U.S. patent application number 09/777528 was filed with the patent office on 2001-07-05 for synthesis of 11-aryl-5,6,-dihydro-11h-dibenz [b,e] azepines.
This patent application is currently assigned to Pharm-Eco Laboratories. Invention is credited to Haider, Reem M., Lombardy, Richard J., Moussa, Adel M., Sun, Minghua.
Application Number | 20010007030 09/777528 |
Document ID | / |
Family ID | 25522078 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010007030 |
Kind Code |
A1 |
Moussa, Adel M. ; et
al. |
July 5, 2001 |
Synthesis of 11-aryl-5,6,-dihydro-11H-dibenz [b,e] azepines
Abstract
Disclosed is a three step synthesis of
11-aryl-5,6-dihydro-11H-dibenz[b,e]- azepines from a
2-aminobenzophenone represented by the following structural
formula: 1 and a starting material represented by the following
structural formula: 2,2 Phenyl Ring A, Phenyl Ring B and Phenyl
Ring C are independently unsubstituted or substituted with one, two
or three substituents. Each substituent on Phenyl Ring A, Phenyl
Ring B and Phenyl Ring C is independently chosen. R is --H, a
aliphatic group, a substituted aliphatic group, an aryl group, a
substituted aryl group, --C(O)--R', --C(O)--H, --C(O)--NHR',
--S(O).sub.2R', --C(O)--C(O)--R', --C(O)--C(O)--H, --C(S)--R',
--C(S)--H, --C(O)--OR', --C(S)--OR', --C(O)--SR', --C(S)--SR',
--C(O)--NR'.sub.2 or --C(O)--C(S)--R'. R' is an aliphatic group, a
substituted aliphatic group, an aryl group or a substituted aryl
group. R.sub.1 is a leaving group. The present invention also
includes novel compounds which are intermediates in the preparation
of 11-aryl-5,6-dihydro-11H-dibenz[b,e]az- epines.
Inventors: |
Moussa, Adel M.;
(Burlington, MA) ; Lombardy, Richard J.; (Waltham,
MA) ; Haider, Reem M.; (Malden, MA) ; Sun,
Minghua; (Libertyville, IL) |
Correspondence
Address: |
Theresa A. Devlin, Esq.
HAMILTON, BROOK, SMITH & REYNOLDS, P.C.
Two Militia Drive
Lexington
MA
02421-4799
US
|
Assignee: |
Pharm-Eco Laboratories
Devens
MA
01432
|
Family ID: |
25522078 |
Appl. No.: |
09/777528 |
Filed: |
February 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09777528 |
Feb 6, 2001 |
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09370819 |
Aug 9, 1999 |
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6201120 |
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09370819 |
Aug 9, 1999 |
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08974472 |
Nov 20, 1997 |
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6063921 |
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Current U.S.
Class: |
540/484 ;
564/342 |
Current CPC
Class: |
C07C 225/22 20130101;
C07D 223/20 20130101; C07C 215/68 20130101 |
Class at
Publication: |
540/484 ;
564/342 |
International
Class: |
C07C 221/00; C07C
223/00; C07C 225/00 |
Claims
What is claimed is:
1. A method of preparing a diphenyl ketone represented by the
following structural formula: 8wherein: Phenyl Ring A, Phenyl Ring
B and Phenyl Ring C are independently unsubstituted or substituted
with one, two or three substituents, wherein each substituent is
independently chosen; and R is --H, an aliphatic group, a
substituted aliphatic group, an aryl group, a substituted aryl
group, --C(O)--R', --C(O)--H, --C(O)--NHR', --S(O).sub.2R',
--C(O)-- C(O)--R', --C(O)--C(O)--H, --C(S)--R', --C(S)--H,
--C(O)--OR', --C(S)--OR', --C(O)--SR', --C(S)--SR',
--C(O)--NR'.sub.2 or --C(O)-- C(S)--R', wherein R' is an aliphatic
group, a substituted aliphatic group, an aryl group or a
substituted aryl group; said method comprising reacting a base, a
2-aminobenzophenone represented by the following structural
formula: 9 and a starting material represented by the following
structural formula: 10 wherein R.sub.1 is a leaving group.
2. The method of claim 1 wherein Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or
monosubstituted.
