U.S. patent application number 09/782415 was filed with the patent office on 2001-08-23 for novel phenyl-substituted tricyclic inhibitors of farnesyl-protein transferase.
Invention is credited to Afonso, Adriano, Kelly, Joseph M., Rosenblum, Stuart B., Weinstein, Jay, Wolin, Ronald L..
Application Number | 20010016585 09/782415 |
Document ID | / |
Family ID | 26727657 |
Filed Date | 2001-08-23 |
United States Patent
Application |
20010016585 |
Kind Code |
A1 |
Afonso, Adriano ; et
al. |
August 23, 2001 |
Novel phenyl-substituted tricyclic inhibitors of farnesyl-protein
transferase
Abstract
Novel phenyl-substituted tricyclic compounds and pharmaceutical
compositions are disclosed which are inhibitors of the enzyme,
farnesyl protein transferase. Also disclosed is a method of
inhibiting Ras function and therefore inhibiting the abnormal
growth of cells. The method comprises administering the novel
halo-N-substituted urea compound to a biological system. In
particular, the method inhibits the abnormal growth of cells in a
mammals such as a human.
Inventors: |
Afonso, Adriano; (West
Caldwell, IN) ; Kelly, Joseph M.; (Parlin, IE)
; Weinstein, Jay; (Upper Montclair, NJ) ; Wolin,
Ronald L.; (Bedminister, NJ) ; Rosenblum, Stuart
B.; (West Orange, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
26727657 |
Appl. No.: |
09/782415 |
Filed: |
February 13, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09782415 |
Feb 13, 2001 |
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09374392 |
Aug 13, 1999 |
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6218401 |
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60049887 |
Jun 17, 1997 |
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Current U.S.
Class: |
514/253.03 ;
514/290; 544/361; 546/93 |
Current CPC
Class: |
C07D 401/04 20130101;
C07D 221/16 20130101; C07D 401/12 20130101; A61P 35/00 20180101;
C07D 401/14 20130101 |
Class at
Publication: |
514/253.03 ;
514/290; 546/93; 544/361 |
International
Class: |
A61K 031/473; A61K
031/496 |
Claims
What is claimed is:
1. A compound of the formula: 80or a pharmaceutically acceptable
salt or solvate thereof, wherein: A represents N or N-oxide; X
represents N, CH or C, such that when X is N or CH, there is a
single bond to carbon atom 11 as represented by the solid line; or
when X is C, there is a double bond to carbon atom 11, as
represented by the solid and dotted lines; R.sup.1 is hydrogen,
bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino,
acylamino or alkoxy; R.sup.2 is hydrogen, halo, trifluoromethyl,
alkyl, alkoxy, --OCF.sub.3, hydroxy, amino or acylamino; R.sup.3 is
hydrogen, bromo, chloro, alkoxy, --OCF.sub.3 or hydroxy; R.sup.4 is
hydrogen, halo, trifluoromethyl, alkyl or alkoxy; provided that at
least one of R.sup.2 or R.sup.3 or R.sup.4 is alkyl or alkoxy and
provided that at least two of R.sup.1, R.sup.2, R.sup.3 or R.sup.4
are substituents other than hydrogen; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 independently represent hydrogen, alkyl or --CONHR.sup.50
wherein R.sup.50 can be any of the values represented for R, below;
Q is hydrogen when there is a single bond to carbon atom 11, or Q
is hydrogen or hydroxy when there is a single bond to carbon 11 and
X is CH, or Q is not a substituent when there is a double bond to
carbon 11; 81Z is .dbd.O or .dbd.S; and R is aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl,
heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.
2. The compound of claim 1 wherein R.sup.1 is H, halo, alkyl,
cycloalkyl or alkenyl; R.sup.2 is H, halo, alkoxy, or alkyl;
R.sup.3 is H, halo, alkoxy, hydroxy or alkyl; and R.sup.4 is H,
halo or alkyl; and R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are
hydrogen.
3. The compound of claim 2 wherein Y is --SO.sub.2CH.sub.3.
4. The compound of claim 2 wherein Y is --COR wherein R is
heteroarylalkyl, or heterocycloalkylalkyl.
5. The compound of claim 2 wherein R.sup.1 is bromo, methyl, ethyl,
cyclopropyl or vinyl.
6. The compound of claim 2 wherein R.sup.2 is methoxy, bromo or
methyl.
7. The compound of claim 2 wherein R.sup.3 is methoxy, bromo or
methyl.
8. The compound of claim 2 wherein R.sup.4 is chloro or methyl.
9. The compound of claim 1 selected from any of the title compounds
of Examples 1-10 and 14-37.
10. The compound of claim 1 selected from any of the title
compounds of Examples 1, 2, 3, 6, 7, 8,10, 16, 18,19, 21, 22, 24,
26, 27, 29, 33, 34, 34, 36 and 37.
11. The compound of claim 1 selected from any of the title
compounds of Examples 3, 21, 22, 24 and 33.
12. A pharmaceutical composition for inhibiting the abnormal growth
of cells comprising an effective amount of compound of claim 1 in
combination with a pharmaceutically acceptable carrier.
13. A method for inhibiting the abnormal growth of cells comprising
administering an effective amount of a compound of claim 1.
14. The method of claim 13 wherein the the cells inhibited are
tumor cells expressing an activated ras oncogene.
15. The method of claim 13 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
prostate tumor cells, breast tumor cells or colon tumors cells.
16. The method of claim 13 wherein the inhibition of the abnormal
growth of cells occurs by the inhibition of ras farnesyl protein
transferase.
17. The method of claim 13 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.
Description
BACKGROUND
[0001] Patent application WO 95/00497 published Jan. 5, 1995 under
the Patent Cooperation Treaty (PCT) describes compounds which
inhibit the enzyme, farnesyl-protein transferase (FTase) and the
farnesylation of the oncogene protein Ras. 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.
[0002] 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).
[0003] In view of the current interest in inhibitors of farnesyl
protein transferase, a welcome contribution to the art would be
additional compounds useful for the inhibition of farnesyl protein
transferase. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
[0004] 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.
[0005] 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. Compounds useful in the
claimed methods are represented by Formula 1.0: 1
[0006] or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0007] A represents N or N-oxide;
[0008] X represents N, CH or C, such that when X is N or CH, there
is a single bond to carbon atom 11 as represented by the solid
line; or when X is C, there is a double bond to carbon atom 11, as
represented by the solid and dotted lines;
[0009] R.sup.1 is hydrogen, bromo, chloro, trifluoromethyl, acyl,
alkyl, cycloalkyl, amino, acylamino or alkoxy;
[0010] R.sup.2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy,
--OCF.sub.3, hydroxy, amino or acylamino;
[0011] R.sup.3 is hydrogen, bromo, chloro, alkoxy, --OCF.sub.3 or
hydroxy;
[0012] R.sup.4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy;
provided that at least one of R.sup.2 or R.sup.3 or R.sup.4 is
alkyl or alkoxy and provided that at least two of R.sup.1, R.sup.2,
R.sup.3 or R.sup.4 are substituents other than hydrogen;
[0013] Q is hydrogen when there is a single bond to carbon atom 11,
or Q is hydrogen or hydroxy when there is a single bond to carbon
11 and X is CH, or Q is not a substituent when there is a double
bond to carbon 11;
[0014] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently
represent hydrogen, alkyl or --CONHR.sup.50 wherein R.sup.50 can be
any of the values represented for R, below; 2
[0015] Z is .dbd.O or .dbd.S; and
[0016] R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or
heterocycloalkylalkyl.
[0017] Preferably in compound (1.0), there is a single bond or a
double bond at carbon atom 11; X is N, CH or C; R.sup.1 is H, halo,
alkyl, cycloalkyl or alkenyl; R.sup.2 is H, halo, alkoxy, or alkyl;
R.sup.3 is H, halo, alkoxy, hydroxy or alkyl; and R.sup.4 is H,
halo or alkyl; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen;
Y is --SO.sub.2CH.sub.3 or --COR wherein R is heteroarylalkyl,
preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl,
preferably piperidinyl-methyl. When R.sup.1 is other than hydrogen,
preferably the halo moiety is bromo, the alkyl is methyl or ethyl,
the cycloalkyl is cyclopropyl or the alkenyl is vinyl. When R.sup.2
is other than hydrogen, preferably the alkoxy moiety is methoxy,
the halo moiety is bromo or the alkyl is methyl. When R.sup.3 is
other than hydrogen, preferably the alkoxy moiety is methoxy, the
halo moiety is bromo or the alkyl is methyl. When R.sup.4 is other
than hydrogen, preferably the halo moiety is chloro or the alkyl is
methyl. Preferred title compounds include those of Examples 1-10
and 14-37, preferably those of Examples 1, 2, 3, 6, 7, 8, 10, 16,
18, 19, 21, 22, 24, 26, 27, 29, 33, 34, 35, 36 and 37, more
preferably those of Examples 3, 21, 22, 24 and 33, disclosed
hereinafter.
