Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-30
2002-12-31
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S187000, C546S188000, C546S205000, C546S206000, C546S197000, C544S003000, C544S008000, C544S332000, C540S492000, C540S524000, C540S544000, C540S545000, C514S211080, C514S212080, C514S218000, C514S316000, C514S319000, C514S321000, C514S222500, C514S222200, C514S274000
Reexamination Certificate
active
06500818
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. A cyclopeptide antagonist (FK-224) selective for both NK
1
and NK
2
receptors has demonstrated clinical efficacy in human patients suffering from asthma and chronic bronchitis. M. Ichinose, et al.,
Lancet,
1992, 340, 1248.
DESCRIPTION
This invention relates to naphthalenecarboxamide compounds N-substituted by an 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 neurokinin 1 (NK
1
) and the neurokinin 2 (NK
2
) 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 N-substituted naphthalenecarboxamide compounds of the present invention show a high degree of both NK
1
and/or NK
2
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 NK
1
and NK
2
receptors can be modified as desired, affording compounds that are predominantly active at either NK
1
or NK
2
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 NK
1
and/or NK
2
antagonism upon oral administration.
Accordingly, the present invention provides the compounds of the general formula (I):
wherein:
R
1
, in one respect, has the formula
wherein R
7
is as defined below to give general formula (Ia).
R
2
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
3
is hydrogen or C
1-6
alkyl for example methyl, ethyl, n-propyl or cyclopropyl. Preferably, R
3
is methyl.
R
4
, R
5
and R
6
are each, independently, 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; C
1-6
alkyl for example methyl or ethyl; cyanoC
1-6
alkyl for example cyanomethyl; 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
alkoxycarbonyl 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 substituted C
1-6
alkyl for example methyl substituted by any of the hereinabove substituents. Additionally, R
6
may be hydrogen.
Favourably, R
4
is C
1-6
alkyl for example methyl or ethyl; C
1-6
alkoxy for example methoxy or ethoxy; or halo for example fluoro, chloro, bromo or iodo. Preferably, R
4
is methyl, ethyl, methoxy, ethoxy or fluoro. More preferably, R
4
is methoxy or ethyl, most preferably, methoxy.
Preferably, R
5
is cyano or nitro; more preferably, R
5
is cyano.
Preferably, R
6
is hydrogen, methoxy, cyano or nitro.
R
7
is —CH
2
CH
2
—, —CH
2
CH
2
CH
2
— or —CH
2
CH
2
CH
2
CH
2
—.
M is —C(═O)— or —S(═O)
2
—.
L is NH or CH
2
.
The compounds of the present invention possess a number of chiral centres, at —CH(Ph-X
1
,X
2
)—, and possibly in the optional substituents (for example the MeSO— substituent) on either (or both) of the phenyl and naphth-1-yl groups. The present invention covers all isomers, diastereoisomers and mixtures thereof that antagonise NK
1
and/or NK
2
.
The preferred configuration at —CH(Ph-X
1
,X
2
)— is shown in formula (Ib) hereinbelow:
X
1
and X
2
are independently hydrogen or halo, provided that at least one of X
1
or X
2
is halo. Favourably, X
1
and X
2
are both chloro. In a preferred aspect Ph-X
1
,X
2
is 3,4-dichlorophenyl.
R
2
is hydrogen; hydroxy; C
1-6
alkoxy for example methoxy or ethoxy; C
1-6
alkanoyloxy for example acetyloxy or propionyloxy; C
1-6
alkanoyl for example acethyl or propionyl; C
1-6
alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; C
1-6
alkanoylamino for example acetylamino; C
1-6
alkyl for example metrhyl or ethyl; carbamoyl; C
1-6
alkylcarbamoyI for example methylcarbamoyl or ethylcarbamoyl or di-C
1-6
alkylcarbamoyl for example dimethylcarbamoyl.
Preferably, R
2
is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. More preferably R
2
is hydrogen or methylcarbamoyl.
A preferred class of compounds is that of the formula (II):
wherein R
3
is as hereinbefore defined and R
4
—R
6
are selected from hydrogen, cyano, nitro, methoxy, methyl, ethyl and fluoro.
The most preferred structure is
Particular compounds of this invention are provided as the Examples hereinbelow. C
Y
-
Z
alkyl, unless otherwise specified, means an alkyl chain containing a minimum Y total carbon atoms and a maximum Z total carbon atoms. These alkyl chains may be branched or unbranched, cyclic, acyclic or a combination of cyclic and acyclic. For example, the following substituents would be included in the general description “C
4
-
7
alkyl”:
Pharmaceutically-acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
The compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithi
Bernstein Peter Robert
Dedinas Robert Frank
Ohnmacht Cyrus John
Russell Keith
Astrazeneca AB
Berch Mark L.
Habte Kahsay
Mitchell Kenneth F.
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