Arylglycinamide derivatives, methods of producing these...

Details Arylglycinamide derivatives, methods of producing these... Arylglycinamide derivatives, methods of producing these...

2000-02-18

2001-06-26

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S377000, C544S393000, C544S400000

Reexamination Certificate

active

06251909

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to new arylglycinamide derivatives 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.
DETAILED DESCRIPTION OF THE INVENTION
The abbreviations used in the 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
In order to show the formulae, a simplified representation is used. In the representation of the compounds all CH
3
-substituents are represented by a single bond, and for example the following formula
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 di-substituted naphthyl, [in which the substituents of the phenyl and naphthyl independently of each other denote halogen (F, Cl, Br, I), OH, (C
1-4
) alkyl, O—(C
1-4
) alkyl, CF
3
, OCF
3
or NR
9
R
10
(wherein R
9
and R
10
independently of each other denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH
2
O— or —O(CH
2
)
2
O—;
R
1
and R
2
together with the N to which they are bound form a ring of the formula
 wherein
p is 2 or 3,
X denotes oxygen, N(CH
2
)
n
R
6
or CR
7
R
8
, wherein
n is 0, 1 or 2,
R
6
is (C
3-7
)cycloalkyl, phenyl or naphthyl, wherein the phenyl may be mono- to tri-substituted by halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
15
R
16
(wherein R
15
and R
16
independently of each other denote H, methyl or acetyl);
R
7
and R
8
have one of the following meanings:
a) R
7
and R
8
represent H if R
3
is unsubstituted or substituted phenyl,
b) R
7
is phenyl, phenyl 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
or OCF
3
], piperidinyl, 1-methylpiperidinyl,
R
3
denotes H, (C
1-4
)alkyl, unsubstituted or mono- to tri-substituted phenyl, wherein the substituents independently of one another represent halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
17
R
18
(wherein R
17
and R
18
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 are halogen (F, Cl, Br, I), (C
1-4
)alkyl, O—(C
1-4
)alkyl, CF
3
, OCF
3
or NR
19
R
20
(wherein R
19
and R
20
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.
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.
Compounds of general formula I may contain acid groups, chiefly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be obtained either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid or sulphonic acid or organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine or triethanolamine, etc.
The compounds according to the invention may occur as racemates but may also be obtained as pure enantiomers, i.e. in (R)- or (S)-form. They may also occur as diastereoisomers or mixtures thereof.
The preferred compounds of general formula I are those wherein
R
1
and R
2
together with the N to which they are bound form a 6-membered ring of the formula
 wherein
X denotes N(CH
2
)
n
R
6
or CR
7
R
8
,
wherein n, R
6
, R
7
and R
8
are defined as in claim
1
.
Particular mention should be made of compounds of formula I wherein
X is N (CH
2
)
n
R
6
wherein n is 0, 1 or 2 and R
6
is (C
3-7
) cycloalkyl or phenyl, particularly those compounds wherein n is 0 and R
6
is (C
3-7
)cycloalkyl, particularly those compounds wherein R
6
is cyclobutyl or cyclohexyl.
Mention should also be made of compounds of formula I wherein
R
7
and R
8
have one of the following meanings:
a) R
7
and R
8
denote H when R
3
is unsubstituted or substituted phenyl,
b) R
7
is phenyl, piperidinyl
if R
8
is H, —CONH
2
, —NHC(O)CH
3
, —N(CH
3
)C(O)CH
3
or CN,
or
c) R
7
and R
8
together form the group
particularly those wherein
R
7
and R
8
have one of the following meanings:
a) R
7
and R
8
denote H when R
3
is unsubstituted or substituted phenyl,
b) R
7
is phenyl,
 when R
8
is H, —CONH
2
or CN, or
c) R
7
and R
8
together form the group
The preferred compounds are those wherein
R
7
denotes phenyl,
and R
8
is H or CN, particularly those wherein R
7
is pyridino and R
8
is H.
Of the compounds defined above, the preferred ones are those wherein
Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), OH, methyl, methoxy, CF
3
, OCF
3
or dimethylaminel or Ar is phenyl substituted by —OCH
2
O—, this group connecting positions 2 and 3 or 3 and 4 of the phenyl, particularly those wherein
Ar denotes unsubstituted or mono- or di-substituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br), methoxy or CF
3
] or Ar is phenyl substituted by —OCH
2
O—, this group connecting positions 2 and 3 or 3 and 4 of the phenyl.
The preferred compounds are those wherein Ar is phenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl.
Of the compounds defined above, particular mention should be made of those wherein R
3
is phenyl or preferably H.
Of the compounds defined above, mention should also be made of those wherein
R
4
denotes phenyl(C
1-3
)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, the substituents independently of one another being halogen (F, Cl, Br, I), methyl, methoxy, CF
3
or OCF
3
; and
R
5
denotes H, (C
1-3
)alkyl, CH
2
COOH, —CH
2
C(O)NH
2
or phenethyl,
particularly those compounds wherein
and R
5
denotes H or CH
3
.
The following compounds are preferred:
The term naphthyl used above includes both 1-naphthyl and 2-naphthyl.
Test results for compounds according to the invention:
The receptor affinity for the NK
1
-receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK
1
-receptors, measuring the displacement of
125
I-labelled substance P. The K
i
-values thus obtained demonstrate the efficacy of the compounds:
K
i
Compound of Example 3:
1.4 nM
Compound of Example 4:
1.0 nM
Compound of Example 5:
1.3 nM
Compound of Example 33:
1.3 nM
Compound of Example 45:
1.6 nM
Compound of Example 46:
1.4 nM
Compound of Example 52:
1.1 nM
Compound of Example 53:
2.3 nM
Compound of Example 58:
6.4 nM
Compound of Example 59:
4.2 nM
Compound of Example 65:
9.2 nM
Compound of Example 66:
1.4 nM
Compound of Example 68:
1.5 nM
Compound of Example 70:
2.8 nM
Compound of Example 71:
2.1 nM
Compound of Example 72:
6.8 nM
Compound of Example 73:
1.7 nM
Compound of Example 74:
11.8 nM 
Compound of Example 75:
180 nM 
Compound of Example 76:
7.0 nM
The compounds according to the invention are v

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