[0018] In another embodiment, the present invention is directed
toward a pharmaceutical composition for inhibiting the abnormal
growth of cells comprising an effective amount of compound (1.0) in
combination with a pharmaceutically acceptable carrier.
[0019] In another embodiment, the present invention is directed
toward a method for inhibiting the abnormal growth of cells,
including transformed cells, comprising administering an effective
amount of compound (1.0) to a mammal (e.g., a human) in need of
such treatment. 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; (3) benign and malignant cells of other
proliferative diseases in which aberrant Ras activation occurs, and
(4) benign or malignant cells that are activated by mechanisms
other than the Ras protein. Without wishing to be bound by theory,
it is believed that these compounds may function either 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, or
through inhibition of ras farnesyl protein transferase, thus making
them useful for their antiproliferative activity against ras
transformed cells.
[0020] The cells to be inhibited can be tumor cells expressing an
activated ras oncogene. For example, the types of cells that may be
inhibited include 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, prostate tumor cells, breast tumor
cells or colon tumors cells. Also, the inhibition of the abnormal
growth of cells by the treatment with compound (1.0) may be by
inhibiting ras farnesyl protein transferase. The inhibition may be
of tumor cells wherein the Ras protein is activated as a result of
oncogenic mutation in genes other than the Ras gene. Alternatively,
compounds (1.0) may inhibit tumor cells activated by a protein
other than the Ras protein.
[0021] This invention also provides a method for inhibiting tumor
growth by administering an effective amount of compound (1.0) 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, prostate carcinoma and breast carcinoma and epidermal
carcinoma.
[0022] 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 N-substituted urea compounds (1.0) 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, lck, and fyn), may be
inhibited by the N-substituted urea compounds (1.0).
[0023] In another embodiment, the present invention is directed
toward a method for inhibiting ras farnesyl protein transferase and
the farnesylation of the oncogene protein Ras by administering an
effective amount of compound (1.0) to mammals, especially humans.
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.
DETAILED DESCRIPTION OF THE INVENTION
[0024] As used herein, the following terms are used as defined
below unless otherwise indicated:
[0025] M.sup.+--represents the molecular ion of the molecule in the
mass spectrum;
[0026] MH.sup.+--represents the molecular ion plus hydrogen of the
molecule in the mass spectrum;
[0027] Bu--represents butyl;
[0028] Et--represents ethyl;
[0029] Me--represents methyl;
[0030] Ph--represents phenyl;
[0031] benzotriazol-1-yloxy represents 3
[0032] 1-methyl-tetrazol-5-ylthio represents 4
[0033] 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; for example methyl, ethyl, propyl, iso-propyl,
n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein
said alkyl group may be optionally and independently substituted
with one, two, three or more of the following: halo (i.e.
trifluoromethyl), alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy
(.dbd.O), aryloxy, --OR.sup.10 (i.e. hydroxymethyl, hydroxyethyl),
--OCF.sub.3, heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sup.10, --SOR.sup.10, --SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 can independently represent hydrogen,
alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl or
heterocycloalkylalkyl;
[0034] acylamino--refers to the moiety --CONR.sup.10R.sup.12
wherein R.sup.10 and R.sup.12 are defined hereinbefore;
[0035] alkoxy--an alkyl moiety of one to 20 carbon atoms covalently
bonded to an adjacent structural element through an oxygen atom,
for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and
the like; wherein said alkoxy group may be optionally and
independently substituted with alkyl, aryl, cycloalkyl, cyano,
--CF.sub.3, oxy (.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3,
heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sup.10, --SOR.sup.10, --SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 are as defined hereinabove;
[0036] aryl (including the aryl portion of aralkyl)--represents a
carbocyclic group containing from 6 to 15 carbon atoms and having
at least one aromatic ring (e.g., aryl is phenyl), wherein said
aryl group optionally can be fused with aryl, cycloalkyl,
heteroaryl or heterocycloalkyl rings; and wherein any of the
available substitutable carbon and nitrogen atoms in said aryl
group and/or said fused ring(s) may be optionally and independently
substituted with one, two, three or more of the following: halo,
alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy (.dbd.O), aryloxy,
--OR.sup.10, --OCF.sub.3, heterocycloalkyl, heteroaryl,
--NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10, --SOR.sup.10,
--SR.sup.10, --NHSO.sub.2, --NO.sub.2, --CONR.sup.10R.sup.12,
--NR.sup.12COR.sup.10, --COR.sup.10, --OCOR.sup.10,
--OCO.sub.2R.sup.10 or --COOR.sup.10, wherein R.sup.10 and R.sup.12
are as defined hereinabove;
[0037] aralkyl--represents an alkyl group, as defined above,
wherein one or more hydrogen atoms of the alkyl moiety have been
substituted with one or more aryl groups; wherein said aralkyl
group may be optionally and independently substituted with one,
two, three or more of the following: halo, alkyl, aryl, cycloalkyl,
cyano, --CF.sub.3, oxy (.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3,
heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sup.10, --SOR.sup.10, --SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.10, or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 are as defined hereinabove;
[0038] aryloxy--represents an aryl group, as defined above, wherein
said aryl group is covalently bonded to an adjacent structural
element through an oxygen atom, for example, phenoxy, wherein said
aryl group optionally can be fused with aryl, cycloalkyl,
heteroaryl or heterocycloalkyl rings; and wherein any of the
available substitutable carbon and nitrogen atoms in said aryloxy
group and/or said fused ring(s) may be optionally and independently
substituted with one, two, three or more of the following: halo,
alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy (.dbd.O), aryloxy,
--OR.sup.10, --OCF.sub.3, heterocycloalkyl, heteroaryl,
--NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10, --SOR.sup.10,
--SR.sup.10, --NHSO.sub.2, --NO.sub.2, --CONR.sup.10R.sup.12,
--NR.sup.12COR.sup.10, --COR.sup.10, --OCOR.sup.10,
--OCO.sub.2R.sup.10 or --COOR.sup.10, wherein R.sup.10 and R.sup.12
are as defined hereinabove;
[0039] cycloalkyl--represents saturated carbocyclic rings branched
or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7
carbon atoms; wherein said cycloalkyl group may be optionally and
independently substituted with one, two, three or more of the
following: halo, alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy
(.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3, heterocycloalkyl,
heteroaryl, --NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10,
--SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10,
--SOR.sup.10, --SR.sup.10, --NHSO.sub.2, --NO.sub.2,
--CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10, --COR.sup.10,
--OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10, wherein
R.sup.10 and R.sup.12 are as defined hereinabove;
[0040] cycloalkylalkyl--represents an alkyl group, as defined
above, wherein one or more hydrogen atoms of the alkyl moiety have
been substituted with one or more cycloalkyl groups; wherein said
cycloalkylalkyl group may be optionally and independently
substituted with one, two, three or more of the following: halo,
alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy (.dbd.O), aryloxy,
--OR.sup.10, --OCF.sub.3, heterocycloalkyl, heteroaryl,
--NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10, --SOR.sup.10,
--SR.sup.10, --NHSO.sub.2, --NO.sub.2, --CONR.sup.10R.sup.12,
--NR.sup.12COR.sup.10, --COR.sup.10, --OCOR.sup.10,
--OCO.sub.2R.sup.10 or --COOR.sup.10, wherein R.sup.10 and R.sup.12
are as defined hereinabove;
[0041] halo--represents fluoro, chloro, bromo and iodo;
[0042] heteroalkyl--represents straight and branched carbon chains
containing from one to twenty carbon atoms, preferably one to six
carbon atoms interrupted by 1 to 3 heteroatoms selected from --O--,
--S-- and --N--; wherein any of the available substitutable carbon
and nitrogen atoms in said heteroalkyl chain may be optionally and
independently substituted with one, two, three or more of the
following: halo, alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy
(.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3, heterocycloalkyl,
heteroaryl, --NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10,
--SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10,
--SOR.sup.10, --SR.sup.10, --NHSO.sub.2, --NO.sub.2,
--CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10, --COR.sup.10,
--OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10, wherein
R.sup.10 and R.sup.12 are as defined hereinabove;
[0043] heteroaryl--represents cyclic groups having at least one
heteroatom selected from O, S and N, said heteroatom(s)
interrupting a carbocyclic ring structure and having a sufficient
number of delocalized pi electrons to provide aromatic character,
with the aromatic heterocyclic groups containing from 2 to 14
carbon atoms,wherein said heteroaryl group optionally can be fused
with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl
rings; and wherein any of the available substitutable carbon or
nitrogen atoms in said heteroaryl group and/or said fused ring(s)
may be optionally and independently substituted with one, two,
three or more of the following: halo, alkyl, aryl, cycloalkyl,
cyano, --CF.sub.3, oxy (.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3,
heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sup.10, --SOR.sup.10, -- SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.12 or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 are as defined hereinabove.
