Amidine derivatives, the preparation and use thereof as...

Details Amidine derivatives, the preparation and use thereof as... Amidine derivatives, the preparation and use thereof as...

2000-01-18

2002-12-03

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S396000, C514S535000, C514S539000, C514S603000, C514S619000, C514S620000, C514S351000, C514S470000, C514S546000, C514S635000, C549S401000, C549S462000, C548S343500, C560S138000, C564S085000, C564S086000, C564S088000, C564S164000, C564S165000, C564S246000, C564S247000, C564S300000

Reexamination Certificate

active

06489365

ABSTRACT:

The invention relates to new amidine derivatives, the preparation thereof using conventional methods and their use in pharmaceutical compositions.
The new amidine derivatives correspond to the formula
wherein
R
1
and R
2
, which may be identical or different, denote CF
3
, halogen, R
5
, OR
5
, COR
6
, SR
6
, SOR
6
, SO
2
R
6
, SO
2
NR
5
R
7
, C(OH)R
5
R
7
or together may also denote the double-bonded groups —CR
8
═CR
9
—CH═CH—, —CH═CR
8
—CR
9
═CH—, —CR
8
═CH—CR
9
═CH—, —O—CHR
10
—CH
2
—, —O—CH
2
—O—, —O—CH
2
—CH
2
—O—, —(CH
2
)
3-4
—, —NH—CO—O—, —NH—CO—CH
2
—O—, —CO—CH
2
—O— or —CO—CH
2
CH
2
—O—, linked with adjacent carbon atoms of the benzene ring, whilst these groups may in turn be substituted by C
1-4
-alkyl,
R
3
denotes halogen, OH, CF
3
, R
5
, OR
6
, COR
6
, CONH
5
R
7
, CH
2
OH, CH
2
—O—(C
1-4
-alkyl), SR
6
, SOR
6
, SO
2
R
6
, SO
2
NR
5
R
7
, NH—CO—(C
1-4
-alkyl) , NH—SO
2
—(C
1-4
-alkyl), NR
5
R
7
or C(OH)R
5
R
7
(whilst if R
3
is the same as R
5
, R
5
can only denote H if at least one of the substituents R
1
and R
2
does not denote H), a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula
 (wherein D, E and G, which may be identical or different, denote CH, N, C—(C
1-4
-alkyl) or C-phenyl and L denotes O or S),
R
4
denotes halogen, NH
2
, NH—(C
1-4
-alkyl), N(C
1-4
-alkyl)
2
, OH, C
1-4
-alkoxy,
R
5
denotes H, C
1-12
-alkyl, phenyl, phenyl optionally substituted by halogen, C
1-4
-alkyl, C
1-4
-alkoxy or C
2-5
-acyl, or phenyl-(C
1-4
-alkyl),
R
6
denotes C
1-12
-alkyl, phenyl, or phenyl optionally substituted by halogen, C
1-4
-alkyl, C
1-4
-alkoxy or C
2
-C
5
-acyl,
R
7
denotes H or C
1-2
-alkyl,
R
8
, R
9
(which may be identical or different) denote H, OH, C
1-4
-alkyl, C
1-4
-alkoxy or C
2-5
-acyl,
R
10
denotes H or C
1-4
-alkyl,
R
11
, R
12
, which may be identical or different, denote H, OH, halogen, CF
3
, C
1-4
-alkyl or C
1-4
-alkoxy,
A denotes one of the groups
B denotes CH═CH, CH═N, S or
A
1
denotes C
2-4
-alkylene, cis- or trans-CH
2
—CH═CH—CH
2
, CH
2
—C—C≡CH
2
or
A
2
denotes C
1-5
-alkylene,
X
1
denotes O, NH, S, SO, SO
2
, CO, CH
2
or
X
2
denotes O, NH, S or
X
3
denotes NH—CO, CO—NH, SO
2
—NH or
X
4
denotes NH—CO, CO—NH, NH—SO
2
, SO
2
—NH or, NH—CO—NH,
and (if they contain one or more chiral centres), may occur in the form of racemates, in enantiomerically pure or concentrated form, possibly as pairs of diastereomers and (if a double bond is present) in cis- or trans-form and as free bases or as salts, preferably with physiologically acceptable acids.
Within the scope of the above definitions, the preferred compounds are the compounds of formula
wherein
R
1
, R
2
, which may be identical or different, denote R
7
, OR
7
, COR
6
, halogen or together denote the double bonded groups —CR
8
═R
9
—CH═CH—, —CH═CR
8
—CR
9
═CH—, —O—CHR
10
—CH
2
— or —CO—CH
2
—CH
2
—O—, linked with adjacent carbon atoms of the benzene ring,
R
3
denotes halogen, CF
3
, R
7
, OR
7
, CO—(C
1-4
-alkyl), NH—CO—(C
1-4
-alkyl), NHSO
2
—(C
1-4
-alkyl) or N(R
10
)
2
(whilst R
7
can only denote H if at least one of the substituents R
1
and R
2
does not denote H) or a heterocyclic five-membered ring such as
R
6
and R
7
are as hereinbefore defined, and
A denotes the group II.
The following may be particularly mentioned as examples of the group of formula —C
6
H
2
R
1
R
2
R
3
:
Of the definitions of A particular mention may be made of:
Special mention should also be made of the compounds of formula
wherein
a denotes 0 or 1,
b denotes 1 or 2,
R denotes C
1-4
-alkyl, and if a=0 or 1 and b=1, and if a=1 and b=2, R may also denote hydrogen, and
