Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-10-02
2002-11-05
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C558S393000
Reexamination Certificate
active
06476077
ABSTRACT:
BACKGROUND
The mammalian neurokinins comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems. The three principal neurokinins are Substance P(SP), Neurokinin A(NKA) and Neurokinin B(NKB). There are also N-terminally extended forms of at least NKA. At least three receptor types are known for the three principal neurokinins. Based upon their relative selectivities favoring the neurokinin agonists SP, NKA and NKB, the receptors are classified as neurokinin 1 (NK
1
), neurokinin 2 (NK
2
) and neurokinin 3 (NK
3
) receptors, respectively. In the periphery, SP and NKA are localized in C-afferent sensory neurons, which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers. C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics. The effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells. Thus, the tachykinins are implicated in the pathophysiology and airway hyperresponsiveness observed in asthmatics; and blockade of the action of released tachykinins may be useful in the treatment of asthma and related conditions.
SUMMARY OF THE INVENTION
This invention relates to naphthalenecarboxamide compounds N-substituted by an aminobutyl group, to pharmaceutical compositions containing such compounds, as well as to their uses and processes for their preparation. These compounds antagonize the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins, particularly at the neurokinin 1 (NK1) receptor. These compounds are useful whenever such antagonism is desired. Thus, such compounds are of value in the treatment of those diseases in which Substance P is implicated, for example, in the treatment of asthma, anxiety, depression, emesis and related conditions.
The N-substituted naphthalenecarboxamide compounds of the present invention show a high degree of NK1 receptor antagonist activity.
DETAILED DESCRIPTION
Accordingly the present invention provides the compounds of the formula (I):
R
1
R
2
N—CH
2
CH
2
—CHAr
1
—CH
2
—NR
3
—CO—R
4
(I)
wherein:
R
1
is hydrogen, C
1-6
alkyl, C
2-6
alkenyl, aryl, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl or arylcarbonyl;
any of such groups being optionally substituted;
R
2
is hydrogen or C
1-6
alkyl; or
R
1
or R
2
are joined to form an optionally substituted morpholino ring;
Ar
1
is phenyl mono- or di-substituted by halo;
R
3
is hydrogen or C
1-6
alkyl;
R
4
is optionally substituted naphth-1-yl;
and pharmaceutically acceptable salts thereof.
When R
1
is optionally substituted C
2-6
alkyl (for example ethyl or propyl), C
2-6
alkenyl (for example propenyl), C
1-6
alkoxycarbonyl (for example methoxycarbonyl or ethoxycarbonyl) and C
1-6
alkanoyl (for example acetyl or propionyl), suitable substituents include halo for example chloro, bromo or fluoro; nitro; cyano; hydroxy; C
1-6
alkoxy for example methoxy or ethoxy; amino; C
1-6
alkylamino for example methylamino or ethylamino; di-C
1-6
alkylamino for example dimethylamino; trifluoromethyl; carboxy; carbamoyl (NH
2
CO—); C
1-6
alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C
1-6
alkylcarbamoyl for example dimethyl-carbamoyl; C
1-6
alkanoyl for example acetyl; mercapto; C
1-6
alkylthio for example methylthio or ethylthio; C
1-6
alkylsulphinyl for example methylsulphinyl or ethylsulphinyl; C
1-6
alkylsulphonyl for example methylsulphonyl or ethylsulphonyl; sulphamoyl; C
1-6
alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; C
3-8
cycloalkyl for example cyclopropyl, cyclopentyl or cyclohexyl; cyclobutyl, aryl; or heteroaryl.
When R
1
is substituted methyl, suitable substituents are C
3-8
cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; aryl; or heteroaryl.
When R
1
is substituted aryl or arylcarbonyl (or when R
1
and R
2
together with the nitrogen atom to which they are joined form a morpholino ring) suitable substituents include those substituents mentioned hereinabove (for other values of R
1
), as well as C
1-6
alkyl for example methyl or ethyl, C
2-6
alkenyl for example allyl or vinyl; or C
2-6
alkynyl for example ethynyl.
