Acylaminoalkenylene-amide derivatives as NK1 and NK2...

Details Acylaminoalkenylene-amide derivatives as NK1 and NK2... Acylaminoalkenylene-amide derivatives as NK1 and NK2...

2000-09-05

2001-11-20

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S524000, C548S495000, C564S152000

Reexamination Certificate

active

06319917

ABSTRACT:

The invention relates to the compounds of formula I
wherein
R is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy,
R
1
is hydrogen or lower alkyl,
R
2
is hydrogen, lower alkyl or phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy,
R
3
is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, lower alkyl, trifluoromethyl, hydroxy and lower alkoxy; or is naphthyl, 1H-indol-3-yl or 1-lower alkyl-indol-3-yl,
R
4
′ and R
4
″ are each independently of the other hydrogen or lower alkyl, at least one of the radicals R
4
′ and R
4
″ being hydrogen, and
R
5
is C
3
-C
8
cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl; and salts thereof, to processes for the preparation of those compounds, to pharmaceutical compositions comprising those compounds, to the use of those compounds in the therapeutic treatment of the human or animal body or in the manufacture of pharmaceutical compositions.
The general terms used hereinabove and hereinbelow preferably have the following meanings within the scope of this Application:
The term “lower” denotes a radical having up to and including 7 and especially up to and including 4 carbon atoms.
Lower alkyl is, for example, C
1
-C
7
alkyl, preferably C
1
-C
4
alkyl, especially methyl and ethyl, and more especially methyl. Examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and n-heptyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine.
Halophenyl is, for example, (fluoro-, chloro-, bromo- or iodo-)phenyl, preferably fluorophenyl or chlorophenyl, especially 4-fluorophenyl or 4-chlorophenyl, and more especially 4-chlorophenyl.
Dihalophenyl is, for example, dichlorophenyl, difluorophenyl or chlorofluorophenyl, preferably dichlorophenyl or difluorophenyl, especially 3,4-dichlorophenyl or 3,4-difluorophenyl, and more especially 3,4-dichlorophenyl.
Trihalophenyl is, for example, trifluorophenyl or trichlorophenyl.
1-Lower alkyl-indol-3-yl is, for example, 1-methyl-indol-3-yl.
C
3
-C
8
Cycloalkyl—and analogously C
5
-C
7
cycloalkyl—is in each case a cycloalkyl radical having the number of ring carbon atoms indicated. C
3
-C
8
Cycloalkyl is therefore, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclohexyl.
D-Azacycloheptan-2-on-3-yl corresponds to the following group
which is derived from D(+)-epsilon-caprolactam (amino-)substituted in the 3-position [≈D-3-amino-epsilon-caprolactam=(R)-3-amino-hexahydro-2-azepinone]. Analogously, L-aza-cycloheptan-2-on-3-yl corresponds to the group
which is derived from L(−)-epsilon-caprolactam (amino-)substituted in the 3-position [≈L-3-amino-epsilon-caprolactam=(S)-3-amino-hexahydro-2-azepinone].
Salts of compounds of formula I are especially pharmaceutically acceptable salts. Compounds of formula I having a basic group may, for example, form acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates.
Where the compounds of formula I contain an acid group, corresponding salts with bases are also possible, for example corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or organic amines, for example ammonium salts.
The compounds of formula I have valuable pharmacological properties. In particular, they act as neurokinin antagonists (NK antagonists) and are therefore capable of preventing disease symptoms that are caused inter alia by the production of substance P (NK1 receptor) and neurokinin A [=NKA] (NK2 receptor).
The respiratory tract is equipped with sensory nerves that contain a number of neuropeptides, especially tachykinins and CGRP (=calcitonin gene-related peptide). The activation of the sensory nerves results in a local release of neuropeptides inside the lungs. More especially substance P and neurokinin A are produced, which trigger an acute inflammatory reaction termed neurogenic inflammation. That inflammatory reaction proceeds mainly via NK1 receptor activation and includes especially vasodilatation, microvascular leakage, recruitment of inflammatory leukocytes and excessive secretion of mucus, and also bronchoconstriction [mainly via activation of the neurokinin 2 receptor (NK2 receptor)]. Those tachykinin effects are typical features of asthma.
The pharmacological action of the compounds of formula I is based especially on the antagonisation of the NK1 receptor and additionally generally also on the antagonisation of the NK2 receptor. The compounds of formula I are therefore capable of inhibiting neurogenic inflammation and tachykinin-induced bronchoconstriction.
The advantageous effects of the compounds of formula I can be demonstrated by various in vitro or in vivo test methods. For example, in vitro they inhibit the [beta-Ala8]NKA(4-10)-induced Ca
2+
influx into ovarian cells of transfected Chinese hamsters, which express recombinant human neurokinin 2 receptors, with IC
50
values from about 10 nM. Furthermore, in an NK-2 binding assay, in which they are tested for their ability to inhibit the binding of
125
I-NKA to hrNK2CHO cells [culture conditions and cell isolation for hrNK2CHO cells, see N. Subramanian et al., Biochem. Biophys. Req. Comm. 200 (1994) 1512-1520], they exhibit IC
50
values from about 1 nM. In addition, they are effective, for example, in vivo in the NK1 bronchospasm test in guinea pigs with ED
50
values of about 0.05-1 mg/kg p.o., the test compounds being given 2, 4, 12 or 24 hours prior to the intravenous administration of 3.0 &mgr;g/kg of [Sar9,Met(O2)11]-substance P[=SarSP]. The challenge by SarSP induces an increase in intratracheal pressure in the guinea pigs. Furthermore, some of the compounds of formula I are effective p.o. also in the in vivo NK2 bronchospasm test in guinea pigs. In that case the increase in intratracheal pressure is induced by intravenous administration of 0.8 &mgr;g/kg of [beta-Ala8]NKA(4-10), the test compounds being administered, for example, 2 hours prior to the challenge.
The compounds of formula I are effective especially as antagonists of NK1 receptors. Their action on that class of receptors and their action on related receptor systems, for example NK2, render the compounds of formula I therapeutically useful in the prevention, the treatment or the diagnosis of a number of diseases, for example diseases of the upper and lower respiratory tract, for example bronchial asthma, allergic asthma, non-allergic asthma, allergic hypersensitivity and hypersecretion conditions, such as chronic bronchitis and cystic fibrosis; pulmonary fibrosis of various aetiologies; diseases of the pulmonary and bronchial circulation, such as pulmonary high blood pressure, angiogenesis, metastases; diseases of the gastrointestinal tract, such as Crohn's disease, Hirsprung's disease, diarrhoea, mal-absorption conditions, inflammatory conditions; in affective, traumatic or inflammatory disorders of the central and peripheral nervous system, such as depression, anxiety states, migraine and other forms of cranial pain, strokes, emesis; diseases of the blood vessels, such as the cranial vessels; diseases relating to the microcirculation in various tissues, such as the skin and eyes; diseases of the immune system and of the reticulohistiocytary system, such as in the splenic and lymphatic tissues; conditions of pain and other disorders in which the action of neurokinins, tachykinins or other related substances are involved in the pathogenesis, pathology an

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