3. The method of claim 2 wherein R.sub.1 is a halide.
4. The method of claim 3 wherein the 2-aminobenzophenone is
represented by the following structural formula: 11the starting
material is represented by the following structural formula:
12wherein: R is --H, --CH.sub.3, benzyl, --C(O)--OCH.sub.3,
--C(O)--C(O)--OH, --C(O)--C(O)--OCH.sub.2CH.su- b.3,
para-chlorobenzoyl, --C(O)--O-(phenyl), benzoyl,
meta-methoxybenzoyl, para-nitrobenzoyl, para-methoxybenzoyl,
para-methylbenzoyl, para-chlorobenzoyl, naphthoyl,
--C(O)--NH-(phenyl), para-methylaminobenzoyl, para-aminobenzoyl or
--C(O)--NH-(4-NO.sub.2-phen- yl); R.sub.2 is --H, --F, --Cl, --Br
or --I; R.sub.3 and R.sub.5 are independently --H, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --F, --Cl, --Br or --I; R.sub.4 is --H or,
taken together with R.sub.3 and the carbon atoms to which R.sub.3
and R.sub.4 are bonded, a phenyl group; and R.sub.6 is --H, --F,
--Cl, --Br or --I.
5. The method of claim 4 wherein R.sub.1 is a halide.
6. The method of claim 4 wherein: a) the base is potassium
carbonate; b) the halide is --Cl or --Br; and c) the diphenyl
ketone is prepared by reacting sodium iodide, the base, the
substituted 2-aminobenzophenone and the starting material.
7. A method of preparing a compound represented by the following
structural formula: 13wherein: Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or substituted with
one, two or three substituents, wherein each substituent is
independently chosen; and R is --H, an aliphatic group, a
substituted aliphatic group, an aryl group, a substituted aryl
group, --C(O)--R', --C(O)-H, --C(O)--NHR', --S(O).sub.2R', --C(O)--
C(O)--R', --C(O)--C(O)--H, --C(S)--R', --C(S)--H, --C(O)--OR',
--C(S)--OR', --C(O)--SR', --C(S)--SR', --C(O)--NR'.sub.2 or
--C(O)--C(S)--R', wherein R' is an aliphatic group, a substituted
aliphatic group, an aryl group or a substituted aryl group;
comprising reacting a ketone reducing agent with a diphenyl ketone
represented by the following structural formula: 14
8. The method of claim 7 wherein Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or
monosubstituted.
9. The method of claim 8 wherein the ketone reducing agent is a
hydride reducing agent.
10. The method of claim 9 wherein the hydride reducing agent is
sodium borohydride.
11. The method of claim 10 wherein the diphenyl ketone is
represented by the following structural formula: 15wherein: R is
--H, --CH.sub.3, benzyl, --C(O)--OCH.sub.3, --C(O)--C(O)--OH,
--C(O)--C(O)--OCH.sub.2CH.su- b.3, para-chlorobenzoyl,
--C(O)--O-(phenyl), benzoyl, meta-methoxybenzoyl,
para-nitrobenzoyl, para-methoxybenzoyl, para-methylbenzoyl,
para-chlorobenzoyl, naphthoyl, --C(O)--NH-(phenyl),
para-methylaminobenzoyl, para-aminobenzoyl or --C(O)--
NH-(4-NO.sub.2-phenyl); R.sub.2 is --H, --F, --Cl, --Br or --I;
R.sub.3 and R.sub.5 are independently --H, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --F, --Cl, --Br or --I; R.sub.4 is --H or,
taken together with R.sub.3 and the carbon atoms to which R.sub.3
and R.sub.4 are bonded, a phenyl group; and R.sub.6 is --H, --F,
--Cl, --Br or --I.
12. The method of claim 7 wherein the diphenyl ketone is prepared
by reacting a base, a substituted 2-aminobenzophenone represented
by the following structural formula: 16and a starting material
represented by the following structural formula: 17wherein R.sub.1
is a leaving group.
13. The method of claim 12 wherein Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or
monosubstituted.
14. The method of claim 13 wherein R.sub.1 is a halide.
15. The method of claim 14 wherein: a) the base is potassium
carbonate; b) the halide is --Cl or --Br; and c) the diphenyl
ketone is prepared by reacting sodium iodide, the base, the
substituted 2-aminobenzophenone and the starting material.
16. A compound represented by the following structural formula:
18and salts thereof; wherein: Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or substituted with
one, two or three substituents, wherein each substituent is
independently chosen; R is --H, an aliphatic group, a substituted
aliphatic group, an aryl group, a substituted aryl group;
--C(O)--R', --C(O)--H, --C(O)--NHR', --S(O).sub.2R', --C(O)--
C(O)--R', --C(O)--C(O)--H, --C(S)--R', --C(S)--H, --C(O)--OR',
--C(S)--OR', --C(O)--SR', --C(S)--SR', --C(O)--NR'.sub.2 or
--C(O)-- C(S)--R', wherein R' is an aliphatic group, a substituted
aliphatic group, an aryl group or a substituted aryl group.
17. The compound of claim 16 wherein Phenyl Ring A, Phenyl Ring B
and Phenyl Ring C are independently unsubstituted or
monosubstituted.