[0044] Representative heteroaryl groups can include, for example,
furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or
2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be
represented as: 5
[0045] heteroarylalkyl--represents an alkyl group, as defined
above, wherein one or more hydrogen atoms have been replaced by one
or more heteroaryl groups; wherein said heteroarylalkyl group may
be optionally and independently substituted with one, two, three or
more of the following: halo, alkyl, aryl, cycloalkyl, cyano,
--CF.sub.3, oxy (.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3,
heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sub.10, --SOR.sup.10, --SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 are as defined hereinabove;
[0046] 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 heteroatoms selected from --O--, --S-- and
--N--, wherein optionally, said ring may contain one or two
unsaturated bonds which do not impart aromatic character to the
ring; and wherein any of the available substitutable carbon and
nitrogen atoms in the ring may be optionally and independently
substituted with one, two, three or more of the following: halo,
alkyl, aryl, cycloalkyl, cyano, --CF.sub.3, oxy (.dbd.O), aryloxy,
--OR.sup.10, --OCF.sub.3, heterocycloalkyl, heteroaryl,
--NR.sup.10R.sup.12, --NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.10, --SO.sub.2R.sup.10, --SOR.sup.10,
--SR.sup.10, --NHSO.sub.2, --NO.sub.2, --CONR.sup.10R.sup.12,
--NR.sup.12COR.sup.10, --COR.sup.10, --OCOR.sup.10,
--OCO.sub.2R.sup.10 or --COOR.sup.10, wherein R.sup.10 and R.sup.12
are as defined hereinabove. Representative heterocycloalkyl groups
can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl,
1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or
3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, 6
[0047] or wherein R.sup.10 is defined hereinbefore and t is 0, 1 or
2.
[0048] heterocycloalkalkyl--represents an alkyl group, as defined
above, wherein one or more hydrogen atoms have been replaced by one
or more heterocycloalkyl groups; wherein optionally, said ring may
contain one or two unsaturated bonds which do not impart aromatic
character to the ring; and wherein said heterocycloalkylalkyl group
may be optionally and independently substituted with one, two,
three or more of the following: halo, alkyl, aryl, cycloalkyl,
cyano, --CF.sub.3, oxy (.dbd.O), aryloxy, --OR.sup.10, --OCF.sub.3,
heterocycloalkyl, heteroaryl, --NR.sup.10R.sup.12,
--NHSO.sub.2R.sup.10, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.10,
--SO.sub.2R.sup.10, --SOR.sup.10, --SR.sup.10, --NHSO.sub.2,
--NO.sub.2, --CONR.sup.10R.sup.12, --NR.sup.12COR.sup.10,
--COR.sup.10, --OCOR.sup.10, --OCO.sub.2R.sup.10 or --COOR.sup.10,
wherein R.sup.10 and R.sup.12 are as defined hereinabove.
[0049] The following solvents and reagents are referred to herein
by the abbreviations indicated: tetrahydrofuran (THF); ethanol
(EtOH); methanol (MeOH); acetic acid (HOAc orAcOH); ethyl acetate
(EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA);
trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT);
m-chloroperbenzoic acid (MCPBA); triethylamine (Et.sub.3N); diethyl
ether (Et.sub.2O); ethyl chloroformate (ClCO.sub.2Et); lithium
di-isopropylamide (LDA) and 1-(3-dimethylaminopropyl)-3-ethyl
carbodiimide hydrochloride (EDCl or DEC).
[0050] 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: 7
[0051] Certain compounds of the invention may exist in different
steroisomeric forms (e.g., enantiomers, diastereoisomers and
atropisomers). The invention contemplates all such steroisomers
both in pure form and in mixture, including racemic mixtures. For
example, the carbon atom at the C-11 position can be in the S or R
steroconfiguration.
[0052] 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.
[0053] Certain basic tricyclic compounds also form pharmaceutically
acceptable salts, e.g., acid addition salts. For example, the
pyrido-nitrogen 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 skilled 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.
[0054] 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 purpopses of the
invention.
[0055] Compounds of the present invention can be prepared according
to the following Schemes I, II or III wherein 8
[0056] A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, Y, the solid and dotted lines are as defined
hereinbefore.
[0057] In Scheme I, compound 1.0 wherein 9
[0058] and Z.dbd.O wherein R is defined hereinbefore, can be
prepared by acylating compound (11, 11.3), (19, 19.3) or (20, 20.3)
with a carboxylic acid of the formula RCOOH (30.0) wherein R is
defined hereinbefore, in an aprotic solvent, at temperatures
ranging from about 0.degree. to 20.degree. C., using about 1 to 2
moles of carboxylic acid (30.0) per mole of compound (11, 11.3),
(19, 19.3) or (20, 20.3).
[0059] Alternatively, compound 1.0 wherein Y.dbd.SO.sub.2R, can be
prepared by reacting compound (11, 11.3), (19, 19.3) or (20, 20.3)
with a sulfonyl chloride of the formula RSO.sub.2Cl (20.7) wherein
R is as defined before, in a solvent such a pyridine and a base
such as 4-dimethylaminopyridine or triethylamine, using 1 to 3
moles of sulfonyl chloride (20.7) per mole of compound (11, 11.3),
(19, 19.3) or (20, 20.3). The amount of base can range from
catalytic to about 1.5 moles per mole of compound (11, 11.3), (19,
19.3) or (20, 20.3).
[0060] The compounds of formula (1.0) wherein A is N--O (i.e. the
N-oxide), can be prepared by treating compound (1.0) wherein A is N
with metachloroperbenzoic acid (MCPBA) in an aprotic solvent such
as methylene chloride at temperatures ranging from about 0.degree.
to 25.degree. C., using 1 to 2 equivalents of MCPBA per mole of
compound (1.0).
[0061] The sulfur-containing compounds of formula (1.0) wherein
Z.dbd.S, can be treating compounds (1.0) wherein Z.dbd.O with a
sulfurating agent such as Lawesson's Reagent in a suitable aprotic
solvent such as toluene at about 100.degree. C. to give the
thioamide (1.0). Alternative sulfurating reagents include
bis-(1,5-cyclooctanediarylboryl)sulfide in hexane at -78.degree.
C.; or phosphorous pentasulfide (P.sub.2S.sub.5, also of the
formula P.sub.4S.sub.10) in toluene at reflux temperatures, or in
THF using ultrasound at 40.degree. C.; or
bis-(9-Borabicyclo[3.3.1]- nonane)sulfide ((9-BBN).sub.2S) in
heptane at reflux temperatures.
[0062] Compounds of formula (1.0) can be isolated from the reaction
mixture using conventional procedures, such as, for example,
extraction of the reaction mixture from water with organic
solvents, evaporation of the organic solvents, followed by
chromatography on silica gel or other suitable chromatographic
media. Alternatively, compounds (1.0) can be dissolved in a
water-miscible solvent, such as methanol, the methanol solution is
added to water to precipitate the compound, and the precipitate is
isolated by filtration or centrifugation.
[0063] Compounds of formula 1.0, 1.0a and 1.0b in Scheme I, wherein
X is CH or N may be racemates. These racemates can be resolved into
their (+) and (-) enantiomers by HPLC procedures on Chiralpak
columns (Daicel Chemical Ind.). Alternatively, (+)-Isomers of
compounds of formula (19, 19.3, 20, 20.3) wherein X is CH can be
prepared with high enantioselectivity by using a process comprising
enzyme catalyzed transesterification. Preferably, a racemic
compound of formula (19, 19.3, 20, 20.3), wherein X is C, the
double bond is present and X.sup.3 is not H, is reacted with an
enzyme such as Toyobo LIP-300 and an acylating agent such as
trifluoroethly isobutyrate; the resultant (+)-amide is then
hydrolyzed, for example by refluxing with an acid such as
H.sub.2SO.sub.4, to obtain the corresponding optically enriched
(+)-isomer wherein X is CH and R.sup.3 is not H. Altematively, a
racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C,
the double bond is present and R.sup.3 is not H, is first reduced
to the corresponding racemic compound of formula (19, 19.3, 20,
20.3) wherein X is CH and then treated with the enzyme (Toyobo
LIP-300) and acylating agent as described above to obtain the
(+)-amide, which is hydrolyzed to obtain the optically enriched
(+)-isomer.
[0064] Compounds of the present invention and preparative starting
materials thereof, are exemplified by the following examples, which
should not be construed as limiting the scope of the
disclosure.
EXAMPLE 1
[0065]
1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo[5,6]cyclohepta[1,2--
b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide 10
Example 1
[0066] Step 1. 11
[0067] To a solution of diisopropylamine (2.28 ml) in THF (10 ml)
at -78.degree. C. under a nitrogen atmosphere, 2.5 M Butyl lithium
in hexanes (6.5 ml) is added dropwise. After stirring the mixture
for 10 mins, a solution of compound A (2.0 g) in THF (10 ml) is
added. The resulting purple reaction mixture is stirred for 10 mins
before adding a solution of 3,5-dimethoxy benzyl chloride (2.07 g)
in THF (10 ml). The reaction mixture is stirred at -78.degree. C.
for 15 mins, 1 hr at 0.degree. C. and then at room temp for 1 hr.
