Tertiary amines

Details Tertiary amines Tertiary amines

1999-12-16

2002-08-27

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S194000, C546S207000, C546S209000, C546S210000, C546S212000, C546S229000, C546S232000, C546S236000, C546S237000, C546S242000, C546S246000, C546S248000, C546S314000, C546S329000, C546S334000, C546S335000, C546S336000, C546S337000, C548S265800, C548S267200, C548S252000, C548S253000, C548S254000, C548S300100, C548S560000, C548S561000, C548S562000, C548S564000, C548S570000, C548S571000, C549S062000, C549S064000, C549S065000, C558S415000, C504S323000, C504S324000, C504S337000, C504S353000

Reexamination Certificate

active

06441177

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The present invention is concerned with novel tertiary amines, a process for their manufacture, pharmaceutical preparations which contain such compounds and the use of these compounds in the production of pharmaceutical preparations.
2. Description
There has been a long felt need in the medical community for antimycoticly active agents and cholesterol-lowering agent. The subject invention addresses this need.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
A
1
is C
1
-C
20
alkyl or C
3
-C
20
alkenyl,
A
2
is C
3
-C
6
cycloalkyl, C
3
-C
6
cycloalkyl-C
1
-C
20
-alkyl, unsubstituted C
1
-C
20
alkyl, unsubstituted C
3
-C
20
alkenyl, C
1
-C
20
alkyl substituted by R
1
, CONH
2
or CN, or C
3
-C
20
alkenyl substituted by R
1
, CONH
2
or CN, and when A
1
is C
1
-C
20
alkyl, A
2
can also be OH, and
A
3
and A
4
are each independently hydrogen or C
1
-C
20
alkyl; or
A
1
and A
2
together form a C
2
-C
8
alkylene, C
4
-C
8
alkenylene, C
6
-C
8
alkadienylene, R
1
substituted C
2
-C
8
alkylene, R
1
substituted C
4
-C
8
alkenylene, or R
1
substituted C
6
-C
8
alkadienylene group A
1
-A
2
,
and in group A
1
-A
2
one or two C atoms can be replaced by one or two groups selected from the group consisting of N atoms and N(C
1
-C
20
alkyl), or
A
1
and A
3
together form a C
2
-C
8
alkylene, C
4
-C
8
alkenylene, C
6
-C
8
alkadienylene, R
1
substituted C
2
-C
8
alkylene, R
1
substituted C
4
-C
8
alkenylene, or R
1
substituted C
6
-C
8
alkadienylene group A
1
-A
3
,
and in group A
1
-A
3
one or two C atoms can be replaced by one or two groups selected from the group consisting of N atoms and N(C
1
-C
20
alkyl);
R
1
is OH, oxo, C
1
-C
20
alkyl(O), C
1
-C
20
alkyl(S) or di(C
1
-C
20
alkyl)amino bonded to a saturated C atom of A
2
, A
1
-A
2
or A
1
-A
3
, provided that a C atom substituted by R
1
or an unsaturated C atom present in A
1
, A
2
, A
1
-A
2
or A
1
-A
3
must be bonded in a position other than the &agr;-position to N(A
1
A
2
);
p=1 and L is phenylene, C
4
-C
11
alkylene which has at least 4 C atoms between the two free valencies or C
3
-C
11
alkenylene which has at least 3 C atoms between the two free valencies, and which is bonded to M directly or via O, NH or N(C
1
-C
20
alkyl) or N(C
1
-C
20
alkanoyl), or L is C
3
-C
6
cycloalkylene-C
1
-C
20
-alkylene, or
p=0 and L is C
6
-C
11
-alkenylene or C
6
-C
11
-alkadienylene, bonded to T;
M is thienylene, pyridylene, 1,4-phenylene, 1,4-phenylene substituted by at least one substituent selected from the group consisting of C
1
-C
20
alkyl, halogen, N(R
2
,R
21
), CONH
2
, CN, NO
2
, CF
3
, OH, C
1
-C
20
alkyl(O), C
1
-C
20
alkyl(S), 1,2,4-triazol-1-yl and tetrazol-1-yl, or a group of the formula:
q is 1 or 0;
R
2
and R
21
are independently H, C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
1
-C
20
alkanoyl or SO
2
—(C
1
-C
20
alkyl);
T is CO, CH(R
3
), C(R
4
,R
5
) or C═NOR
6
and, when M is a group M
1
and q=0, T can also be SO
2
;
R
3
is OH, F, C
1
-C
20
alkoxy or C
1
-C
20
alkanoyloxy;
R
4
is OH and R
5
is C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
2
-C
20
alkinyl, cycloalkyl or CF
3
, or
R
4
and R
5
together are the group CH
2
, CH
2
O or CH
2
CH
2
;
R
6
is H, C
1
-C
20
alkyl or C
2
-C
20
alkenyl;
Q is C
3
-C
6
cycloalkyl, C(R
7
,R
8
), phenyl substituted by at least one substituent selected from the group consisting of C
1
-C
20
alkyl, halogen, N(R
9
,R
10
), CONH
2
, CN, NO
2
, CF
3
, 1,2,4-triazol-1-yl and tetrazol-1-yl, or a straight-chain C
6
-C
13
alkyl, C
6
-C
13
alkenyl, C
6
-C
13
alkadienyl or C
6
-C
13