18. The compound of claim 17 wherein the compound is represented by
the following structural formula: 19wherein: R is --H, --CH.sub.3,
benzyl, --C(O)--OCH.sub.3, --C(O)--C(O)--OH,
--C(O)--C(O)--OCH.sub.2CH.sub.3, para-chlorobenzoyl,
--C(O)--O-(phenyl), benzoyl, meta-methoxybenzoyl,
para-nitrobenzoyl, para-methoxybenzoyl, para-methylbenzoyl,
para-chlorobenzoyl, naphthoyl, --C(O)--NH-(phenyl),
para-methylaminobenzoyl, para-aminobenzoyl or --C(O)--
NH-(4-NO.sub.2-phenyl); R.sub.2 is --H, --F, --Cl, --Br or --I;
R.sub.3 and R.sub.5 are independently --H, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --F, --Cl, --Br or --I; R.sub.4 is --H or,
taken together with R.sub.3 and the carbon atoms to which R.sub.3
and R.sub.4 are bonded, a phenyl group; and R.sub.6 is --H, --F,
--Cl, --Br or --I.
19. A compound represented by the following structural formula:
20and salts thereof; wherein: Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C are independently unsubstituted or substituted with
one, two or three substituents, wherein each substituent is
independently chosen with the provisos that 1) at least one of Ring
A, Ring B or Ring C is substituted; 2) when Ring B and Ring C are
unsubstituted, Ring A is not substituted with --Cl para to the
carbon bonded to the nitrogen atom; and 3; when Ring A and Ring C
are unsubstituted, Ring B is not substituted with --OCH.sub.3 at
positions three, four and five relative to the carbon atom bonded
to the methyl amino group; and R is --H, an aliphatic group, a
substituted aliphatic group, an aryl group, a substituted aryl
group; --C(O)--R', --C(O)--H, --C(O)--NHR', --S(O).sub.2R',
--C(O)--C(O)--R', --C(O)--C(O)--H, --C(S)--R', --C(S)--H,
--C(O)--OR', --C(S)--OR', --C(O)--SR', --C(S)--SR',
--C(O)--NR'.sub.2 or --C(O)--C(S)--R', wherein R' is an aliphatic
group, a substituted aliphatic group, an aryl group or a
substituted aryl group.
20. The compound of claim 19 wherein Phenyl Ring A, Phenyl Ring B
and Phenyl Ring C are independently unsubstituted or
monosubstituted.
21. The compound of claim 20 wherein the compound is represented by
the following structural formula: 21wherein: R is --H, --CH.sub.3,
benzyl, --C(O)--OCH.sub.3, --C(O)--C(O)-OH,
--C(O)-C(O)--OCH.sub.2CH.sub.3, para-chlorobenzoyl,
--C(O)--O-(phenyl), benzoyl, meta-methoxybenzoyl,
para-nitrobenzoyl, para-methoxybenzoyl, para-methylbenzoyl,
para-chlorobenzoyl, naphthoyl, --C(O)--NH-(phenyl),
para-methylaminobenzoyl, para-aminobenzoyl or
--C(O)--NH-(4-NO.sub.2-phen- yl) ; R.sub.2 is --H, --F, --Cl, --Br
or --I; R.sub.3 and R.sub.5 are independently --H, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --F, --Cl, --Br or --I; R.sub.4 is --H or,
taken together with R.sub.3 and the carbon atoms to which R.sub.3
and R.sub.4 are bonded, a phenyl group; and R.sub.6 is --H, --F,
--Cl, --Br or --I.
Description
RELATED APPLICATION(S)
[0001] This application is a divisional of application Ser. No.
09/370,819, filed Aug. 9, 1999 which is a divisional of application
Ser. No. 08/974,472 which was filed on Nov. 20, 1997. The entire
teachings of the above applications are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Compounds which inhibit the Ca.sup.2+-activated potassium
channel (Gardos channel) of cells are useful in the treatment of a
wide variety of diseases. For example, Sickle Cell Anemia can be
treated with compounds which inhibit the Ca.sup.2+-activated
potassium channel of erythrocytes (Stuart et al., J. Haematol. 86:
820 (1994). In addition, agents capable of inhibiting
Ca.sup.2+-activated potassium channels have been shown to be useful
in the treatment of arteriosclerosis (U.S. Pat. No. 5,358,959 to
Halperin et al.) Moreover, cell proliferation is dependent on the
regulated movement of ions across various cellular compartments,
including activation of Ca.sup.2+-activated potassium channels
(Magni et al., J. Biol. Chem. 261: 9321 (1991)). Thus, agents which
inhibit Ca.sup.2+-activated potassium channels can be used in the
treatment of proliferative diseases, including cancer, blood vessel
proliferative disorders, fibrotic disorders and arteriosclerotic
conditions.