The pale burgundy color reaction is diluted with ice/water and
extracted with dichloromethane. The crude product obtained on
evaporation of the organic extract is evaporated and flash
chromatographed on silica gel (200 ml). Elution with 10%
ethylacetate-hexane affords the title compound B as an oil (2.3 g,
75% yield): MS m/e 421, 423(MH),
Example 1
[0068] Step 2. 12
[0069] Phosphorous oxychloride (12 ml) is added dropwise to a
solution of B (2.3 g) in toluene (20 ml). The mixture is heated in
an oil bath (115.degree. C.). After one hour a droplet of DMF is
added, the solution is heated for an additional 4 hrs and is then
cooled to room temp before evaporation under reduced pressure. The
residual oil is dissolved in ethylacetate (50 ml) and ice/water (20
ml) and stirred while adding 10% sodium hydroxide until the aqueous
phase is basic. The basic solution is extracted with ethylacetate,
the organic extracts are combined, washed with brine, dried and
evaporated. The crude product is dissolved in ethylacetate and
filtered through a silica gel plug. The colorless filtrate is
concentrated under reduced pressure and diluted slowly with hexane
to afford the title compound C as a crystalline solid (1.62 g,
85%): m.p. 106-107.degree. C.; MS m/e 347, 349 (MH).
Example 1
[0070] Step 3. 13
[0071] Aluminum Chloride (1.0 g) is added in small lots during 10
minutes to a well stirred solution of C (1.16 g) in dichloroethane
(100 ml). The pale yellow solution is stirred at room temperature
for 1 hr and is then worked up by the addition of ice/water and 10%
sodium hydroxide to pH 10. The mixture is extracted several times
with dichloromethane, and the crude product obtained on evaporation
of the combined extracts is flash chromatographed on silica gel
(100 ml). Elution with 10% methanol-2% ammonium
hydroxide-ethylacetate affords the intermediate imine D (0.89
g).
Example 1
[0072] Step 3a. 14
[0073] Product D of Step 3 is dissolved in 2N hydrochloric acid.
The solution is heated in an oil bath (120.degree. C.) for 1.5 hrs,
cooled, made basic with 10% sodium hydroxide and extracted with
dichloromethane (4.times.50 ml portions). The crude product is
obtained by concentration of the combined extract filtered through
a silica gel plug; evaporation of the filtrate affords the title
ketone E as an amorphous solid (0.81 g, 91%). MS m/e 348, 350
(MH).sup.+.
Example 1
[0074] Step 4. 15
[0075] Sodium borohydride (0.09 g) is added in portions, with
stirring, to a solution of ketone E (0.8 g) in methanol (20 ml) at
0.degree. C. The reaction is then stirred at room temperature for
one hour, acidified with acetic acid-water and most of the solvent
is removed by evaporation under reduced pressure. The residual
mixture is made basic with 10% sodium hydroxide to pH 10 followed
by extraction with ethylacetate (4.times.50 ml). The combined
extract is filtered through a plug of silica gel and the filtrate
is evaporated to afford product F as a resin puff (0.79 g). MS m/e
350, 352 (MH).
Example 1
[0076] Steps 5 and 6. 16
[0077] Phosphorous oxychloride (2.0 ml) is added dropwise to a
solution of product F (0.45 g) in dichloromethane (5 ml) under
nitrogen. The reaction mixture is stirred at room temperature for
one hour and is then evaporated under reduced pressure at
45.degree. C. The dark residual gum is azeotroped with toluene
(2.times.10 ml) and is then dissolved in acetonitrile (15 ml)
containing piperazine (0.5 g). The reaction mixture is stirred at
room temperature for 2 hrs and is worked up by evaporating under
reduced pressure and diluting with water followed by addition of
10% sodium hydroxide(5 ml). The product is extracted with
dichloromethane (5.times.20 ml) and flash chromatographed on silica
gel. Elution with 10% methanol-2% ammonium
hydroxide-dichloromethane affords product G as a tan puff (0.22 g).
MS m/e 418, 420 (MH).
Example 1,
[0078] Step 7. 17
[0079] A solution of product G (0.2 g), 1-hydroxybenzotriazole
(0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in
dimethylformamide (3.0 ml) is cooled in ice and treated with
N-(3-dimethyl aminopropyl)-N'-ethylcarb- odiimide hydrochloride
(0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is
allowed to warm to room temperature overnight and is then
evaporated under reduced pressure. The residual gum is stirred with
10% sodium carbonate and extracted with dichloroethane. The crude
product obtained by evaporation of the extract is flash
chromatographed on silica gel (30 ml). Elution with 5% methanol-2%
ammonium hydroxide-dichlorometha- ne affords product H as a pale
tan foam (0.25 g). MS m/e 553, 555 (MH).
EXAMPLE 2.
[0080]
4-(6,11-dihydro-10-methoxy-3,8-dimethyl-5H-benzo[5,6]cyclohepta[1,2-
-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-15 oxide
18
Example 2
[0081] Step 1. 19
[0082] Using similar reaction conditions as described in Step 1,
Example 1, reagent A (5-methyl-t-butyl amide) is first treated with
di-isopropylamine and butyl lithium, then reacted with
benzylbromide 2 to give compound B.
Example 2
[0083] Step 2. 20
[0084] Using similar reaction conditions as described in Step 2,
Example 1, the crude product B is reacted with phosphorous
oxychioride to afford compound C: m.p. 188-190.degree. C., MS: m/e
301 (MH).
Example 2
[0085] Step 3. 21
[0086] Nitrile compound C (1.65 g) is added with stirring to cold
(0.degree. C.) triflic acid (30 ml). The solution is stored
overnight at room temperature, diluted with ice/water (50 ml) and
heated in an oil bath (120.degree. C.) for 4 hrs. The reaction
mixture is then cooled, neutrallized with 50% sodium hydroxide and
the crude product is extracted with dichloromethane (6.times.50 ml)
and flash chromatographed on silica gel (300 ml). Elution with 1:1
ethylacetate-hexane followed by crystallization from
ethylacetate-hexane affords compound D (1.54 g): MS m/e 302
(MH).
Example 2
[0087] Step 4. 22
[0088] A solution of E (0.8 M, 13.2 ml) in THF is added with
stirring under nitrogen to a cold (ice bath) solution of D (1.6 g)
in THF ( 30 ml). The reaction is stirred for 30 min and is then
diluted with ice/water followed by extraction with dichlorometrhane
(3.times.50 ml). The crude product obtained by evaporation of the
extract is flash chromatographed on silica gel (100 ml). The column
is first eluted with 10% methanol-dichloromethane to remove
impurities; elution with 10% methanol-3% ammonium
hydroxidel-dichloromethane affords compound F as an amorphous solid
(1.6 g): MS m/e 401 (MH).
Example 2
[0089] Step 5. 23
[0090] A solution of ethylchloroformate (1.5 ml) in toluene (20 ml)
is added dropwise during 10 min. with stirring to a solution of
compound F (1.5 g) and triethylamine (0.9 ml) in toluene (30 ml)
heated in an oil bath at 85.degree. C. The reaction is heated for
an additional 45 min and is then cooled and stirred with ice-water,
followed by washing with 10% sodium carbonate. The crude product is
isolated by extraction with ethylacetate and is flash
chromatographed on silica gel to afford compound G. MS m/e 459
(MH).
Example 2
[0091] Step 6. 24
[0092] A solution of compound G (1.2 g) in ethanol (40 ml) and 10%
palladium-carbon is hydrogenated in a Parr flask at 50 psi for 6
hrs. The catalyst is removed by filtration and the filtrate is
evaporated. The residue is dissolved in ethylacetate and the
solution is washed with 10% sodium carbonate. The organic layer is
evaporated to afford compound H.
Example 2
[0093] Step 7. 25
[0094] A paste obtained by combining compound H (0.58 g) with
polyphosphoric acid (PPA) (1.5 ml) is heated in an oil bath at
100.degree. C. for 30 min. The dark brown liquid is cooled and
stirred with ice-water (10 ml), the resulting solution is made
basic with 50% sodium hydroxide and then extracted with
dichloromethane (5.times.30 ml). The extract is filtered through a
plug of silica gel which is then eluted with 10%
methanol-dichloromethane. The combined filtrates are evaporated and
chromatographed on silica gel (50 ml). Elution with
5%methanol-dichloromethane affords compound I as a tan solid. MS
m/e 407 (MH).
Example 2
[0095] Step 8. 26
[0096] A solution of compound I (0.5 g) in 4 N hydrochloric acid
(20 ml) is heated in an oil bath (130.degree. C.) for 14 hrs. The
reaction is cooled and made basic with 50% sodium hydroxide to pH 8
and extracted with dichloromethane. The extract is dried over
sodium sulfate and evaporated to dryness to afford compound J.
