Arylglycinamide derivatives, method of producing said...

Details Arylglycinamide derivatives, method of producing said... Arylglycinamide derivatives, method of producing said...

2000-11-01

2002-12-24

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S252020, C514S252110, C514S252140, C514S253010, C514S254010, C514S255020, C514S255040, C544S121000, C544S238000, C544S295000, C544S357000, C544S360000, C544S372000, C544S377000, C544S382000, C544S384000, C544S400000

Reexamination Certificate

active

06498162

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to new arylglycinamide derivatives of general formula
and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
The abbreviations used in this specification and claims are explained as follows:
CDI=Carbonyldiimidazole
DCCI=Dicyclohexylcarbodiimide
HOBt=1-Hydroxybenzotriazole
THF=Tetrahydrofuran
DMF=Dimethylformamide
RT=Room temperature
DMAP=4-Dimethylaminopyridine
TBTU=O-Benzotriazolyl-tetramethyluronium-tetrafluoroborate
The formulae are shown in simplified form. In representing the compounds, for example, all the CH
3
-substituents are represented by a hyphen and CH is represented by , thus, for example:
denotes
The invention relates to new arylglycinamide derivatives of general formula I
or the pharmaceutically acceptable salts thereof, wherein
Ar denotes unsubstituted or mono- to penta-substituted phenyl, or unsubstituted or mono- or disubstituted naphthyl [wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
12
R
13
(wherein R
12
and R
13
independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —O—CH
2
—O—or —O—(CH
2
)
2
—O—;
R
1
and R
2
together with the N to which they are bound denote a ring of the formula
or
wherein
r, s and t are 2 or 3;
R
6
denotes
H.
(C
1-5
)alkyl,
(C
3-5
)alkenyl
propynyl,
hydroxy (C
2-4
)alkyl,
methoxy(C
2-4
)alkyl,
di (C
1-3
)alkylamino (C
2-4
)alkyl,
amino (C
2-4
)alkyl,
amino,
di(C
1-3
)alkylamino,
monofluoro- to perfluoro(C
1-2
)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl,
pyrazinyl,
pyridazinyl
or the group —CH
2
—C(O)NR
14
R
15
,
wherein
R
14
is H or (C
1-4
)alkyl and
R
15
is H, (C
1-4
)alkyl, (C
3-6
)cycloalkyl, hydroxy(C
2-4
)alkyl, alkoxy(C
2-3
)alkyl, phenyl(C
1-4
)alkyl, or R
14
and R
15
together with the N to which they are bound form a ring (1-pyrrolidinyl, piperidino, morpholino or 1-methylpiperazin-4-yl);
R
7
has one of the definitions (a) to (d),
(a) hydroxy
(b) 4-piperidinopiperidyl,
(c)
wherein R
16
and R
17
independently of one another denote
H,
(C
1-4
)alkyl,
(C
3-6
)cycloalkyl,
hydroxy (C
2-4
)alkyl,
(C
1-3
) alkoxy(C
2-4
)alkyl,
phenyl(C
1-4
)alkyl or
di(C
1-3
)alkylamino(C
2-4
)alkyl,
or if R
16
is H or (C
1-4
)alkyl,
R
17
may also be —CH
2
C(O)NR
18
R
19
, wherein R
18
and R
19
are defined as R
14
and R
15
hereinbefore;
(d)
wherein R
20
denotes
H,
(C
1-4
)alkyl,
(C
4-6
)cycloalkyl or
—CH
2
C(O)NR
21
R
22
,
wherein R
21
and R
22
are defined as R
14
and R
15
hereinbefore;
R
8
is H
R
9
and R
10
independently of each other denote (C
1-4
)alkyl;
R
11
denotes
H,
(C
1-5
)alkyl,
(C
3-5
)alkenyl,
propynyl,
hydroxy(C
2-4
)alkyl,
methoxy(C
2-3
)alkyl,
di (C
1-3
)alkylamino (C
2-3
)alkyl,
amino(C
2-3
)alkyl,
amino,
di(C
1-3
)alkylamino,
monofluoro- to perfluoro (C
1-2
)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl,
pyrazinyl,
pyridazinyl
or the group —CH
2
—C(O)NR
23
R
24
,
wherein R
23
and R
24
are defined as R
14
and R
15
hereinbefore;
R
3
denotes H, (C
1-4
)alkyl, unsubstituted or mono- to trisubstituted phenyl, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
25
R
26
(wherein R
25
and R
26
independently of one another denote H, methyl or acetyl);
R
4
denotes phenyl(C
1-4
)alkyl or naphthyl(C
1-4
)alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
27
R
28
(wherein R
27
and R
28
independently of one another denote H, methyl or acetyl); and
