Optically active intermediates for the preparation of...

Details Optically active intermediates for the preparation of... Optically active intermediates for the preparation of...

2000-10-13

2001-07-24

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C556S420000, C556S419000, C548S230000, C548S540000, C560S030000, C564S303000, C564S304000

Reexamination Certificate

active

06265614

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to optically active intermediates, processes for preparing the optically active intermediates, and processes employing the optically active intermediates for preparing optically active substituted oximes, hydrazones and olefins useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK
1
) and/or neurokinin-2 receptor (NK
2
) and/or neurokinin-3 receptor (NK
3
).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease.
In particular, NK
1
receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK
2
receptors have been associated with smooth muscle contraction, making NK
1
and NK
2
receptor antagonists especially useful in the treatment and prevention of asthma. These NK
1
and NK
2
receptor antagonists are also useful in the treatment of cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, and various gastrointestinal disorders such as Crohn's disease.
Substituted oximes, hydrazones and olefins which may be made from the intermediates and processes of the present invention include the oximes, hydrazones and olefins described in International Application No. PCT/US 96/05659, filed on May 1, 1996, the contents of which are fully incorporated herein by reference. It is believed that these compounds exhibit greater activity as neurokinin antagonists when they are in the form of their R-enantiomers. Thus, it is desirable to have intermediates and processes that can be used to make such R-enantiomers. The present invention satisfies this objective.
SUMMARY OF THE INVENTION
The intermediates of the present invention comprise a compound having the formula
wherein B
I
is —CH
2
OH or —CH
2
OR
P
, and R
P
is an alcohol protecting group;
a is 1, 2, or 3;
T
I
is —OH or
Q is R
5
-phenyl, R
5
-naphthyl or R
5
-heteroaryl;
R
5
represents 1-3 substituents independently selected from the group consisting of H, halogeno, —OR
6
, —OC(O)R
6
, —OC(O)N(R
6
)(R
7
), —N(R
6
)(R
7
), C
1-6
alkyl, —C
3
, —CF
2
F
5
, —COR
6
, —CO
2
R
6
, —CON(R
6
)(R
7
), —S(O)
e
R
13
, —CN, —OCF
3
, —NR
6
CO
2
R
16
, —NR
6
COR
7
, —NR
8
CON(R
6
)(R
7
), R
15
-phenyl,
R
15
-benzyl, NO
2
, —N(R
6
)S(O)
2
R
13
or —S(O)
2
N(R
6
)(R
7
); or adjacent R
5
substituents can form an —O—CH
2
O— group;
R
6
, R
7
, R
8
, and R
13
are independently selected from the group consisting of H, C
1-6
alkyl, C
2
-C
6
hydroxyalkyl, C
1
-C
6
alkoxy-C
1
-C
6
alkyl, R
15
-phenyl, and R
15
-benzyl; or R
6
and R
7
, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of —O—, —S— and —N(R
19
)—;
R
15
is 1 to 3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, halogeno, —CF
3
, —C
2
F
5
, —COR
10
, —CO
2
R
10
, —C(O)N(R
10
)
2
, —S(O)
e
R
10a
, —CN, —N(R
10
)COR
10
, —N(R
10
)CON(R
10
)
2
and —NO
2
;
R
16
is C
1-6
alkyl, R
15
-phenyl or R
15
-benzyl;
R
10
and R
10a
are independently selected from the group consisting of H and C
1-6
alkyl;
R
19
is H, C
1
-C
6
alkyl, —C(O)N(R
10
)
2
, —CO
2
R
10
, —(C(R
8
)(R
9
))
f
—CO
2
R
10
or —(C(R
8
)(R
9
))
u
—C(O)N(R
10
)
2
;
R
9
is selected from the group consisting of R
6
and —OR
6
;
e is 0, 1 or 2, provided that when e is 1 or 2, R
13
and R
10a
are not H;
f is an integer from 1 to 6; and
u is an integer from 0 to 6;
said intermediate having an enantiomeric excess of the R enantiomer over the corresponding S enantiomer of greater than 85%.
