HOBT
in 5 mL of dry CH.sub.2Cl.sub.2 at -15 .degree. C. and under a
nitrogen atmosphere was added dropwise 0.17 mL (1.5 mmol) of
Et.sub.3N followed by a solution of 363 mg (1.g mmol) of DEC in 5
mL of dry CH.sub.2Cl.sub.2. The reaction mixture was slowly allowed
to warm to room temperature. After 4 hours the mixture was poured
into water and extracted several times with CH.sub.2Cl.sub.2. The
combined organic portions were dried over MgSO.sub.4, filtered, and
concentrated in vacuo to give a product which was purified via
flash chromatography (3% MeOH saturated with ammonia in
CH.sub.2Cl.sub.2) 155 mg of
1-(4-pyridylacetyl)-4-(8-chloro-5,6-dihydro-1-
1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine as a
solid: mp 152-155.degree. C.
[0525] By essentially the same procedure as set forth in Example 1,
but using the carboxylic acids set forth in column 1, of Table 2
below, in place of 4-pyridylacetic acid, one can obtain the
compounds listed in column 2 of Table 2. The compounds listed in
Table 2 refer to compounds of Formula 500.00: 251
[0526] wherein R is the substituent in Column 2.
9TABLE 2 EXAMPLE COLUMN 1 COLUMN 2 COMPOUND 2 252 253 glass 3 254
255 white powder 4 256 257 white solid 5 258 259 white crystals mp
200.degree. C. 6 260 261 mp 122-125.degree. C. 7 262 263 -- 8 264
265 off white powder 9 266 267 glass 10 268 269 white solid 11 270
271 white solid 12 272 273 glass 13 274 275 white solid 14 276 277
glass 15 278 279 mp 176-178.degree. C. 16 280 281 glass 17 282 283
mp 200-204.degree. C. 18 284 285 glass 19 286 287 glass 20 288 289
yellow solid 21 290 291 off white solid 22 292 293 white solid mp
228.degree. C. (dec) 23 294 295 white solid mp 205-207.degree. C.
24 296 297 white powder 25 298 299 white powder 26 300 301 glass 27
302 303 glass 28 304 305 glass 29 306 307 glass 30 308 309 mp
211-215.degree. C. 31 310 311 yellow solid 32 312 313 white solid
33 314 315 white solid 34 316 317 glass 35 318 319 solid mp
190-193.degree. C. 36 320 321 solid 37 322 323 glass 38 324 325
white solid 39 326 327 glass 40 328 329 mp 218-220.degree. C. 41
330 331 light brown solid mp =92.7-93.degree. C. MS M+ = 459 42 332
333 white solid mp =114.2-115.8.degree. C. MS M+ = 506 43 334 335
white solid mp =93.3-94.6.degree. C. MS M+ = 506 44 336 337 white
solid mp =112-114.6.degree. C. MS M+ = 428 45 338 339 white solid
mp =94.3-95.5.degree. C. MS M+ = 474 46 340 341 white solid mp
=126.5-127.5.degree. C. MS M+ = 607 47 342 343 white solid mp =
83.6-85.0.degree. C. 48 344 345 white solid mp =82.7-83.8.degree.
C. MS M+ = 456 49 346 347 white solid MS M+ = 534 49a 348 349 white
solid mp =73.5-73.8.degree. C. 288 350 351 white solid MH.sup.+ 452
Preparative Ex. 25 299 352 353 off white solid MH.sup.+ 459
Preparative Ex. 26 300 354 355 white solid MH.sup.+ 459 Preparative
Ex.10
EXAMPLE 50
[0527]
1-(2-Thiopheneacetyl-4-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohep-
ta[1,2-b]Pyridin-11-Ylidene)Piperidine 356
[0528] To a solution of 1.0 gm (3.22 mmole) of
4-(8-chloro-5,6-dihydro-11H- -benzo[5,6]cyclohepta
[1,2-b]pyridin-11-ylidene) piperidine and 0.29 mL of pyridine in 20
mL of dry CH.sub.2Cl.sub.2 at 0.degree. C. and under an argon
atmosphere was added dropwise 0.438 mL (3.55 mmol) of
2-thiopheneacetyl chloride. After 30 minutes the mixture was washed
with 1.0 N aqueous NaOH and then brine. The organic portion was
dried over Na.sub.2SO.sub.4, filtered and converted in vacuo to
provide a residue which was purified via flash chromatography (3%
MeOH in CH.sub.2Cl.sub.2) and treated with activated carbon to
provide the title compound as a glass.
EXAMPLE 51
[0529] By essentially the same procedure as set forth in Example
50, but using the acid chlorides set forth in Column 1, in Table 3
below, in place of 2-thiopheneacetyl chloride, one can obtain the
compounds listed in Column 2 of Table 3. The compounds listed in
Table 3 refer to compounds of Formula 500.00: 357
[0530] wherein R is the substituent in Column 2
10TABLE 3 EXAMPLE COLUMN 1 COLUMN 2 COMPOUND 52 358 359 solid 53
360 361 solid mp 158-160.degree. C. 54 362 363 glass 55 364 365
white powder 56 366 367 soldi mp 126-128.degree. C. 57 368 369
solid mp 137-139.degree. C. 58 370 371 solid mp 155-157.degree.
C.
EXAMPLE 65
[0531] By essentially the same procedures as set forth in Example
50 above, or Example 4 of U.S. Pat. No. 5,089,496, but using
372
[0532] in place of
4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]-
-pyridin-11ylidene)piperidine, one can obtain the compound 373
[0533] as a white solid.
EXAMPLE 75
[0534]
1-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclo-Hepta[1,2-b]Pyridin-11--
Yl-4-(4-Pyridylacetyl)-Piperazine 374
[0535] To a mixture of 8.5 g (27.2 m mole) of 8-chloro-11-(1
-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
(Preparative Example 7) in 256 mL of anhydrous DMF at room
temperature and under an argon atmosphere was added 2.98 g (27.2 m
mole of 4-methyl-morpholine, 7.81 g (27.2 m mole) of DEC, 3.68 g
(27.2 m mole) of HOBT, and 3.72 g (27.2 m mole) of 4-pyridylacetic
acid. The mixture was stirred at room temperature for 22 hours. The
mixture was poured into 3300 mL of CH.sub.2Cl.sub.2 and washed with
500 mL of water. The aqueous layer was extracted with 500 mL of
CH.sub.2Cl.sub.2. The combined organic portions were dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography using a solution of
1.5% (10% NH.sub.4OH in MeOH) in CH.sub.2Cl.sub.2. The product was
obtained as a white amorphous solid, M.S. (Mass Spec) M+=433.
[0536] By essentially the same procedures as set forth in Example
75 above but using the compounds set forth in Column 1, Table 4
below, in place of 4-pyridylacetic acid, one can obtain compounds
of the formula 375
[0537] wherein R is as listed in Column 2 of Table 4.
11TABLE 4 EX. COLUMN 1 COLUMN 2 CMPD 76 376 377 white amorphous
solid Mass Spec M+ = 501 77 378 379 white amorphous solid Mass Spec
M+ = 512 78 380 381 white amorphous solid Mass Spec M+ = 433 79 382
383 white amorphous solid Mass Spec M+ = 508 80 384 385 white
amorphous solid Mass Spec M+ = 432 81 386 387 white amorphous solid
Mass Spec M+ = 459
EXAMPLE 82
[0538]
8-CHLORO-11-[1-(2-(4-Pyridyl)Acetyl)-4-Piperidyl]-6,11-Dihydro-5H-B-
enzo[5,6]Cyclohepta[1,2-b]-Pyridine 388
[0539] Dissolve 0.1 g (0.32 m mole) of
8-chloro-11-4-piperidyl]-6,11-dihyd-
ro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine (from Example 233), 0.06
g (0.32 m mole) of 4-pyridylacetic acid, 0.092 g (0.48 m mole) of
DEC, 0.065 g (0.48 m mole) of HOBT and 0.048 g (0.50 m mole) of
N-methyl morpholine in 5 mL of DMF and stir at room temperature for
18 hours under nitrogen. Concentrate under vacuo and partition
between 100 mL each of EtOAc and water. Dry the organic layer over
sodium sulfate and concentrate under vacuo. The resulting residue
is chromatographed on silica gel using 98% dichloro methane and 2%
MEOH, saturated with ammonia as the solvent, giving the product as
a white waxy solid, mass spec M+=431.
EXAMPLE 82A
[0540]
8-Chloro-11-[1-(2-(Pyridyl)Acetyl)-4-Piperidyl]-6,11-Dihydro-5H-Ben-
zo[5,6]Cyclohepta[1,2-b]Pyridine 389
[0541] By essentially the same procedure as set forth in Example
82, but using 3-pyridylacetic acid instead of 4-pyridylacetic acid,
the title compound is obtained as a white solid (M+=431,
mp=81.7-82.degree. C.).
EXAMPLE 83
[0542]
8-Chloro-11-[1-(2-Methylsulfonyloxy-1-Phenylethyl-Carbonyl)-4-Piper-
idylidene]-6,11-Dihydro-5H-Benzo[5,6]- cyclohepta[1,2-b]-Pyridine
390
[0543] Dissolve 0.40 g (0.9 m mole) of
8-chloro-11-[1-(2-hydroxy-1-phenyle-
thylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]-cyclohepta-[1,2-
-]pyridine (Example 41 of Table 2) in 10 mL of pyridine and stir
under nitrogen. Add 0.15 g (1.3 m mole) of methanesulfonyl chloride
and stir for 20 hours. Concentrate under vacuo and triturate the
residue with ether. Purify the resulting solid by silica gel
chromatography using 2% MeOH saturated with amonia, and 98%
CH.sub.2Cl.sub.2 as the solvent. The product is obtained as a white
solid, mp=110.7-111.6.degree. C.
EXAMPLE 84
[0544]
8-Chloro-11-[1-(2-Acetylmercapto-1-Phenylethyl-Carbonyl)-4-Piperidy-
lidene]-6,11-Dihydro-5H-Benzo[5,6]-Cyclohepta[1,2-b]-Pyridine
391
[0545] Dissolve 0.3 g (0.56 m mole) of
8-chloro-11-[1-(2-methanesulfonyl-o-
xy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo-[5,6]cyc-
lohepta-[1,2-b]pyridine (Formula 5.6 of Example 83) in 5 mL of DMF
and add 0.2 g (0.6 m mole) of cesium thioacetate (preparation
described in Synthetic Communications, 13, 553, 1983). Stir the
reaction at 80.degree. C. for twenty hours then concentrate under
vacuo. Purify the residue by silica gel chromatography using 70%
EtOAc and 30% hexane as the solvent. The product is obtained as a
light brown solid, mp=92.7-93.degree. C.
EXAMPLE 85
[0546]
8-Chloro-11-[1-(1-(2,3-Dihydro-3-Oxo-1,2-Benzoiso-Thiazol-S,S-Dioxi-
de-2-Yl)Methylcarbonyl)-4-Piperidyl-Idene]-6,11-Dihydro-5H-Benzo[5,6]Cyclo-
hepta[1,2-b]-Pyridine 392
[0547] Dissolve 0.46 g (1.7 m mole) of
8-chloro-11-[1-(2-hydroxyethyl-carb-
onyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2,b]pyridi-
ne (Example 49a of Table 2) in 30 mL of DMF and stir at 0.degree.
C. under nitrogen. Add 0.55 g (2.1 m mole) of triphenyl phosphine
and 0.36 g (2.1 m mole) of diethyl azodicarboxylate. Stir reaction
mixture at 70.degree. C. for 3 days, then concentrate under vacuo.
The residue was dissolved in 50 mL of 1 N HCl and washed with 100
mL of EtOAc. The water layer was neutralized with 1 N NaOH and the
mixture was extracted with EtOAc. The organic layer was dried over
MgSO.sub.4 and concentrated under vacuo. The residue was purified
by silica gel chromatography using 90% EtOAc and 10% hexane as the
solvent, giving the product as a white solid, mass spec.
M+=534.
EXAMPLE 86
[0548]
8-Chloro-11-[1-(1-(3-Pyridyl)Methylthiocarbonyl)-4-Piperidylidene]--
6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]-Pyridine 393
[0549] Dissolve 0.50 g (0.12 m mole) of
8-chloro-11-[1-(1-(3-pyridyl)-meth-
ylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclo-hepta[1,2-b]-
-pyridine (Example 2 of Table 2) and 0.5 g (0.12 m mole) of
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
(Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at
room temperature and 18 hours at 80.degree. C., under nitrogen.
Filter the reaction mixture and concentrate under vacuo. Disolve
the residue in 50 mL of 1N HCl and extract with 200 mL of
CH.sub.2Cl.sub.2. The water layer was neutralized with
Na.sub.2CO.sub.3 and extracted with CH.sub.2Cl.sub.2. The organic
layer was dried over MgSO.sub.4 and concentrated under vacuo giving
the product as a white solid, mp=92-93.degree. C.
EXAMPLE 87
[0550] 10,11-Dihydro-5-[1-(1
-(4-Pyridyl)Methylcarbonyl)-4-Piperidylidene]-
-5H-Dibenzo[a,d]Cycloheptene 394
[0551] Dissolve 0.15 g (0.6 m mole) of
10,11-dihydro-5-(4-piperidylidene)-- 5H-dibenzo[a,d]cycloheptene,
0.096 g (0.55 m mole) of 4-pyridylacetic acid hydrochloride, 0.16 g
(0.83 m mole) of DEC and 0.075 g (0.55 m mole) of HOBT in 5 mL of
DMF and stir at room temperature for 18 hours under nitrogen.
Concentrate under vacuo and partition between 100 mL each of EtOAc
and 10% aqueous sodium hydrogenphosphate. Dry the organic layer
over MgSO.sub.4 and concentrate under vacuo. The resulting residue
is chromatographed on silica gel using 98% dichloro methane and 2%
MeOH, saturated with ammonia as the solvent, giving the product as
a white waxy solid, mp=162.8-163.4.degree. C.
EXAMPLE 180
[0552]
1-1-(4-Pyridinylacetyl)-4-[3.8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]C-
yclohepta[1,2-b]Pyridin-11-Ylidene]-Piperidine 395
[0553] Dissolve 0.18 g (0.51 mmole) of 3,8-dichloro
11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cycohepta[1,2-b]-
pyridine, 0.088 g (0.51 mmole) 4-pyridylacetic acid, 0.117 g (0.61
mmole) of DEC, 0.082 g (0.61 mmole) HOBT and 0.071 g (0.71 mmole)
N-methyl morpholine in 5 mL of DMF and stir for 18 hours under
nitrogen. Concentrate under vacuo and partion between EtOAc and
water. Dry organic layer over sodium sulfate and concentrate in
vacuo. The resulting residue is chromatogaphed on silica gel using
95% CH.sub.2Cl.sub.2 and 5% MeOH, saturated with ammonia as the
solvent. The product is obtained as white solid, mp=113-114.degree.
C.
EXAMPLE 181
[0554] 396
[0555] By essentially the same procedure as set forth in Exampe
180, but using
8-bromo-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6]c-
yclohepta[1,2-b]pyridine instead of
3,8-dichloro-11-(1-acetyl-4-piperidyli-
dene)-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine,
compound 5.48 was obtained as an off-white solid,
mp=94.3-94.7.degree. C.
EXAMPLE 182
[0556] 397
[0557] To a stirred solution of phenyl isocyanate (1.27 mmole) in
15 ml of anhydrous CH.sub.2Cl.sub.2 at room temperature and under
an argon atmosphere was added dropwise over 20 minutes, a solution
of 8-chloro-11-(1-piperazinyl)-6,11
-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]p- yridine (1.27 mmole) in 5
ml of anhydrous CH.sub.2Cl.sub.2. The mixture was stirred at room
temperature for 20 hours. The mixture was poured into 700 ml of
CH.sub.2Cl.sub.2 and washed with 100 ml of saturated NaHCO.sub.3.
The organic portion was dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography using a solution of 1.0% (10% NH.sub.4OH in MeOH) in
CH.sub.2Cl.sub.2. The product was obtained as a white amorphous
solid, M.S. (Mass Spec) M+=433.
EXAMPLE 183
[0558] 398
[0559] To a 5.0 ml reaction vial was added
8-chloro-11-(1-piperazinyl)-6,1-
1-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (1.0 mmole) and
N-ethoxycarbonyl-4-aminopyridine (0.99 mmole). The vial was capped
and placed in an oil bath at 170.degree. C. and stirred for 5
hours. The residue was purified by silica gel chromatography using
a solution of 3.0% (10% NH.sub.4OH in MeOH) in CH.sub.2Cl.sub.2.
The product was obtained as a white amorphous solid, M.S. (Mass
Spec) M+=434.
EXAMPLE 184
[0560]
1-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b)Pyridin-11-Y-
l)-4-(3-Pyridinylacetyl)piperazine 1-N-Oxide 399
[0561] The title compound from Preparative Example 11 D (0.5 grams)
(1.5 mmoles) was reacted with 3-pyridylacetic acid (0.208 grams)
(1.5 mmoles) under the conditions described in Example 75 to give
the title compound (Yield: 0.439 grams, 95%, MH.sup.+449).
EXAMPLE 185
[0562] 1-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta
[1,2-b]Pyridin-11-Yl)-4-(3-Pyridinylacetyl 1-N-Oxide)Piperazine
1-N-OXIDE 400
[0563] The title compound from Preparative Example 11D (0.5 grams)
(1.5 mmoles) was reacted with the title compound from Preparative
Example 8 (0.232 grams) (1.5 mmoles) under the conditions described
in Example 75 to give the title compound (Yield: 0.6454 grams, 92%,
MH.sup.+465.2).
EXAMPLE 186
[0564] N-Benzyl
4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyr-
idin-11-Yl)-1-Piperazinecarboxamide 401
[0565] The title compound from Example 75 was reacted with benzyl
isocyanate under the conditions described in Example 182 above to
give the title compound (Yield: 79%, MH.sup.+447).
EXAMPLE 187
[0566] By essentially the same procedure as Example 183, with the
exception that 3-ethoxycarbonylaminopyridine or
2-ethoxycarbonylaminopyri- dine (Preparative Example 12) is used
instead of using 4-ethoxy-carbonylaminopyridine, the compound
402
[0567] was obtained, respectively.
EXAMPLE 188
[0568]
4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Y-
l)-N-Methyl-N-(3-Pyridinyl)-1-Piperazine-Carboxamide 403
[0569] Compound 6.7 from Example 187 (10 grams) (23.1 mmoles) in
DMSO (37.6 ml.) was added to a solution of powdered KOH (2.62
grams) (23.1 mmoles) in DMSO (25 ml.) and the mixture was stirred
at 25.degree. C. for 3 minutes. lodomethane (1.4518 ml.) (23.1
mmoles) was added and the mixture was stirred at 25.degree. C. for
15 minutes. The mixture was poured into water and extracted with
CH.sub.2Cl.sub.2. The latter was dried (magnesium sulphate),
filtered and evaporated to dryness. The product was purified by
chromatography on silica gel using 3-5%(10% concentrated ammonium
hydroxide in MeOH)--CH.sub.2Cl.sub.2 as the eluant to give the
title compound (Yield: 6.28 grams, 61%, MH.sup.+448).
EXAMPLES 189-218
[0570] By essentially the same procedures as set forth in Example
75 above but using the compounds set forth in Column 1, Table 5
below, in place of 4-pyridylacetic acid, one can obtain compounds
of the formula 404
[0571] wherein R is as listed in Column 2 of Table 5.