SUMMARY OF THE INVENTION
[0003] The present invention is a method of preparing
11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines. The present invention
also includes novel compounds which are intermediates in the
preparation of 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines and
methods of preparing the intermediates.
[0004] In one embodiment, the present invention is a method of
preparing an 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented
by Structural Formula (I): 3
[0005] Phenyl Ring A, Phenyl Ring B and Phenyl Ring C are
independently unsubstituted or substituted with one, two or three
substituents. Each substituent on the
11-aryl-5,6-dihydro-11H-dibenzo[b,e]azepine is independently
chosen.
[0006] R is --H, an aliphatic group, a substituted aliphatic group,
an aryl group, a substituted aryl group, --C(O)--R', --C(O)--H,
--C(O)--NHR', --S(O).sub.2R', --C(O)--C(O)--R', --C(O)--C(O)--H,
--C(S)--R', --C(S)--H, --C(O)--OR', --C(S)--OR', --C(O)--SR',
--C(S)-- SR', --C(O)--NR'.sub.2 or --C(O)--C(S)--R'. R' is an
aliphatic group, a substituted aliphatic group, an aryl group or a
substituted aryl group.
[0007] The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[
b,e]azepine represented by Structural Formula (I) comprises a first
step in which a base, a substituted 2-aminobenzophenone and a
starting material are reacted to form a diphenyl ketone. The
2-aminobenzophenone, the starting material and the diphenyl ketone
are represented by Structural Formulas (II), (III) and (IV),
respectively: 4
[0008] In Structural Formulas (II)-(IV), R.sub.1 is a leaving group
and R, Phenyl Ring A, Phenyl Ring B, and Phenyl Ring C are as
described for Structural Formula (I).
[0009] The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[
b,e]azepine represented by Structural Formula (I) comprises a
second step in which the diphenyl ketone represented by Structural
Formula (IV) is reacted with a ketone reducing agent to form an
intermediate represented by Structural Formula (V): 5
[0010] In Structural Formula (V), R, Phenyl Ring A, Phenyl Ring B,
and Phenyl Ring C are as described for Structural Formula (I).
[0011] The method of preparing an 11-aryl-5,6-dihydro-11H-dibenz[
b,e]azepine represented by Structural Formula (I) comprises a third
step in which the intermediate represented by Structural Formula
(V) is reacted with one or more Lewis acids to form the
11-aryl-5,6-dihydro-11H-- dibenz[ b,e]azepine.
[0012] Another embodiment of the present invention is a method of
forming a diphenyl ketone represented by Structural Formula (IV).
The method comprises reacting a base, a 2-aminobenzophenone
represented by Structural Formula (II) and a starting material
represented by Structural Formula (III) to form the diphenyl
ketone.
[0013] Another embodiment of the present invention is a method of
forming an intermediate represented by Structural Formula (V). The
method comprises reacting a diphenyl ketone represented by
Structural Formula (IV) with a ketone reducing agent to form said
intermediate.
[0014] Another embodiment of the present invention is a method of
forming an intermediate represented by Structural Formula (V). The
method comprises a first step of reacting a base, a
2-aminobenzophenone represented by Structural Formula (II) and a
starting material represented by Structural Formula (III) to form a
diphenyl ketone represented by Structural Formula (IV) and a second
step of reacting the diphenyl ketone with a ketone reducing agent
to form the intermediate represented by Structural Formula (V).
[0015] Another embodiment of the present invention is a method of
forming a 11-aryl-5,6-dihydro-11H-dibenz[ b,e]azepine from a
diphenyl methanol. The 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine
and the diphenyl methanol are represented by Structural Formulas
(I) and (V), respectively, with the provisos that 1) at least one
of Ring A, Ring B or Ring C is substituted; 2) when Ring B and Ring
C are unsubstituted, Ring A is not substituted with --Cl para to
the carbon atom bonded to the amino group; and 3) when Ring A and
Ring C are unsubstituted, Ring B is not substituted with
--OCH.sub.3 at positions three, four and five with respect to the
carbon bonded to the methyl amino group. Thus,
11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines and diphenyl methanols
represented by Structural Formulas (VI)-(VIII) and (IX)-(XI),
respectively, are excluded: 6
[0016] Another embodiment of the present invention is a method of
forming a 11-aryl-5,6-dihydro-11H-dibenz[ b,e]azepine represented
by Structural Formula (I). The method comprises a first step of
reacting a ketone reducing agent with a diphenyl ketone represented
by Structural Formula (IV) to form an intermediate represented by
Structural Formula (V) and reacting the intermediate with a Lewis
acid to form the 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine.