Example 2
[0097] Step 9. 27
[0098] Diisobutylaluminum hydride (DIBAL H) (1M solution in
toluene, 4.8 ml) is added dropwise with stirring to a solution of
compound J (0.45 g) in dry toluene (10 ml) at 15.degree. C. The
reaction mixture is stirred at room temperature for 2 hrs and is
then quenched by addition of water (10 ml) and 10% sodium
hydroxide. The mixture is extracted with dichloromethane and the
crude product is chromatographed on silica gel (30 ml). Elution
with 10% methanol-2% ammonium hydroxide-dichloromethane affords
compound J: MS m/e 337 (MH).
Example 2
[0099] Step 10. 28
[0100] A solution of product J (0.2 g), 1-hydroxybenzotriazole
(0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in
dimethylformamide (3.0 ml) is cooled in ice and treated with
N-(3-dimethyl aminopropyl)-N'-ethylcarb- odiimide hydrochloride
(0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is
allowed to warm to room temperature overnight and is then
evaporated under reduced pressure. The residual gum is stirred with
10% sodium carbonate and extracted with dichloromethane. The crude
product obtained by evaporation of the extract is flash
chromatographed on silica gel (30 ml). Elution with 5% methanol-2%
ammonium hydroxide-dichlorometha- ne affords product K as a pale
tan foam. MS 471 (Cl) 472.
EXAMPLE 3.
[0101] (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11
-dihydro-5H-benzo[5,6]cyc-
lohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N1-oxide 29
Example 3
[0102] Steps 1 & 2. 30
[0103] Following the procedures as described in Example 1, Steps 1
and 2, except that reactant 2 is substituted for reactant 2 of
Example 1, gives intermediate compounds B and C.
Example 3
[0104] Step 3. 31
[0105] A 0.5M solution of 1-methyl-4-piperidyl magnesium chloride
in THF (28 ml) is added dropwise to a solution of compound C (4.8
g) in THF (60 ml) under argon. The dark color reaction is heated at
55.degree. C. for 15 min., cooled in an ice bath, quenched with
water and extracted with ethylacetate (4.times.50 ml). The combined
extract is dried over sodium sulfate and evaporated under reduced
pressure. The resulting intermediate is dissolved in 4N HCl (40 ml)
and methanol (20 ml) and the solution is heated on a steam bath for
1 hour, cooled in an ice bath and made basic with 10% NaOH followed
by extraction with ethylacetate. The extract is evaporated and
flash chromatographed on silica gel. Elution with 10%
ethylacetate-hexane affords compound D (2.7 g): MS m/e 431
(MH).
Example 3
[0106] Step 4. 32
[0107] Triflic acid (55 ml) is added with stirring to compound D
(2.9 g) and the dark syrupy solution is stored overnight at
4.degree. C. The reaction mixture is worked up by pouring on ice,
making basic with 50% NaOH, followed by extraction with
dichloromethane (3.times.50 ml). The extract is evaporated under
reduced pressure and the crude product is flash chromatographed on
silica gel. Elution with 5% methanol-dichloromethane affords
compound E (1.37 g); MS m/e 413 (MH).
Example 3
[0108] Step 5. 33
[0109] Following the procedure as described in Example 2, Step 5
gives intermediate compound F.
Example 3
[0110] Steps 6 & 7. 34
[0111] Following the procedures as described in Example 2, Steps 8
and 9, gives intermediate compounds G and H. Compound H is resolved
into its (+) and (-) enatiomers by dissolving 0.580 g in
i-propanol/hexane (0.2% dea) containing EtOH with heating on a
steambath. The solution is applied to a preparative HPLC chiralpac
AD, 5 by 50 cm column (Daicel Chemical Ind.), and eluted with
i-propanov/hexane (0.2% DEA) with a flow rate at 20 ml/min and
collecting 500 ml fractions. After the first peak is eluted the
solvent is changed to 25/75 i-propanol/hexane (0.2% DEA) at a flow
rate of 40 ml/min. The (+) enantiomer (0265 g) is obtained in
fraction 2. Optical rotation =+2.69 at concentration of (5.2 mg/2
ml EtOH) at 20.5.degree. C. The (-) enantiomer (0.2280 g) is
obtained from fractions 7 to 8. Both the (+) and (-) enantiomers
are determined pure by analytical HPLC on a chiralpak AD 0.46 cm by
25 cm column.
Example 3
[0112] Step 8. 35
[0113] Following the procedures as described in Example 1, Step 7,
gives the desired title compound I, a racemate.
EXAMPLE 4.
[0114] (+,-)-4-(6,11
-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohepta[-
1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-1 oxide
36
[0115] Following the procedures as described in Example 2, Steps
1-9, except that reactant 2 is substituted for reactant 2 in
Example 2, gives intermediate compounds A-K, and the desired title
compound L, a racemate.
EXAMPLE 5
[0116]
(+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11H-benzo[5,6]cyc-
lohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine
N1-oxide 37
[0117] By substituting 3-methyl-2-chloro-5-methoxybenzylchloride
for reagent 2 and 3-methyl-2-t-butyl carboxamidopyridine for
compound A in Example 3, Step 1, and by following Example 3, Steps
1-8 but omitting Example 3, Step 7 with DIBALH, the title compound
is obtained.
EXAMPLE 6
[0118]
(+,-)-4-(3-Bromo-10-hydroxy-8-methyl--5,6-dihydro-11H-benzo[5,6]cyc-
lohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine
N1-oxide 38
[0119] By starting with 5-bromo-3-methyl-2-t-butyl carboxamido
pyridine and by following Example 3, Step 1-6 gives compound A,
below. 39
[0120] Compound A (500 mg,1.34 mmol) is stirred in triflic acid (3
ml) at 80.degree. C., for 2 hours, then cooled to room temperature.
The reaction mixture is diluted with ice (20 g), basified with 10%
sodium carbonate, then extracted with CH.sub.2Cl.sub.2 (2.times.60
ml). The organic layer is separated, dried over MgSO.sub.4,
filtered, and evaporated solvent, to yield an oil, which
chromatographs on silica gel eluting with 7% (v/v)
methanol-methylene chloride containing 2% ammonium hydroxide,
yielding Compound B, as a white solid. Using the procedure of
Example 1, Step 7, substituting an equivalent amount of Compound B
for Compound G, gives the title compound. FABS 519 MH.
EXAMPLE 7
[0121]
4-(5,6-dihydro-10-methoxy-3,8-dimethyl-11H-benzo[5,6]cyclohepta[1,2-
-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide
40
[0122] By substituting 3-methyl-5-methoxybenzylchloride for reagent
2 and 3,5-dimethyl-2-t-butyl carboxamidopyridine for compound A in
Example 1, Step 1, and by following Example 1, Steps 1-7, the title
compound is obtained.
EXAMPLE 8
[0123]
(+,-)-4-(3-bromo-10-methoxy-8-methyl-5,6-dihydro-11H-benzo[5,6]cycl-
ohepta[1,2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine
N1-oxide 41
[0124] By starting with intermediate G of Example 3, Step 6 and by
following Example 1, Steps 1-7, the title compound is obtained.
EXAMPLE 9
[0125]
(+,-)-4-(3-Bromo-10-hydroxy-8-methyl-5,6-dihydro-11H-benzo[5,6]cycl-
ohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N1-oxide 42
[0126] By following the procedure of Example 6, except that the
procedure of Example 2, Step 9 is carried out prior to the
procedure of Example 1, Step 7, to give the title compound.
EXAMPLE 10
[0127]
(+,-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cycl-
ohepta[1,2-b]pyridin-1 1-yl)-4-(4-pyridinylacetyl)piperazine
N4-oxide 43
[0128] By substituting 3-methyl-5-methoxybenzylchloride for reagent
2 in Example 1, Step 1, and by following Example 1, Steps 1-7, the
title compound is obtained.
EXAMPLE 14
[0129]
(+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2--
b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide 44
[0130] By substituting 2-methylbenzylchloride for reagent 2 in
Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 15
[0131]
(+,-)-1-(3-Bromo-7,10-dimethyl-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide
45
[0132] By substituting 2,5-dimethylbenzyl chloride for reagent 2 in
Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 16
[0133]
(+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2--
b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide 46
[0134] By substituting 3-methylbenzylchloride for reagent 2 in
Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 17
[0135]
(+,-)-1-(3-Bromo-6,11-dihydro-8-methoxy-5H-benzo[5,6]cyclohepta[1
,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide 47
[0136] By substituting 3-methoxybenzylchloride for reagent 2 in
Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 18
[0137] (+,--)-1-(3-Bromo-6,11
-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohep-
ta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide
48
[0138] By substituting 3,5-dimethylbenzylbromide for reagent 2 in
Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 19
[0139]
(-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cycloh-
epta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide,
(-) enantiomer 49
[0140] The racemic title compound of Example 10 (67 mg) is
dissolved into 50/50 i-propanol/hexane containing 0.2% diethylamine
and the solution is injected into a preparative high performance
liquid chromatography column, chiralpak AD 5 by 50 cm column
(Daicel Chemical Ind.). Elution with ethanol (EtOH)/Hexane
(containing 0.2% diethylamine or DEA) at 20 ml/min for two hours,
then changing the eluting phase to 7% EtOH/Hexane (0.2% DEA) and
increasing the flow rate to 40 ml/min (500 ml fractions are
collected) gives: fractions 10-12, 30.9 mg of title compound of
Example 19: [.alpha.].sub.D.sup.23-18.8.degree. (c. 0.32, ethanol),
mp=111-116.degree. C.