12TABLE 5 EX. COLUMN 1 COLUMN 2 CMPD 189 405 406 white amorphous
solid MH.sup.+ 475 190 407 408 white amorphous solid MH.sup.+ 460
191 409 410 white amorphous solid MH.sup.+ 447 192 411 412 white
amorphous solid MH.sup.+ 467 193 413 414 white amorphous solid
MH.sup.+ 539 194 415 416 white amorphous solid MH.sup.+ 467 195 417
418 white amorphous solid MH.sup.+ 439 196 419 420 white amorphous
solid MH.sup.+ 433 197 421 422 white amorphous solid MH.sup.+ 449
198 423 424 white amorphous solid MH.sup.+ 461 199 425 426 white
amorphous solid MH.sup.+ 467 200 427 428 white amorphous solid
MH.sup.+ 467 201 429 430 white amorphous solid MH.sup.+ 453 202 431
432 white amorphous solid MH.sup.+ 525 203 Trifluroacetic Acid
deprotection of Compound 5.75 of Example 202 433 white amorphous
solid MH.sup.+ 525 204 434 435 white amorphous solid MH.sup.+ 497
205 436 437 white amorphous solid MH.sup.+ 481 206 438 439 white
amorphous solid MH.sup.+ 453 207 440 441 white amorphous solid
MH.sup.+ 505 208 442 443 white amorphous solid MH.sup.+ 471 209 444
445 white amorphous solid MH.sup.+ 489 210 446 447 white amorphous
solid MH.sup.+ 505 211 448 449 white amorphous solid MH.sup.+ 505
212 450 451 white amorphous solid MH.sup.+ 505 213 452 453 white
amorphous solid MH.sup.+ 595 214 454 455 white amorphous solid
MH.sup.+ 561 215 456 457 white amorphous solid MH.sup.+ 461 216 458
459 white amorphous solid MH.sup.+ 591 217 460 461 white amorphous
solid MH.sup.+ 503 218 462 463 white amorphous solid MH.sup.+
519
EXAMPLE 218-222
[0572] By essentially the same procedure as set forth in Example 1,
but using the acids set forth in Column 1 of Table 6 below in place
of 4-pyridylacetic acid, the compounds listed in Column 2 of Table
6 are obtained. The compounds listed in Table 6 refer to compounds
of Formula 500.00: 464
[0573] wherein R is the substituent in Column 2.
13TABLE 6 EX. COLUMN 1 COLUMN 2 CMPD 219 465 466 white amorphous
solid MH.sup.+ 482 m.p. =192-193.degree. C. 220 467 468 white
amorphous solid MH.sup.+ 502 m.p. =282-285.degree. C. 221 469 470
white amorphous solid MH.sup.+ 485 222 471 472 white amorphous
solid MH.sup.+ 514
EXAMPLE 223
[0574] A.
(+)-1-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(R)-Yl)-4-(3-Pyridinylacetyl)Piperazine 473
[0575] The title R(+) diastereoisomer from Preparative Example 19
was reacted with 3-pyridylacetic acid under the same conditions as
described in Example 75 to give the title compound (Yield: 88%,
MH.sup.+433).
[0576] B.
(-)-1-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(S)-Yl)-4-(3-pyridinylacetyl)Piperazine 474
[0577] The title S(-) diastereoisomer from Preparative Example 19
above was reacted with 3-pyridylacetic acid under the same
conditions as described in Example 75 to give the title compound
(Yield: 96%, MH.sup.+433).
EXAMPLE 224
[0578] A.
(+)-4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(R)-Yl)-N-(3-Pyridinyl)-1-Piperazine-Carboxylate 475
[0579] The title R(+) diastereoisomer from Preparative Example 19
was reacted with 3-ethoxycarbonylaminopyridine under the same
conditions as described in Example 75 to give the title compound
(Yield: 81%, MH.sup.+434).
[0580] B.
(-)-4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(S)-Yl)-N-(3-Pyridinyl)-1-Piperazine-Carboxamide 476
[0581] The title S(-) diastereoisomer from Preparative Example 19
was reacted with 3-ethoxycarbonylaminopyridine under the same
conditions as described in Example 75 to give the title compound
(Yield: 80%, MH.sup.+434).
EXAMPLE 225
[0582] A.
(+)-1-(8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(R)-Yl)-4[(1-Acetyl-4-Piperidinyl)-Acetyl]Piperazine 477
[0583] The title R(+) diastereoisomer from Preparative Example 19
above was reacted with 1-N-acetylpiperidinyl-3-acetic acid under
the same conditions as described in Example 75 to give the title
compound (Yield: 52%, MH.sup.+481).
[0584] B.
(-)-1-(8-chloro-5,6-Dihydro-11H-Benzo[5,6]cyclohepta[1,2-b]Pyrid-
in-11(S)-Yl)-4-[(1-Acetyl-4-Piperidinyl)-Acetyl]Piperazine 478
[0585] The title S(-) diastereoisomer from Preparative Example 19
above was reacted with 1-N-acetylpiperidinyl-3-acetic acid under
the same conditions as described in Example 75 to give the title
compound (Yield: 53%, MH.sup.+481).
EXAMPLE 226
[0586] A.
(+)-1-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(R)-Yl)-4-[(1-Acetyl-4-Piperidinyl)-Carbonyl]Piperazine
479
[0587] The title R(+) diastereoisomer from Preparative Example 19
was reacted with 1-N-acetylisonipecotic acid under the same
conditions as described in Example 75 to give the title compound
(Yield: 90%, MH.sup.+467).
[0588] B.
(-)-1-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyrid-
in-11(S)-Yl)-4-[(1-Acetyl-4-Piperidinyl)-Carbonyl]Piperazine
480
[0589] The title S(-) diastereoisomer from Preparative Example 19
was reacted with 1-N-acetylisonipecotic acid under the same
conditions as described in Example 75 to give the title compound
(Yield: 93%, MH.sup.+467).
EXAMPLE 227
[0590]
4-(8-Chloro-5,6-Dihydro-11H-Benzo-[5,6]Cyclohepta[1,2-b]Pyridin-11--
Ylidene)-1-[(4-Pyridinyl)Acetyl]-Piperidine N1Oxide 481
[0591] To a mixture of 0.933 g(3 mmol) of
4-(8-chloro-5,6-dihydro-11H-benz-
o-[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product
from Preparative Example 1, step G), 0.46 g(3 mmol) of 4-pyridyl
acetic acid N-Oxide (prepared as described in Preparative Example
8) 1-hydroxybenzo-triazole (0.40g, 3 mmol) in 20 mL of DMF at
.about.4.degree. C. and under nitrogen atmosphere was added N-
methyl morpholine(1.65 mL, 15 mmol) followed by DEC an reaction
stirred overnight at room temperature. The volatiles were stripped
off and the resulting semi-solid was partitioned between water and
EtOAc. The aqueous phase was washed twice with EtOAc. Combined
EtOAc fractions were dried over Na.sub.2SO.sub.4 and concentrated.
The crude product was purified via flash chromatography on silica
gel (first eluting with 3% and then 5% MeOH saturated with ammonia
in CH.sub.2Cl.sub.2) to give the title compound as a light brown
solid(0.2 g mp=128-130.degree. C. MH.sup.+446).
EXAMPLE 228
[0592]
4-(8-CHLORO-5,6-Dihydro-11H-Benzo-[5,6]Cyclohepta[1,2-b]Pyridin-11--
Ylidene)-1-[(3-Pyridinyl)Acetyl]-Piperidine N1 Oxide 482
[0593] By essentially the same procedure as set forth in Example
227, but using 3-pyridyl acetic acid N-oxide (Preparative Example
9) instead of 4-pyridyl acetic acid N-oxidethe title compound was
obtained as a white solid (mp=120-121.degree. C.,
MH.sup.+=466).
EXAMPLE 229
[0594]
4-(8-Chloro-5,6-Dihydro-11H-Benzo-[5,6]Cyclohepta[1,2-b]Pyridin-11--
Ylidene)-1-[(3-Pyridinyl)Acetyl]-Piperidine N4 Oxide 483
[0595]
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11--
ylidene)-1-[(3-pyridinyl)acetyl]-piperidine (1.0 g, 2.33 mmol) was
dissolved in dry CH.sub.2Cl.sub.2(50 mL) at -10.degree. C. MCPBA
(80-85% purity 1.1 g, 5.13 mmol) was added and the reaction stirred
at that temperature for 95 minutes. The reaction mixture was washed
with sodium bisulfite and then with 10% NaOH. The organic phase was
dried over MgSO.sub.4 and then concentrated. Purification on silica
gel eluting, first with 4%, 6% and then 10% MeOH in
CH.sub.2Cl.sub.2 gave rise to the title compound as a white solid
(0.2 g, 0.77 mmol MH.sup.+=446).
EXAMPLE 230
[0596]
4-(8-Chloro-5,6-Dihydro-11H-Benzo-[5,6]Cyclohepta[1,2-b]Pyridin-11--
Ylidene)-1-[(4-Pyridinyl)Acetyl]-Piperidine N4 Oxide 484
[0597] By essentially the same procedures as set forth in Example
229 above, but using
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]-
pyridin-11-ylidene)-1-[(4-pyridinyl)acetyl]-piperidine instead of
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yliden-
e)-1-[(3-pyridinyl)acetyl]-piperidine the title compound was
obtained as an off-white solid (MH.sup.+=446).
EXAMPLE 231
[0598] A.
8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidyl-Idene)-6,11-Dihydro-5H-
-Benzo[5,6]Cyclohepta[1,2-b]Pyridine N-Oxide 485
[0599]
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-ben-
zo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in
CH.sub.2Cl.sub.2 at -10.degree. C. 3-Chlorobenzoic acid(4.9 g,
15.67 mmmol) was then added and the reaction mixture stirred for 95
minutes. The reaction mixture was taken up in CH.sub.2Cl.sub.2 and
extracted with sodium bisulfite, 10% NaOH. The crude reaction
product was purified on silica gel eluting first with 1% and then
with 2% MeOH in CH.sub.2Cl.sub.2 to give the title compound (2.7 g,
MH.sup.+399).
[0600] B.
8-Chloro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohe-
pta[1,2-b]Pyridine N-Oxide 486
[0601] By essentially the same procedures as set forth in
Preparative Example 1 step G, but using
8-chloro-11-(1-ethoxycarbonyl-4-piperidyliden-
e)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine N-oxide
instead of
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6-
]cyclohepta[1,2-b]pyridine, the title compound was obtained and
used for the next reaction without further purification
(MH+327).
[0602] C. 4-(8-Chloro-5,6-Dihydro-11
H-Benzo[5,6]Cyclohepta(1,2-b]Pyridin--
11-Ylidene)-1-[(3-Pyridinyl)Acetyl]-Piperidine N1,N4 Dioxide
487
[0603] By essentially the same procedure as set forth in Example
227, but using 3-pyridyl acetic acid N-oxide (Preparative Example
9) instead of 4-pyridyl acetic acid N-oxide and
8-chloro-11-(4-piperidylidene)-6,11-dih-
ydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine N-oxide instead of
8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b-
]pyridine, the title compound was obtained as a white solid
(mp=105-107.degree. C., MH.sup.+=462).
EXAMPLE 232
[0604]
4-(8--Chloro-5,6-Dihydro-11H-Benzo-[5,6]Cyclohepta[1,2-b]Pyridin-11-
-Ylidene)-1-[(4-Pyridinyl)Acetyl]-Piperidine N1,N4 Dioxide 488
[0605] By essentially the same procedure as set forth in Example
227, but using
8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridine N-oxide instead of
8-chloro-11-(4-piperidylidene)-6,11-dih-
ydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, the title compound was
obtained as a light brown solid( MH.sup.+=462).
EXAMPLE 233
[0606] A.
8-Chloro-6,11-Dihydro-11-(4-Piperidinyl)-5H-Benzo[5,6]Cyclohepta-
[1,2-b]Pyridine (Product A) and
[0607] 6,11
-Dihydro-11-(4-Piperidinyl)-5H-Benzo[5,6]-Cyclohepta[1,2-b]Pyr-
idine (Product B) 489
[0608] To a solution 66.27 g (0.21 mole)
of4-(8-chloro-5,6-dihydro-11H-ben-
zo[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product
from Preparative Example 1 Example, step G), in THF (1L) was added
lithium aluminum hydride (24.32 g, 0.64 mole) and the reaction
mixture was heated to reflux overnight. The reaction mixture was
then cooled to room temperature and .about.3L of diethyl ether is
added followed by dropwise addition of saturated sodium sulfate
until a white gray precipitate forms. MgSO.sub.4 was then added to
the separated organic layer and stirred for 30 minutes. All the
volatiles were then removed and the resulting crude mixture was
chromatographed on a silica gel column eluting with 10% MeOH
saturated with ammonia in CH.sub.2Cl.sub.2. The material obtained
contained both the desired compound and the des-chloro compound.
Separation on HPLC using reverse phase column and eluting with 40%
MeOH-water afforded the desired compounds as white solids (Product
A's mp=95.2-96.1.degree. C., Product B's mp=145.1-145.7.degree.
C.).
[0609] B.
4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-1-
1-Yl)-1-[(3-Pyridinyl)Acetyl]-Piperidine N1 Oxide 490
[0610] By essentially the same procedure as set forth in Example
227, but using 3-pyridyl acetic acid N-oxide(Preparative Example 9)
instead of 4-pyridyl acetic acid N-oxide and
8-chloro-6,11-dihydro-11-(4-piperidinyl-
)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (product from Example
233A) instead of
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta(1,2-b]pyridi-
n-11-ylidene)-piperidine, the title compound was obtained as a
white solid (mp=117-118.degree. C., MH.sup.+=414).
EXAMPLE 234
[0611]
4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta(1,2-b]Pyridin-11-Y-
l)-1-[(4-Pyridinyl)Acetyl]-Piperidine N1 Oxide 491
[0612] By essentially the same procedure as set forth in Example
227, but using
8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta-[1-
,2-b]pyridine (product from Example 233A) instead of
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yliden-
e)-piperidine (product from Preparative Example 1, step G), the
title compound was obtained as a white solid (mp=125-126.degree.
C., MH.sup.+=414).
EXAMPLE 235
[0613] A.
Ethyl4-(8-Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]Pyr-
idin-11-YL)-1- Piperidine-Carboxylate 492
[0614]
8-Chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta-[1-
,2-b]pyridine (product from Example 233A) (4.18 g, 13 mmol) was
dissolved in toluene (175 mL). Ethyl chloroformate(11.6 g,110 mmol,
10.2 mL) was then added and the reaction mixture was heated to
.about.120.degree. C. overnight. All volatiles were stripped off
and the crude product was purified on silica gel column eluting
with 50% EtOAc-hexanes to give the title compound as a white
solid(MH.sup.+385).
[0615] B. Ethyl
4-(8-Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]Py-
ridin-11-Yl)-1-Piperidinecarboxylate N Oxide 493
[0616] By essentially the same procedure as set forth in Example
231, but using ethyl
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta(1,2-b]pyrid-
in-11-yl)-1-piperidinecarboxylate (product from Example 235A)
instead of
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6-
]cyclohepta[1,2-b]pyridine, the title compound was obtained as a
white solid (mp=81.7-82.5.degree. C., MH.sup.+=400).
[0617] C.
4-(8-Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]Pyridin--
11-Yl)-1-Piperidine N Oxide 494
[0618] By essentially the same procedure as set forth in
Preparative Example 1 step G, but using ethyl
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]-
cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate N1 oxide
(product from Example 235B) instead of
8-chloro-11-(1-ethoxycarbonyl-4-piperidylid-
ene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, the title
compound was obtained as a solid (MH.sup.+=329).
[0619] D.
4-(8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta(1,2-b]Pyridin-1-
1-Yl)-1-[(3-Pyridinyl)Acetyl]-Piperidine N4 Oxide 495
[0620] By essentially the same procedure as set forth in Example
227, but using 3-pyridyl acetic acid instead of 4-pyridyl acetic
acid N-oxide and
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1--
piperidine N oxide (product from Example 235C) instead of
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yliden-
e)-piperidine, the title compound was obtained as a white solid
(mp=61.8-62.3.degree. C., MH.sup.+=448).
EXAMPLE 236
[0621]
4-(8-Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]Pyridin-11--
Yl)-1-[(4-Pyridinyl)Acetyl]-Piperidine N4 Oxide 496
[0622] By essentially the same procedure as set forth in Example
227, but using 4-pyridyl acetic acid instead of 4-pyridyl acetic
acid N-oxide and
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta(1,2-b]pyridin-11-yl)-1--
piperidine, N oxide (product from Example 235C) instead of
4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yliden-
e)-piperidine, the title compound was obtained as a white solid
(mp=116.7-117.6.degree. C., MH.sup.+=448).
EXAMPLE 237
[0623]
4-(8--Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]PYRIDIN-11-
-Yl)-1-[(3-Pyridinyl)Acetyl]-Piperidine N1, N4 Oxide 497
[0624]
4-(8-Chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta(1,2-b]pyridin-11--
yl)-1-[(3-pyridinyl)acetyl]-piperidine, from Example 82A, (0.5 g,
1.2 mmol) was disolved in CH.sub.2Cl.sub.2 at about -18.degree. C.
MCPBA (0.62 g, 3.6 mmol) was added and the reaction stirred for 1.5
hours. The reaction mixture was extracted with 10% sodium
bisulfite, 10% NaOH and then dried with MgSO.sub.4, filtered and
concentrated. The crude product was purified on silica gel eluting
with 7% MeOH saturated with ammonia in CH.sub.2Cl.sub.2 to give the
title compound as a white solid(0.51 g, 91% yield MH.sup.+464).
EXAMPLE238
[0625]
4-(8-Chloro-6,11-Dihydro-5H-Benzo-[5,6]Cyclohepta(1,2-b]Pyridin-11--
Yl)-1-[(4-Pyridinyl)Acetyl]-Piperidine N1, N4 Oxide 498
[0626] By essentially the same procedure as set forth in Example
237, but using
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11--
yl)-1-[(4-pyridinyl)acetyl]-piperidine (product from Example 82)
instead of
4-(8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-yl)-
-1-[(3-pyridinyl)acetyl]-piperidine, the title compound was
obtained as a white solid (mp=85-85.6.degree. C.,
MH.sup.+=464).
EXAMPLE 239
[0627]
4-(8-Chloro-3Methoxy-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]Py-
ridin-11-Ylidene)-1-[(3-Pyridinyl]Acetyl]-Piperidine 499
[0628] By essentially the same procedure as set forth in Example
180, but using
8-chloro-3-methoxy-11-(4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6-
]-cyclohepta[1,2-b]pyridine (Preparative Example 20) instead of
3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]-cy-
clohepta[1,2-b]pyridine the title compound was obtained as a white
solid (MH.sup.+460).
EXAMPLE 240
[0629]
4-(8-Chloro-3-Hydroxy-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]P-
yridin-11-Ylidene)-1-[(3-Pyridinyl]-Acetyl]-Piperidine 500
[0630]
4-(8-Chloro-3-methoxy-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]py-
ridin-11-ylidene)-1-[(3-pyridinyl]acetyl]-piperidine (0.24 g, 0.54
mmol) (Example 239) was dissolved in CH.sub.2Cl.sub.2 at 0.degree.
C. under nitrogen atmosphere. Bromine tribromide(0.9 g, 3.6 mmol,
3.6 mL) was added and the reaction was run at room temperature for
two days. The reaction mixture was concentrated and chromatographed
on a silica gel column eluting with 3% MeOH saturated with ammonia
in CH.sub.2Cl.sub.2 to give an off white borate salt solid (0.14 g,
61% yield, MH.sup.+446).