R
5
denotes H, (C
1-4
)alkyl, (C
3-6
)cycloalkyl, CH
2
COOH, CH
2
C(O)NH
2
, OH or phenyl(C
1-4
)alkyl.
Preferred compounds of general formula I are those wherein
Ar denotes unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl, or Ar is phenyl substituted by —O—CH
2
—O— or —O—(CH
2
)
2
—O—;
R
1
and R
2
together with the N to which they are bound denote a ring of the formula
or
wherein
r is 2 or 3 and
s and t are 2;
R
6
, R
7
, R
8
, R
9
, R
10
and R
11
are as hereinbefore defined;
R
3
is H or (C
1-4
)alkyl,
R
4
denotes phenyl(C
1-4
)alkyl or naphthyl(C
1-4
)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another are halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
or OCF
3
; and
R
5
denotes H, (C
1-4
)alkyl, (C
3-6
)cycloalkyl, OH or (C
1-4
)alkylphenyl.
Particular mention should be made of compounds of formula I wherein
Ar is unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), methyl, methoxy, CF
3
or OCF
3
] or Ar is phenyl substituted by —O—CH
2
—O— or —O—(CH
2
)
2
—O—;
particularly those wherein Ar is phenyl, naphthyl, phenyl substituted in position 3 and/or 4 by methoxy or halogen, or phenyl in which positions 2 and 3 or 3 and 4 are linked by —O—CH
2
—O—, preferably those compounds wherein
Ar is phenyl,
phenyl substituted by methoxy in positions 3 and 4 or phenyl wherein positions 3 and 4 or 2 and 3 are linked by —O—CH
2
—O—.
Of the compounds defined above, special mention should be made of those wherein, in the ring
r is 2 or 3 and
R
6
denotes
H,
(C
1-5
)alkyl,
(C
3-5
)alkenyl,
propynyl,
hydroxy (C
2-4
)alkyl,
methoxy (C
2-4
)alkyl,
di(C
1-3
)alkylamino(C
2-4
)alkyl,
amino (C
2-4
)alkyl,
amino,
di(C
1-3
)alkylamino,
monofluoro- to perfluoro(C
1-2
)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl, or
particularly those wherein
r is 3 and R
6
is methyl;
and those wherein
r is 2 and
R
6
is
H,
(C
1-4
)alkyl,
propenyl,
propynyl,
hydroxy (C
2-3
)alkyl,
methoxyethyl,
di(C
1-2
)alkylamino (C
2-3
)alkyl,
aminoethyl,
amino,
dimethylamino,
CH
2
CF
3
,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl, or
preferably those wherein
r is 2 and
R
6
is H, (C
1-3
)alkyl, allyl, 2-propynyl, —CH
2
CH
2
OCH
3
, —CH
2
CH
2
N(CH
3
)
2
, N-methylpiperidinyl, 2-pyrimidinyl or
r is 2 and
R
6
is H, CH
3,
C
3
H
7,
CH(CH
3
)
2
, CH
2
CH
2
OH, CH
2
CH
2
OCH
3
or CH
2
CH
2
N (CH
3
)
2
.
Of the compounds defined above, mention should also be made of those wherein R
1
and R
2
together with the N to which they are bound form the ring
wherein R
8
is H and
R
7
is OH
wherein R
16
and R
17
independently of one another denote:
H
(C
1-3
)alkyl,
(CH
2
)
n
OH wherein n is 2, 3 or 4
(CH
2
)
2
OCH
3
—(CH
2
)
n
Ph wherein n is 2 or 4
(CH
2
)
2
N(CH
3
)
2
particularly those wherein
R
16
and R
17
are both CH
3
or C
2
H
5
or
R
16
is H or CH
3
and R
17
is (C
1-3
)alkyl,
(CH
2
)
2
OH,
(CH
2
)
4
OH or
and those wherein
R
7
denotes
especially those wherein
R
1
and R
2
together with the N to which they are bound form the ring
 wherein
(a) R
8
is H and
R
7
is
wherein R
16
and R
17
both represent CH
3
, C
2
H
5
or CH
2
CH
2
OH or R
16
is H or CH
3
and R
17
is (C
1-3
)alkyl,
(CH
2
)
2
OH or
(CH
2
)
4
OH or
(b) R
8
is H and R
7
denotes
Of the compounds defined above, mention should also be made of those wherein
R
1
and R
2
together with the N to which they are bound form the ring
Of the compounds defined above, special mention should also be made of those wherein
R
1
and R
2
together with the N to which they are bound form the ring
wherein R
11
is H or (C
1-3
)alkyl, particularly those wherein
R
11
is —CH(CH
3
)
2
Of the compounds defined above, the ones of particular interest are those wherein R
3
is H; and/or
R
4
denotes phenyl(C
1-4
)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
or OCF
3
; and/or
R
5
denotes H, (C
1-4
)alkyl, (C
3

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