EXAMPLE 20
[0141]
(+)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cycloh-
epta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide,
(+) enantiomer 50
[0142] Following the preparative high performance liquid
chromatography procedure described in Example 19, the title
compound is obtained: fractions 14-16, the title compound of
Example 20: [.alpha.].sub.D.sup.23+19.6.degree. (c. 0.28, ethanol),
mp=110-117.degree. C.
EXAMPLE 21
[0143]
(+,-)-1-(3,10-Dibromo-6,11-dihydro-8-methyl-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide
51
[0144] By substituting 3-methyl-5-bromobenzyl bromide for reagent 2
in Example 1, Step 1, and by following Example 1, Steps 1-7 (except
for Steps 3 and 3a), and by substituting the procedure of Example
2, Step 3 in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 22
[0145]
(+,-)-1-(3,8-Dibromo-6,11-dihydro-10-methyl-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide
52
[0146] By substituting 3-bromo-5-methyl-benzyl bromide for reagent
2 in Example 1, Step 1, and by following Example 1, Steps 1-7
(except for Steps 3 and 3a), and by substituting the procedure of
Example 2, Step 3 with heating to 60.degree. C. for 4 hours with
triflic acid, in place of Example 1, Step 3 and 3a, gives the title
compound.
EXAMPLE 23
[0147]
(+,-)-4-[6,11-dihydro-3-(1-hydroxy-1-methylethyl)-10-methoxy-8-meth-
yl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-(4-pyridinylacetyl)piper-
idine N1-oxide 53
[0148] A nitrogen blanketed solution of the compound A of Example
27, Step 1 (0.4 g) in tetrahydrofuran (8 ml) is cooled to
-78.degree. C. and then treated with 2.5M solution of butyl lithium
in hexanes (0.4 ml). After stirring for 5 minutes, acetone (0.4 ml)
is added and after 5 minutes the reaction mixture is evaporated
under reduced pressure to yield an oil that is flash
chromatographed on silica gel (50 ml). Elution with 3%
methanol-dichloromethane affords B as white powder (0.13 g). MS(Cl)
479. 54
[0149] Product B from Step 1 is converted to intermediate C by
following the procedures described in Steps 3 and 4, Example 27.
Tan powder, MS(Cl)381. 55
[0150] Product C from Step 2 is converted to the title compound D
by following the procedure described in Example 1, Step 7. White
powder, MS(CI) 516.
EXAMPLE 24
[0151]
(+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cycloh-
epta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperidine N1-oxide,
(+) enantiomer 56
[0152] By substituting 3-methyl-5-methoxy-benzylbromide for reagent
2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and
using the resolved (+) enantiomer H of Step 7, the title compound
is obtained. Optical rotation: +31.9.degree. at concentration of
5.7 mg/2 ml ethanol at 22.degree. C. (sodium D line).
EXAMPLE 25
[0153]
(-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo[5,6]cycloh-
epta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperidine N1-oxide,
(-) enantiomer 57
[0154] By substituting 3-methyl-5-methoxy-benzylbromide for reagent
2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and
using the resolved (-) enantiomer H of Step 7, the title compound
is obtained. Optical rotation: -31.6.degree. at concentration of
6.2 mg/2 ml ethanol at 22.4.degree. C. (sodium D line).
EXAMPLE 26
[0155] (+,-)-1-(3-Bromo-8-methoxy-10-methyl-6,11
-dihydro-5H-benzo[5,6]cyc- lohepta[1
,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperzazine N4-oxide
58
[0156] By substituting 3-methoxy-5-methyl-benzylbromide for reagent
2 in Example 1, Step 1, and by following Example 1, Steps 1-7
(except for Steps 3 and 3a), and by substituting the procedure of
Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the
title compound.
EXAMPLE 27
[0157]
4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohep-
ta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N1-Oxide
59
[0158] Step 1. 1,1
-Dimethylethyl-4-(3-bromo-5,6-dihydro-10-methoxy-8-meth-
yl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxyl-
ate 60
[0159] Add di-tert-butyldicarbonate (2.0 g,9.16 mmol) in methylene
chloride (5 ml) to a solution of the intermediate compound G of
Example 3, Step 6 (1.0 g, 2.51 mmol) in methylene chloride (15 ml)
at 20.degree. C., then stir 1 hour at room temperature. The solvent
is evaporated, and the residual oil is chromatographed on silica
gel eluting with 15% (v/v) ethyl acetate-hexanes yielding the
product as a white solid (1.1 g, 92% yield). MS (Cl) 499, MH.
[0160] Step 2. 1,1
-Dimethylethyl-4-(3-ethenyl-5,6-dihydro-10-methoxy-8-me-
thyl-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarbox-
ylate. 61
[0161] Add tributylvinyltin (3 ml, 10.26 mmol) to a solution of the
title compound of Step 1 (950 mg, 1.90 mmol), lithium chloride (1.0
g, 23.6 mmol), tris(dibenzylideneacetone)dipalladium (180 mg), and
tri-2-furoyl phosphine (90 mg, 0.38 mmol) in toluene (6 ml) at room
temperature, then stir at 100.degree. C. overnight. The reaction is
cooled, extracted with ethyl acetate (100 ml), washed with water
(50 ml), dried over magnesium sulfate, filtered and the solvent
evaporated, yielding an oil, which chromatographs on silica gel
eluting with 40%(v/v) ethylacetate-hexanes yielding the product as
a white solid (800 mg, 95% yield). MS (Cl) 447,MH.
[0162] Step 3.
4-(3-Ethenyl-5,6-dihydro-10-methoxy-8-methyl-11H-benzo[5,6]-
cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine 62
[0163] A 20% solution of trifluoroacetic acid in methylene chloride
(10 ml) is added to the title compound of Step 2 (400 mg,0.89 mmol)
at room temperature, then stirred for 1/2 hour at 20.degree. C.
Water (20 ml), methylene chloride (20 ml), and 1N NaOH (3 ml) are
added, and the organic layer is separated, dried over MgSO.sub.4,
filtered, and the solvent evaporated, yielding a solid (305 mg, 98%
yield) MS(Cl) 347 ,MH.
[0164] Step 4.
3-Ethenyl-6,11-Dihydro-10-Methoxy-8-Methyl-11-(4-Piperidiny-
l)-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine 63
[0165] A 1 M solution of DIBAL in toluene (3 ml, 3 mmol) is added
dropwise to a solution of the title compound of Step 3 (310 mg,
0.89 mmol) in toluene (2 ml) at 20.degree. C., then stirred 45
minutes. Water (15 ml), EtOAc (30 ml) and 1N NaOH (5 ml) are added.
The organic layer is separated, dried over MgSO.sub.4, filtered,
and the solvent evaporated to yield an oil, which chromatographs on
silica gel eluting with 10% methanol-methylene chloride containing
2% NH.sub.4OH, yielding the product as a white solid. (200 mg,65%
yield), MS (FABS) 349,MH.
[0166] Step 5.
4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]-
cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N.sub.1-Oxide. 64
[0167] EDCl (50 mg,0.26 mmol),1-hydroxybenzotriazole, monohydrate
(40 mg, 0.29 mmol) and 4-methyl morpholine (0.5 ml, 4.5 mmol) are
added to a solution of the title compound of Step 4 (50 mg, 0.14
mmol) and 4-pyridyl-N-oxide acetic acid (50 mg, 0.326 mmol) in
dimethylformamide (anhydrous,2 ml) at 0.degree. C., then stirred at
room temperature overnight. The solvent is evaporated, and the
residue extracted with methylene chloride (60 ml), and water (25
ml). The organic layer is separated, washed with saturated sodium
carbonate (2.times.5 ml), dried over MgSO.sub.4, filtered and the
solvent evaporated to yield an oil which chromatographs on silica
gel eluting with 10% MeOH-MeCl.sub.2 containing 2% NH.sub.4OH
yielding the product as a white solid (55 mg,79% yield), MS (FABS)
484, MH.
EXAMPLE 28
[0168]
4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cyclohep-
ta[1,2-b]pyridin-11-yl)-1-(methylsulfonyl)piperidine 65
[0169] Methanesulfonyl chloride (0.5 ml, 6.46 mmol) is added to a
solution of the title compound of Example 27, Step 4 (30 mg, 0.086
mmol) in anhydrous pyridine (2 ml) at 0.degree. C., then
4-dimethylaminopyridine (10 mg, 0.08 mmol) is added, and the
solution stirred overnight at 20.degree. C. The solvent is
evaporated, water (30 ml) and CH.sub.2Cl.sub.2 (60 ml) are added.