EXAMPLE 246
[0631]
1-1(4-Pyridinylacetyl)-4-[3-Bromo8-Chloro5-6-Dihydro-11H-Benzo[5,6]-
Cyclohepta[1,2-b]Pyridin-11Ylidene]-Piperidine 501
[0632] By essentialy the same procedure as set forth in Example 180
but using
4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyri-
din-11-ylidene)-piperidine instead of
4-(3,8-dichloro-5,6-dihydro-11H-benz-
o-[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine, the title
compound was obtained as a glassy solid (MH.sup.+508).
EXAMPLE 247
[0633]
1-1(3-Pyridinylacetyl)-4-[3-Bromo8-Chloro5-6-Dihydro-11H-Benzo[5,6]-
Cyclohepta[1,2-b]Pyridin-11Ylidene]-Piperidine 502
[0634] By essentialy the same procedure as set forth in Example
180, but using
4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyri-
din-11-ylidene)-piperidine instead of
4-(3,8-dichloro-5,6-dihydro-11H-benz-
o[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine and 3-pyridyl
acetic acid instead of 4-pyridyl acetic acid, the title compound
was obtained as a white solid (mp=92-93.degree. C.
MH.sup.+508).
EXAMPLE 248
[0635]
4-[4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-
-11-Ylidene]-1-(4-Pyridinylacetyl)-Piperidine and
[0636] 4-[2.8-Dichloro-5,6-Dihydro-11
H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridi-
n-11-Ylidene]-1-(4-Pyridinylacetyl)-Piperidine 503
[0637] A solution of the title compound from Example 230 (1.7
grams) and phosphorous oxychloride (21 mL) dissolved in chloroform
(12 mL) was stirred at reflux for 1 hour. Concentration in vacuo
provided a residue which was diluted with CH.sub.2Cl.sub.2 and
washed with saturated aqueous sodium bicarbonate and brine. The
organic phase was dried over anhydrous MgSO.sub.4, concentrated in
vacuo, and purified by flash column chromatography (silica gel)
using 2% MeOH--CH.sub.2Cl.sub.2 to afford the title 4,8-dichloro
compound (0.34 grams, 20% yield, mp 84-91.degree. C., MH.sup.+464)
and the title 2,8-dichloro compound (0.18 grams, 11% yield, mp
163.8-164.6.degree. C., MH.sup.+464).
EXAMPLE 249
[0638] 4-[4-[(1
H-Benzotriazol-1-Yl)Oxy]-8-Chloro-5,6-Dihydro-11H-Benzo[5,-
6]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-1-(4-Pyridinylacetyl)-Piperidine
504
[0639] A mixture of the 4,8-dichloro compound from Example 248 (0.5
grams), HOBT hydrate (0.4 grams) and anhydrous DMF (20 mL) was
stirred at 25.degree. C. under N.sub.2 for 5 days. The mixture was
concentrated in vacuo, diluted with CH.sub.2Cl.sub.2, and washed
with 1N aqueous NaOH. The organic phase was dried over anhydrous
MgSO.sub.4, concentrated in vacuo and purified by flash column
chromatography (silica gel) using 3-5% MeOH--CH.sub.2Cl.sub.2 to
give the title compound (0.58 grams, 96%, mp 98.6-101.6.degree. C.,
MH.sup.+563).
EXAMPLE 250
[0640]
4-[4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin--
11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine 505
[0641] A mixture of the 4,8-dichloro product from Preparative
Example 28 (1.91 grams), 3-pyridylacetic acid hydrochloride (2.1
grams), DEC (1.6 grams), 4-methylmorpholine (1.4 mL) and anhydrous
DMF (100 mL) was stirred at 25.degree. C. overnight. Concentration
in vacuo provided a residue which was diluted with CH.sub.2Cl.sub.2
and water. The organic phase was dried over anhydrous MgSO.sub.4
and concentrated in vacuo to provide the title compound (2.2 grams,
87%, mp 59.8-63.5.degree. C., MH.sup.+464).
EXAMPLE 251
[0642]
4-[4-[(1H-Benzotriazol-1-Yl)Oxy]-8-Chloro-5,6-Dihydro-11H-Benzo[5,6-
]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine
506
[0643] The 4,8-dichloro compound from Example 250 (0.8 grams) was
added to a solution of HOBT (1.2 grams) and sodium hydride (0.14
grams, 60% in mineral oil) in anhydrous dimethyl-formamide (60 mL).
The resulting solution was irradiated with a 200 W lamp while
stirring at 25.degree. C. for 60 hours. The solution was poured
into 1N aqueous NaOH while stirring and an additional 400 mL of
water was added to the resulting mixture. Filtration provided a
solid which was washed with water several times. The solid was
dissolved in CH.sub.2Cl.sub.2-acetone, dried over anhydrous
MgSO.sub.4, and concentrated in vacuo to proved the title compound
(0.87 grams, 90%, mp=120-122.degree. C., MH.sup.+563).
EXAMPLE 252
[0644]
4-[4-Hydroxy-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]P-
yridin-11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine 507
[0645] To a solution of the title compound form Example 251 (0.8
grams) and glacial acetic acid (30 mL) was added zinc dust (0.4
grams). After stirring at 25.degree. C. for 18 hour, the mixture
was filtered through celite and the filtrate concentrated in vacuo.
The residue was diluted with EtOAc, washed with saturated aqueous
sodium bicarbonate and brine. The organic layer was separated,
dried over MgSO.sub.4 and concentrated in vacuo to give the title
compound (Yield 0.346 grams, 58%, MH+446).
EXAMPLE 253
[0646]
4-[3-Bromo-4-Hydroxy-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[-
1,2-b]Pyridin-11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine 508
[0647] To a solution of the title compound from Example 252 (0.19
grams) and glacial acetic acid (4 mL) was added a 0.7 M
bromine-acetic acid solution (0.7 mL) at 25.degree. C. under
N.sub.2. After 10 minutes, water was added and the resulting solid
was filtered and washed with water several times and dried to give
the title compound (0.18 grams, 71%, MH.sup.+526).
EXAMPLE 255
[0648]
4-[8-Chloro-4-(Methylthio)-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-
-b]Pyridin-11-yl]dene]-1-(3-Pyridinylacetyl)-Piperidine 509
[0649] A mixture of the title compound from Example 250 (0.26
grams), sodium methylthiolate (0.06 grams) and anhydrous DMF (10
mL) was stirred while being irradiated with a 200 W lamp for 1
hour. After stirring an additional 12 hours at room temperature
without irradiation, the mixture was concentrated in vacuo, diluted
with CH.sub.2Cl.sub.2, and washed with 1N aqueous NaOH and brine.
The organic phase was dried over anhydrous MgSO.sub.4 and
concentrated in vacuo to afford the title compound as a white foam
(0.3 grams, 100%, MH.sup.+476).
EXAMPLE 256
[0650]
4-[8-Chloro-4-(Methylsulfinyl)-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta-
[1,2-b]Pyridin-11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine 510
[0651] To the title compound from Example 255 (0.18 grams)
dissolved in anhydrous THF (10 mL) was added 30% aqueous hydrogen
peroxide (3 mL) and the resulting solution was stirred for 12 hours
at 73.degree. C. The solution was concentrated in vacuo, diluted
with CH.sub.2Cl.sub.2, and washed with water. The organic phase was
dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford
the title compound after preparative plate chromatography (silica
gel) using 3% MeOH--CH.sub.2Cl.sub.2 (0.04 grams, 26%,
MH.sup.+492).
EXAMPLE 257
[0652] Methyl
[[8-Chloro-6,11-Dihydro-11-[1-[1-Oxo-2-(3-Pyridinyl)Ethyl]-4-
-Piperidinylidene]-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-4-Yl]Thio]Acetate
511
[0653] A mixture of the title compound from Example 250 (0.26
grams), sodium hydride (0.08 grams, 60% in mineral oil), methyl
thioglycolate (0.19 mL) and anhydrous DMF (15 mL) was stirred while
being irradiated with a 200 W lamp for 16 hours. The mixture was
diluted with MeOH, concentrated in vacua, diluted with
CH.sub.2Cl.sub.2 and water, and washed with 1N aqueous NaOH and
brine. The organic phase was dried over anhydrous MgSO.sub.4 and
concentrated in vacuo and the residue purified by preparative plate
chromatography (silica gel) using 3% MeOH--CH.sub.2Cl.sub.2 to
afford the title compound (0.05 grams, 15%, MH.sup.+534).
EXAMPLE 258
[0654]
4-[8-Chloro-5,6-Dihydro-4-(Phenylmethylthio)-11H-Benzo[5,6]Cyclohep-
ta[1,2-b]Pyridin-11-Ylidene]-1-(3-Pyridinylacetyl)-Piperidine
512
[0655] A mixture of the title compound from Example 250 (0.25
grams), sodium hydride (0.11 grams, 60% in mineral oil), benzyl
mercaptan (0.13 mL) and anhydrous DMF (15 mL) was stirred while
being irradiated with a 200 W lamp for 10 days. Isolation and
purification as in Example 257 provided the title compound (0.02
grams, 8%, MH.sup.+552).
EXAMPLE 259
[0656]
4-[8-Chloro-5,6-Dihydro-4-[(2-Methyl-2H-Tetrazol-5-Yl)thio]-11H-Ben-
zo[5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene-1-(3-Pyridinylacetyl)-Piperidin-
e 513
[0657] A mixture of the title compound from Example 250 (0.24
grams), 5-mercapto-1-methyltetrazole sodium salt (0.6 grams) and
anhydrous DMF (10 mL) was stirred while being irradiated with a 200
W lamp for 10 days. Isolation and purification as in Example 257
provided the title compound (0.2 grams, 68%, MH.sup.+544).
EXAMPLE 260
[0658] 1.1 -Dimethylethyl
[2-[[8-Chloro-6,11-Dihydro-11-[1-[1-Oxo-2-(3-Pyr-
idinyl)Ethyl]-4-Piperidinylidene]-5H-Benzo[5,6]-Cyclohepta[1,2-b]Pyridin-4-
-Yl]Thio]Ethyl] Carbamate 514
[0659] A mixture of the title compound from Preparative Example 32
(0.032 grams), 3-pyridylacetic acid hydrochloride (0.05 grams), DEC
(0.03 grams), Et.sub.3N (0.08 mL) and anhydrous DMF (4 mL) was
stirred at 25.degree. C. for 48 hours. Concentration in vacuo
provided a residue which was diluted with CH.sub.2Cl.sub.2 and
washed with 1N aqueous NaOH. The organic phase was dried over
anhydrous MgSO.sub.4 and concentrated in vacuo to provide the title
compound (0.02 grams, 50%, mp 59.8-63.5.degree. C.,
MH.sup.+605).
EXAMPLE 261
[0660]
4-(4.8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin--
11-Ylidene)-N-(3-Pyridyl)-1-Piperidinecarboxamide 515
[0661] A portion of the stock solution of 3-pyridylisocyanate (32
mL) prepared as described in Preparative Example 33 was added to
the 4,8-dichloro product from Preparative Example 28 (1.37 grams)
and the mixture was stirred at 25.degree. C. for 4 days. The
mixture was evaporated to dryness and the residue was taken up in
CH.sub.2Cl.sub.2 and washed with saturated aqueous sodium
bicarbonate and then water. The organic solution was dried over
MgSO.sub.4, filtered and evaporated to dryness. The residue was
purified by flash column chromatography silica gel) using 2%
MeOH--CH.sub.2Cl.sub.2 as eluent to give the title compound (Yield
1.25 grams, 70%, MH+465).
EXAMPLE 262
[0662]
4-[4-[(1H-Benzotriazol-1-Yl)OXY]-8-chloro-5,6-Dihydro-11H-Benzo[5,6-
]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-N-(3-Pyridyl)-1-Piperidinecarboxamid-
e 516
[0663] To a solution of the title compound from Example 261 (1.0
grams) in dry DMF (60 mL) was added HOBT (1.4 grams), sodium
hydride (0.2 grams, 60% in mineral oil) and distilled water (0.5
mL). The solution was stirred at 25.degree. C. under nitrogen while
being irradiated with a 200 Watt lamp for 20 hours. The reaction
mixture was concentrated in vacuo, diluted with CH.sub.2Cl.sub.2
and saturated aqueous sodium bicarbonate and after two hours, the
organic phase was separated, dried over MgSO.sub.4 and
concentrated. Purification by flash column chromatography (silica
gel) using 3-5% MeOH--CH.sub.2Cl.sub.2 afforded the title compound
(Yield 1.1 grams, 87%, MH+564).
EXAMPLE 263
[0664]
4-[4-Hydroxy-8-Chloro-5.6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b]P-
yridin-11-Ylidene]-N-(3-Pyridyl)-1-Piperidinecarboxamide 517
[0665] To a solution of the title compound form Example 262 (0.86
grams) and glacial acetic acid (20 mL) was added zinc dust (0.5
grams). After stirring at 25.degree. C. for 1.5 hours, the mixture
was filtered through celite and the filtrate concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel) using 5-10% MeOH--CH.sub.2Cl.sub.2 saturated with ammonium
hydroxide to give the title compound (Yield 0.47 grams, 69%,
MH+448).
EXAMPLE 264
[0666]
4-[3-Bromo-4-Hydroxy-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[-
1,2-b]Pyridin-11-Ylidene]-N-(3-Pyridyl)-1-Piperidinecarboxamide
518
[0667] To a solution of the title compound from Example 263 (0.34
grams) and glacial acetic acid (10 mL) was added a 0.7 M
bromine-acetic acid solution (4 mL) at 25.degree. C. under N.sub.2.
After 10 minutes, water was added and the resulting solid was
filtered and washed with water several times and dried to give the
title compound (Yield 0.31 grams, 67%, MH.sup.+527).
EXAMPLE 266
[0668]
4-(8-Chloro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Yl)-1-(3-Pyrid-
inylacetyl)-Piperidine 519
[0669] The title compound from Preparative Example 34C (2.0 g, 6.4
mmole) was dissolved in anhydrous DMF (70 mL) and the solution was
cooled with an ice bath for 30 minutes. 4-Methylmorpholine (3.3 g,
32 mmole), DEC (1.8 g, 9.7 mmole) and HOBT (0.87 g 6.4 mmole) were
added to the cold solution. 3-Pyridylacetic acid (0.88 g, 6.4
mmole) was added and the cooling bath removed. Stir the mixture at
room temperature for 18 hours. The reaction mixture was evaporated
to dryness and the residue was diluted with water (50 mL). The
aqueous mixture was extracted with EtOAc and the combined extracts
dried (MgSO.sub.4), filtered and evaporated. The resulting residue
was purifed by silica gel chromatography using a gradient of 97%
CH.sub.2Cl.sub.2/3% MeOH saturated with ammonia to 93%
dichlormethane/7% MeOH saturated with ammonia as eluent to give the
title compound (0.87 g MH.sup.+430).
EXAMPLE 267
[0670] E.
4-(8-Chloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Yl)-N-(3-P-
yridinyl)-1-Piperidinecarboxamide 520
[0671] The title compound from Preparative Example 34C was treated
with 3-pyridylisocyanate, similar to the procedure in Example 261,
to afford the title compound (MH.sup.+431).
EXAMPLE 268
[0672]
4-(8-Chloro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Yl)-1-[2-Methy-
l-2-(3-Pyridinyl)-1-Oxopropyl]-Piperidine 521
[0673] The title compound from Preparative Example 34C was treated
as described in Example 266, using
.alpha.,.alpha.-dimethyl-3-pyridylacetic acid (described in
Preparative Example 10B) in place of 3-pyridylacetic acid, to
afford the title compound (M+458).
EXAMPLE 269
[0674]
4-(8-Chloro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Yl)-1-(4-Pyrid-
inylacetyl)-Piperidine 522
[0675] The title compound from Preparative Example 34C above was
treated as descibed in Example 266, using 4-pyridylacetic acid in
place of 3-pyridylacetic acid, to give the title compound
(M.sup.+430).
EXAMPLE 270
[0676]
4-(8-Chloro-9-Ethyl-5H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-11-Yl)-1-
-(3-Pyridinylacetyl)-Piperidine 523
[0677] The title compound from Preparative Example 2A was treated
as descibed in Example 266 to give the title compound (M+=458,
mp=67.2-69.8.degree. C.).
EXAMPLE 273
[0678]
4-(4.8-Dichloro-5H-Benzo[5,6]Cyclohepta[1,2-B]Pyridin-11-Yl)-1-(3-P-
yridinylacetyl)-Piperidine 524
[0679] The title compound from Preparative Example 36C was treated
as descibed in Example 266 to give the title compound (mp
100.1-103.4.degree. C.).
EXAMPLE 274
[0680]
4-(4,8-Dichloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11-Yl)-N-(3--
Pyridinyl)-1-Piperidinecarboxamide 525
[0681] The title compound from Preparative Example 36C (0.75 g,
2.17 mmol) was treated with a pyridine solution of
3-pyridylisocyanate (from Preparative Example 33). The reaction
mixture was evaporated to dryness and the residue dissolved in
CH.sub.2Cl.sub.2. This solution was washed with saturated sodium
bicarbonate solution and brine, dried (MgSO.sub.4), filtered and
evaporated to give a dark syrup. The syrup was purified by silica
gel chromatography using a gradient of 97% CH.sub.2Cl.sub.2/3% MeOH
saturated with ammonia to 93% CH.sub.2Cl.sub.2/7% MeOH saturated
with ammonia. The title compound was obtained as a yellow solid
(0.13 g, 13%, M+465)
EXAMPLE 276
[0682]
4-(8-Chloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11Ylidene)-1-(3--
Pyridinylacetyl)-Piperidine 526
[0683] The title compound from Preparative Example 37B was treated
as descibed in Example 266 to give the title compound
(MH.sup.+428).
EXAMPLE 277
[0684]
4-(8Chloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11Ylidene)-N-(3-P-
yridinyl)-1-Piperidinecarboxamide 527
[0685] The title compound from Preparative Example 37B above was
treated as descibed in Example 261 above to give the title compound
(mp 95.9-97.6.degree. C.).
EXAMPLE 278
[0686]
4-(8-Chloro-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridin-11Ylidene)-1-[2--
Methyl-2-(3-Pyridinyl)-1-Oxo-Propyl]-Piperidine 528
[0687] The title compound from Preparative Example 37B was treated
as descibed in Example 266 using
.alpha.,.alpha.-dimethyl-3-pyridylacetic acid (described in
Preparative Example 10B) in place of 3-pyridylacetic acid, to give
the title compound (M+456).
EXAMPLE 279
[0688]
4-(8-Chloro-5,6-Dihydro-5-OXO-11H-Benzo[5,6]Cyclohepta[1,2-b]Pyridi-
n-11Ylidene)-1-(3-Pyridinylacetyl)-Piperidine 529
[0689] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, J. J.; Wong, J. K.; Chan, T. -M.; Green, M.
J.; and Ganguly, A. K. The procedure described in Example 266 was
followed using
8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-
-b]-pyridin-5-one to give the title compound (M.sup.+443).
EXAMPLE 280
[0690]
4-(8-Chloro-5,6-Dihydro-5-Hydroxy-11H-Benzo-[5,6]Cyclohepta[1,2-b]P-
yridin-11Ylidene)-1-(3-Pyridinyl-Acetyl)-Piperidine 530
[0691] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, J. J.; Wong, J. K.; Chan, T. -M.; Green, M.
J.; and Ganguly, A. K. The procedure described in Example 266 was
followed using
8-chloro-6,11-dihydro-5-hydroxy-11-(4-piperidinylidene)-5H-benzo[5,6]cycl-
ohepta[1,2-b]pyridine to give the title compound (MH.sup.+446).