[0017] Another embodiment of the present invention is a compound
represented by Structural Formula (IV). Yet another embodiment of
the present invention is a compound represented by Structural
Formula (V) with the proviso that the compound is not represented
by Structural Formulas (IX), (X) or (XI).
[0018] It is reported that 11-aryl-5,6-dihydro-11H-dibenz[
b,e]azepines inhibit Ca.sup.2+-activated potassium channels and are
therefore useful in treating sickle cell anemia, asteriosclerosis
and proliferative diseases. The methods described herein can be
used to prepare 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine in three
reaction steps in overall yields of between about 10% and 35%. The
starting materials and reagents are readily available and
inexpensive. Thus, the present invention is an efficient and
cost-effective method of preparing pharmacologically active agents
useful in the treating sickle cell anemia, proliferative diseases
such as cancer, blood vessel proliferative disorders, fibrotic
disorders and arteriosclerotic conditions.
BRIEF DESCRIPTION OF THE FIGURE
[0019] FIG. 1 is a schematic showing the disclosed method of
preparing 11-aryl-5,6-dihydro-11H-dibenz[b,e]azepines.
[0020] FIGS. 2A through 2I-1 show structural formulas of exemplary
compounds which have been prepared by the methods of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The features and details of the invention will now be more
particularly described below and pointed out in the claims. It will
be understood that the particular embodiments of the invention are
shown by way of illustration and not as limitations of the
invention. The principal features of this invention can be employed
in various embodiments without departing from the scope of the
invention.
[0022] Suitable substituents for Phenyl Ring A, Phenyl Ring B and
Phenyl Ring C and suitable groups for R include those which are
compatible with the reactions and reagents used in the methods of
the present invention. A substituent or group is compatible with a
reaction when the substituent or group does not significantly
reduce the yield of the reaction and does not cause a significant
amount of side reactions. The reagents used in the methods of the
present invention are well known in the field of organic chemistry.
Thus, the skilled person will readily recognize those groups and
substituents which are not compatible with these reagents, and, as
a consequence, will also recognize those groups and substituents
which are not compatible with a reaction used in the methods
disclosed herein.
[0023] Examples of groups and substituents which are not compatible
with the conversion of a diphenyl ketone represented by Structural
Formula (IV) to a diphenyl methanol represented by Structural
Formula (V) include acidic groups such as alcohols, phenols,
carboxylic acids and sulfonic acids. Functional groups such as
ketones, imines, aldehydes and, in certain cases, esters, can also
react with ketone reducing agents. Functional groups which can act
as Lewis bases, for example, amines, alcohols and phenols, react
with Lewis acids and are therefore incompatible with the ring
closure reaction in which a diphenyl methanol represented by
Structural Formula (V) is converted to a
11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by
Structural Formula (I).
[0024] Although certain functional groups, for example, those
described in the previous paragraphs, are not compatible with at
least one reaction used in the method of the present invention,
these functional groups can be present if they are first converted
to a suitable protected form. The protecting group can then be
removed after the reaction with which the functional group is
incompatible is performed. Protecting groups are well known in the
art and are described in, for example, Greene and Wuts, "Protective
Groups in Organic Synthesis", John Wiley & Sons (1991), the
entire teachings of which are incorporated into this application by
reference. The skilled artisan can select, using no more than
routine experimentation, suitable protecting groups for use in the
disclosed synthesis as well as conditions for applying and removing
the protecting groups.
[0025] Examples of suitable substituents for Phenyl Ring A, Phenyl
Ring B and Phenyl Ring C include aliphatic groups, substituted
aliphatic groups, aryl groups, substituted aryl groups, halogens
(e.g., fluoro, chloro, bromo and iodo), halogenated alkyl groups
(e.g., trihalomethyl) nitro, nitrile, --CONH(aliphatic group,
substituted aliphatic group, aryl group or substituted aryl group),
--CON(aliphatic group, substituted aliphatic group, aryl group or
substituted aryl group).sub.2, --O-(aliphatic group, substituted
aliphatic group, aryl group or substituted aryl group),
--N(aliphatic group, substituted aliphatic group, aryl group or
substituted aryl group).sub.2, --S(aliphatic group, substituted
aliphatic group, aryl group or substituted aryl group),
--S(O)(aliphatic group, substituted aliphatic group, aryl group or
substituted aryl group), --S(O).sub.2(aliphatic group, substituted
aliphatic group, aryl group or substituted aryl group). Also
included are aryl groups, for example, a phenyl group, which are
fused onto Phenyl Ring A, Phenyl Ring B or Phenyl Ring C. Ring B is
preferably substituted meta to the carbon atom bonded to the
aminomethyl group with electron donating substituents. Examples
include alkoxy groups, --Cl, --Br, --I, aliphatic groups,
substituted aliphatic groups, aryl groups, substituted aryl group,
--N(aliphatic group).sub.2 and --N(substituted aliphatic
group).sub.2, --N(aryl group).sub.2 and --N(substituted aryl
group).sub.2, --NH--CO(aliphatic group), --NH-- CO(substituted
aliphatic group), --NH--CO(aryl group) and --NH--CO(substituted
aryl group).