alkatrienyl group Q′ with 0 to 3 methyl substituents, and a group Q′ can be substituted by at least one substituent selected from the group consisting of OH and N(R
9
,R
10
),
R
7
and R
8
are C
5
-C
11
-alkyl, C
5
-C
11
-alkenyl or C
5
-C
11
-alkadienyl, and
R
9
and R
10
are H, C
1
-C
20
alkyl, C
2
-C
20
alkenyl or C
1
-C
20
alkanoyl, provided that
(a) A
2
must not be C
1
-C
20
alkyl or C
3
-C
20
alkenyl, or A
1
and A
2
together must not be C
2
-C
8
alkylene in a compound of formula I in which T is a group CO or CHOH, L is phenylene or an C
4
-C
11
alkylene or C
3
-C
11
alkenylene group bonded to M directly or via O or N(C
1
-C
20
alkyl), M is 1,4-phenylene or 1,4-phenylene monosubstituted by C
1
-C
20
alkyl, C
1
-C
20
alkyl(O), halogen, CN, NO
2
or CF
3
, and Q is substituted phenyl, C
6
-C
13
alkenyl, C
6
-C
13
alkyl or C
6
-C
13
alkyl substituted by OH,
(b) M must not be pyridylene in a compound of formula I in which A
1
and A
2
together are C
2
-C
8
alkylene or C
2
-C
8
alkylene substituted by R
1
, A
2
is C
1
-C
20
hydroxyalkyl or A
1
and A
2
are each C
1
-C
20
alkyl, and
(c) in a compound of formula I in which T is a group C(OH, R
51
), wherein R
51
is C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
2
-C
20
alkynyl or C
3
-C
6
cycloalkyl, M is 1,4-phenylene or substituted 1,4-phenylene and L is an alkylene group bonded to M via a O atom, the alkylene must be a C
5
-C
11
alkylene containing at least 5 C atoms between the 2 free valencies,
and pharmaceutically usable acid addition salts thereof.
Of particular importance are compounds of the formula:
wherein
A
100
is C
1
-C
6
alkyl;
A
200
is C
3
-C
6
cycloalkyl, C
3
-C
6
alkenyl, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl-C
13
-alkyl;
L
100
is C
4
-C
6
alkylene, C
3
-C
6
alkenylene, or C
3
-C
6
cycloalkylene-C
1
-C
13
-alkylene;
a is 1;
R
100
is O;
M
100
is 1,4-phenylene, 1,4-phenylene substituted with at least one substituent selected from the group consisting of halogens,
T
100
is C═O, C═N—O—(C
1
-C
6
alkyl), C═CH
2
, C(C
1
-C
6
alkyl, OH); and
Q
100
is phenyl substituted with at least one substituent selected from the group consisting of the halogens,
and pharmaceutically salts acid addition salts thereof.
Especially preferred are compounds wherein
A
100
is C
1
-C
3
alkyl;
A
200
is C
3
-C
6
cycloalkyl, C
3
-C
6
alkenyl;
L
100
is C
3
-C
5
alkenylene or C
3
-C
6
cycloalkylene-C
1
-C
3
-alkylene;
a is 1;
R
100
is O;
M
100
is 1,4, phenylene, 1,4 phenylene substituted with at least one fluorine;
T
100
is C═O, C═N—O—(C
1
-C
3
alkyl), C═CH
2
, C(C
1
-C
3
alkyl, OH); and
Q
100
is phenyl substituted with at least one halogen atom,
and pharmaceutically usable acid addition salts thereof.
And more preferred compounds are wherein
A
100
is methyl;
A
200
is cyclopropyl or allyl;
L
100
is cyclopropylene-methylene or propenylene;
R
100
is O;
M
100
is 1,4-phenylene or 3 fluoro-1,4-phenylene;
T
100
is C═O or C(CH
3
)OH; and
Q
100
is bromophenyl,
and pharmaceutically usable acid addition salts thereof.
Compounds of the structures:
and pharmaceutically usuable acid addition salts thereof are favored.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention, but are not to be construed as limiting.
The invention is concerned with tertiary amines of the formula
wherein
A
1
is alkyl or alkenyl and
A
2
is cycloalkyl, cycloalkyl-alkyl or an alkyl or alkenyl group optionally substituted by a group R
1
, CONH
2
or CN and, where A
1
is alkyl, A
2
can also be OH,
A
3
and A
4
are hydrogen or alkyl or
A
1
and A
2
or A
3
together form an alkylene, alkenylene or alkadienylene group A
1
-A
2
or A
1
-A
3
with up to 5 C atoms optionally substituted by R
1
,
and in a group A
1
-A
2
or A
1
-A
3
up to 2 C atoms can be replaced by one (or two) N atom(s) and/or by a N-alkyl group,
R
1
is OH, oxo, alkyl(O or S) or dialkylamino bonded to a saturated C atom of A
2
, A
1
-A
2
or A
1
-A
3
, provided that a C atom substituted by R
1
or an unsaturated C atom present in A
1
, A
2
, A
1
-A
2
or A
1
-A
3
must be bonded in a position other than the &agr;-position to N(A
1
A
2
),
p=1 and L is phenylene, or alkylene or alkenylene which has a total of up to 11 C atoms and at least 4 or, respectively

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