EXAMPLE 281
[0692]
4-(8-Chloro-5,6-Dihydro-5-Oxo-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyrid-
in-11Ylidene)-1-(4-Pyridinylacetyl)-Piperidine 531
[0693] The procedure of Example 279 was followed with the exception
that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid
to give the title compound (MH.sup.+444).
EXAMPLE 282
[0694]
4-(8--Chloro-5,6-Dihydro-5-Hydroxy-11H-Benzo-[5,6]Cyclohepta[1,2-b]-
Pyridin-11Ylidene)-1-(4-Pyridinylacetyl)-Piperidine 532
[0695] The procedure of Example 280 was followed with the exception
that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid
to give the title compound (MH.sup.+446).
EXAMPLE 283
[0696]
4-(8-Chloro-5,6-Dihydro-6-Oxo-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyrid-
in-11Ylidene)-1-(3-Pyridinylacetyl)-Piperidine 533
[0697] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, J. J.; Wong, J. K.; Chan, T. -M.; Green, M.
J.; and Ganguly, A. K. The procedure described in Example 266 was
followed using
8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-
-b]pyridin-6-one to give the title compound (M.sup.+444).
EXAMPLE 284
[0698]
4-(8-Chloro-5,6-Dihydro-6-Hydroxy-11H-Benzo-[5,6]Cyclohepta[1,2-b]P-
yridin-11Ylidene)-1-(3-Pyridinylacetyl)-Piperidine 534
[0699] The preparation of the starting material for this reaction
was described in The Journal of Organic Chemistry, 1990, 55, pp.
3341-3350 by Piwinski, J. J.; Wong, J. K.; Chan, T. -M.; Green, M.
J.; and Ganguly, A. K. The procedure described in Example 266 above
was followed using
8-chloro-6,11-dihydro-6-hydroxy-11-(4-piperidinylidene)-5H-benzo[5,6]-cyc-
lohepta[1,2-b]pyridine to give the title compound
(MH.sup.+446).
EXAMPLE 285
[0700]
4-(8-Chloro-5,6-Dihydro-6-Oxo-11H-Benzo[5,6]-Cyclohepta[1,2-b]Pyrid-
in-11Ylidene)-1-(4-Pyridinylacetyl)-Piperidine 535
[0701] The procedure of Example 283 was followed with the exception
that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid
to give the title compound (M.sup.+444).
EXAMPLE 286
[0702]
4-(8-Chloro-5,6-Dihydro-6-Hydroxy-11H-Benzo-[5,6]Cyclohepta[1,2-b]P-
yridin-11Ylidene)-1-(4-Pyridinylacetyl)-Piperidine 536
[0703] The procedure of Example 284 was followed with the exception
that 4-pyridylacetic acid was used in place of 3-pyridylacetic acid
to give the title compound (MH.sup.+446).
EXAMPLES 287, 289 AND 290
[0704] By essentially the same procedure as in Example 1, but using
either
(R)-(+)-.alpha.-methoxy-.alpha.-(trifluromethyl)-phenylacetic acid
(Example 290),
(S)-(-)-.alpha.-methoxy-.alpha.-(trifluromethyl)-phenylace- tic
acid (Example 287), or .alpha.,.alpha.-dimethylphenylacetic acid
(Example 289), the compounds of Example 290, 287 and 289 were
obtained. The structures for these compounds are in Table 7. Data
for these compounds are: compound of Example 290, white solid
MH+527; compound of Example 287, white solid MH+527; and compound
of Example 289, white solid M+457.
EXAMPLES 291, 292, 294, 313 AND 314
[0705] By essentially the same procedure as in Example 183, and
using either 4-, 3-, or 2-ethoxycarbonylaminopyridine and either
4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene-
)piperidine or
8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclo-
hepta[1,2-b]pyridine (product of Example 233A), the compounds of
Examples 291, 292, 294, 313 and 314 were obtained. The structures
for the compounds of Examples 291, 292, and 294 are given in Table
7. The structures for the compounds of Examples 313 and 314 are
given in Table 10. Data are: the compound of Example 291 was a
yellow solid (MH.sup.+431), the compound of Example 292 was an off
white solid (MH.sup.+431), the compound of Example 294 was an off
white solid (MH.sup.+431), the compound of Example 313 was a white
solid (MH.sup.+433), and the compound of Example 314 was a white
solid (MH.sup.+433).
EXAMPLE 301
[0706]
1-1-(4-Pyridinylacetyl)-4-[3-Methyl-8-Chloro-5,6-Dihydro-11H-Benzo[-
5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-Piperidine 537
[0707] By essentially the same procedure as set forth in Example
180, but using
4-(8-chloro-3-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,-
6]cyclohepta[1,2-b]pyridine (from Preparative Example 3E) instead
of
4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohept-
a[1,2-b]pyridine, the title compound was obtained as an off-white
solid MH+444
EXAMPLE 303
[0708]
1-1-(3-Pyridinylacetyl)-4-[3-Methyl-8-Chloro-5,6-Dihydro-11H-Benzo[-
5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-Piperidine 538
[0709] By essentially the same procedure as set forth in Example
180, but using
4-(8-chloro-3-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,-
6]cyclohepta[1,2-b]pyridine (from Preparative Example 3E) instead
of
4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohept-
a[1,2-b]pyridine, and 3-pyridylacetic acid instead of
4-pyridylacetic acid, the title compound was obtained as white
solid MH+444.
EXAMPLE 307
[0710] By essentially the same procedure as in Example 1, using the
title compound from Preparative Example 37B, and 4-pyridylacetic
acid the compound of Example 307, identified in Table 8, was
obtained, MH.sup.+428.
EXAMPLE 309
[0711]
1-1-(4-Pyridinylacetyl)-4-[2-Methyl-8-Chloro-5,6-Dihydro-11H-Benzo[-
5,6]Cyclohepta[1,2-b]Pyridin-11-Ylidene]-Piperidine 539
[0712] By essentially the same procedure as set forth in Example
180, but using
4-(8-chloro-2-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,-
6]cyclohepta[1,2-b]pyridine (from Preparative Example 3E) instead
of
4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohept-
a[1,2-b]pyridine, and 3-pyridylacetic acid instead of
4-pyridylacetic acid, the title compound was obtained as white
solid MH+444.
EXAMPLE 311
[0713] 1-1-(4-Pyridinylacetyl)-4-[8,9
Dichloro-5,6-Dihydro-11H-Benzo[5,6]C-
yclohepta[1,2-b]Pyridin-11-Ylidene]- Piperidine 540
[0714] By essentially the same procedure as set forth in Example
180, but using
4-(8,9-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]-cy-
clohepta[1,2-b]pyridine (from Preparative Example 1H) instead of
4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6]cyclohept-
a[1,2-b]pyridine, and 3-pyridylacetic acid instead of
4-pyridylacetic acid, the title compound was obtained as white
solid MH+464.
EXAMPLE 312
[0715] By essentially the same procedure as in Example 182, with
the exception that 8-chloro-6,11
-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyc-
lohepta[1,2-b]pyridine is used instead of
8-chloro-11-(1-piperazinyl)-6,11-
-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, the compound of
Example 312 was obtained as a white solid (MH.sup.+432). The
structure for this compound is given in Table 10.
EXAMPLE 350
[0716]
8-Chloro-11H-Benzo[5,5]Cyclohepta[1,2-b]Pyridin-11-Ylidene)-4-(3-Py-
ridinylacetyl)Piperazine 541
[0717] By substituting in Example 75, 0.4 g (1.28 mmoles) of
8-chloro-11-(1-piperazinyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine
(Preparative Example 38) for 8-chloro-11
-(1-piperazinyl)-6,11-dihydro-5H-
-benzo[5,6]-cyclohepta[1,2-b]pyridine and 0.1765 g (1.28 mmoles) of
3-pyridylacetic acid for 4-pyridylacetic acid and using the same
method as described in Example 75, one obtains the title compound
(0.513 g, 93%, MH.sup.+431).
EXAMPLE 351
[0718]
1-(3-Bromo-8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyri-
din-11-Yl)-4-(3-Pyridinylacetyl)Piperazine 542
[0719] By substituting in Example 75,
3-bromo-8-chloro-11-(1-piperazinyl)--
6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0. 32 g, 0.81
mmoles) (Preparative Example 40) for
8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H--
benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid (0.117
g, 0.86 mmoles) for 4-pyridylacetic acid and using the method
described in Example 75, one obtains the title compound (0.3942 g,
95%, MH.sup.+511).
EXAMPLES 352-353
[0720] By essentially the same procedures as set forth in Example
351, but using 543
[0721] in place of 3-pyridylacetic acid, one obtains compounds of
the formulas 544
[0722] respectively. The compound of Example 352 is a white
amorphous solid, yield 65%, Mass Spec MH.sup.+555. The compound of
Example 353 is a white amorphous solid, yield 59%, Mass Spec
MH.sup.+539.
EXAMPLE 354
[0723] 4-(3-Bromo
8-Chloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyri-
din-11-Yl)-N-(3-Pyridinyl)-1-Piperazinecarboxamide 545
[0724] The title compound from Preparative Example 40 (0.37 g, 0.94
mmoles) was reacted with 3-ethoxycarbonylaminopyridine (Preparative
Example 12) (0.123 g, 0,94 mmoles) under essentially the same
conditions as described in Example 183, to give the title compound
(0.3164 g, 66%, MH.sup.+512).
EXAMPLE 355
[0725]
1-(4,8-Dichloro-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta-[1,2-b]Pyridin-
-11-Yl)-4-(3-Pyridylacetyl)Piperazine 546
[0726] By substituting in Example 75,
4,8-chloro-11-(1-piperazinyl)-6,11-d-
ihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0.3 g, 0.86 mmoles)
(Preparative Example 41) for
8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H--
benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid
(0.1181 g, 0.86 mmoles) for 4-pyridylacetic acid and using the
method described in Example 75, one obtains the title compound
(0.357 g, 88%, MH.sup.+467).
EXAMPLE 356
[0727]
4-[3-Bromo-4,8-Dichloro-5,6-Dihydro-11H-Benzo[5,6]-Cyclohepta[1,2-b-
]Pyridin-11-Ylidene]-1-(4-Pyridinylacetyl)-Piperidine 547
[0728] A mixture of the title compound from Preparative Example 46
(0.68 grams), 4-pyridylacetic acid hydrochloride (0.60 grams), DEC
(0.65 grams), 4-methyl-morpholine (0.6 mL) and anhydrous DMF (20
mL) was stirred at 25.degree. C. for 48 hours. Concentration in
vacuo provided a residue which was diluted with CH.sub.2Cl.sub.2
and washed with 1 N aqueous NaOH and brine. The organic phase was
dried over anhydrous MgSO.sub.4 and concentrated in vacuo to
provide a residue which was purified by flash column chromatography
(silica gel) using 2-5% MeOH--CH.sub.2Cl.sub.2 saturated with
ammonium hydroxide to afford the title compound (0.06 grams, 7%,
MH.sup.+544).
EXAMPLE 358
[0729] A.
4-(8-Chloro-3-Nitro-5.6-Dihydro-11-(4-Piperidylidene)-11H-Benzo[-
5,6]Cyclohepta[1,2-b]Pyridine 548
[0730] Hydrolyze the title compound of Preparative Example 47A
(10.0 g, mmol) by dissolving in conc. HCl (250mL) and heating to
100.degree. C. for 16 h. The cooled acidic mixture was neutralized
with 1M NaOH (950 mL). The mixture was extracted with
CH.sub.2Cl.sub.2. The latter was dried over MgSO.sub.4. Filtration
and concentration afforded the title compound in 99% yield as a
solid. MH+358.
[0731] B.
1-1-(4-Pyridinylacetyl)-4-[3-Bromo-8-Chloro-5,6-Dihydro-11H-Benz-
o[5,6]Cycloheptal[1,2-]Pyridin-11-Ylidene]-Piperidine 549
[0732] By essentially the same procedure as set forth in Example
180, but using
4-(8-chloro-3-nitro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo[5,6-
]cyclohepta[1,2-b]pyridine instead of
4-(3,8-dichloro-5,6-dihydro-11-(4-pi-
peridylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine, the title
compound was obtained as an off-white solid. Mp=111.3-112.2.degree.
C., MH+475.
EXAMPLE 400
[0733] 550
[0734] The product of Preparative Example 48, Step B, is reacted
with 4-pyridyl acetic acid via essentially the same procedure as
described in Example 180 to give the product compound (5.210). Mass
Spec.: MH.sup.+=556
[0735] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 400:
14 Starting Analytical Compound Product Compound Data Preparative
Example 49 551 Mass Spec: MH.sup.+ = 458 Preparative Example 53C
552 Mass Spec.: MH.sup.+ = 528.2 Preparative Example 53C 553 Mass
Spec.: MH.sup.+ = 524.2 Preparative Example 53C 554 Mass Spec.:
MH.sup.+ = 524.1 Preparative Example 51A 555 Mass Spec.: MH.sup.+ =
512.1 Preparative Example 51A 556 Mass Spec.: MH.sup.+ = 528
Preparative Example 53C 557 Mass Spec.: MH.sup.+ = 508.0
Preparative Example 49 558 Mass Spec.: MH.sup.+ = 530.2 Preparative
Example 51A 559 Mass Spec.: MH.sup.+ = 532.3 Preparative Example 49
560 Mass Spec.: MH.sup.+ = 530.2 Preparative Example 49 561 Mass
Spec.: MH.sup.+ = 526 Preparative Example 56, Step C 562 Mass
Spec.: MH.sup.+ = 581 Preparative Example 49 563 Mass Spec.:
MH.sup.+ = 449.2 Preparative Example 51A 564 m.p. =
62.8.degree.-63.5.degree. C. Mass Spec.: MH.sup.+ = 451 Preparative
Example 53B 565 Mass Spec.: MH.sup.+ = 602
EXAMPLE 401
[0736] 566
[0737] The product of Preparative Example 48, Step B, is reacted
with 4-pyridyl acetic acid N-oxide via essentially the same
procedure as described in Example 227 to give the product compound
(5.209). Mass Spec.: MH.sup.+=572
[0738] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 401:
15 Starting Analytical Compound Product Compound Data Preparative
Example 50 567 Mass Spec: MH.sup.+ = 462
EXAMPLE 402
[0739] 568
[0740] The product of Example 358, Step B, is reduced via
essentially the same procedure as described in Step B of
Preparative Example 47 to give the product compound.
mp=133.2-133.4.degree. C. MH.sup.+445
[0741] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 402:
16 Starting Com- Analytical pound Product Compound Data Example
411-B 569 Mass Spec.: MH.sup.+ =445.2
EXAMPLE 403
[0742] 570
[0743] Combine 0.3 g (0.67 mmol) of the product of Example 402, 5
mL of pyridine and 0.1 g (1.01 mmol) of acetic anhydride and stir
the mixture at room temperature for 2 days. Add another 100 .mu.L
of acetic anhydride, warm to 60.degree. C. and stir for 6 h.
Neutralize the reaction mixture then basify with 1 N NaOH (aqueous)
to pH=10. Extract with CH.sub.2Cl.sub.2, dry the extract over
MgSO.sub.4 and concentrate to a residue. Purify the residue by HPLC
eluting 8% MeOH/CH.sub.2Cl.sub.2+co- ncentrated NH.sub.4OH
(aqueous) to give 0.22 g of the product compound. Mass Spec.:
MH.sup.+=487
EXAMPLE 404
[0744] 571
[0745] The product of Example 402 is reacted with methanesulfonyl
chloride via substantially the same procedure as described for
Example 403 to give the 0.32 g of the product compound. Mass Spec.:
MH.sup.+=523
EXAMPLE 405
[0746] 572
[0747] Combine 1.5 g (3.37 mmol) of the product of Example 402 and
10 mL of AcOH, then add 3.37 mL of a solution of bromine in AcOH
and stir the mixture at room temperature overnight. Basify the
mixture with 1N NaOH (aqueous) to basic pH, then extract with
EtOAc. Concentrate the extract to a residue and chromatograph
(silica gel, 90% EtOAc/hexane, then 5% Et.sub.3N/EtOAc) to give the
product compound. Mass Spec.: MH.sup.+=525.
EXAMPLE 406
[0748] 573
[0749] Combine 0.5 g (1.12 mmol) of the product of Example 402 and
10 mL of acetone, add 230 .mu.L of conc. HCl (aqueous) and 4 mL of
water, and cool to -10.degree. C. Add a solution of 0.085 g
NaNO.sub.2 in 4 mL of water, stir for 15 min., then add the
reaction mixture to a solution of CuCN [freshly prepared by adding
0.336 g (1.34 mmol) of CuSO.sub.4 in 2 mL of water to H.sub.2O a
solution of 0.365 g (5.6 mmol) of KCN in 2 mL of H.sub.2O]. Heat
the mixture to 60.degree.-70.degree. C., then at
70.degree.-80.degree. C. to remove acetone. Cool the mixture and
dilute with H.sub.2O, then exhaustively extracted with
CH.sub.2Cl.sub.2. Concentrate the extracts to a residue then purify
by HPLC using 3% methanolic ammonia in CH.sub.2Cl.sub.2 to give
0.25 g (50% yield) of the product compound. Mass Spec.:
MH.sup.+=455.
EXAMPLE 407
[0750] 574
[0751] Combine 0.55 g (1.25 mmol) of the product of Example 402 and
50 mL of dilute H.sub.2SO.sub.4 at room temperature. Cool the
mixture to -10.degree. C., add a solution of 0.092 g of NaNO.sub.2
in 5 mL of water was added and stir for 15 min. Slowly add a
solution of 0.46 g (4.7 mmol) of KSCN and 0.3 g (2.49 mmol) of
CuSCN in 15 mL of water over a period of 0.5 hours. Stir for 0.5
hour then heat at reflux for 15 min. Cool the mixture and adjust
the pH to .about.7, then extract with CH.sub.2Cl.sub.2. Concentrate
the extracts to a residue and chromatograph (silica gel, 3%
MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to give the product compound.
Mass Spec.: MH.sup.+=487
EXAMPLE 410
[0752] 575
[0753] The product of Preparative Example 50 was reacted with
4-pyridylacetic acid via substantially the same procedure as
described for Example 180 to give the product compound. Mass Spec.:
MH.sup.+=446
[0754] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 410:
17 Starting Analytical Compound Product Compound Data Preparative
Example 49A 576 Mass Spec.: MH.sup.+ = 526 Preparative Example 49A
577 Mass Spec.: MH.sup.+ = 542 Preparative Example 49A 578 Mass
Spec.: MH.sup.+ = 542 Preparative Example 52 579 m.p. =
67.degree.-69.degree. C. Mass Spec.: MH.sup.+ = 430 Preparative
Example 52A 580 m.p. = 77.degree.-78.degree. C. Mass Spec.:
MH.sup.+ = 444 Preparative Example 52A 581 m.p. =
78.degree.-79.degree. C. Mass Spec.: MH.sup.+ = 444 Preparative
Example 49 582 m.p. = 137.degree.-138.degree. C. Mass Spec.:
MH.sup.+ = 565 Preparative Example 1 583 Mass Spec.: MH.sup.+ =
451.2 Preparative Example 49 584 Mass Spec.: MH.sup.+ = 531.2
Preparative Example 49A 585 m.p. = 108.8.degree.-109.7.degree. C.