R preferably denotes CH
3
, C
2
H
5
or H, and for a=1, b is preferably 1.
In the above definitions, the term halogen denotes F, Cl, Br or I, preferably F, Cl. If the groups listed are alkyl chains or contain alkyl chains, these may be straight-chained or branched. The alkyl chains in R
5
, R
6
and R
7
preferably contain up to 6 carbon atoms, more particularly 1 to 4 carbon atoms. In particular, as a constituent of COR
6
, R
6
denoting alkyl may also be mono- or poly-fluorine-substituted. Particular examples of substituents of ring systems are alkyls such as methyl, ethyl and the propyl. A preferred acyl group is COCH
3
, a preferred alkoxy group is CH
3
O. The bridged A preferably contains 4 to 6 members. The group is arranged between the two ring systems in formula I and in corresponding formulae so as to correspond to the written form of formulae II to VI, whereas the groups which are valid for both R
1
and R
2
are not listed in the proper orientation. If R
1
and R
2
together denote a double bonded group, R
3
preferably denotes H or C
2-5
-acyl, e.g. acetyl. The groups R
1
, R
2
and R
3
should not all simultaneously denote CF
3
, COR
6
, SR
6
, SOR
6
, SO
2
R
6
, SO
2
NR
5
R
7
or C(OH)R
5
R
7
, but rather these groups as well as OR
5
, with the definition phenoxy or substituted phenoxy, preferably occur only once or possibly twice, whilst alkyl, acyl and halogen, in particular, may occur as further substituents. The bonds or CH
2
groups in IX/IXa/IXb are generally in the &agr;-position to one another. Typical groups for A are, for example, O—(CH
2
)
2
—O, O—(CH
2
)
4
—O, whilst one of the O-atoms may be replaced by S, NH or CO, as well as groups such as CH
2
—CH
2
—CONH, CH
2
—CH
2
—NH—CO, CO—NH—CH
2
—CH
2
or NH—CO—CH
2
—CH
2
. The amidino group is usually in the para-position relative to the carbon atom to which A is linked.
The new compounds are prepared by conventional methods.
1. Reaction of imidoesters of the formula
wherein R
1
to R
4
, A and B are as hereinbefore defined and R preferably represents a C
1-6
-alkyl group or benzyl (but if desired the man skilled in the art can also use derivatives of other alcohols), and ammonia. The reaction is preferably carried out in an organic solvent at temperatures between about 0° C. and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100° C. or the boiling temperature, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol and propanol.
If the starting materials are sufficiently acid-resistant the reaction may be carried out via the corresponding acid imide chlorides instead of the imidoesters.
2. In order to prepare compounds of formula I wherein A is linked via O or S to at least one of the ring systems:
Reaction
(a) of a phenol or thiophenol of formula
 wherein Z denotes OH or SH and R
1
, R
2
and R
3
are as hereinbefore defined, with a compound of the formula
 wherein A
1
, A
2
, B, R
4
, X
2
and X
3
are as hereinbefore defined and L represents a nucleofugic leaving group, or
(b) of a phenol or thiophenol of the formula
 wherein B, R
4
and Z are as hereinbefore defined, with a compound of the formula
 wherein A
1
, A
2
, R
1
, R
2
, R
3
and Z are as hereinbefore defined.
The reaction is carried out in aprotic solvents such as dimethylsulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a basel(metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140° C. or the boiling temperature of the reaction mixture.
The phenols or thiophenols may also be used in the form of salts, e.g. alkali metal salts. Examples of suitable nucleofugic leaving groups include halogens such as Br and Cl.
3. Reduction of an amidoxime of the formula
wherein A, B and R
1
to R
4
are as hereinbefore defined.
For the reduction of XIX it is appropriate to use catalytic hydrogenation, particularly with Raney nickel in a lower alcohol such as methanol. Conveniently, the amidoxime of formula XIX is dissolved in methanol, with the addition of the calculated amount of the particular acid the salt of which is the desired end product, and hydrogenated at ambient temperature under gentle pressure, e.g. up to 5 bar, until the uptake of hydrogen has ended

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