The intermediates of the present invention also comprise a compound having the formula
wherein a is 1, 2, or 3;
Q is as defined above;
R
a
and R
c
are the same, and are H, or are selected from alkyl, cycloalkyl and aryl groups, said groups being optionally substituted with one or more substituents selected from alkyl, cycloalkyl, aryl, or —OH; or R
a
and R
c
together with the C—N—C chain to which they are bound, form a 5-7 membered ring;
R
b
and R
d
are the same, and are H, or are selected from alkyl, cycloalkyl and aryl groups, said groups being optionally substituted with one or more substituents selected from alkyl, cycloalkyl, aryl, or —OH; and
D is a directing group capable of directing lithiation alpha to a nitrogen atom of a nitrogen compound having D as a substituent bound to the nitrogen atom when said nitrogen compound is reacted with s-butyl lithium, said nitrogen compound having the formula
wherein R
a
, R
b
,R
c
, and R
d
are as defined above;
said intermediate having an enantiomeric excess of of the R enantiomer over the corresponding S enantiomer of greater than 85%.
The present invention further provides a process for making an optically active R-enantiomer intermediate having the formula:
wherein B is —CH═CH
2
, —CH
2
OH, or —CH
2
OR
P
, and R
P
is an alcohol protecting group;
a is as defined above;
Q is R
5
-phenyl, R
5
-naphthyl or R
5
-heteroaryl;
R
5
, R
6
, and R
7
are as defined above;
R
a
, R
c
, R
b
and R
d
are as defined above; and
D is a directing group capable of directing lithiation alpha to a nitrogen atom of a nitrogen compound having D as a substituent bound to the nitrogen atom when said nitrogen compound is reacted with s-butyl lithium, said nitrogen compound having the formula
wherein R
a
, R
b
, R
c
, and R
d
are as defined above;
said process comprising reacting a compound having the formula
wherein R
a
, R
b
, R
c
, and R
d
are as defined above, with a compound having the formula
wherein B, a, and Q are as defined above, and R
e
and R
f
are independently selected from the group consisting of alkyl, alkoxy, cycloalkyl and aryl groups, said groups being optionally substituted with one or more substituents selected from alkyl, alkoxy, cycloalkyl, aryl, NH
2
, or —OH, or R
e
and R
f
together with the nitrogen atom to which they are bound, form a 5-7 membered ring.
The present invention further provides a process for making a compound having the formula:
from a compound having the formula
wherein for the formulas above,
B is —CH═CH
2
, —CH
2
OH, or —CH
2
OR
P
, and R
P
is an alcohol protecting group;
A is ═N—OR
1
, ═N—N(R
2
)(R
3
), ═C(R
11
)(R
12
) or ═NR
25
;
a is 1,2, or 3;
T is H, R
4
-aryl, R
4
-heterocycloalkyl, R
4
-heteroaryl, phthalimidyl, R
4
-cycloalkyl or R
10
-bridged cycloalkyl;
Q is R
5
-phenyl, R
5
-naphthyl, or R
5
-heteroaryl;
R
1
is H, C
1-6
alkyl, —(C(R
6
)(R
7
))
n
—G, —G
2
, —(C(R
6
)(R
7
))
p
—M—(C(R
13
) (R
14
))
n
—(C(R
8
)(R
9
))
u
—G, —C(O)N(R
6
)—(C(R
13
) (R
14
))
n
—(C(R
8
)(R
9
))
u
—G or —(C(R
6
)(R
7
))
p
—M—(R
4
-heteroaryl);
R
2
and R
3
are independently selected from the group consisting of H, C
1-6
alkyl, —CN, —(C(R
6
)(R
7
))
n
—G, —G
2
, —C(O)—(C(R
8
)(R
9
))
n
—G and —S(O)
e
R
13
; or R
2
and R
3
, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of —O—, —S— and —N(R
19
)—;
R
4
and R
5
are independently 1-3 substituents independently selected from the group consisting of H, halogeno, —OR
6
, —OC(O)R
6
, —OC(O)N(R
6
)(R
7
), —N(R
6
)(R
7
), C
1-6
alkyl, —CF
3
, —CF
3
F
5
, —COR
6
, —CO
2
R
6
, —CON(R
6
)(R
7
), —S(O)
e
R
13
, —CN, —OCF
3
, —NR
6
CO
2
R
16
, —NR
6
COR
7
, —NR
8
CON(R
6
)(R
7
), R
15
-phenyl, R
15
-benzyl, NO
2
, —N(R
6
)S(O)
2
R
13
or —S(O)
2
N(R
6
)(R
7
); or adjacent R
4
su

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