Mass Spec.: MH.sup.+ = 465.4 Preparative Example 53 586 Mass Spec.:
MH.sup.+ = 475.2 Preparative Example 57 587 m.p. =
151.degree.-153.degree. C. Mass Spec.: MH.sup.+ = 560 Preparative
Example 49A 588 m.p. = 164.8.degree.-165.2.degree. C. Mass Spec.:
MH.sup.+ = 546 Preparative Example 49A 589 m.p. =
124.2.degree.-125.degree. C. Mass Spec.: MH.sup.+ = 546 Preparative
Example 49 590 m.p. = 102.6.degree.-103.degree. C. Mass Spec.:
MH.sup.+ = 601.2 Preparative Example 73 591 Mass Spec.: MH.sup.+ =
569 Preparative Example 49 592 m.p. = 97.degree. C. (dec.) Mass
Spec.: MH.sup.+ = 595 Preparative Example 49 593 m.p. =
132.6.degree. C. (dec.) Mass Spec.: MH.sup.+ = 576 Preparative
Example 49 594 m.p. = 111.2.degree. C. (dec.) Mass Spec.: MH.sup.+
= 608 Preparative Example 49 595 m.p. = 85.1.degree. C. (dec.) Mass
Spec.: MH.sup.+ = 556 Preparative Example 49 596 m.p. = 114.degree.
C. (dec.) Mass Spec.: MH.sup.+ = 588 Preparative Example 49 597
m.p. = 122.5.degree.-126.0.degree. C. Mass Spec.: MH.sup.+ =
572
EXAMPLE 411
[0755] 598
[0756] The product of Preparative Example 49 was reacted with
2-methyl-2-(4-pyridyl)propanoic acid via substantially the same
procedure as described for Example 180 to give the product
compound. Mass Spec.: MH.sup.+=538
[0757] Using the appropriate carboxylic acid (or carboxylate salt,
e.g. lithium carboxylate) and the starting compound indicated, the
following compounds were prepared via substantially the same
procedure as described for Example 410:
18 Starting Analytical Compound Product Compound Data Preparative
Example 49 599 Mass Spec.: MH.sup.+ = 554 Example 411-A Preparative
Example 53A 600 Mass Spc.: MH.sup.+ = 475.2 Example 411-B
Preparative Example 55 601 m.p. = 155.2.degree.-158.9.degree. C.
Mass Spec.: MH.sup.+ = 446 Example 411-C Preparative Example 49 602
Mass Spec.: MH.sup.+ = 554 Example 411-D Preparative Example 1 603
Mass Spec.: MH.sup.+ = 474 Example 411-E Preparative Example 72 604
Mass Spec.: MH.sup.+ = 526.1 Example 411-G Preparative Example 71
605 Mass Spec.: MH.sup.+ = 498 Example 411-H Preparative Example
53B 606 Mass Spec.: MH.sup.+ = 586 Example 411-J Preparative
Example 53B 607 Mass Spec.: MH.sup.+ = 581 Example 411-K
Preparative Example 59 608 m.p. = 97.degree.-98.degree. C. Mass
Spec.: (FAB) MH.sup.+ =463.1 Example 411-L Preparative Example 60
609 Mass Spec.: MH.sup.+ = 448 Example 411-M Preparative Example 60
610 Mass Spec.: MH.sup.+ = 464 Example 411-N Preparative Example 60
611 Mass Spec.: MH.sup.+ = 492 Example 411-O Preparative Example 60
612 Mass Spec.: MH.sup.+ = 448 Example 411-P Preparative Example 60
613 Mass Spec.: MH.sup.+ = 464 Example 411-Q Preparative Example 60
614 Mass Spec.: MH.sup.+ = 469 Example 411-R Preparative Example 60
615 Mass Spec.: MH.sup.+ = 469 Example 411-S Preparative Example
60A 616 Mass Spec.: MH.sup.+ = 465 Example 411-T Preparative
Example 60A 617 Mass Spec.: MH.sup.+ = 481 Example 411-U
Preparative Example 60A 618 Mass Spec.: MH.sup.+ = 485 Example
411-V Preparative Example 60A 619 Mass Spec.: MH.sup.+ = 481
Example 411-W Preparative Example 60A 620 Mass Spec.: MH.sup.+ =
485 Example 411-X Preparative Example 1 Step G 621 -- Example 411-Z
Preparative Example 51A 622 m.p. = 125.degree.-125.4.degree. C.
Mass Spec.: MH.sup.+ = 528 Example 411-AA Preparative Example 3
Step E 623 m.p. = 186.6.degree.-187.degree. C. Mass Spec.: MH.sup.+
= 464 Example 411-BB Preparative Example 3 Step E 624 Mass Spec.:
MH.sup.+ = 464 Example 411-CC Preparative Example 51A 625 --
Example 411-DD Preparative Example 49 626 m.p. =
83.degree.-86.degree. C. Mass Spec.: MH.sup.+ = 616 Example 411-EE
Preparative Example 49 627 m.p. = 167.degree.-171.degree. C. Mass
Spec.: MH.sup.+ = 526 Example 411-FF Preparative Example 49 628
m.p. = 134.degree.-140.degree. C. Mass Spec.: MH.sup.+ = 593
Example 411-GG
EXAMPLE 412
[0758] 629
[0759] Combine 50 mg (0.11 mmol) of the compound of Example 400-N,
and 1.5 mL of SOCl.sub.2 and stir a room temperature overnight.
Concentrate in vacuo to a residue, add 2.0 mL of DMF to the
residue, then add 20 mg (0.2 mmol) of 1,2,4-triazole sodium salt
and heat to 100.degree. C. overnight. Cool the mixture, concentrate
in vacuo to remove most of the solvent, wash with water (3 times),
then dry the resiude over Na.sub.2SO.sub.4. Comcentrate in vacuo to
a residue and chromatograph (silica gel, 75% (10%NH.sub.4OH in
MeOH) in CH.sub.2Cl.sub.2) to give 26 mg of the product compound.
Mass Spec.: MH.sup.+=498
[0760] Using the appropriate starting compound and substantially
the same procedure as described for Example 412, but substituting
the amine nucleophile indicated in place of the 1,2,4-triazole
sodium salt, the following compounds were prepared:
19 Amine Analytical Nucleophile Product Compound Data piperidine
(solvent is CH.sub.2Cl.sub.2 instead of DMF) 630 Mass Spec.:
MH.sup.+ = 514.2 Example 412-A thiomorpholine (solvent is
CH.sub.2Cl.sub.2 instead of DMF) 631 Mass Spec.: MH.sup.+ = 532.1
Example 412-B piperazine (solvent is CH.sub.2Cl.sub.2 instead of
DMF) 632 Mass Spec.: MH.sup.+ = 515 Example 412-C morpholine
(solvent is CH.sub.2Cl.sub.2 instead of DMF) 633 Mass Spec.:
MH.sup.+ = 516.1 Example 412-D imidazole (solvent is
CH.sub.2Cl.sub.2 instead of DMF) 634 Mass Spec.: MH.sup.+ = 497.2
Example 412-E N-(2-methyl- phenyl)- piperazine (solvent is
CH.sub.2Cl.sub.2 instead of DMF) 635 Mass Spec.: MH.sup.+ = 605.1
Example 412-F 4(3H)- pyrimidone 636 Mass Spec.: MH.sup.+ = 525.1
Example 412-G thiomorpholine 637 m.p. = 105.degree.-105.6.degree.
C. Mass Spec.: MH.sup.+ = 536 Example 412-H thiomorpholine 638 m.p.
102.5.degree.-102.9.degree. C. Mass Spec.: MH.sup.+ = 550 Example
412-J
EXAMPLE 413
[0761] 639
[0762] Combine 0.32 g of the product from Preparative Example 46
and 2 mL of anhydrous CH.sub.2Cl.sub.2 and add 6 mL of a mixture of
4.17 g of N-methyl-4-piperidylacetic acid, 1.03 mL of
methanesulfonyl chloride, 6.83 mL of Et.sub.3N and 50 mL of
CH.sub.2Cl.sub.2. Stir at 25.degree. C. overnight, then add 1 N
NaOH (aqueous) and shake well. Separate the layers, dry the organic
phase over MgSO.sub.4, and concentrate to a residue. Chromatograph
the residue (silica gel, 3% MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to
give 0.19 g (45% yield) of the product compound. m.p.=105.degree.
C. (dec); Mass Spec.: MH.sup.+=564.
EXAMPLE 414
[0763] 640
[0764] Combine 84 mg of the product from Preparative Example 46, 5
mL of pyridine and 0.04 mL of phenylisocyanate and stir at
25.degree. C. for 48 hours. Concentrate in vacuo to a residue,
dilute with CH.sub.2Cl.sub.2 and wash with saturated NaHCO.sub.3
(aqueous). Dry over MgSO.sub.4, concentrate to s residue and
chromatograph (silica gel, 50-70% hexane/EtOAc) to give 14 mg (13%
yield) of the product compound. m.p.=125.6.degree. C. (dec); Mass
Spec.: MH.sup.+=544
[0765] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 414:
20 Starting Analytical Compound Product Compound Data Preparative
Example 28 641 m.p. = 131.8.degree. C. (dec.) Mass Spec.: MH.sup.+
= 464 Example 414-A Preparative Example 53A 642 Mass Spec.:
MH.sup.+ = 475.2 Example 414-B
EXAMPLE 415
[0766] 643
[0767] Combine 0.64 g of the product from Example 411-C and 16 mL
of glacial HOAc, and add 15 mL of a 0.54 M solution of bromine in
HOAc at 25.degree. C. under N.sub.2. After 10 minutes, pour the
mixture into water, filter to collect the resulting solid, and wash
with water. Dry the solid under vacuum, then chromatograph (silica
gel, 6-15% MeOH/CH.sub.2Cl.sub.2) to give 0.26 grams (35% yield) of
the product compound. m.p.=150.0.degree. C. (dec), Mass Spec.:
MH.sup.+=526
EXAMPLE 416
[0768] 644
[0769] Combine 0.33 g of the product from Preparative Example 57, 2
mL of anhydrous CH.sub.2Cl.sub.2, and 10 mL of a mixture of 7.20 g
of 4-pyridylacetic acid hydrochloride, 1.61 mL of
methanesulfonylchloride, 27 mL of Et.sub.3N and 60 mL of
CH2Cl.sub.2, and stir at 25.degree. C. for 48 hours. Dilute the
mixture with CH.sub.2Cl.sub.2, wash with saturated NaHCO.sub.3
(aqueous), then with brine. Dry over MgSO.sub.4, concentrate to a
residue and chromatograph (silica gel, 5%
MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to give 0.23 g (55% yield) of the
product compound. m.p.=142.degree. C. (dec); Mass Spec.:
MH.sup.+=540
EXAMPLE 417
[0770] 645
[0771] React the product from Preparative Example 35 with
4-pyridylacetic acid via substantially the same procedure as
described for Example 266 to give the product compound. Mass Spec.:
MH.sup.+=458
[0772] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 417:
21 Starting Analytical Compound Product Compound Data Preparative
Example 37B 646 Mass Spec.: MH.sup.+ = 444 Preparative Example 58
647 Mass Spec.: MH.sup.+ = 522 Example 417-B
EXAMPLE 418
[0773] 648
[0774] Follow the procedure of Example 283 except using
4-pyridylacetic acid N-oxide to give the product compound. Mass
Spec.: MH.sup.+=460
EXAMPLE 419
[0775] 649
[0776] Dissolve 4.01 g (8.42 mmol) of the compound of Example 410-L
in EtOAc and add 14.25 g (63.1 mmol) of finely powdered SnCl.sub.2
dihydrate and stir the mixture for 5 hours. Add 150 mL of saturated
NaF (aqueous) and stir for 15 min, then separate the layers and dry
the organic phase over MgSO.sub.4. Filtration and concentrate in
vacuo to a residue, then chromatograph (silica gel, 95%
CH.sub.2Cl.sub.2/MeOH+NH.sub.4OH) to give 2.95 g of the product
compound. Mass Spec.: MH.sup.+=461
EXAMPLE 420
[0777] 650
[0778] Combine 0.50 g (1.08 mmol) of the compound of Example 419
and 10 mL of anhydrous CH.sub.2Cl.sub.2, and add 0.11 mL (1.62
mmol) of CH.sub.3COCl. Add 0.34 mL (4.32 mmol) of pyridine and stir
at room temperature for 2.5 hours. Dilute the mixture with
saturated NaHCO.sub.3 (aqueous), extract with CH.sub.2Cl.sub.2,
wash the extracts with brine and dry over MgSO.sub.4. Concentratein
vacuo to a residue and chromatograph (silica gel, 10%
MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to give 0.271 g of the product
compound. Mass Spec.: MH.sup.+=503
EXAMPLE 421
[0779] 651
[0780] Combine 0.65 g (1.41 mmol) of the product compound of
Example 419, 20 mL of CH.sub.2Cl.sub.2, 0.22 mL (3.52 mmol) of
methyl iodide, 4.4 mL of 10% NaOH (aqueous) and 68 mg (0.21 mmol)
of tetra-n-butyl-ammonium bromide. Stir the mixture for 5 hours,
then separate the layers and dry the organic phase over MgSO.sub.4.
Concentrate in vacuo to a residue and chromatograph (silica gel, 5%
MeOH/CH.sub.2Cl.sub.2+NH.sub.4OH) to give 169 mg of the product
compound. Mass Spec.: MH.sup.+=475
EXAMPLE 422
[0781] 652
[0782] Combine 0.1 g (0.21 mmol) of the product compound of Example
411-L and 10 mL of CH.sub.2Cl.sub.2, add 0.11 g (0.66 mmol) of
MCPBA and stir at ambient temperature for 1 hour. Wash with
saturated NaHCO.sub.3 (aqueous), dry over MgSO.sub.4, and
concentrate in vacuo to give 0.14 gm of the product compound.
m.p.=100.degree.-104.degree. C.
[0783] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 422:
22 Starting Analytical Compound Product Compound Data Example 423
653 Mass Spec.: (FAB) MH.sup.+ =480.2 Example 422-A
EXAMPLE 423
[0784] 654
[0785] Combine 0.4 g (1.22 mmol) of the product compound of
Preparative Example 59 and 0.2 g (1.2 mmol) of
4-aminopyridylethylcarbamate and heat to 180.degree. C. under a dry
N.sub.2 atmosphere for 2 hours. Cool the mixture and crystallize
the product by adding EtOAc to give 0.49 g of the product compound.
m.p.=206.4.degree.-207.degree. C.; Mass Spec.: (FAB)
MH.sup.+=464.0
[0786] Using the appropriate ethylcarbamate and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 423:
23 Starting Analytical Compound Product Compound Data Preparative
Example 1, Step G 655 -- Example 423-A Preparative Example 1, Step
G 656 -- Example 423-B
EXAMPLE 424
[0787] 657
[0788] Combine 1 g of the product of Example 402 and 20 mL of MeOH,
cool to .about.0.degree. C., and adjust to pH=3 by adding 1 N HCl
(aqueous). Add 1.25 mL of CH.sub.3CHO and 1.41 g of NaCNBH.sub.3,
and stir the mixture for 1 hour. Concentrate in vacua to a residue,
extract with 100 mL of CH.sub.2Cl.sub.2 and wash the extract with
100 mL of 10% NaHCO.sub.3, then with 100 mL of water. Dry over
MgSO, concentrate in vacua to a residue and chromatograph (silica
gel, 1.5% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give 0.158
g of the product compound of Example 424 and 0.198 g of the product
compound Example 424-A. Analytical data for Example 424: Mass
Spec.: MH.sup.+=474 Analytical data for Example 424-A: Mass Spec.:
MH.sup.+=502
EXAMPLE 425
[0789] 658
[0790] React the products of Preparative Example 7, Step C and
Preparative Example 26, via substantially the same procedure as
described for Example 75 to give the title compound. Mass Spec.:
MH.sup.+=461.35
[0791] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 425:
24 Starting Analytical Compound Product Compound Data Preparative
Example 7 659 Mass Spec.: MH.sup.+ = 477.2 Example 425-A
Preparative Example 7 660 Mass Spec.: MH.sup.+ = 449.3 Example
425-B Preparative Example 7 661 Mass Spec.: MH.sup.+ = 477.2
Example 425-C Preparative Example 19 (R+)-isomer 662 Mass Spec.:
MH.sup.+ = 449.2 Example 425-D Preparative Example 19 (S-)-isomer
663 Mass Spec.: MH.sup.+ = 449.2 Example 425-E Preparative Example
19 R(+)-isomer 664 Mass Spec.: MH.sup.+ = 449.3 Example 425-F
Preparative Example 19 (S-)-isomer 665 Mass Spec.: MH.sup.+ = 449.3
Example 425-G Preparative Example 40 666 Mass Spec.: MH.sup.+ =
527.0 Example 425-H Preparative Example 40 667 Mass Spec.: MH.sup.+
= 555.3 Example 425-J Preparative Example 40 668 Mass Spec.:
MH.sup.+ = 527.1 Example 425-K Preparative Exampld 38 669 Mass
Spec.: MH.sup.+ = 447.2 Example 425-L Preparative Example 19
R(+)-isomer 670 Mass Spec.: MH.sup.+ = 453 Example 425-M
Preparative Example 19 S(-)-isomer 671 Mass Spec.: MH.sup.+ = 453
Example 425-N Preparative Example 40 672 Mass Spec.: MH.sup.+ =
531.25 Example 425-O Preparative Example 41 673 Mass Spec.:
MH.sup.+ = 487.35 Example 425-P Preparative Example 38 674 Mass
Spec.: MH.sup.+ = 451.35 Example 425-Q Preparative Example 19
R(+)-isomer 675 Mass Spec.: MH.sup.+ = 453.35 Example 425-R
Preparative Example 19 S(-)-isomer 676 Mass Spec.: MH.sup.+ =
453.35 Example 425-S Preparative Example 7 Step C 677 Mass Spec.:
MH.sup.+ = 539.45 Example 425-T Preparative Example 40 678 Mass
Spec.: MH.sup.+ = 531.35 Example 425-U Preparative Example 38 679
Mass Spec.: MH.sup.+ = 451.4 Example 425-V
EXAMPLE 426
[0792] 680
[0793] React the product of Preparative Example 40 and
3-pyridylacetic acid via substantially the same procedure as
described for Example 351 to give the title compound. Mass Spec.:
MH.sup.+=511
[0794] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 426:
25 Starting Analytical Compound Product Compound Data Preparative
Example 41 681 Mass Spec.: MH.sup.+= 483.2
EXAMPLE 427
[0795] 682
[0796] Combine 0.288 g (1.76 mmol) of the product of Preparative
Example 63 and 25 mL of anhydrous toluene, heated at (110.degree.