“Aryl” in the terms “aryl” and “arylcarbonyl” means phenyl and naphthyl.
Preferably R
1
is hydrogen, C
1-6
alkyl optionally substituted by phenyl, C
2-6
alkenyl, phenyl or benzoyl.
In particular R
1
is hydrogen, methyl, ethyl, n-propyl, isopropyl, propen-2-yl, phenyl or benzoyl.
Preferably R
2
is hydrogen or methyl.
In a particularly preferred aspect R
1
is methyl or ethyl and R
2
is hydrogen or methyl, for example R
1
R
2
N— is methylamino.
In another preferred aspect R
1
and R
2
together with the nitrogen atom to which they are attached form a morpholino ring.
Favourably Ar
1
is phenyl di-substituted by chloro, for example Ar
1
is 3,4-dichlorophenyl.
R
3
is hydrogen or C
1-6
alkyl for example methyl, ethyl or n-propyl. Preferably R
3
is methyl.
R
4
is optionally substituted naphth-1-yl. Suitable substituents, which are optional, for the naphth-1-yl group include hydroxy; cyano; nitro; trifluoromethoxy; trifluoromethyl; C
1-6
alkylsulfonyl for example methylsulphonyl; halo for example chloro, bromo, fluoro or iodo; C
1-6
alkoxy for example methoxy, ethoxy or propoxy; methylenedioxy (—OCH
2
O—), C
1-6
alkyl for example methyl or ethyl; C
2-6
alkenyl for example ethenyl, prop-1-enyl or prop-2-enyl; C
2-6
alkynyl for example ethynyl; carboxy, C
1-6
alkoxy-carbonyl for example methoxycarbonyl; carbamoyl; C
1-6
alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; di-C
1-6
alkylcarbamoyl for example di-methylcarbamoyl; C
1-6
alkanoyl for example acetyl or propionyl; C
1-6
alkanoylamino for example acetylamino or propionylamino; aminosulfonyl; and C
1-6
alkyl for example methyl substituted by any of the hereinabove substituents.
Favourably the naphth-1-yl group is unsubstituted or is substituted by up to three substituents. Preferred substituents for the naphth-1-yl group include cyano; nitro; C
1-6
alkylsulfonyl for example methylsulphonyl; halo for example chloro, bromo, fluoro or iodo; C
1-6
alkoxy for example methoxy, ethoxy, n-propoxy or isopropoxy; methylenedioxy (—OCH
2
O—); C
1-6
alkyl for example methyl or ethyl; C
2-6
alkenyl for example prop-2-enyl; C
2-6
alkynyl for example ethynyl; carboxy, carbamoyl; C
1-6
alkyl-carbamoyl for example methylcarbamoyl; di-C
1-6
alkylcarbamoyl for example di-methylcarbamoyl; C
1-6
alkanoyl for example acetyl; C
1-6
alkanoylamino for example acetylamino; aminosulfonyl; and cyano C
1-6
alkyl for example cyanomethyl.
More preferred substitutents for the naphth-1-yl group are cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyl and acetylamino.
In particular the naphth-1-yl group may be substituted by up to two substituents selected from cyano, methoxy, ethyl, fluoro and nitro. A particularly preferred substitution pattern for the naphth-1-yl group is 3-cyano. A further particularly preferred substitution pattern is 3-cyano, 2-methoxy. Another particularly preferred substitution pattern is 2,3-dimethoxy. Another particularly preferred substitution pattern is 3-cyano, 2-ethyl.
The compounds of the present invention possess a chiral centre, at —CHAr
1
— and possibly in the optional substituents. The present invention covers all isomers, diastereoisomers and mixtures thereof that antagonise NK1 receptors.
The preferred configuration at —CHAr
1
— is shown in formula (Ia) hereinbelow:
Thus a preferred class of compounds of the present invention is that of the formula (Ia) wherein R
1
is hydrogen, methyl or ethyl; R
2
is hydrogen or methyl; R
3
is methyl; Ar
1
is 3
Astrazeneca AB
McKane Joseph K.
Mitchell Kenneth F.
Shameem Golam M. M.
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