The organic layer is separated, dried over MgSO.sub.4, filtered,
and solvent evaporated to yield an oil, which chromatographs on
silica gel eluting with 70% v/v EtOAC-hexanes yielding the product
as a white solid (30 mg, 69% yield), MS(Cl) 427, MH.
EXAMPLE 29
[0170] 4-(3-Ethyl-6,11 -dihydro-10-methoxy-8-methyl-5H-5
benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine-
, N.sub.1-Oxide 66
[0171] Step 1.
3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-11-(4-piperidinyl)-
-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 67
[0172] Ammonium formate (200 mg, 2.08 mmol) and 10% Pd/C (20 mg)
are added to a solution of the title compound of Example 27, Step 4
(90 mg, 0.258 mmol) in methanol (5 ml) at 20.degree. C., then
refluxed for 4 hours. Methanol (20 ml) is added, and the reaction
is filtered through a celite pad, then washed with methanol (10 ml)
and CH.sub.2Cl.sub.2 (3.times.20 ml). The filtrate and wash are
combined, concentrated, and the residue extracted with
CH.sub.2Cl.sub.2 (50 ml) and water (25 ml). The organic layer is
separated, dried over MgSO.sub.4, filtered and solvent removed
yielding a white solid (75 mg, 84% yield).
[0173] Step 2.
4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo[5,6]cy-
clohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine,
N.sub.1-Oxide 68
[0174] EDCl (75 mg, 0.39 mmol), HOBT (70 mg, 0.51 mmol) and NMM
(0.5 ml, 4.5 mmol) are added to a solution of the title compound of
Step 1 (75 mg, 0.214 mmol) and 4-pyridyl N-oxide acetic acid (75
mg, 0.48 mmol) in DMF(anhydrous, 3 ml) at 0.degree. C., then
stirred at room temperature overnight. The solvent is evaporated,
and the residue extracted with CH.sub.2Cl.sub.2 (60 ml) and water
(25 ml), the organic layer separated, washed with 10%
Na.sub.2CO.sub.3 (2.times.20 ml), dried over MgSO.sub.4, filtered,
and the solvent evaporated to yield an oil, which chromatographs on
silica gel eluting with 7% v/v MeOH:methylene chloride (MeCl.sub.2)
containing 2% NH.sub.4OH yielding product as white solid (75 mg,76%
yield), MS (FABS) 486 (MH).
EXAMPLE 30
[0175]
(+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl)-1-(4-piperidinylacetyl)piperazine 69
[0176] By substituting 3,5-dimethylbenzylbromide for reagent 2 and
by substituting the corresponding 5-bromo-t-butyl amide for reagent
A in Example 1, Step 1, and by following Example 1, Steps 1-6
(except for Steps 3, 3a and 7), and by substituting the procedure
of Example 2, Step 3 with heating to 60.degree. C. using triflic
acid, in place of Example 1, Step 3 and 3a, gives the 8,10-dimethyl
analog of Example 1, Step 6, compound G. By following the procedure
of Example 1, Step 7, substituting 4-pyridyl acetic acid N-oxide
with an equivalent amount of N-BOC-4-piperidyl acetic acid, then
removing the BOC group with trifluoroacetic acid, the title
compound is obtained.
EXAMPLE 31
[0177]
(+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridin-11-yl)-1-(4-piperidinylacetyl-N-carboxamido)
piperazine 70
[0178] Starting with the title compound of Example 30, and treating
with 3 equivalents of trimethylsilylisocyanate in methylene
chloride at 25.degree. C., then removing the silyl group with
excess sodium bicarbonate, the title compound is obtained.
EXAMPLE 32
[0179]
(+,-)-4-(3-cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo[5,6]cyclohe-
pta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine 71
[0180] Ethereal diazomethane generated from Diazald (15 g) is added
dropwise with stirring to a solution of compound A (0.11 g) from
Example 27 (Step 2), and palladium acetate (7 mg) in benzene (1 ml)
until a TLC sample showed completion of the reaction. Evaporation
under reduced pressure affords compound B as a white powder. MS(Cl)
461. 72
[0181] Product B from Step 1 is converted to intermediate C by
following the procedures described in Steps 3 and 4, Example 27.
Tan powder, MS(Cl) 362 73
[0182] The product C from Step 2 is converted to the title compound
D by following the procedure described in Example 1, Step 7. White
powder, MS(Cl) 498.
EXAMPLE 33
[0183] (+)
4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohep-
ta[1,2-b]pyridin-11-yl)-1 -(4-pyridinylacetyl)piperidine N.sub.1
-Oxide 74
[0184] By substituting 5-bromo-t-butyl amide for reagent A and
3-methyl-5-bromobenzyl bromide for reagent 2 in Example 2, Step 1
and by following Example 2, Steps 1-10-except in step 3, the
reaction with triflic acid is carried out at 60.degree. C. for 4
hours, and by omitting step 6, the title compound is obtained as a
racemate. MS(FABS) m/e 584 (MH). The racemate is resolved into its
enantiomers using a preparative HPLC chiralpak AD column (Daicel
Chemical Industries,) and eluting with 30% isopropanol-hexanes
(0.2% DEA). The desired (+) enantiomer elutes last. MS (FABS) m/e
584 (MH) Rotation=+51.7.degree. @20.degree. C., c=0.211.
EXAMPLE 34
[0185] (-)
4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H-benzo[5,6]cyclohep-
ta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N.sub.1-Oxide
[0186] Essentially the same procedure is followed as in Example 33
except that the (-) enantiomer is also collected MS (FABS) m/e 584
(MH) Rotation=-47.5.degree. @20.degree. C., c=0.2125.
EXAMPLE 35
[0187] (+)
4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5-
,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N.sub.1-Oxide 75
[0188] By following the procedures used to prepare title compound
of Example 33,--steps 6,7 and 9, from example 2 are omitted--the
title compound is obtained, as a racemate (+,-). FABS MS m/e 599.9
(MH). The racemate is resolved using the same procedure as Example
33. The (+)enantiomer elutes first MS (FABS) m/e 599.9(MH),
Rotation=+10.4.degree. @20.degree. C., c=0.1155.
EXAMPLE 36
[0189] (-)
4-(3-Bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl-5H-benzo[5-
,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine
N.sub.1-Oxide
[0190] Essentially the same procedure is followed as in Example 35,
except that the (-) enantiomer elutes second MS (FABS) m/e 599.9
(MH) Rotation=-7.3.degree. @20.degree. C., c=0.1375.
EXAMPLE 37
[0191]
-(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11H-benzo[5,6]cyclohepta[1,-
2-b]pyridin-11-ylidene)-1-(4-pyridinylacetyl)piperidine
N.sub.1-Oxide 76
[0192] By following procedures used to prepare the title compound
of Example 33--steps 6, and 9--from example 2 are omitted, the
title compound is obtained. MS (FABS) m/e 582 (MH).
[0193] PREPARATION OF STARTING MATERIALS
[0194] Starting materials useful in preparing the compounds of the
present invention are exemplified by the following preparative
examples, which should not be construed to limit the scope of the
disclosure. The pyridyl and phenyl compounds used as starting
materials, such as compounds (1, 1.3, 3, 3.5), inorganic and
organic bases, and alcohols can be prepared using known methods in
the art, such as taught in See J. K. Wong et al., Bioorganic &
Medicinal Chemistry Letters, Vol. 3, No. 6, pp. 1073-1078, (1993);
U.S. Pat. Nos. 5,089,496; 5,151,423; 4,454,143; 4,355,036; PCT
/US94/11390 (WO95/10514); PCT/US94/11391 (WO 95/10515);
PCT/US94/11392 (WO95/110516); Stanley R. Sandier and Wolf Karo,
Organic Functional Group Preparations, 2nd Edition, Academic Press,
Inc., San Diego, Calif., Vol. 1-3, (1983), and in J. March,
Advanced Organic Chemistry, Reactions & Mechanisms, and
Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp.
(1985). Alternative mechanistic pathways and analogous structures
within the scope of the invention may be apparent to those skilled
in the art. 77 78
[0195] wherein for Schemes II and III,
[0196] 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, the solid and dotted lines are as defined
hereinbefore.
[0197] In Schemes II and III, respectively, for Step A, compound 5
and 5.3 is prepared by alkylating compound 1 and 1.3 with an
electrophile compound 3 and 3.3 employing a base such as lithium
di-isopropylamide (LDA) in an aprotic solvent such as THF, toluene,
benzene, ether and the like, at temperatures ranging from about
-78.degree. to 20.degree. C., using about 1 to 1.5 moles of
electrophile compound 3 per mole of compound 1 and 1.3.
[0198] In Step B, compound 7 and 7.3 is prepared by treating
compound 5 and 5.3 with a dehydrating agent such as phosphorus
oxychloride (POCl.sub.3) or thionyl chloride in an aprotic solvent,
at temperatures ranging from about 80.degree. to 120.degree. C.,
using about 3 to 10 moles of dehydrating agent per mole of compound
5 and 5.3.