C.) for 0.5 hours, then cool to 25.degree. C. Add a solution of 0.1
g (0.293 mmol) of the product Preparative Example 7, Step C, in 1.5
mL of anhydrous toluene, and stir at 25.degree. C. under an argon
atmosphere for 112 hours. Concentrate in vacuo to a residue and
chromatograph (silica gel, 3%-4% (10% NH.sub.4OH in
MeOH)/CH.sub.2Cl.sub.2) to give 0.065 g of the title compound. Mass
Spec.: MH.sup.+=450.3
[0797] Using the appropriate azide and the starting compound
indicated, the following compounds were prepared via substantially
the same procedure as described for Example 427:
26 Starting Analytical Compound Product Compound Data Preparative
Example 7, Step C 683 Mass Spec.: MH.sup.+= 450.1 Preparative
Example 40 684 Mass Spec.: MH.sup.+= 528.1 Preparative Example 40
685 Mass Spec.: MH.sup.+= 528.1
EXAMPLE 428
[0798] 686
[0799] Combine 14.73 g (27.3 mmol) of the compound from Example 193
and 125 mL of anhydrous MeOH, and add (in portions) 300 mL of a 10%
solution of concentrated H.sub.2SO.sub.4 in dioxane. Stir the
mixture at 25.degree. C. for 2 hours, then pour into water and
adjust to pH=13 with 50% NaOH (aqueous). Extract with
CH.sub.2Cl.sub.2, wash the extract with water and dry over
MgSO.sub.4. Concentrate in vacuo to a residue and chromatograph
(silica gel, 10% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give
8.9 g of the title compound. Mass Spec.: MH.sup.+=539
[0800] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 428:
27 Starting Analytical Compound Product Compound Data Example 425-T
687 Mass Spec.: MH.sup.+= 439.45
EXAMPLE 429
[0801] 688
[0802] Combine 0.5 g (1.14 mmol) of the compound of Example 428 and
10 mL of 0.6 N HCl in CH.sub.2Cl.sub.2, stir for 10 minutes and
concentrate n vacuo to a residue. Add 20 mL of anhydrous MeOH, then
add 0.2006 g (4.56 mmol) of CH.sub.3CHO, 0.0859 g (1.36 mmol)
NaCNBH.sub.3 and 0.5 g of 3A molecular sieves, and heat at
40.degree. C. for 115 hours. Filter the mixture, wash the sieves
with MeOH and concentrate the combined filtrates in vacuo to a
residue. Dissolve the residue in CH.sub.2Cl.sub.2 and wash with
saturated NaHCO.sub.3 (aqueous), then water and dry over
MgSO.sub.4. Concentrate in vacuo to a residue and chromatograph
(silica gel, 8% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give
the title compound. Mass Spec.: MH.sup.+467.3
EXAMPLE 430
[0803] 689
[0804] Combine 0.5 g (1.14 mmol) of the compound of Example 428 and
5 mL of anhydrous THF, add 0.1076 g (1.14 mmol) ClCO.sub.2CH.sub.3,
and stir at 25.degree. C. for 1 hour. Concentrate in vacuo to a
residue, add CH.sub.2Cl.sub.2 and wash with saturated NaHCO.sub.3
(aqueous), then water. Dry the organic phase over MgSO.sub.4,
concentrate in vacuo to a residue and chromatograph (silica gel,
1.5% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give 0.4213 g of
the title compound. Mass Spec.: MH.sup.+=497.35
[0805] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 430:
28 Starting Analytical Compound Product Compound Data Example 428-A
690 Mass Spec.: MH.sup.+=497.35
EXAMPLE 431
[0806] 691
[0807] Combine 0.5 g (1.14 mmol) of the compound of Example 428 and
5 mL of anhydrous CH.sub.2Cl.sub.2, add 0.2624 g (2.28 mmol) of
trimethylsilylisocyanate and stir under argon at 25.degree. C. for
22 hours. Add 0.1312 g (1.14 mmol) of trimethylsilylisocyanate and
stir for 8 hours, then dilute with CH.sub.2Cl.sub.2 and wash with
saturated NaHCO.sub.3 (aqueous), then water. Dry over MgSO.sub.4,
concentrate in vacuo to a residue and chromatograph (silica gel, 5%
(10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give 0.3878 g of the
title compound. Mass Spec.: MH.sup.+=482.2
[0808] Using the isocyanate (or isothiocyanate) and starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 431:
29 Starting Analytical Compound Product Compound Data CH.sub.3NCO
and Example 428 692 Mass Spec.: MH.sup.+= 496.45
CH.sub.3CH.sub.2NCO and Example 428 693 Mass Spec.: MH.sup.+=
510.35 CH.sub.3(CH.sub.2).sub.2NCO and Example 428 694 Mass Spec.:
MH.sup.+= 524.35 (CH.sub.3).sub.3C--NCO and Example 428 695 Mass
Spec.: MH.sup.+= 538.35 CH.sub.3NCS and Example 428 696 Mass Spec.:
MH.sup.+= 512.25 (CH.sub.3).sub.3Si--NCO and Example 428-A 697 Mass
Spec.: MH.sup.+= 482.3 CH.sub.3NCO and Example 428-A 698 Mass
Spec.: MH.sup.+= 496.35
EXAMPLE 432
[0809] 699
[0810] Combine 0.5 g (1.6 mmol) of the compound of Preparative
Example 7 and 1.098 g (6.4 mmol) of the compound from Preparative
Example 65 and heat in a sealed vessel at 160.degree. C. for 17
hours. Cool the mixture, add CH.sub.2Cl.sub.2, wash with water and
dry the organic phase over MgSO.sub.4. Concentrate in vacuo to a
residue and chromatograph (silica gel, 1.5% (10% NH.sub.4OH in
MeOH)/CH.sub.2Cl.sub.2) to give 0.0364 g of the title compound.
Mass Spec.: MH.sup.+=454.25
EXAMPLE 433
[0811] 700
[0812] React 0.5 g (1.59 mmol) of the compound of Example 428 and
0.3232 g (2.39 mmol) of N-(tert-butoxycarbonyl)-L-alanine (0.3232
grams) (2.39 mmoles) via essentially the same conditions as
described in Example 425 to give the product compound. 701
[0813] Combine the product of Step A, 5 mL of MeOH and 10 mL of 10%
concentrated H.sub.2SO.sub.4 in dioxane and stir at 25.degree. C.
for 2 hours. Neutralize with Biorad AG1X8 (OH.sup.-) ion exchange
resin, filter, wash the resin with 1:1 MeOH/water and concentrate
the filtrate to a residue. Chromatograph the residue (silica gel,
8% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2) to give the title
compound. Mass Spec.: MH.sup.+=510.35
[0814] Using the appropriate BOC-amino acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 433:
30 Starting Analytical Compound Product Compound Data BOC-L-serine
and Example 428 702 Mass Spec.: MH.sup.+= 526.2 BOC-L-methionine
and Example 428 703 Mass Spec.: MH.sup.+= 570.3 BOC-glycine and
Example 428 704 Mass Spec.: MH.sup.+= 496.35
EXAMPLE 434
[0815] 705
[0816] React the product of Preparative Example 67 with
4-pyridylacetic acid via essentially the same procedure as
described for Example 411 to give the title compound. Mass Spec.:
MH.sup.+=410
[0817] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 434:
31 Starting Analytical Compound Product Compound Data Preparative
Example 68 706 m.p. =68.6.degree.-70.3.degree. C. Mass Spec.:
MH.sup.+= 454
EXAMPLE-435
[0818] 707
[0819] Dissolve 3.04 g (6.7 mmol) of the compound of Example 434-A
in 100 mL of MeOH. Add 100 mL of a12% KOH (aqueous) and stir for
one hour at 25.degree. C. Remove the MeOH under vacuum, neutralize
to pH 7 with 12 N HCl and concentrate in vacua to a residue. Dry
under vacuum and triturate with 10 mL of EtOH, then filter,
concentrate the filtrate in vacuo to give the title compound.
m.p.=238.degree.-240.degree. C.; Mass Spec.: MH.sup.+=440
EXAMPLE 436
[0820] 708
[0821] Dissolve 0.5 g (1.14 mmol) of the product of Example 435 in
25 mL of DMF, add 0.122 g (1.14 mmol) of benzylamine, 0.33 g (1.7
mmol) of DEC, 0.15 g (1.1 mmol) of HOBT, and 0.23 g (2.27 mmol) of
N-methyl-morpholine, and stir at 25.degree. C., under nitrogen for
18 hours. Concentrate in vacuo to a residue, add 20 mL of water and
extract with 50 mL of EtOAc. Dry the organic layer over MgSO.sub.4
and concentrate in vacuo to a residue. Chromatograph (silica gel,
98% CH.sub.2Cl.sub.2/MeOH+NH.sub.4OH) to give the product compound.
m.p.=118.degree.-120.degree. C.; Mass Spec.: MH.sup.+=529
[0822] Using the appropriate amine and the starting compound
indicated, the following compounds were prepared via substantially
the same procedure as described for Example 436:
32 Starting Analytical Compound Product Compound Data S-phenyl-
alanine methyl ester and Example 435 709 m.p. =
116.9.degree.-118.4.degree. C. Mass Spec.: MH.sup.+= 622 analine
and Example 435 710 m.p. = 137.8.degree.-139.9.degr- ee. C. Mass
Spec.: MH.sup.+= 516 ethanolamine and Example 435 711 m.p. =
130.9.degree.-132.5.degree. C. Mass Spec.: MH.sup.+= 482 NH.sub.4Cl
and Example 435 712 m.p. = 133.2.degree.-133.5.degree. C. Mass
Spec.: MH.sup.+= 439
EXAMPLE 437
[0823] 713
[0824] Dissolve 0.18 g (0.41 mmol) of the product of Example 435 in
2 mL of toluene, add 0.12 g (0.43 mmol) of diphenylphosphoryl
azide, 0.041 g (0.41 mmol) of Et.sub.3N, and 0.092 g (0.44 mmol) of
benzyl alcohol and heat at reflux under nitrogen for 18 hours.
Concentrate in vacuo to a residue and chromatograph (silica gel 95%
CH.sub.2Cl.sub.2/MeOH) to obtain the title compound.
m.p.=132.8.degree.-133.7.degree. C.; MH.sup.+=545
EXAMPLE 438
[0825] 714
[0826] React the product of Preparative Example 70 with
4-pyridylacetic acid via essentially the same procedure as
described for Example 411 to give the title compound. Mass Spec.:
(FAB) MH.sup.+=456
[0827] Using the appropriate carboxylic acid and the starting
compound indicated, the following compounds were prepared via
substantially the same procedure as described for Example 438:
33 Starting Analytical Compound Product Compound Data Preparative
Example 70 715 Mass Spec.: (FAB)MH.sup.+= 476 Preparative Example
70 716 Mass Spec.: (FAB)MH.sup.+= 472
EXAMPLE 439
[0828] 717
[0829] Combine 1.7 g (5 mmol) of the product of Preparative Example
70, Step D, and 10 mL of anhydrous pyridine at 0.degree. C. under
N.sub.2 atmosphere, then slowly add (dropwise) 1 mL (7 mmol) of
TFAA and stir at 25.degree. C. overnight, Dilute with 100 ml of
cold water, extract with CH.sub.2Cl.sub.2 (2.times.75 mL), wash the
extracts successfully with 10% CuSO.sub.4 (aqueous) and brine, then
dry over MgSO.sub.4. Concentrate in vacua to a residue and
chromatograph (silica gel 30%40% EtOAc/hexane) to give 1.75 g of
the title compound. Mass Spec.: (FAB) MH.sup.+=433
EXAMPLE 440
[0830] 718
[0831] Combine 0.07 g (0.154 mmol) of the product of Example 438, 7
mL of EtOH and 12 mg of PtO.sub.2, and hydrogenate at 25.degree. C.
and atmospheric pressure for 1 hour. Filter, wash with EtOH and
concentrate in vacuo to give 0.066 g of the title compound. Mass
Spec.: (FAB) MH.sup.+=458
[0832] Using the starting compound indicated, the following
compounds were prepared via substantially the same procedure as
described for Example 440:
34 Starting Analytical Compound Product Compound Data Example 438-B
719 Mass Spec.: (FAB)MH.sup.+= 474
EXAMPLE 441
[0833] 720
[0834] Combine 0.07 g of the compound of Example 410-R, 2 mL of
THF, 0.5 mL of water, 10 drops of glacial HOAc, and 0.1 g of
powdered Zn, and stir the mixture for 0.5 hours at 25.degree. C.
Purify the mixture by preparative thin layer chromatography (Prep
TLC), (silica gel, 10% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2),
to give a total of 68 mg of the crude product. Purify again by Prep
TLC), (silica gel, 13% (10% NH.sub.4OH in MeOH)/CH.sub.2Cl.sub.2),
to give 33 mg of the product compound. Mass Spec.: MH.sup.+=555
[0835] ASSAYS
[0836] 1. In vitro enzyme assays: Inhibition of farnesyl protein
transferase and geranylgeranyl protein transferase.
[0837] Both farnesyl protein transferase (FPT) and geranylgeranyl
protein transferase (GGPT) I were partially purified from rat brain
by ammonium sulfate fractionation followed by Q-Sepharose
(Pharmacia, Inc.) anion exchange chromatography essentially as
described by Yokoyama et al (Yokoyama, K., et al., (1991), A
protein geranylgeranyltransferase from bovine brain: Implications
for protein prenylation specificity, Proc. Natl. Acad. Sci USA 88:
5302-5306, the disclosure of which is incorporated herein by
reference thereto). Human farnesyl protein transferase was also
expressed in E. coli, using cDNA clones encoding both the .alpha.
and .beta. subunits. The methods used were similar to those
published (Omer, C. et al., (1993), Characterization of recombinant
human farnesyl protein transferase: Cloning, expression, farnesyl
diphosphate binding, and functional homology with yeast
prenyl-protein transferases, Biochemistry 32:5167-5176). Human
farnesyl protein transferase was partially-purified from the
soluble protein fraction of E. coli as described above. The
tricyclic farnesyl protein transferase inhibitors disclosed herein
inhibited both human and rat enzyme with similar potencies. Two
forms of val.sup.12-Ha-Ras protein were prepared as substrates for
these enzymes, differing in their carboxy terminal sequence. One
form terminated in cysteine-valine-leucine-serine (Ras-CVLS) the
other in cystein-valine-leucine-leucine (Ras-CVLL). Ras-CVLS is a
substrate for the farnesyl protein transferase while Ras-CVLL is a
substrate for geranylgeranyl protein transferase I. The cDNAs
encoding these proteins were constructed so that the proteins
contain an amino-terminal extension of 6 histidine residues. Both
proteins were expressed in Escherichia coli and purified using
metal chelate affinity chromatography. The radiolabelled isoprenyl
pyrophosphate substrates, [.sup.3H]farnesyl pyrophosphate and
[.sup.3H]geranylgeranyl pyrophosphate, were purchased from
DuPont/New England Nuclear.
[0838] Several methods for measuring farnesyl protein transferase
activity have been described (Reiss et al 1990, Cell 62: 81;
Schaber et al 1990, J. Biol. Chem. 265: 14701; Manne et al 1990,
PNAS 87: 7541; and Barbacid & Manne 1993, U.S. Pat. No.
5,185,248). The activity was assayed by measuring the transfer of
[.sup.3H]farnesyl from [.sup.3H]farnesyl pyrophosphate to Ras-CVLS
using conditions similar to those described by Reiss et al. 1990
(Cell 62: 81) The reaction mixture contained 40 mM Hepes, pH 7.5;
20 mM magnesium chloride; 5 mM dithiothreitol; 0.25 .mu.M
[.sup.3H]farnesyl pyrophosphate; 10 .mu.l Q--Sepharose-purified
farnesyl protein transferase; the indicated concentration of
tricyclic compound or dimethylsulfoxide (DMSO) vehicle control (5%
DMSO final); and 5 .mu.M Ras-CVLS in a total volume of 100 .mu.l.
The reaction was allowed to proceed for 30 minutes at room
temperature and then stopped with 0.5 ml of 4% sodium dodecyl
sulfate (SDS) followed by 0.5 ml of cold 30% trichloracetic acid
(TCA). Samples were allowed to sit on ice for 45 minutes and
precipitated Ras protein was then collected on GF/C filter paper
mats using a Brandel cell harvester. Filter mats were washed once
with 6% TCA, 2% SDS and radioactivity was measured in a Wallac 1204
Betaplate BS liquid scintillation counter. Percent inhibition was
calculated relative to the DMSO vehicle control.
[0839] The geranylgeranyl protein transferase I assay was
essentially identical to the farnesyl protein transferase assay
described above, with two exceptions:
[.sup.3H]geranylgeranylpyrophosphate replaced farnesyl
pyrophosphate as the isoprenoid donor and Ras-CVLL was the protein
acceptor. This is similar to the assay reported by Casey et al
(Casey, P. J., et al., (1991), Enzymatic modification of proteins
with a geranylgeranyl isoprenoid, Proc. Natl. Acad. Sci, USA 88:
8631-8635, the disclosure of which is incorporated herein by
reference thereto).
[0840] 2. Cell-Based Assay: Transient expression of
valI.sup.12-Ha-Ras-CVLS and val.sup.12-Ha-Ras-CVLL in COS monkey
kidney cells: Effect of farnesyl protein transferase inhibitors on
Ras processing and on disordered cell growth induced by
transforming Ras.
[0841] COS monkey kidney cells were transfected by electroporation
with the plasmid pSV--SPORT (Gibco/BRL) containing a cDNA insert
encoding either Ras-CVLS or Ras-CVLL, leading to transient
overexpression of a Ras substrate for either farnesyl protein
transferase or geranylgeranyl protein transferase I, respectively
(see above).
[0842] Following electroporation, cells were plated into 6-well
tissue culture dishes containing 1.5 ml of Dulbecco's-modified
Eagle's media (GIBCO, Inc.) supplemented with 10% fetal calf serum
and the appropriate farnesyl protein transferase inhibitors. After
24 hours, media was removed and fresh media containing the
appropriate drugs was re-added.
[0843] 48 hours after electroporation cells were examined under the
microscope to monitor disordered cell growth induced by
transforming Ras. Cells expressing transforming Ras become more
rounded and refractile and overgrow the monolayer, reminiscent of
the transformed phenotype. Cells were then photographed, washed
twice with 1 ml of cold phosphate-buffered saline (PBS) and removed
from the dish by scraping with a rubber policeman into 1 ml of a
buffer containing 25 mM Tris, pH 8.0; 1 mM ethylenediamine
tetraacetic acid; 1 mM phenylmethylsulfonyl fluoride; 50 .mu.M
leupeptin; and 0.1 .mu.M pepstatin. Cells were lysed by
homogenization and cell debris was removed by centrifugation at
2000.times.g for 10 min.
[0844] Cellular protein was precipitated by addition of ice-cold
trichloroacetic acid and redissolved in 100 .mu.l of
SDS-electrophoresis sample buffer. Samples (5-10 .mu.l) were loaded
onto 14% polyacrylamide minigels (Novex, Inc.) and electrophoresed
until the tracking dye neared the bottom of the gel. Proteins
resolved on the gels were electroblotted onto nitrocellulose
membranes for immunodetection.
[0845] Membranes were blocked by incubation overnight at 4.degree.
C. in PBS containing 2.5% dried milk and 0.5% Tween-20 and then
incubated with a Ras-specific monoclonal antibody, Y13-259 (Furth,
M. E., et al., (1982), Monoclonal antibodies to the p21 products of
the transforming gene of Harvey murine sarcome virus and of the
cellular ras gene family, J. Virol. 43: 294-304), in PBS containing
1% fetal calf serum for one hour at room temperature. After
washing, membranes were incubated for one hour at room temperature
with a 1:5000 dilution of secondary antibody, rabbit anti-rat IgG
conjugated to horseradish peroxidase, in PBS containing 1% fetal
calf serum. The presence of processed and unprocessed Ras-CVLS or
Ras-CVLL was detected using a colorimetric peroxidase reagent
(4-chloro-1-naphthol) as described by the manufacturer (Bio-Rad).
3. Cell Mat Assay:
[0846] Normal human HEPM fibroblasts were planted in 3.5 cm dishes
at a density of 5.times.10.sup.4 cells/dish in 2 ml growth medium,
and incubated for 3-5 d to achieve confluence. Medium was aspirated
from each dish and the indicator tumor cells, T24-BAG4 human
bladder carcinoma cells expressing an activated H-ras gene, were
planted on top of the fibroblast monolayer at a density of
2.times.10.sup.3cells/dish in 2 ml growth medium, and allowed to
attach overnight. Compound-induced colony inhibition was assayed by
addition of serial dilutions of compound directly to the growth
medium 24 h after tumor cell planting, and incubating cells for an
additional 14 d to allow colony formation. Assays were terminated
by rinsing monolayers twice with phosphate-buffered saline (PBS),
fixing the monolayers with a 1% glutaraldehyde solution in PBS,
then visualizing tumor cells by staining with X-Gal (Price, J., et
al., Lineage analysis in the vertebrate nervous system by
retrovirus-mediated gene transfer, Proc. Natl. Acad. Sci.84,
156-160(1987)). In the colony inhibition assay, compounds were
evaluated on the basis of two IC.sub.50 values: the concentration
of drug required to prevent the increase in tumor cell number by
50% (tIC.sub.50) and the concentration of drug required to reduce
the density of cells comprising the cell mat by 50% (mIC.sub.50).
