Benzylamine and phenylethylamine derivatives, processes for...

Details Benzylamine and phenylethylamine derivatives, processes for... Benzylamine and phenylethylamine derivatives, processes for...

2000-04-03

2001-09-11

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S385000, C564S389000, C564S165000, C560S027000, C560S042000, C562S451000, C514S329000, C514S539000, C514S570000, C514S620000, C514S655000, C546S245000

Reexamination Certificate

active

06288277

ABSTRACT:

The present invention relates to new benzylamine derivatives and phenylethylamine derivatives, processes for preparing them and their use as pharmaceutical compositions.
Benzyl- or phenylethylamine derivatives according to the invention correspond to general formula I
wherein
X denotes O, NH, N(CH
3
), CH
2
;
Y denotes O, NH, N(CH
3
), CH
2
;
R
1
denotes H, F, Cl, Br, I, C
1-6
-alkyl, OH, O—C
1-6
-alkyl, CF
3
;
R
2
denotes H, F, Cl, Br, I, C
1-6
-alkyl, OH, O—C
1-6
-alkyl, CF
3
;
R
3
denotes H, NH
2
, NHCOR
5
;
R
4
denotes H, CH
2
NH
2
, CH
2
NHCOR
5
;
R
5
denotes H, C
1-6
-alkyl, phenyl, O—(C
1-6
-alkyl), whilst the phenyl ring may be substituted up to twice by: F, Cl, Br, I, R
a
, OR
a
, CF
3
,
R
a
denotes H, C
1-6
-alkyl;
A denotes CR
6
R
7
, CO, SO
x
, O;
x denotes an integer 0, 1 or 2;
R
6
denotes H, C
1-4
-alkyl, C
3-6
-cycloalkyl, —(CH
2
)
y
COOR
8
, CF
3
, —(CH
2
)
y
OR
8
, OR
8
;
y denotes an integer 0, 1, 2, 3 or 4;
R
7
denotes H, C
1-4
-alkyl, C
3-6
-cycloalkyl, —(CH
2
)
z
COOR
8
, —(CH
2
)
z
OR
8
, CF
3
;
z denotes an integer 0, 1, 2, 3 or 4, whilst R
6
and R
7
together may optionally form a C
3-6
-cycloalkyl ring;
R
8
denotes H, C
1-6
-alkyl;
B denotes C
1-6
-alkyl, CONR
9
R
10
, Ar, and, if A represents —C(CH
3
)
2
: CH
2
NR
9
R
10
, CH
2
NR
9
COR
11
;
Ar denotes phenyl, naphthyl, thienyl, pyridyl—optionally substituted up to twice with R
12
,
R
9
denotes H, C
1-6
-alkyl;
R
10
denotes H, C
1-6
-alkyl, whilst R
9
and R
10
together with the nitrogen atom may form a ring having 3 to 7 carbon atoms;
R
11
denotes H, C
1-6
-alkyl, —O—(C
1-6
-alkyl), phenyl;
R
12
denotes H, C
1-6
-alkyl, O—(C
1-6
-alkyl), F, Cl, Br, I, R
a
, CF
3
, CHF
2
, C(CH
3
)
2
-phenylene-OH, COOR
a
, CONR
a
R
b
, OR
c
;
R
a
denotes H, C
1-6
-alkyl;
R
b
denotes H, C
1-6
-alkyl, whilst optionally R
a
and R
b
together with the nitrogen atom may form a ring having 3 to 7 carbon atoms;
R
c
denotes H, C
1-6
-alkyl, COOR
d
, COR
d
or a group of formula
l, m, n denote an integer 0, 1, 2, 3 or 4 whilst l+m+n≦4;
R
d
denotes C
1-6
-alkyl, phenyl,
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—with the proviso that R
3
and R
4
together cannot denote hydrogen.
Preferred compounds of general formula I are those wherein
X denotes O;
Y denotes O;
R
1
denotes H, F, Cl, Br, I, C
1-6
-alkyl, OH, O—C
1-6
-alkyl, CF
3
;
R
2
denotes H, F, Cl, Br, I, C
1-6
-alkyl, OH, O—C
1-6
-alkyl, CF
3
;
R
3
denotes NH
2
;
R
4
denotes H;
A denotes CR
6
R
7
, O;
R
6
denotes H, C
1-4
-alkyl, CF
3
;
R
7
denotes H, C
1-4
-alkyl, CF
3
, whilst R
6
and R
7
together may optionally form a C
3-6
-cycloalkyl ring;
B denotes phenyl, optionally substituted up to twice with F, Cl, Br, I, R
a
, OR
c
, CF
3
;
R
a
denotes H, C
1-6
-alkyl;
R
c
denotes H, C
1-6
-alkyl, COOR
d
, COR
d
or a group of formula
l, m, n denote an integer 0, 1, 2, 3 or 4 whilst l+m+n≦4;
R
d
denotes C
1-6
-alkyl, phenyl
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.
Unless otherwise stated in specific instances, the general definitions are used in the following sense:
C
1-4
-alkyl, C
1-6
-alkyl or C
1-8
-alkyl generally represents a branched or unbranched hydrocarbon group with 1 to 4 or 6 or 8 carbon atom(s), which may optionally be substituted by one or more halogen atom(s)—preferably fluorine—which may be identical to or different from one another. 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-ethylproypyl, 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 stated, lower alkyl groups with 1 to 4 carbon atoms, such as methyl; ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, are preferred.
It has been found that the compounds of formula I according to the invention are characterised by their multiplicity of uses in the therapeutic field and by their oral efficacy. Special mention should be made of those possible uses in which the LTB
4
-receptor-antagonistic properties play a part. The following deserve particular mention:
arthritis, asthma, chronic obstructive lung diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastropathy or enteropathy induced by non-steroidal antiinflammatories, cystic fibrosis, Alzheimer's disease, shock, reperfusion damage/ischaemias, atherosclerosis and multiple sclerosis.
The new compounds can also be used to treat diseases or conditions wherein the passage of cells from the blood through the vascular endothelium into the tissues is of importance (e.g. metastasis) or diseases and conditions wherein the combination of LTB
4
or another molecule (such as 12-HETE) with the LTB
4
-receptor influences cell proliferation (e.g. chronic myeloid leukaemia).
The new compounds may also be used in conjunction 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, NSAIDs and glucocorticoids. The substances may be administered topically, orally, transdermally, nasally, by parenteral route or by inhalation.
Pharmacological and biochemical testing of the activity ratios may be carried out using tests as described, for example, in WO 93/16036, pages 15 to 17—to which reference is hereby made.
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 disease. For oral administration the dose is between 1 and 500 mg, preferably between 20 and 250 mg. For inhalation the dose is between about 0.5 and 25, preferably between about 2 and 20 mg of active substance.
Inhalable solutions generally contain between about 0.5 and 5% 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 and suppositories.


REFERENCES:
patent: 5686496 (1997-11-01), Anderskewitz et al.
patent: 5731332 (1998-03-01), Anderskewitz et al.

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