Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-07
2002-06-11
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S327000, C546S188000, C544S316000
Reexamination Certificate
active
06403601
ABSTRACT:
This invention relates to tetrahydronaphthalenecarboxamide compounds N-substituted by a substituted piperidinylbutyl 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 neurokinin1 (NK1) and the neurokinin 2 (NK2) receptors. 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 and Neurokinin A are implicated, for example, in the treatment of asthma, anxiety, depression, emesis, urinary incontinence and related conditions.
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 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) 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. A cyclopeptide antagonist (FK-224) selective for both NK1 and NK2 receptors has demonstrated clinical efficacy in human patients suffering from asthma and chronic bronchitis. M. Ichinose, et al.,
Lancet
, 1992, 340, 1248.
In particular the N-substituted tetrahydronaphthalenecarboxamide compounds of the present invention show a high degree of NK1 and/or mixed NK1/NK2 receptor antagonist activity. Additionally, by manipulation of the substituents on the naphthalene and piperidine rings of the formula (I), the ratio of activity at the NK1 and NK2 receptors can be modified as desired, affording compounds that are predominantly active at NK1 receptors or affording compounds with a balanced activity and, as such, are particularly useful when combined antagonism of both receptors is desired. In particular, the compounds of the present invention also possess a high degree of NK1 and/or mixed NK1/NK2 antagonism upon oral administration.
Accordingly the present invention provides the compounds of the formula (I):
wherein:
R is hydrogen, hydroxy, C
1-6
alkoxy, C
1-6
alkanoyloxy, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl, C
1-6
alkanoylamino, C
1-6
alkyl, carbamoyl, C
1-6
alkylcarbamoyl or di-C
1-6
alkylcarbamoyl;
R
1
is a phenyl group substituted in the ortho position by C
1-6
alkylthio, C
1-6
alkyl-sulfinyl, C
1-6
alkylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, C
1-6
alkane-sulfonamido, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl, succinamido, carbamoyl, C
1-6
alkyl-carbamoyl, di-C
1-6
alkylcarbamoyl, C
1-6
alkoxy-C
1-6
alkylcarbamoyl, C
1-6
alkanoylamino, ureido, C
1-6
ureido, di-C
1-6
alkylureido, amino, C
1-6
alkylamino or di-C
1-6
alkylamino, which phenyl group optionally may bear further substituents;
or R
1
is a group of the formula (1a):
wherein Z is NH or CH
2
.
R
2
is an optionally substituted 5,6,7,8-tetrahydronaphth-1-yl group and X
1
and X
2
are independently hydrogen or halo, provided that at least one of X
1
or X
2
is halo; and pharmaceutically acceptable salts thereof.
Suitable further substituents, which are optional, for R
1
when it is an ortho-substituted phenyl ring include C
1-6
alkylthio for example methylthio or ethylthio; C
1-6
alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propoxysulfinyl; C
1-6
alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; carboxy; C
1-6
alkoxycarbonyl for example methoxycarbonyl; C
1-6
alkanoyl for example acetyl or propionyl; nitro; amino; C
1-6
alkylamino for example methylamino or ethylamino; di-C
1-6
alkylamino where the alkyl groups may be the same or different, for example dimethylamino; trifluoromethyl; CF
3
S(O)
x
wherein x is 0, 1 or 2, for example trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; C
1-6
alkanoylamino for example acetylamino or propionylamino; C
1-6
alkalkylsulphonamido for example methylsulphonamido; ureido; C
1-6
alkylureido for example methylureido (MeNHCONH—), di-C
1-6
alkylureido for example dimethylureido (Mc,NCONH—); carbamoyl; C
1-6
alkylcarbamoyl for example methylcarbamoyl; di-C
1-6
alkylcarbamoyl where the alkyl groups may be the same or different, for example dimethylcarbamoyl; and C
1-6
alkyl for example methyl substituted by any of the hereinabove substituents.
Suitable substituents, which are optional, for the 5,6,7,8-tetrahydronaphth-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.
When R
1
is a phenyl ring it is ortho-substituted by C
1-6
alkylthio for example methylthio; C
1-6
alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C
1-6
alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C
1-6
alkanesulfonamido for example methanesulfonamido; C
1-6
alkanoyl for example acetyl or propionyl; C
1-6
alkoxy-carbonyl for example methoxycarbonyl; succinamido; carbamoyl; C
1-6
alkylcarbamoyl for example methylcarbamoyl; di-C
1-6
alkylcarbamoyl for example dimethylcarbamoyl; C
1-6
alkoxy-C
1-6
alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C
1-6
alkanoylamino for example acetylamino; ureido, C
1-6
ureido for example methylureido; di-C
1-6
alkylureido for example dimethylureido; amino; C
1-6
alkylamino for example methylamino or ethylamino; or di-C
1-6
alkylamino for example dimethylamino.
Preferred values for the ortho-substituent are methylsulfinyl, ethylsulfinyl, propylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, methanesulfonamido, acetyl, methoxycarbonyl, succinamido, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, N-methoxy, N-methylcarbamoyl, acetylarnino, ureido, methylureido, dimethylureido, amino, methylamino or dimethylamino.
In particular the ortho-substituent is methylsulfinyl, methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino. Of these methylsulfinyl is particularly preferred.
Favourably the ortho-substituted phenyl ring is not substituted further or is substituted by up to three optional substituents. In particular the ortho-substituted phenyl ring is not substituted further or is substituted at the 4-position, that is the position para- to the bond with the piperidine ring, so forming a 2, 4-disubstituted
Astrazeneca AB
Ford John M.
Mitchell Kenneth F.
LandOfFree
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