Both IC.sub.50 values were obtained by determining the density of
tumor cells and mat cells by visual inspection and enumeration of
cells per colony and the number of colonies under the microscope.
The therapeutic index of the compound was quantitatively expressed
as the ratio of mIC.sub.50/tIC.sub.50, with values greater than one
indicative of tumor target specificity.
[0847] RESULTS OF ASSAYS--TABLES 7 TO 28
[0848] The compounds listed in Table 7 refer to compounds of
Formula 500.00:
35TABLE 7 721 FPT EXAMPLE R IC.sub.50 (.mu.M) 1 722 0.25 2 723 0.47
3 724 0.66 88 725 1.0 4 726 1.0 0.8 5 727 1.5 5 728 1.7 89 729 1.8
6 730 2.0 7 731 2.3 8 732 2.3 90 733 3.4 91 734 3.9 92 735 3.9 93
736 3.9 94 737 4.0 9 738 4.0 95 739 4.2 10 740 4.3 11 741 4.3 12
742 4.3 96 743 4.3 97 744 4.4 98 745 4.4 99 746 4.4 13 747 4.5 100
748 4.5 101 749 4.6 102 750 4.6 14 751 4.6 103 752 4.6 104 753 4.7
15 754 4.7 16 755 4.8 17 756 4.8 52 757 4.9 18 758 4.9 105 759 5.0
19A 760 5.1 20 761 5.2 54 762 5.3 106 763 5.3 21 764 5.9 55 765 5.9
22 766 6.0 23 767 6.0 24 768 6.2 25 769 6.25 26 770 6.3 108 771 6.9
109 772 7.2 27 773 7.3 28 774 7.3 56 775 7.9 29 776 8.0 30 777 5.7
31 778 8.3 110 779 8.3 111 780 8.5 32 781 8.7 33 782 8.7 112 783
8.8 34 784 9.8 57 785 9.8 35 786 9.9 113 787 10.3 114 788 11.1 36
789 11.2 37 790 11.4 38 791 12.1 39 792 13.4 115 793 14.2 58 794
14.4 116 795 15.7 117 796 16.2 118 797 22.3 59 798 26.9 119 799 41%
at 11 .mu.M 120 800 4% at 39 .mu.M 121 801 1.4 40 802 44% at 13
.mu.M 122 803 23% at 12.5 .mu.M 123 804 23% at 12.6 .mu.M 124 805
37% at 12.8 .mu.M 125 806 10.3 126 807 2.9 127 808 3.5 2.7 128 809
3.0 129 810 32% at 11.8 .mu.M 41 811 6.1 42 812 0.6 43 813 0.6 44
814 0.8 45 815 1.2 0.87 46 816 1.2 47 817 1.3 1.01 48 818 1.3 49
819 1.4 84 820 0.29 83 821 0.59 19 822 1.0 85 823 2.0 219 824 6.64
220 825 2.49 221 826 3.71 222 827 0.38 227 828 0.53 228 829 7.5 287
830 0.72 5.02 288 831 1.11 289 832 1.44 1.4 290 833 3.8 2.55 291
834 0.87 292 835 0.99 293 836 1.76 0.47 294 837 2.11 295 838 2.4
296 839 4.1 297 840 2.71 298 841 4.58 299 842 1.34 300 843 0.96
[0849] The compounds listed in Table 8 refer to compounds of
Formula 505.00:
36TABLE 8 844 FPT IC.sub.50 EXAMPLE A B (.mu.M) 74B 845 CH.sub.3
4.0 74C 846 CH.sub.3 11.6 74A 847 CH.sub.3 25% at 14.2 .mu.M 130
848 CH.sub.3 7% at 12.1 .mu.M 131 849 850 16% at 13.4 .mu.M 73 851
CH.sub.3 27% at 15.6 .mu.M 132 852 CH.sub.3 22% at 15 .mu.M 133 853
CH.sub.3 16% at 14.1 .mu.M 134 854 855 7% at 12.2 .mu.M 135 856
CH.sub.3 7.7 62 857 CH.sub.3 7.8 64 858 CH.sub.3 10.6 136 859
CH.sub.3 11.5 66 860 CH.sub.3 22% at 50 .mu.M 137 861 CH.sub.3 15%
at 16.3 .mu.M 63 862 CH.sub.3 1% at 16.4 .mu.M 139 863 CH.sub.3 37%
at 15.2 .mu.M 140 864 CH.sub.3 15.7 71A 865 CH.sub.3 17.6 141 866
CH.sub.3 29% at 50 .mu.M 143 867 CH.sub.3 35.4 71B 868 CH.sub.3
56.0 144 869 CH.sub.3 30% at 50 .mu.M 144a 870 871 47% at 46 .mu.M
71C 872 CH.sub.3 38% at 15.5 .mu.M 145 873 874 >10 146 875 876
45% at 12 .mu.M 147 877 CH.sub.3 0% at 18.8 .mu.M 301 878 879 0.04
0.075 180 880 881 0.072 0.04 303 882 883 0.55 304 884 885 2.63 305
886 887 40% @4 .mu.M 230 888 889 2.06 307 890 891 0.22 0.14 235 892
893 3.57 309 894 895 0.93 310 896 897 3.6 311 898 899 0.61 323 900
901 4.9 5.39 902 903 2.3 358 904 905 0.57 360 906 907 0.59 361 908
909 0.32 362 910 911 1.16 365 912 913 5.0 366 914 915 4.0 367 916
917 3.3
[0850] Table 9 lists FPT IC.sub.50 results for additional
compounds
37TABLE 9 EX- FPT IC.sub.50 FPT IC.sub.50 FPT IC.sub.50 AMPLE
(.mu.M) EXAMPLE (.mu.M) EXAMPLE (.mu.M) 229 4.38 231 44% @ 232 6.0
(5.104) (5.106) 12 .mu.M (5.107) 236 1.48 237 18% @ 238 26% @
(5.111) (5.112) 4 .mu.M (5.113) 4 .mu.M 239 1.75 240 3.12 246 0.06
(5.114) (5.115) (5.121) 247 0.16 248 1.2 248 0.19 (5.122) (5.124)
(5.123) 249 0.64 250 0.95 256 4.9 (5.125) (5.126) (5.132) 257 2.3
258 10.8 259 2.2 5.133 (5.134) (5.135) 260 9.9 266 0.46 269 0.72
(5.136) (5.138) (5.140) 0.46 276 1.77 279 7.7 280 23 (5.145)
(5.147) (5.148) 281 2.9 282 4.5 283 0.48 (5.149) (5.150) (5.151)
0.55 284 4.3 285 0.76 286 1.5 (5.152) (5.153) (5.154) 278 0.88 274
0.91 270 2.8 1.38
[0851] The compounds listed in Table 10 refer to compounds of
Formula 510.00:
38TABLE 10 918 EXAMPLE R FPT IC.sub.50 (.mu.M) 149 919 10.8 150 920
38% at 16.9 .mu.M 75 921 0.36 0.16 76 922 0.82 77 923 2.04 78 924
1.0 0.42 79 925 2.5 80 926 2.73 81 927 2.78 82 928 0.16 0.36 312
929 0.9 313 930 0.97 314 931 0.83 234 932 0.33 316 933 1.26 317 934
13.3 318 935 4.1 182 936 1.09 183 937 0.97 0.90 321 938 6 368 939
14 @12 .mu.M
[0852] Table 11 lists FPT IC.sub.50 results for additional
compounds.
39TABLE 11 EX- FPT IC.sub.50 FPT IC.sub.50 FPT IC.sub.50 AMPLE
(.mu.M) EXAMPLE (.mu.M) EXAMPLE (.mu.M) 187 1.34 187 0.95 188 4.6
(6.7) (6.8) (6.9) 189 2.44 190 3.3 191 4.9 (5.62) (5.63) (5.64) 192
1.24 194 4.3 195 6.8 (5.65) (5.67) (5.68) 196 0.36 197 1.17 198
0.85 (5.69) (5.70) (5.71) 199 10.8 199 10.2 200 0.87 (5.72A)
(5.72B) (5.73) 201 1.4 202 20% @ 203 11.3 (5.74) (5.75) 11 .mu.M
(5.76) 205 3.1 206 1.19 207 40% @ (5.78) (5.79) (5.80) 12 .mu.M 208
4.80 209 7.92 210 7.93 (5.81) (5.82) (5.83) 211 8.17 212 7.92 213
23% @ 5.84 5.85 (5.86) 10 .mu.M 214 0% @ 215 30% @ 216 34% @ (5.87)
10 .mu.M (5.88) 13 .mu.M (5.89) 10 .mu.M 217 6.75 218 9.92 233 0.67
(5.90) (5.91) (5.108) 251 0.76 261 1.3 351 0.17 (5.127) (6.12) 352
0.74 353 0.76 354 0.21 355 0.88 273 0.84 267 1.33 (5.143) (6.17)
356 0.062 264 26% @ 262 0.82 0.073 (6.15) 3.8 .mu.M (6.13) 263 9.8
253 4.3 350 2.1 (6.14) (5.129) 252 7.2 182 1.09 268 1.22 (5.128)
(6.4) (5.139) 277 2.3 193 7.4 204 13.3 (6.20) 355 0.88 352 0.74 353
0.76 0.38 0.30
[0853] The compounds listed in Table 12 refer to compounds of
Formula 525.00:
40TABLE 12 940 FPT IC.sub.50 EXAMPLE A B (.mu.M) 184 (5.60) 941 942
0.91 185 (5.61) 943 944 3.8 223 (5.96) 945 946 2.1 223 (5.97) 947
948 0.19 0.72 0.61 224 (6.10) 949 950 3.2 224 (6.11) 951 952 0.46
225 (5.98) 953 954 3.5 225 (5.99) 955 956 1.6 226 (5.100) 957 958
4.1 226 (5.101) 959 960 1.8 351 961 962 0.17 354 963 964 0.21
[0854] The compounds listed in Table 13 refer to compounds of
Formula 515.00:
41 965 EXAMPLE R FPT IC.sub.50 (.mu.M) 151 966 15.0 152 967 15.0
153 968 29.6 87 969 1.14
[0855] Additional FPT IC.sub.50 results were (1) Example 180,
compound 5.47, 0072 .mu.M; (2) Example 181, compound 5.48, 023
.mu.M; (3) Example 182, compound 6.4, 1.09 .mu.M; and (4) Example
183, compound 6.5, 0.97 .mu.M.
[0856] Tables 20-22 disclose FPT Inhibition data for additional
comnpounds.
42TABLE 20 EXAMPLE FPT IC.sub.50 (.mu.M) EXAMPLE FPT IC.sub.50
(.mu.M) 400 (5.210) 0.068 401 (5.209) 0.063 0.08 400-B (5.203)
0.068 400-C (5.200) 0.030 400-D (5.217) 0.21 400-E (5.208) 0.04
400-F (5.201) 0.036 400-G (5.204) 0.024 400-H (5.220) 0.24 400-J
(5.212) 0.14 400-K (5.218) 0.21 400-L (5.206) 0.095 0.09
[0857]
43TABLE 21 EXAMPLE FPT IC.sub.50 (.mu.M) EXAMPLE FPT IC.sub.50
(.mu.M) 411 0.32 411-A 0.59 411-B 0.32 402-A 0.45 0.56 411-D 0.62
411-E 1.14 411-F 1.28 411-G 0.7 411-L 0.82 402 1.0 405 1.3 406 1.4
413 0.103 414-A 1.90 414 0.90 417 1.16 418 1.85 417-A 0.85 417-B
0.14 419 <0.12 420 0.23 422 0.60 423 >4.3 422-A >1.2 35
(4.3) 22 (1.2) 411-N .about.2 411-M 0.65 44 (1.3) 411-R .about.4
411-S 2.1 29 (1.30) 411-P 3.8 411-Q .about.10 33 (4.3) 411-O
.about.5 411-X 0.45 39 (4) 411-V 0.27 411-T 0.58 411-W 0.16 411-U
1.12 0.17 425 1.74 425-B 0.74 425-A 2.2 425-C 1.26 425-E 0.49 425-D
1.2 425-G 2.3 425-F 7 426 (5.207) 0.012 425-H (5.202) 0.059 0.059
0.049 0.075 bv 425-J 0.39 425-K 0.40 0.41 425-L 4.5 426-A 0.33 427
1.8 427-A 2.2 425-N 0.64 428 1.25 429 1.27 425-M 1.8 431 0.82 431-C
0.88 431-B 0.92 431-D 1.0 431-A 1.05 430 1.3 431-E 0.88 425-O
(5.126) 0.17 0.14 0.122 0.118 0.178 bv 425-P 0.45 425-Q 1.37 425-S
0.6 425-R 1.7 428-A 1.1 431-F 1.75 430-A 7 431-G 7 425-T 12.2 425-U
(5.211) 0.10 0.14 425-V 1.66 434 0.26 70 (0.48) 434-A 3.5 435 7.0
437 1000 411-Z 1.5 36 (11) 427-B 0.21 427-C 0.24 432 0.66 415
>3.8 411-C 6.0 400-M 0.9 411-DD 3.1 411-EE 10 (3.3) 411-FF
1.8
[0858]
44 TABLE 22 EXAMPLE FPT IC.sub.50 (.mu.M) EXAMPLE FPT IC.sub.50
(.mu.M) 410 0.70 410-A 0.086 410-B 0.084 410-C 0.052 410-D 410-E
1000 31 (4.5) 410-F 2.2 410-G 0.21 410-H 7 410-J 1.9 412 0.52 410-L
2.9 403 1000 404 4.6 401-A 1.7 400-A 2.6 412 0.52 416 3.7 410-M
.about.12 424 1.3 27 (3.6) 424-A 1000 433 2.5 22 (4) 433-A 1.1
433-B 1.89 433-C 2.5 436 17 436-A 1000 436-B 1000 17 (9.6) 2 (10.6)
436-C 1000 436-D 0.75 36 (10) 410-S 1000 410-T 1.8 32 (3.4) 410-U 5
410-V 1.17 40 (3.3) 410-W 1.16
[0859]
45TABLE 14 COMPARISON OF FPT INHIBITION AND GGPT INHIBITION ENZYME
INHIBITION ENZYME INHIBITION EXAMPLE FPT IC.sub.50 .mu.M GGPT
IC.sub.50 .mu.M 1 0.25 >46 2 0.47 >46 3 0.66 >39 5 1.7
>46 7 2.3 >45 8 2.3 42 181 0.23 >42 78 2.19 >46 0.53
0.74 0.76 0.97 77 2.04 >39 79 2.5 >50 76 0.82 >40
[0860]
46TABLE 23 COMPARISON OF FPT INHIBITION AND GGPT INHIBITION ENZYME
INHIBITION ENZYME INHIBITION EXAMPLE FPT IC.sub.50 .mu.M GGPT
IC.sub.50 .mu.M 400-D 0.21 >38 400-C 0.030 >38 400-B 0.068
>38 400-E 0.04 1000 30 (38) 400-F 0.036 1000 0 (36) 400-G 0.024
>39 400-H 0.24 1000 0 (36) 400-J 0.14 1000 6 (36) 400-K 0.21
1000 0 (37) 400 0.068 1000 29 (36) 401 0.063 1000 0.08 7 (34) 413
0.103 >35 417-B 0.14 1000 15 (32) 419 <0.12 1000 0 (41) 411-W
0.16 1000 0.17 3 (42) 426 0.012 >39 425-H 0.059 >38 0.059
0.049 0.075 bv 425-O 0.17 >38 0.14 0.122 0.118 0.178 bv 425-U
0.10 >38 0.14 400-L 0.095 38 0.09
[0861]
47TABLE 24 COMPARISON OF FPT INHIBITION AND GGPT INHIBITION ENZYME
INHIBITION ENZYME INHIBITION EXAMPLE FPT IC.sub.50 .mu.M GGPT
IC.sub.50 .mu.M 410-G 0.21 1000 32 (33) 410-A 0.086 .about.40 47
(35) 410-B 0.084 1000 21 (35)
[0862]
48TABLE 15 ACTIVITY IN COS CELLS Inhibition of Ras Inhibition of
Ras Processing Processing Example IC.sub.50 (.mu.M) Example
IC.sub.50 (.mu.M) 1 1.0 -- -- 82 1.2 156 (5.46) 2.7 75 3.7 2 3.7 45
4.2 157 4.5 78 <4.6 42 5.8 19 6.2 89 6.3 83 7.4 5 9.2 77 9.2 43
9.7 6 10.0 49 10.7 47 11.1 44 11.6 87 12.7 46 >8.0 85 >37.4
84 >9.7 3 >10 76 39.9 154 (5.28) >10.0 48 10.7 5 >12 88
>12 53 >13 181 (5.48) 1.1 278 2.6 274 8.0
[0863] In Table 15, the numbers in parenthesis in the Example
column refer to the formula number for the compound used in the
indicated example. Also, the compound of Example 157 is: 970
49TABLE 25 ACTIVITY IN COS CELLS Inhibition of Ras Inhibition of
Ras Processing Processing Example IC.sub.50 (.mu.M) Example
IC.sub.50 (.mu.M) 411 .about.1 411-A 0.7 93 (5) 411-B 1.8 411-D 1.6
400-D 2.0 400-C 0.7 402 >10 411-G 5.1 400-G 0.58 400-H 2.5 100
(5) 400-K 2.2 411-B 1.8 100 (5) 400-D 2.0 400-C 0.7 400-G 0.58 413
1.5 417 4.0 418 >10 425-E 5.0 426 0.38 425-H 0.63 425-J 5.0 0.45
425-K 0.45 426-A >5.0 425-O 0.1 425-P 5.7 tox (10) 0.4 425-U
0.45 434 <<5 tox (10) 400-L 0.6 0.65
[0864]
50TABLE 26 ACTIVITY IN COS CELLS Inhibition of Ras Inhibition of
Ras Processing Processing Example IC.sub.50 (.mu.M) Example
IC.sub.50 (.mu.M) 410-G 4.0 410-D 18.5
[0865]
51TABLE 16 INHIBITION OF TUMOR CELL GROWTH MAT ASSAY Tumor Normal
Tumor Normal IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example
(.mu.M) (.mu.M) Example (.mu.M) (.mu.M) 75 2.5 >50.0 -- -- -- 1
3.1 25.0 82 3.1 40.0 5 6.3 >50.0 89 6.3 >25.0 127 6.3
>50.0 45 6.3 >50.0 88 8.0 >50.0 6 12.5 50.0 49 12.5
>50.0 47 12.5 >50.0 48 12.5 25.0 79 12.5 >50.0 158 (5.36)
12.5 18.0 2 25.0 >50.0 10 25.0 >50.0 128 25.0 >50.0 44
25.0 25.0 164 (5.30) 25.0 >50.0 43 25.0 50.0 165 (5.34) 25.0
50.0 53 25.0 >50.0 166 (5.26) 37.0 >50.0 159 (5.31) 37.0
>50.0 167 (5.32) 37.0 50.0 160 (5.39) 37.0 50.0 168 (5.44) 37.0
>50.0 161 (5.45) 37.0 >50.0 5 37.5 100.0 162 (5.29) 37.0
>50.0 93 40.0 >50.0 94 40.0 80.0 88 >50.0 >50.0 3
>50.0 >50.0 7 50.0 100.0 90 50.0 >50.0 91 50.0 80.0 95
>50.0 >50.0 11 >50.0 >50.0 12 50.0 >50.0 96 50.0
>50.0 97 >50.0 >50.0 98 50.0 >50.0 121 50.0 >50.0
126 50.0 >50.0 163 (5.27) 50.0 >50.0 42 50.0 >50.0 154
(5.28) >50.0 >50.0 169 (5.33) >50.0 >50.0 46 50.0
>50.0 80 >50.0 >50.0 77 >50.0 >50.0 76 >50.0
>50.0 81 >50.0 >50.0 173 (5.35) >50.0 >50.0 170
(5.37) 50.0 >50.0 174 (5.38) 50.0 50.0 171 (5.40) 50.0 >50.0
87 50.0 >50.0 172 (5.42) >50.0 >50.0 175 (5.43) >50.0
>50.0 180 (5.47) 18 >50.0 181 (5.48) <3.1 >50.0
[0866] In Table 16, the numbers in parenthesis in the Example
column refer to the formula number for the compound used in the
indicated example.