[0026] Examples of suitable values for R include --H, an aliphatic
group, a substituted aliphatic group, an aryl group, a substituted
aryl group, --C(O)--R', --C(O)--H, --C(O)-- NHR', --S(O).sub.2R',
--C(O)--C(O)--R', --C(O)--C(O)--H, --C(S)--R', --C(S)--H,
--C(O)--OR', --C(S)--OR', --C(O)--SR', --C(S)--SR', --C(O)--
NR'.sub.2 or --C(O)--C(S)--R', wherein R' is an aliphatic group, a
substituted aliphatic group, an aryl group or a substituted aryl
group. R' is preferably a C1-C8 straight or branched chain alkyl
group, a phenyl group, a substituted phenyl group, a naphthyl group
or a substituted naphthyl group.
[0027] Phenyl Ring A, Phenyl Ring B and Phenyl Ring C are
independently unsubstituted or substituted with one, two or three
substituents which are independently chosen. Thus, the number of
substituents and the substitution pattern on one of these phenyl
rings are independent of the number of substituents and
substitution patterns on the other two rings. In addition, the
selection of each substituent is independent of the other
substituents on the same phenyl ring or the other two phenyl
rings.
[0028] Preferably, Phenyl Ring A, Phenyl Ring B and Phenyl Ring C
in Structural Formulas (I)-(V) are independently unsubstituted or
monosubstituted. Thus, the substitution pattern and selection of
the substituent on a phenyl ring is independent of the substitution
patterns and selection of substituents on the other two phenyl
rings. More preferably, the 11-aryl-5,6-dihydro-11H-dibenz[
b,e]azepine represented by Structural Formula (I), the
2-aminobenzophenone represented by Structural Formula (II), the
starting material, represented by Structural Formula (III), the
diphenyl ketone represented by Structural Formula (IV) and the
diphenyl methanol represented by Structural Formula (V) are
represented by Structural Formulas (XII)-(XVI), respectively: 7
[0029] In Structural Formulas (XII)-(XVI):
[0030] R is --H, --CH.sub.3, benzyl, --C(O)--OCH.sub.3,
--C(O)--C(O)--OH, --C(O)--C(O)--OCH.sub.2CH.sub.3,
para-chlorobenzoyl, --C(O)--O-(phenyl), benzoyl,
meta-methoxybenzoyl, para-nitrobenzoyl, para-methoxybenzoyl,
para-methylbenzoyl, para-chlorobenzoyl, naphthoyl,
--C(O)--NH-(phenyl), para-methylaminobenzoyl, para-aminobenzoyl or
--C(O)--NH-(4-NO.sub.2-phen- yl);
[0031] R.sub.1 is a halide;
[0032] R.sub.2 is --H, --F, --Cl, --Br or --I;
[0033] R.sub.3 and R.sub.5 are independently --H, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --F, --Cl, --Br or --I;
[0034] R.sub.4 is --H or, taken together with R.sub.3 and the
carbon atoms to which R.sub.3 and R.sub.4 are bonded, a phenyl
group; and
[0035] R.sub.6 is --H, --F, --Cl, --Br or --I.
[0036] As used herein, aliphatic groups include straight chained,
branched or cyclic C.sub.1-C.sub.8 hydrocarbons which are
completely saturated or which contain one or more units of
unsaturation.
[0037] Aryl groups include carbocyclic aromatic groups such as
phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and
heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole,
2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl,
3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole,
4-thiazole, 5-thiazole, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.
[0038] Aryl groups also include fused polycyclic aromatic ring
systems in which a carbocyclic aromatic ring or heteroaryl ring is
fused to one or more other heteroaryl rings. Examples include
2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl,
2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazole,
2-benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl,
1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and
acridinyl.
[0039] Suitable substituents for an aryl group or an aliphatic
group are those which are compatible with reactions and reagents
used in the methods of the present invention, including those
discussed hereinabove for Phenyl Ring A, Phenyl Ring B and Phenyl
Ring C.
