Neurokinin antagonists, processes for preparing them and...

Details Neurokinin antagonists, processes for preparing them and... Neurokinin antagonists, processes for preparing them and...

2000-05-09

2001-08-21

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S218000, C514S256000, C514S341000, C540S467000, C540S470000, C540S553000, C544S330000, C546S223000

Reexamination Certificate

active

06277840

ABSTRACT:

The invention relates to new guanidine and amidine 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.
The abbreviations used in this specification and claims are explained as follows:
Boc=t-butyloxycarbonyl
DC=thin layer chromatogram
DMF=dimethylformamide
EE=ethyl acetate
FAB-MS fast atom bombardment mass spectroscopy
RT=room temperature
TBTU=O-benzotriazolyl-tetramethyluronium tetrafluoroborate
TEA=triethylamine
THF=tetrahydrofuran
A simplified format is used for the formulae. In the representations of compounds, all CH
3
substituents are indicated by a hyphen, e.g.
denotes
The invention relates to new guanidine and amidine derivatives of general formula I
or the pharmaceutically acceptable salts thereof, wherein
X denotes N−R
3
or CH−R
4
, wherein R
3
denotes
wherein R
5
, R
6
and R
7
independently of one another denote H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, alkanoyl, benzoyl, heteroaryl, dialkylamino, dialkylaminoalkyl, trialkylammoniumalkyl, cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, O-alkyl or O-aryl, wherein the alkyl groups contain 1 to 5 carbon atoms, the cycloalkyl groups contain 3 to 6 carbon atoms, the alkenyl groups,contain 2 to 5 carbon atoms,
aryl denotes phenyl, or phenyl or naphthyl substituted by methyl or halogen (F, Cl, Br, I);
or R
5
and R
6
or R
6
and R
7
together form the group (CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, (CH
2
)
5
— or —(CH
2
)
2
O(CH
2
)
2
;
R
3
denotes
and R
4
denotes
wherein R
5
to R
7
are as hereinbefore defined and R
8
=H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6 carbon atoms or
R
7
+R
8
together form the group —(CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, —(CH
2
)
5
— or —(CH
2
)
2
O(CH
2
)
2
—;
or R
4
denotes
wherein R
5
is as hereinbefore defined;
Y denotes CH
2
or (CH
2
)
2
;
Z denotes C or H
2
;
Ar denotes unsubstituted or mono- to 5-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), 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 one another denote H, methyl or acetyl)] or Ar is phenyl substituted by —OCH
2
O— or —O(CH
2
)
2
O—;
R
1
denotes phenyl(C
1
-
4
)alkyl or phenyl(C
1
-
4
)alkanoyl or naphthyl(C
1
-
4
)alkyl or naphthylacetyl, 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
19
R
20
(wherein R
19
and R
20
independently of one another denote H, methyl or acetyl); and
R
2
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, mainly carboxyl groups, and/or basic groups such as amino functions, for example. Compounds of general formula I may therefore occur as internal salts, 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) or as salts with pharmaceutically acceptable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, etc.
The compounds according to the invention may occur as racemates, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Compounds which occur as racemates or in the (S) form are preferred.
Results of investigations into the compound 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, by measuring the displacement of
125
I-labelled substance P. The K
i
values thus obtained show the efficacy of the compounds.
Example no.
K
i
[nMol/L]
1
0.45
2
0.30
3
0.20
4
0.53
5
6.28
6
0.88
7
1.45
8
0.19
9
0.14
10
0.12
12
0.32
27
1.11
28
4.16
29
0.87
30
0.17
31
8.96
32
0.20
33
13.25
34
0.37
35
0.78
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:
For preventing or treating inflammatory or allergic diseases
of the respiratory tract such as asthma, chronic bronchitis, hyperreactive respiratory tract, emphysema, rhinitis, cough,
of the eyes, such as conjunctivitis and iritis,
of the skin, such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites, itching, sensitive or hypersensitive skin,
of the gastrointestinal tract such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel, Hirschsprung's disease,
of the joints, such as rheumatoid arthritis, reactive arthritis and Reiter syndrome;
for treating diseases of the central nervous system, such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy; Parkinson's disease, stroke,
for treating Herpes zoster and postherpetic pain, tumours, collagenoses, dysfunction of the urinary tract, haemorrhoids, nausea and vomiting, triggered by radiation or cytostatic therapy, for example, or movement and pain of all kinds.
The invention therefore also relates to the use of the compounds according to the invention as curative agents and pharmaceutical preparations which contain 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, by inhalation, by transdermal route, if desired with the aid of iontophoresis or enhancers known from the literature, and by oral route. For parenteral administration the compounds of formula I or the physiologically acceptable salts thereof are brought into solution, suspension or emulsion, optionally with the substances conventionally used for this, such as solubilisers; emulsifiers or other adjuvants. Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propandiol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of different solvents.
Moreover, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
Preferred compounds of general formula 1 are those wherein
X denotes N—R
3
or CH—R
4
, wherein R
3
denotes
wherein R
5
, R
6
and R
7
independently of one another denote H, alkyl, cycloalkyl, aryl, aralkyl, alkanoyl, benzoyl, dialkylamino, dialkylaminoalkyl, trialkylammoniumalkyl, cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, O-alkyl or O-aryl,
wherein the alkyl groups contain 1 to 4 carbon atoms, the cycloalkyl groups contain 3 to 6 carbon atoms, aryl denotes phenyl or phenyl substituted by methyl or halogen (F, Cl, Br, I);
or R
5
and R
6
or R
6
and R
7
together form the group —(CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, —(CH
2
)
5
— or —(CH
2
)
2
O(CH
2
)
2
;
or R
3
is
and R
4
is
wherein R
5
to R
7
are as hereinbefore defined and
R
8
=H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6 carbon atoms or
R
7
+R
8
together form the group —(CH
2
)
2
—, —

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