[0199] In Step C, compound 7.5 and 7.53 is prepared by treating
compound 7 and 7.3 with a Lewis acid such as triflic acid
(CF.sub.3SO.sub.3H) or aluminum chloride (AlCl.sub.3). The reaction
can be practised neat (i.e. no additional solvents). Optionally,
when AlCl.sub.3 is used, a solvent such as dichloroethane can be
employed. The reaction can be conducted at temperatures ranging
from about 20.degree. to about 175.degree. C., using about 3 to 10
moles of the Lewis acid per mole of compound 7 and 7.3.
[0200] In Step D, compound 8 and 8.3 is prepared by treating
compound 7.5 and 7.53 with a dilute acid such as aqueous
hydrochloric or aqueous sulfuric acid, at temperatures ranging from
about 20.degree. C. to reflux of the reaction mixture, using about
20 to 100 volumes of the aqueous acid per mole of compound 7.5 and
7.53.
[0201] In Step E, compound 13a and 13.3a is prepared by treating
compound 8 and 8.3 with a Grignard reagent 12 derived from
N-methyl-4-chloropiperi- dine in an aprotic solvent, at
temperatures ranging from about 0.degree. to 50.degree. C., using
about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 8
and 8.3.
[0202] In Step F, compound 13b and 13.3b is prepared by treating
compound 13a and 13.3a with ethylchloroformate in an aprotic
solvent, at temperatures ranging from about 60.degree. to
90.degree. C., using 5 to 10 moles of ethylchloroformate per mole
of compound 13a and 13.3a.
[0203] In Step G, compound 13c is prepared by subjecting compound
13b to catalytic hydrogenation at pressures ranging from
atmospheric (ambient) to 50 pounds per square inch (psi) using
hydrogen (H.sub.2) and 10% palladium (Pd)/Carbon (C) as a catalyst.
Altematively, compound 13c can be prepared by treating compound 13b
with a hydrogen source such as ammonium formate, using 10% Pd/C as
a catalyst at atmospheric pressure, at temperatures ranging from
50.degree. to 70.degree. C., optionally using a protic solvent such
as methanol or ethanol.
[0204] In Step H, compound 15 and 15.3 is prepared by treating
compound 13c and 13.3c with an acid such as polyphosphoric acid
(PPA). The reaction can be practised neat. The reaction can be
conducted at temperatures ranging from about 60.degree. to
100.degree. C., using about 5 to 10 volumes of polyphosphoric acid
per mole of compound 13c and 13.3c. Alternatively, in Step H,
compound 13d and 13.3d can be prepared by treating compound 13c and
13.3b with aqueous hydrochloric acid (HCl) or aqueous sulfuric acid
(H.sub.2SO.sub.4) such as 2N to concentrated hydrochloric acid at
temperatures ranging from about 80.degree. to 100.degree. C., using
5 to 10 volumes of the aqueous acid per mole of compound 13c and
13.3b.
[0205] In Step I, compound 19 and 19.3 is prepared by treating
compound 15 and 15.3 with an aqueous acid such as 3N to
concentrated hydrochloric acid (HCl), at temperatures ranging from
about 80.degree. to 100.degree. C., using 5 to 10 volumes of the
aqueous acid per mole of compound 15 and 15.3.
[0206] In Step J, compound 20 and 20.3 is prepared by treating
compound 19 and 19.3 with a reducing agent such as diisobutyl
aluminum hydride (DBAHAI) in an aprotic solvent, at temperatures
ranging from about 0.degree. to 20.degree. C., using 1 to 4 moles
of reducing agent per moles of compound 19 and 19.3.
[0207] In Step EE, alcohol compound 9 and 9.3 is prepared by
reducing compound 8 and 8.3 with a reducing agent such as as sodium
borohydride (NaBH.sub.4) in a protic solvent such as methanol,
ethanol and acetic acid, at temperatures ranging from 0.degree. to
20.degree. C., using one to three moles of the reducing agent per
mole of compound 8 and 8.3.
[0208] In Step FF, compound 10 and 10.3 is prepared by treating
alcohol compound 9 and 9.3 with a chlorinating agent such as
thionyl chloride or phosphorous oxychloride (POCl.sub.3) in an
aprotic solvent such as 1,2-dichoroethane or methylene chloride, at
temperatures ranging from 0.degree. to 25.degree. C., using one to
two moles of the chlorinating agent per mole of compound 9 and
9.3
[0209] In Step GG, compound 11 and 11.3 is prepared by reacting
compound 10 and 10.3 with a piperazine compound 12 and 12.3 in a
solvent such as acetonitrile, toluene or methylene chloride at
temperatures ranging from 0.degree. to 60.degree. C., using one to
10 moles of piperazine compound 12 and 12.3 per mole of compound 10
and 10.3.
[0210] In Step K, the desired compound of formula 1.0 can prepared
from compounds (11, 11.3), (13d, 13.3d), (19, 19.3) or (20, 20.3)
as described in Scheme I described hereinbefore. 79
[0211] wherein for Scheme IV,
[0212] 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, the solid and dotted lines are as defined
hereinbefore.
[0213] In Scheme IV, in Steps A and B, compounds 5.3 and 7.3 are
prepared as described in Scheme III, hereinbefore.
[0214] In Step L, compound 25 is prepared by reacting compound 7.3
with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine
in an aprotic solvent, at temperatures ranging from about 0.degree.
to 50.degree. C., using about 1 to 1.5 moles of Grignard reagent 12
per mole of compound 7.3.
[0215] In Step M, compound 26 is prepared by treating compound 25
with a dilute acid such as aqueous hydrochloric or aqueous sulfuric
acid, at temperatures ranging from about 20.degree. C. to reflux of
the reaction mixture, using about 20 to 100 volumes of the aqueous
acid per mole of compound 25.
[0216] In Step N, compound 27 is prepared by treating compound 25
with a Lewis acid such as triflic acid or aluminum chloride
(AlCl.sub.3). The reaction can be practised neat (i.e. no
additional solvents). When triflic acid is used, the reaction can
be conducted at temperatures ranging from 0.degree. to 70.degree.
C., using 5 to 100 moles of triflic acid per mole of compound 25.
Optionally, when AlCl.sub.3 is used, a solvent such as
dichloroethane can be employed. The reaction can be conducted at
temperatures ranging from about 20.degree. to about 175.degree. C.,
using about 3 to 10 moles of the Lewis acid per mole of compound
25.
[0217] In Step O, compound 28 is prepared by treating compound 27
with ethylchloroformate in an aprotic solvent, at temperatures
ranging from about 60.degree. to 90.degree. C., using 5 to 10 moles
of ethylchloroformate per mole of compound 27.
[0218] In Step P, compound 29 is prepared by treating compound 28
with an aqueous acid such as 3N to concentrated hydrochloric acid
(HCl), at temperatures ranging from about 80.degree. to 100.degree.
C., using 5 to 10 volumes of the aqueous acid per mole of compound
28.
[0219] In Step Q, compound 30 is prepared by treating compound 29
with a reducing agent such as diisobutyl aluminum hydride (DIBALH)
in an aprotic solvent, at temperatures ranging from about 0.degree.
to 20.degree. C., using 1 to 4 moles of reducing agent per moles of
compound 29.
[0220] In Step K, compound 30 is converted to desired compound
(1.0) as described in Scheme I, described hereinbefore.
[0221] ASSAYS
[0222] 1. In vitro enzyme assays: FPT IC.sub.50 (inhibition of
farnesyl protein transferase, in vitro enzyme assay) are determined
by the methods disclosed in WO/10515 or WO 95110516. 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.
[0223] 2. Cell-based assay. COS IC.sub.50 values refer to the COS
cells activity inhibition of Ras processing, are determined by the
methods disclosed in WO/10515 or WO 95/10516.
1 FPT IC.sub.50 FPT IC.sub.50 Example (.mu.M) Example (.mu.M) 1
0.0670 21 0.0048 2 0.0340 22 0.0099 3 0.0032 23 >0.200 4 0.1400
24 0.0036 5 >0.2 25 0.2200 6 0.0450 26 0.058 7 0.0600 27 0.0590
8 0.0300 28 0.1320 9 0.1200 29 0.0740 10 0.0160 30 -- 14 0.1100 31
0.2000 15 0.1300 32 >0.200 16 0.0640 33 0.0012 17 0.2900 34
>0.016 18 0.0430 35 0.0108 19 0.0042 36 0.0054 20 >0.180 37
0.0054
[0224] 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.
[0225] 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.
[0226] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection.
[0227] Liquid form preparations may also include solutions for
intranasal administration.
[0228] 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.
[0229] 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.
[0230] 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.
[0231] Preferably the compound is administered orally.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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.
[0236] 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.
2 Pharmaceutical Dosage Form Examples EXAMPLE A-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
[0237] 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.
3 EXAMPLE B-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
Method of Manufacture
[0238] 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.
[0239] 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.
* * * * *