[0040] With respect to the reaction of the 2-aminobenzophenone and
starting material to form the diphenylketone represented by
Structural Formula (IV) (the "alkylation reaction"), "leaving
group" refers to a functional group which can be facilely displaced
with a nucleophilic reagent such as an amine. Leaving groups are
generally functional groups which are strongly electron withdrawing
and include --Cl, --Br--, --I and sulfonate esters such as
mesylates, benzenesulfonate, tosylate, brosylate and
nitrobenzenesulfonate. Preferred leaving groups are --Cl or --Br,
in which case an iodide salt such as sodium iodide or a tetraalkyl
iodide is generally included in the reaction mixture. About one to
about five equivalents of the iodide salt with respect to starting
material, preferably about 1.0 to about 1.2 equivalents, is
used.
[0041] Suitable bases for the alkylation reaction include carbonate
bases, hydroxide bases, alkoxide bases, hydride bases, amide bases
and alkyl lithium bases. Generally, with respect to the
2-aminobenzophenone, about one to about five equivalents of base
are used, preferably about 1.5 to about 2.5 equivalents. Carbonate
bases, for example, potassium carbonate, are preferred. Equimolar
amounts of starting material and 2-aminobenzophenone are generally
used. However, excesses as large as one to two fold of either
reactant can be used.
[0042] Polar organic solvents are generally used for the alkylation
reaction. Examples include acetonitrile, nitromethane, methylene
chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide and
dimethoxyethane. Acetonitrile is preferred. The alkylation is
performed at concentrations, for example, ranging from about 0.01 M
to about 5.0 M, preferably from about 0.1 M to about 1.0 M. The
reaction temperature ranges, for example, from about room
temperature to about 150.degree. C., preferably from about
90.degree. C. to about 110.degree. C.
[0043] An example of specific conditions suitable for performing
the alkylation reaction is provided in Example 1, infra.
[0044] Suitable reagents for reducing ketone groups are well known
in the art and include, for example, hydride reducing agents such
as sodium borohydride, lithium aluminum hydride, lithium
borohydride, alkali metal trialkyl borohydrides and alkali metal
trialkoxy aluminum hydides. Conditions suitable for reducing a
ketone to an alcohol with hydride reducing agents are well known in
the art and are described, for example, in Brown et al.,
Aldrichimica Acta 12: 3 (1979) and references cited therein, the
entire teachings of which are incorporated herein by reference.
Borane reagents such as diborane tetrahydrofuran, diborane dimethyl
sulfide, alkyl boranes and dialkyl boranes can also be used as
ketone reducing agents. Conditions suitable for reducing a ketone
to an alcohol with borane reagents are well known in the art and
are described, for example, in Lane, Aldrichimica Acta 10: 41
(1977) and references cited therein, the entire teachings of which
are incorporated herein by reference. There are many other reagents
suitable for reducing a ketone to alcohol which are known in the
art. It is to be understood that these reagents are also
encompassed by the term "ketone reducing agent".
[0045] With respect to the reduction of the diphenyl ketone
represented by Structural Formula (IV) to the diphenyl methanol
represented by Structural Formula (V) (the "reduction"), sodium
borohydride is a preferred ketone reducing reagent. The reduction
with sodium borohydride is typically performed in an etheral
solvent, such as diethyl ether, tetrahydrofuran, glyme or
1,4-dioxane, an alcoholic solvent such as methanol, ethanol or
iso-propanol, or mixtures thereof. The reduction with other hydride
reducing agents is generally performed in etheral solvents.
Generally, about 0.75 to about 3.0 equivalents of reducing agent
with respect to diphenylketone are used, preferably about 0.9 to
about 1.25 equivalents. The reduction is performed at
concentrations, for example, ranging from about 0.01 M to about 5.0
M, preferably from about 0.1 M to about 1.0 M. The reaction
temperature ranges, for example, from about 0.degree. to about
50.degree. C., preferably at ambient temperature.
[0046] Specific conditions for performing the reduction are
provided in Example 2.
[0047] Lewis acids suitable for use in the preparation of
11-aryl-5,6-dihydro-11H-dibenz[b,e]azepine represented by
Structural Formula (I) from diphenylmethanols represented by
Structural Formula (V) (the "ring closure reaction") are those
which can bring about the ionization of secondary alcohols in
solution. Examples include sulfonic acids (e.g., methanesulfonic
acid, benzesulfonic acid, toluenesulfonic acid, triflic acid and
chlorosulfonic acid), sulfuric acid, phosphorus pentoxide,
polyphosphoric acid and mixtures thereof. The reaction is typically
performed in a polar organic solvent such as chloroform, methylene
chloride, acetonitrile, nitromethane or 1,4-dioxane, preferably
methylene chloride, at temperatures ranging from about 0.degree. C.
to about 50.degree. C., preferably at ambient temperature. Excesses
up to about ten to about fifteen fold of Lewis acid relative to the
diphenyl alcohol can be used. Preferebly the Lewis acid is a
mixture of phosphorus pentoxide and methansulfonic acid with about
4.5 to about 5.5 equivalents of each relative to the diphenyl
alcohol. Specific conditions for performing the ring closure
reaction are provided in Example 3.
