Neurokinin antagonists

Details Neurokinin antagonists Neurokinin antagonists

2000-02-08

2001-02-20

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S253010, C514S256000, C544S162000, C544S168000, C544S330000, C544S350000, C544S392000, C544S398000, C546S190000, C546S191000, C546S229000, C546S234000

Reexamination Certificate

active

06191135

ABSTRACT:

The invention relates to new compounds of general formula I
and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin)-antagonists.
The International Patent Application WO 93/10073 describes compounds having a similar structure and a neurokinin-antagonistic activity. These compounds are specifically excluded from the subject matter of the present application.
The present invention relates to compounds of general formula I
and the pharmaceutically acceptable salts thereof, wherein
A denotes Ar, Ar—CH
2
—, Ar—CH(Ph)—, Ar—(CH
2
)
2
—, Ar—CH(Ph)—CH
2
—, Ar—CH
2
—CH(Ph)— or Ar—CH(Ph)—CH(Ph)—, wherein Ar denotes phenyl, naphthyl, pyridyl or thienyl and Ph denotes phenyl, whilst the phenyl groups contained in these groups may be unsubstituted or substituted by one, two or three R
4
groups, wherein these
R
4
groups independently of one another denote (C
1-6
)alkyl, (C
1-6
)alkyl substituted by 1 to 3 fluorine atoms, (C
1-6
)alkoxy, (C
1-6
)alkylthio or halogen, or two adjacent R
4
groups together denote —O—(CH
2
)—O— or —(CH
2
)
3-5
—;
B denotes
—CH(R
12
)—,
—CH
2
—CH
2
—,
—C(O)—N
—C(O)—CH
2
— or
—C(O)—CH
2
—CH
2
—;
wherein
R
12
denotes H or CH
3
;
R
1
denotes H, (C
1-6
)alkyl or phenyl;
R
2
denotes H, (C
1-6
)alkyl or —C(O)(C
1-3
)alkyl, wherein the alkyl groups contained therein may be substituted by a phenyl group;
R
3
denotes hydrogen, (C
1-6
)alkyl, (C
1-6
)alkyl substituted by 1 to 3 fluorine atoms, halogen or (C
1-6
)alkoxy;
m is 1, 2 or 3;
Z is di(C
1-6
)alkylamine,
wherein
R
7
denotes
hydrogen,
(C
3-7
)cycloalkyl, phenyl
(C
1-6
)alkyl,
allyl,
—(CH
2
)
2-6
OH,
—(C
1-3
)alkylphenyl,
diphenylmethyl or
—(C
1-3
)alkyl(C
3-7
)cycloalkyl,
whilst the phenyl groups contained in the above-mentioned groups may be unsubstituted or substituted by one or two substituents, namely CH
3
, F, Cl, OCH
3
, SCH
3
, CF
3
, OH or NO
2
, or they may be substituted by —O—CH
2
—O— linked to 2 adjacent carbon atoms of the phenyl;
R
8
and R
9
have the meanings given under the definition of R
7
or denote
—CH
2
OH
—OH
wherein the last six groups mentioned are in position 3 or 4, in the case of R
8
, and in position 3, in the case of R
9
, and wherein
R
14
denotes
H,
(C
1-6
) alkyl,
phenyl or
cyclohexyl,
whilst if one of the R
14
groups is phenyl or cyclohexyl, the other R
14
must be hydrogen;
With the exception of compounds of general formula I wherein
A, R
3
and m are as herein before defined;
B denotes —CH—
2
,
R
1
denotes H, alkyl or phenyl,
R
2
is H and
Z is —N(CH
3
)
2
,
Compounds of general formula I contain basic groups. The compounds of general formula I can therefore occur in the form of salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid).
The compounds of general formula I may contain chiral centres: the formulae given includes the mixtures of isomers as well as the individual isomers.
The terms “alkyl” and “alkoxy” appearing in the definitions include both branched and unbranched alkyl and alkoxy groups.
Preferred compounds of general formula I are those wherein
A represents Ar, Ar—CH
2
—, Ar—CH(Ph)—, Ar—(CH
2
)
2
—, Ar—CH(Ph)—CH
2
—, Ar—CH
2
—CH(Ph)— or Ar—CH(Ph)—CH(Ph)—, wherein Ar denotes phenyl or naphthyl and Ph represents phenyl, whilst the phenyl groups contained in these groups may be unsubsituted or may be substituted by one, two or three R
4
groups, wherein these
R
4
groups independently of one another denote (C
1
-C
3
)alkyl, (C
1
-C
3
)alkyl substituted by one to three fluorine atoms, (C
1
-C
3
) alkoxy, (C
1
-C
3
)alkylthio or halogen, or two adjacent R
4
groups together denote —O—(CH
2
)—O—;
B denotes
—CH(R
12
)—,
—CH
2
—CH
2
—,
—C(O)—,
—C(O)—NH—,
—C(O)—CH
2
— or
—C(O)—CH
2
—CH
2
—;
wherein
R
12