52TABLE 27 INHIBITION OF TUMOR CELL GROWTH MAT ASSAY Tumor Normal
Tumor Normal IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example
(.mu.M) (.mu.M) Example (.mu.M) (.mu.M) 411-A 1.6 >25 411 18
>25 411-B 6.25 >25 402-A 3.1 >25 411-D 8 >25 411-E
>25 >25 400-D 4 >25 400-C <1.6 >25 402 18 >25
400-B <1.6 6.25 411-G 6.25 >25 400-E <1.6 18 4 >12.5
400-F <1.6 >25 405 12.5 >25 400-G 1.6 >25 400 1.6
>25 401 <1.6 >25 411-B 6.25 >25 402-A 3.1 >25 400-D
4 >25 400-C <1.6 >25 400-B <1.6 >25 400-G 1.6 >25
413 >6.25 10 417 10 18 418 25 >25 417-B <1.6 >25 425
12.5 >25 425-B 12.5 >25 425-E 1.6 >25 426 3.1 25 425-H
<1.6 >25 <0.8 >12.5 425-J 3.1 >25 425-K 6.25 >25
426-A 6.25 >25 428 12.5 18 425-O 3.1 6.25 425-P >3.1 3.1
<0.8 6.25 425-U 6.25 10 400-L <1.6 >25 <0.8
>12.5
[0867]
53TABLE 28 INHIBITION OF TUMOR CELL GROWTH MAT ASSAY Tumor Normal
Tumor Normal IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example
(.mu.M) (.mu.M) Example (.mu.M) (.mu.M) 410-D 10 >50
[0868]
54TABLE 17 COS CELLS Activity Inhibition of Tumor Cell Enzyme
Inhibition of Growth Inhibition Ras MAT Assay GGPT Processing
IC.sub.50 (.mu.M) Example IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) Tumor
Normal 180 >42 1.0 18 >50 6.3 12.5 50 2.4 12.5 >50 182
(6.4) >40 12.0 37 >50 183 (6.5) >40 10.5 5 18 184 (5.60)
-- 11.5 12.5 >50 185 (5.61) -- >20 -- -- 187 (6.7) >46 4.8
37 >50 25 >50 187 (6.8) >46 1.3 9 >50 4 50 189 (5.62)
42 7.0 37 >50 190 (5.63) -- -- >50 >50 191 (5.64) -- --
<3.1 50 192 (5.65) >43 4.9 25 >50 37 >50 196 (5.69)
>46 5.0 37 >50 25 >50 197 (5.70) -- 11.1 25 >50 198
(5.71) -- 6.1 12.5 >50 200 (5.73) -- 2.7 18 >50 201 (5.74) --
0.93 3.1 12.5 206 -- 2.4 <3.1 16 208 (5.81) -- -- >50 >50
209 (5.82) -- -- 25 >50 211 (5.84) -- -- 37 >50 212 (5.85) --
-- 25 37 217 (5.90) -- -- 37 50 218 (5.91) -- -- 37 50 219 (5.92)
-- -- 25 >50 220 (5.93) -- -- 25 >50 221 (5.94) -- -- 6.25
>50 222 (5.95) -- 4.7 18 37 223 (5.96) -- 10.5 25 >50 223
(5.97) -- 1.3 8 >50 224 (6.11) -- 7.3 37 >50 225 (5.98) -- --
12.5 50 225 (5.99) -- 6.2 12.5 >50 226 (5.100) -- -- 25 >50
226 (5.101) -- 6.5 12.5 >50 227 (5.102) >41 1.0 4 >50 229
(5.104) -- -- 37 >50 230 (5.105) -- >20 37 >50 233 (5.108)
-- 10 18 >50 235 -- 9.1 12.5 >50 236 (5.111) >45 3.5 4
>50 237 (5.112) -- -- >50 >50 238 (5.113) -- -- >50
>50 239 (5.114) -- 4.6 37 >50 246 (5.121) >40 >3.9 12.5
50 3.1 <3.1 >50 0.91 247 (5.122) >40 >3.9 25 >50 3.5
8 >50 248 (5.124) -- 2.05 18 >50 248 (5.123) -- 4.6 18 >50
250 (5.126) -- 8.6 18 >50 251 (5.127) -- 8.1 -- -- 261 (6.12) --
9.1 -- -- 266 (5.138) -- 0.77 3.1 6.25 0.89 267 (6.17) -- 12.5 --
-- 269 (5.140) -- 0.69 6.25 12.5 276 (5.145) -- 2.9 12.5 50 281
(5.149) -- 7.0 4 >50 283 (5.151) -- 5.6 10 >50 285 (5.153) --
5.2 12.5 >50 10.1 286 (5.154) -- 8.3 25 >50 287 >40 >10
3.1 >50 >10 50 >50 25 >50 288 -- 2.8 8 >50 289
>40 >10 12.5 >50 18 >50 12.5 >50 290 >38 -- 12.5
>50 6.25 >50 8 >50 291 >46 3.6 18 >50 292 >44 6.8
6.25 >50 293 >40 >11.1 12.5 >50 6.5 12.5 >50 12.5
>50 294 -- 5.2 18 >50 2.8 295 -- 20.8 -- -- 297 41 -- >50
>50 298 >35 >9 >50 >50 299 1000 -- -- -- 300 -- 2.6
<3.1 >50 301 40 4.4 12.5 >50 1.0 <3.1 >50 <3.1
>50 303 >43 3.4 8 >50 304 >40 -- 50 >50 305 -- -- 25
>50 307 -- 4.6 12.5 50 0.85 309 35.1 >10 -- -- 310 -- -- 25
>50 311 41.3 9.5 10 >50 312 >46 3.8 12.5 >50 313 >46
1.5 6.25 >50 314 >46 3.0 4 >50 234 >43 2.2 3.1 >50
316 >43 18.4 25 >50 318 -- -- 37 37 321 -- -- 6.25 >50 322
-- 2.8 8 >50 351 1000 2.8 6.25 25 354 1000 -- 6.25 25 365 -- 3.1
6.25 >50 366 -- 3.3 3.1 >50 367 -- 6.2 6.25 >50 78 >46
-- -- -- 77 >39 -- -- -- 79 >50 5.1 -- -- 76 >50 -- -- --
350 -- 3.7 -- -- 355 -- 0.89 8 >25 352 -- 2.2 1.6 >25 353 --
0.9 6.25 >25
[0869] RESULTS:
[0870] 1. Enzymology.
[0871] The data demonstrate that the compounds of the invention are
inhibitors of Ras-CVLS farnesylation by partially purified rat
brain farnesyl protein transferase (FPT). The data also show that
there are compounds of the invention which can be considered as
potent (IC.sub.50 <10 .mu.M) inhibitors of Ras-CVLS
farnesylation by partially purified rat brain FPT.
[0872] The data also demonstrate that compounds of the invention
are poorer inhibitors of geranylgeranyl protein transferase (GGPT)
assayed using Ras-CVLL as isoprenoid acceptor. Generally, the
compounds of the invention are inactive or weakly active as
geranylgeranyl transferase inhibitors at 20 .mu.g/mL. For example,
with reference to Table 14, the compound of Example 1 inhibits GGPT
24% at 46 .mu.M and is at least 184-fold selective for FPT
inhibition. The compound of Example 2, for example, inhibits GGPT
25% at 46 .mu.M and is at least 98-fold selective for FPT
inhibition. For another example, the compound of Example 3 inhibits
GPPT 3% at 39 .mu.M and is at least 59-fold selective for FPT. This
selectivity is important for the therapeutic potential of the
compounds used in the methods of this invention, and increases the
potential that the compounds will have selective growth inhibitory
properties against Ras-transformed cells.
[0873] 2. Cell-Based: COS Cell Assay
[0874] Western blot analysis of the Ras protein expressed in
Ras-transfected COS cells following treatment with the tricyclic
farnesyl protein transferase inhibitors of this invention indicated
that they inhibit Ras-CVLS processing, causing accumulation of
unprocessed Ras (see Table 15). The compound of Example 1, for
example, inhibited Ras-CVLS processing with an IC.sub.50 value of 1
.mu.M (0.44 .mu.g/mL), but did not block the geranylgeranylation of
Ras-CVLL at concentrations up to 20 .mu.g/mL. Microscopic and
photographic examination of the Ras-transfected COS cells following
treatment with two of the tricyclic farnesyl transferase inhibitors
of this invention indicated that they also blocked phenotypic
changes induced by expression of oncogenic Ras. Cells expressing
oncogenicRas-CVLS or Ras-CVLL overgrew the monolayer and formed
dense foci of cells. The compound of Example 1 inhibited the
morphological changes induced by Ras-CVLS in a dose-dependent
manner over the concentration range of 2 to 20 .mu.g/mL. The
compound of Example 1 had little effect at 0.2 or 0.5 .mu.g/mL.
Importantly, 20 .mu.g/mL of the compound of Example 1 did not
prevent the morphological changes induced by Ras-CVLL.
[0875] These results provide evidence for specific inhibition of
farnesyl protein transferase, but not geranylgeranyl transferase I,
by compounds of this invention in intact cells and indicate their
potential to block cellular transformation by activated Ras
oncogenes. 3. Cell-Based: Cell Mat Assay
[0876] Tricyclic farnesyl protein transferase inhibitors of this
invention also inhibited the growth of Ras-transformed tumor cells
in the Mat assay without displaying cytotoxic activity against the
normal monolayer.
[0877] In Vivo Anti-Tumor Studies:
[0878] Tumor cells (5.times.10.sup.5 to 8.times.10.sup.6 of M27
(mouse Lewis lung carcinoma), A431 (human epidermal carcinoma) or
SW620 (human colon adenocarcinoma [lymph node metastasis])) are
innoculated subcutaneously into the flank of 5-6 week old athymic
nu/nu female mice. For the C-f-1 (mouse fibroblast transformed with
c-fos oncogene) tumor model, 2 mm.sup.3 tumor fragments are
transplanted subcutaneously into the flank of 5-6 week old athymic
nu/nu female mice. Tumor bearing animals are selected and
randomized when the tumors are established. Animals are treated
with vehicle (beta cyclodextran for i.p. or corn oil for p.o.) only
or compounds in vehicle twice a day (BID) for 5 (1-5), 6 (1-6), or
7 (1-7) days per week for 2 (.times.2) or 4 (.times.4) weeks. The
percent inhibition of tumor growth relative to vehicle controls are
determined by tumor measurements. The results are reported in Table
18.
55TABLE 18 In-Vivo Anti-Tumor Results s.c. Route & Ex Ex Ex Ex
Ex Ex Ex Tumor Schedule 2 1 3 7 78 79 75 M27 po, BID, 61.2 -- 27.3
58.2 -- -- -- 1-7, .times.4 A431 ip, BID, -- 20.5 0 0 -- -- -- 1-5,
.times.4 A431 po, BID 45.6 -- 8 29.1 -- -- -- 1-5, .times.4 A431
po, BID, 36.5 -- 26 -- -- -- -- 1-5, .times.4 A431 po, BID, -- --
-- -- 31 0 34.5 1-6, .times.4 C-f-1 ip, BID, 8 0 8 39.7 -- -- --
1-5, .times.2 C-f-1 po, BID, 9.6 -- 0 39.3 -- -- -- 1-5, .times.4
C-f-1 po, BID, -- -- -- -- 26.7 25 20 1-5, .times.4 SW- ip, BID, 0
0 27 19.6 -- -- -- 620 1-5, .times.4 SW- po, BID, 46.1 0 15.8 48.6
-- -- -- 620 1-5, .times.2 SW- po, BID, 33.5 -- -- 0 -- -- -- 620
1-5, .times.4 SW- po, BID, -- -- -- -- 59.6 26.7 43.4 620 1-5,
.times.4
[0879] Additional in-vivo anti-tumor results are reported in Table
19. In Table 23, LOX is a human memanoma cell line, and the
schedule "10/wk, .times.4", for example, means 10 times per week
(twice a day Monday to Friday) for 4 weeks.
56TABLE 19 In-Vivo Anti-Tumor Results Example Average or Dose Route
& % Tumor Structure Tumor (MPK) Schedule Inhibition Ex. 2 SW620
100 ip, 10/wk, x2 0 SW620 100 po, 10/wk, x2 0 SW620 100 po, 10/wk,
x4 1 M27 100 po, 14/wk, x4 45 Ex. 4 SW620 100 po, 10/wk, x4 2 Ex. 7
SW620 100 po, 10/wk, x2 13 SW620 100 po, 10/wk, x4 0 M27 100 po,
14/wk, x4 40 Ex. 45 SW620 100 po, 10/wk, x4 0 SW620 100 po, 10/wk,
x4 19 M27 100 po, 10/wk, x3 0 Ex. 47 SW620 100 po, 10/wk, x4 0
SW620 100 po, 10/wk, x4 30 M27 100 po, 10/wk, x3 19 Ex. 49 SW620
100 po, 10/wk, x4 0 SW620 100 po, 10/wk, x4 27 M27 100 po, 10/wk,
x3 30 Ex. 75 SW620 100 po, 10/wk, x4 26 SW620 100 po, 10/wk, x4 4
SW620 100 po, 10/wk, x4 54 SW620 100 po, 10/wk, x4 7 M27 100 po,
10/wk, x4 0 Ex. 82 SW620 100 po, 10/wk, x4 25 SW620 100 po, 10/wk,
x4 32 Ex. 88 SW620 100 po, 10/wk, x4 43.25* M27 100 po, 10/wk, x4
19 SW620 100 po, 10/wk, x4 38* LOX 100 po, 10/wk, x4 70 SW620 100
po, 10/wk, x4 38 SW620 100 po, 10/wk, x4 37 SW620 50 po, 10/wk, x4
30 SW620 50 po, 10/wk, x4 30 SW620 25 po, 10/wk, x4 4 SW620 25 po,
10/wk, x4 0 SW620 100 po, 10/wk, x4 27.4* LOX 100 po, 10/wk, x4 33
SW620 100 po, 10/wk, x4 28 SW620 100 po, 10/wk, x4 38 Ex. 127 SW620
100 po, 10/wk, x4 25 SW620 100 po, 10/wk, x4 42 M27 100 po, 10/wk,
x3 22 Ex. 187 (6.8) SW620 100 po, 10/wk, x4 11 SW620 100 po, 10/wk,
x4 21 Ex. 192 SW620 100 po, 10/wk, x4 29 SW620 100 po, 10/wk, x4 40
Ex. 287 SW620 100 po, 10/wk, x4 14 SW620 100 po, 10/wk, x4 0 Ex.
290 SW620 100 po, 10/wk, x4 41 SW620 100 po, 10/wk, x4 16 Ex. 293
SW620 100 po, 10/wk, x4 5 SW620 100 po, 10/wk, x4 47 Ex. 301 SW620
100 po, 10/wk, x4 16 SW620 100 po, 10/wk, x4 0 Ex. 82A SW620 100
po, 10/wk, x4 27 SW620 100 po, 10/wk, x4 26 Ex. 342 SW620 100 po,
10/wk, x4 39 SW620 100 po, 10/wk, x4 31 5.21 SW620 100 po, 10/wk,
x4 19 SW620 100 po, 10/wk, x4 17 M27 100 po, 10/wk, x4 0 5.25 SW620
100 po, 10/wk, x4 7 SW620 100 po, 10/wk, x4 36 *Average of several
results
[0880] The compound of Example 342 (Table 19) is: 971
[0881] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 70 percent active ingredient. Suitable solid
carriers are known in the art, e.g. magnesium carbonate, magnesium
stearate, talc, sugar, lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration.
[0882] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides or cocoa butter is first melted,
and the active ingredient is dispersed homogeneously therein as by
stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool and thereby solidify.
[0883] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection.
[0884] Liquid form preparations may also include solutions for
intranasal administration.
[0885] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas.
[0886] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0887] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0888] Preferably the compound is administered orally.
[0889] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0890] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.1 mg to 1000 mg,
more preferably from about 1 mg. to 300 mg, according to the
particular application.
[0891] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
increments until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0892] The amount and frequency of administration of the compounds
of the invention and the pharmaceutically acceptable salts thereof
will be regulated according to the judgment of the attending
clinician considering such factors as age, condition and size of
the patient as well as severity of the symptoms being treated. A
typical recommended dosage regimen is oral administration of from
10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four
divided doses to block tumor growth. The compounds are non-toxic
when administered within this dosage range.
[0893] The following are examples of pharmaceutical dosage forms
which contain a compound of the invention. The scope of the
invention in its pharmaceutical composition aspect is not to be
limited by the examples provided.
Pharmaceutical Dosage Form Examples
EXAMPLE A
[0894]
57 Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound
100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 as
a 10% paste in Purified Water 4. Corn Starch, Food Grade 45 40 5.
Magnesium Stearate 3 7 Total 300 700
Method of Manufacture
[0895] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.
Granulate the mixture with Item No. 3. Mill the damp granules
through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the
damp granules. Screen the dried granules if necessary and mix with
Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for
1-3 minutes. Compress the mixture to appropriate size and weigh on
a suitable tablet machine.
EXAMPLE B
[0896]
58 Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound
100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4.
Magnesium Stearate NF 7 7 Total 253 700
[0897] Method of Manufacture
[0898] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15
minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture
into suitable two-piece hard gelatin capsules on a suitable
encapsulating machine.
[0899] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit
and scope of the present invention.
[0900] In addition to the examples provided above, the following
compounds were prepared using the product of Preparative Example 40
and following substantially the same procedures as described for
Examples 193, 428, 431, 433-A, and 183, as appropriate:
59 Example Analytical No. Compound Data 500 972 Mass Spec.:
MH.sup.+ = 619.15 501 973 Mass Spec.: MH.sup.+ = 517 502 974 Mass
Spec.: MH.sup.+ = 560 503 975 Mass Spec.: MH.sup.+ = 604.2 504 976
Mass Spec.: MH.sup.+ = 532.15
EXAMPLE 505
[0901] 977
[0902] React the compound of Example 501 with an excess of acetic
anhydride in MeOH via standard procedures to form the product
compound in 91% yield. Mass Spec.: MH.sup.+=559
EXAMPLE 506
[0903] 978
[0904] React the compound of Preparative Example 4g with
4-(2-bromopyridyl)acetic acid via the substantially the same
procedure as described for Example 410 to give the product
compound. m.p. =134.degree.-136.1.degree. C.; Mass Spec.:
MH.sup.+=588
* * * * *