[0048] All reactions can be monitored for completion by methods
known in the art, for example, by thin layer chromatography, high
pressure liquid chromatography or gas chromatography.
[0049] When preparing 11-aryl-5,6-dihydro-11H-dibenz[ b,e]azepine
represented by Structural Formula (I) in which R is --C(O)--R',
--C(O)--H, --C(O)--NHR', --S(O).sub.2R', --C(O)--C(O)--R',
--C(O)--C(O)--H, --C(S)--R', --C(S)--H, --C(O)--OR', --C(S)-- OR',
--C(O)--SR', --C(S)--SR', --C(O)--NR'.sub.2 or --C(O)--C(S)--R', it
is preferred to first prepare the corresponding
11-aryl-5,6-dihydro-11H-dibe- nz[b,e]azepine in which R is --H and
then add the desired group to the secondary amine. Methods of
adding these groups to secondary amines are well known in the art.
Specific examples are provided in co-pending application
"SUBSTITUTED 11-PHENYL DIBENZAZEPINE COMPOUNDS AND ANALOGUES
THEREOF USEFUL FOR THE TREATMENT OR PREVENTION OF SICKLE CELL
DISEASE OR DISEASES CHARACTERIZED BY ABNORMAL CELL PROLIFERATION",
the entire teachings of which have been incorporated herein by
reference.
[0050] Also included in the present invention are salts of the
compounds represented by Structural Formulas (IV) and (V). Salts of
an amine can be obtained, for example, by reacting with a suitable
organic or inorganic acid, such as hydrogen chloride, hydrogen
bromide, acetic acid, perchloric acid and the like. Compounds with
a quaternary ammonium group also contain a counteranion such as
chloride, bromide, iodide, acetate, perchlorate and the like.
[0051] The invention is illustrated by the following examples which
are not intended to be limiting in any way.
EXEMPLIFICATION
Example 1
Synthesis of Diphenyl Ketones Represented by Structural Formula
(IV)
[0052] A mixture of an appropriately substituted
2-aminobenzophenone (1 equivalent), an appropriately substituted
benzyl chloride (1 equivalent), potassium carbonate (2 equivalents)
and sodium iodide (1 equivalent) in acetonitrile was refluxed for
12 hours. The reaction mixture was cooled to room temperature and
water added. The mixture was extracted with ethyl acetate. The
combined ethyl acetate extracts were washed with water then dried
over sodium sulfate. Evaporation of the solvent followed by column
chromatography gave the diphenyl ketone in about 55-80% yield.
Example 2
Synthesis of Diphenyl Methanols Represented by Structural Formula
(V) from Diphenyl Ketones Represented by Structural Formula
(IV)
[0053] The diphenyl ketone (1 equivalent) was dissolved in a 3:1
mixture of tetrahydrofuran:methanol. Sodium borohydride (10
equivalents) was slowly added and the reaction mixture was stirred
at room temperature for 12 hours. The reaction was quenched by
adding 2 N aqueous hydrochloric acid solution. The reaction mixture
was neutralized by adding 4 N aqueous sodium hydroxide solution
followed by extraction with ethyl acetate. The combined ethyl
acetate extracts were dried over sodium sulfate. Evaporation of the
solvent followed by column chromatography gave the diphenyl
methanol in about 40-60% yield.
Example 3
Preparation of 11-Aryl-5,6-Dihydro-11H-Dibenzo[ b,e]azepines
Represented by Structural Formula (I) from Diphenyl Methanols
Represented by Structural Formula (D)
[0054] A mixture of substituted N-alkyl-2-amino-benzylalcohol
derivative (1 equivalent), phosphorous pentoxide (5 equivalents)
and methanesulfonic acid (5 equivalents) in dichloromethane was
stirred at room temperature for 12 hours. The mixture was
neutralized by adding aqueous sodium carbonate and then extracted
with dichloromethane. The organic solution was dried over sodium
sulfate. Evaporation of the solvent followed by column
chromatography gave the substituted 11-aryl-5,6-dihydro-11H-dibenz-
(b,e)azepine derivative in about 45-70% yield.
EQUIVALENTS
[0055] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
spirit and scope of the invention as defined by the appended
claims. Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
specifically herein. Such equivalents are intended to be
encompassed in the scope of the claims.
* * * * *