denotes H or CH
3
;
R
1
denotes H, (C
1-3
)alkyl or phenyl;
R
2
denotes H, (C
1-3
)alkyl or —C(O)(C
1-3
)alkyl, whilst the alkyl groups contained therein may be substituted by a phenyl group;
R
3
denotes hydrogen, (C
1-3
)alkyl, (C
1-3
)alkyl substituted by 1 to 3 fluorine atoms, halogen or (C
1-3
)alkoxy;
m is 1, 2 or 3;
and Z is as herein before defined.
Particular mention should be made of compounds of general formula 1 wherein A is phenyl, benyzl, diphenylmethyl or naphthyl, particularly compounds wherein A is unsubstituted phenyl or phenyl substituted by 1 or 2 R
4
groups, these R
4
groups independently of one another representing methyl, trifluoromethyl, methoxy, thiomethyl, fluorine or chlorine, preferably compounds wherein A is phenyl or methoxyphenyl; and/or
B is
—CH
2
—,
—CH—(CH
3
)—,
—CH
2
—CH
2
—,
—C(O)—,
—C(O)—NH— or
—C(O) —CH
2
—
and/or R
1
is hydrogen; and/or R
2
is —C(O)CH
3
or hydrogen; and/or
R
3
is hydrogen, methyl, trifluoromethyl, methoxy, i-propoxy, fluorine or chlorine and/or
m is 1 or 2;
particularly wherein m is 2 and are R
3
is trifluoromethyl in positions 3 and 5 or wherein m is one and R
3
is i-propoxy in position 3; and/or
Z denotes
wherein R
7
denotes
(C
5
-C
7
)cycloalkyl,
(C
1
-C
3
)alkyl, allyl,
—(CH
2
)
2
OH,
—(C
1
-C
2
)alkylphenyl,
diphenylmethyl or
—(C
1
-C
2
)alkylcyclohexyl,
wherein the phenyl groups contained in the above-mentioned groups may be unsubstituted or substituted by one or two substituents., namely CH
3
, F, Cl, OCH
3
, SCH
3
, CF
3
, OH or NO
2
or may be substituted by —O—CH
2
—O— which is linked to two adjacent carbon atoms of the phenyl, particularly wherein Z is piperazinyl substituted by R
7
or wherein Z is homopiperazinyl substituted by R
7
or wherein R
7
is (C
5
-C
7
)cycloalkyl, preferably cyclohexyl, or wherein
wherein R
8
is preferably —OH
in position 4.
Test results for compounds according to the invention:
The receptor affinity for the NK
1
-receptor (substance P-receptor) was determined on intact human lymphoblastoma cells (IM-9) which express NK
1
-receptors, and the displacement of
125
I labelled substance P was measured.
The IC
50
or K
i
values thus obtained are:
Compound
IC
50
K
i
Example No.
[nM]
[nM]
001
333
002
909
003
800
019
580
020
520
022
154
023
108
026
7
027
111
028
102
029
119
030
90
031
93
032
23
034
38
035
16
036
18
039
16
049
37
053
5
054
20
057
64
058
23
061
851
062
276
064
273
065
7
066
23
067
14
068
3
069
16
075
700
078
250
079
46
080
43
081
90
082
52
083
209
086
368
089
80
091
2
096
185
097
300
105
78
107
250
108
34
110
28
111
12
112
1000
113
403
114
490
115
30
116
24
117
15
120
36
121
124
123
600
142
650
146
115
147
190
148
286
150
717
151
215
156
479
158
905
166
150
167
1000
169
888
170
84
171
898
172
173
175
230
176
92
177
10
The compounds according to the invention are valuable neurokinin (tachykinin)-antagonists which have both substance P-antagonism and also neurokinin A- or neurokinin B-antagonistic properties. They are useful for the-treatment and prevention of neurokinin-mediated diseases such as respiratory complaints, e.g. asthma, bronchitis, rhinitis, coughs or expectoration as well as inflammatory eye diseases such as conjunctivitis, inflammatory skin diseases such as dermatitis and urticaria, inflammatory intestinal disorders such as ulcerative colitis or Crohn's disease, other inflammatory diseases such as polyarthritis or osteoarthritis and pain (e.g. migraine or vascular headaches) and vomiting.
The invention therefore also relates to the use of the compounds according to the invention as remedies and pharmaceutical preparations which comprise these compounds. They are preferably used in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route or by inhalation, transdermally, optionally with the aid of iontophoresis or enhances known from the literature, and by oral route.
For parenteral use the compounds of formula I or the physiologically acceptable salts thereof, optionally together with conventional subst

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