Benzamidine derivatives and the use thereof as medicaments...

Details Benzamidine derivatives and the use thereof as medicaments... Benzamidine derivatives and the use thereof as medicaments...

2000-12-01

2001-07-24

Aulakh, Charanjit S. (Department: 1625)

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

Organic compounds

Amino nitrogen containing

C544S062000, C564S225000, C564S247000

Reexamination Certificate

active

06265612

ABSTRACT:

The present invention relates to new benzamidine derivatives, processes for preparing them and their use in pharmaceutical compositions. The new benzamidine derivatives corresponcd to general formula 1
wherein
A denotes —O—C
2-4
-alkylene-O— or —C
1-3
-alkylene-O—
R
1
denotes branched or unbranched C
1-6
-alkyl, branched or unbranched C
3-6
-alkenyl, preferably allyl or F, Cl, Br, I;
R
2
denotes hydrogen, branched or unbranched C
1-6
-alkyl, branched or unbranched C
3-6
-alkenyl, preferably allyl or F, Cl, Br, I;
R
3
and R
4
, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C
1-6
-alkyl, branched or unbranched C
3-6
-alkenyl, preferably allyl, C
1-6
-alkoxy, (C
1-4
-alkyl)OC(O)O—, OH or CF
3
or together denote a fused-on mono- or fused bi-cyclic ring system which is completely or partially conjugated and optionally contains one or two heteroatoms from the group oxygen, sulphur or nitrogen, and which may be optionally substituted by OH, C
1-4
-alkoxy or C
1
-C
4
-alkyl;
R
5
denotes hydrogen, aryl, preferably phenyl, —O-phenyl, —CR
7
R
8
-phenyl, —C(O)phenyl, —SO
2
phenyl, —CH(OH)phenyl, wherein the phenyl ring may be substituted by OH, —C
1-4
-alkoxy, or it denotes —C(O)NR
9
R
10
;
R
6
denotes hydrogen, C
1-6
-alkoxycarbonyl, (C
1-5
-alkyl)-carbonyl or —C(O)—O—(C
1-6
-alkylene)-NR
11
R
12
;
R
7
and R
8
, which may be identical or different, denote hydrogen, branched or unbranched C
1-8
-alkyl, or CF
3
;
R
9
and R
10
, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C
1-8
-alkyl;
R
11
and R
12
, which may be identical or different, independently of one another denote hydrogen, branched or unbranched C
1-8
-alkyl;
optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Preferred compounds of general formula 1 are those wherein
A denotes —OCH
2
CH
2
O—, —CH
2
O—, —CH
2
CH
2
CH
2
O—;
R
1
denotes branched or unbranched C
1-5
-alkyl, allyl;
R
2
denotes hydrogen;
R
3
denotes hydrogen, C
1-6
-alkyl, OCH
3
, C
2
H
5
OC(O)O—, OH, Cl, F, CF
3
;
R
4
denotes hydrogen, —OCH
3
, OH;
R
3
and R
4
together denote a fused-on benzene ring, 3,4-dihydrocoumarin or 1,3-dioxolane which may be substituted by OH, C
1
-C
3
-alkyl or OCH
3
;
R
5
denotes hydrogen, phenyl, O-phenyl, —CR
7
R
8
-phenyl, -SO
2
phenyl, wherein the phenyl ring may be substituted by OH or OCH
3
, or it denotes —C(O)NR
9
R
10
;
R
6
denotes hydrogen or C
1-4
-alkoxycarbonyl or —C(O)—O(CH
2
)
2
—N(C
2
H
5
)
2
;
R
7
and R
8
, which may be identical or different, independently of one another denote hydrogen, CH
3
or CF
3
;
R
9
and R
10
, which may be identical or different, denote hydrogen, branched or unbranched C
1
-C
8
-alkyl.
Unless specifically stated otherwise the general definitions are used as follows:
C
1-8
-alkyl, C
1-5
-alkyl and C
1-4
-alkyl generally denote a branched or unbranched hydrocarbon group having 1 to 4 or 5 or 8 carbon atoms, which may optionally be substituted with one or more halogen atoms—preferably fluorine—which may be the same as or different: from each other. The following hydrocarbon groups are mentioned by way of example:
methyl,ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise specified, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl are preferred.
Accordingly, alkylene denotes a branched or unbranched double-bonded hydrocarbon bridge having 1 to 8 carbon atoms which may optionally be substituted with one or more halogen atoms—preferably fluorine—which may be the same as or different from each other.
Aryl generally denotes an aromatic group having 6 to 10 carbon atoms—as well as in compositions, where the aromatic group may be substituted by one or more lower alkyl groups, trifluoromethyl groups, cyano groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms, which may be identical to or different from one another; the preferred aryl group is an optionally substituted phenyl group, whilst the preferred substituents are halogen—such as fluorine, chlorine or bromine—and hydroxyl.
Alkoxy generally denotes a straight-chained or branched hydrocarbon group having 1 to 8 carbon atoms, bound via an oxygen atom. A lower alkoxy group having 1 to 3 carbon atoms is preferred. The methoxy group is particularly preferred.
As has been found, the compounds of formula 1 are characterised by their wide range of possible applications in the therapeutic field. Particular mention should be made of those applications in which the LTB
4
-receptor-antagonistic properties play a part. Examples include, in particular:
arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by nonsteroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemia, atherosclerosis and multiple sclerosis.
The new compounds may also be used to treat diseases or conditions in which the passage of cells from the blood through the vascular endothelium into the tissues is of importance (such as metastasis) or diseases and conditions in which the combination of LTB
4
or another molecule (such as 12-H ETE) with the LTB
4
-receptor influences cell proliferation (such as chronic myeloid leukaemia).
The new compounds may also be used in combination with other active substances, e.g. those which are used for the same indications, or for example with antiallergics, secretolytics, &bgr;
2
-adrenergics, inhaled steroids, antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.
The activity ratios may be investigated pharmacologically and biochemically using tests such as those described in WO 93/16036, pp. 15 to 17—the contents of which are referred to herein.
The therapeutic or prophylactic dose depends not only on the potency of the individual compounds and the body weight of the patient but also on the nature and gravity of the illness. For oral administration the dose is between 10 and 500 mg, preferably between 20 and 250 mg. For inhalation the patient is given between about 0,5 and 25 mg, preferably between about 2 and 20 mg of active substance.
Inhalable solutions generally contain between about 0.5 and 5% of active substance. The new compounds may be administered in conventional preparations, e.g. as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, inhalable aerosols, ointments or suppositories.
The Examples which follow show some possible ways of formulating the preparations:


REFERENCES:
patent: 5246965 (1993-09-01), Ag
patent: 5731332 (1998-03-01), Anderskewitz et al.
patent: 44 24 713 A1 (1996-01-01), None
patent: 195 46 452 A1 (1997-06-01), None
patent: 0 496 378 A1 (1992-07-01), None
patent: 0 518 818 A1 (1992-12-01), None
patent: 0 574 808 A1 (1993-12-01), None
patent: WO 93 16036 A1 (1993-08-01), None

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