Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-04-08
2003-12-30
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S478000, C514S507000, C514S520000, C514S522000, C514S535000, C514S598000, C514S616000, C514S538000, C514S623000, C514S624000, C558S411000, C558S415000, C560S024000, C560S027000, C560S042000, C560S312000, C564S048000, C564S050000, C564S051000, C564S052000, C564S155000, C564S185000, C564S184000, C564S188000
Reexamination Certificate
active
06670400
ABSTRACT:
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is very important in the etiology and treatment of numerous medical problems (R. A. Glennon,
J. Med. Chem
., 30, 1 [1987]). Many 5-HT receptors have already been identified and represent interesting objects for the selective handling of the serotoninergic function. The subtype 5-HT
1A
is especially interesting to the extent that compounds acting on this receptor may be used in the treatment of anxiety, depression, sleeping problems or cardiovascular problems (Brain 5-HT
1A
receptors: Behavioural and Neurochemical Pharmacology; Editors: C. T. Dourish, S. Ahlenius, P. H. Huston; Ellis Horwood, Ltd., Chichester [1987]). The 5-HT
1A
counteracting agents can likewise be used as anti-emetics (U. Wells, M. Ravenscroft, P. Bhandari, P. L. R. Andrews,
Med. Sci. Symp., Ser
. 5, 179 [1993]); F. Okada, Y. Torii, H. Saito, N. Matsuki,
Jpn. J. Pharmacol
., 64,109 [1994]), or as anti-secretion agents (J. S. Gidda, J. M. Schaus, EP 455,510 A2; D. C. Evans, J. S. Gidda,
Gastroenterology
, 104, A76 [1993]).
The present invention concerns new derivatives of phenoxyethylamine having a high affinity for the 5-HT
1A
receptors, procedures for their preparation, pharmaceutical compounds comprising them, and their use especially as secretion inhibitors for gastric acid or as anti-emetics.
Object of the invention are also products of general formula I:
in which:
Ar represents a phenyl substituted by one or more substitutes;
R represents a hydrocarbonated radical containing 1 to 10 carbon atoms chosen from among the alkyl, alkenyl, linear or branched alkynyl radicals, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl, monocyclic or polycyclic radicals, saturated or unsaturated;
the pyridyl or isoquinolyl radical;
a phenyl, which may be substituted by one or more substitutes, as well as the salts of these products.
Object of the invention is more especially products of general formula I such as defined above, characterized in that the substitute(s) which may carry the phenyl radical which represents Ar are chosen from among the halogen, lower alkyl, lower alkoxy, cyano, nitro, hydroxy, C(O)NR
1
R
2
, C(O)NHOR
3
, NHC(O)R
4
, NHC(O)NHR
5
, CH
2
NHC(O)NHR
6
, CH
2
OR, CH
2
NHC(O)R
8
, CO
2
R
9
, NHCO
2
R
10
, C(O)R
11
, [and] SR
12
radicals;
in which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
are independently a hydrogen atom or a lower alkyl and R
9
, R
10
, R
11
, R
12
are independently a lower alkyl;
and the substitute(s) which may bear the phenyl radical which may represent R are chosen from among the lower alkyl, lower alkoxy, halogen, hydroxy, nitro, amino or acylamino radicals.
In the definitions indicated above, the expression halogen represents an atom of fluorine, of chlorine, of bromine, or of iodine, preferably fluorine or iodine. The expression lower alkyl represents preferably an alkyl radical having 1 to 6 carbon atoms, linear or branched, and in particular an alkyl radical having 1 to 4 atoms of carbon such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
Among the alkenyl radicals, one may cite the vinyl, allyl, [and] butenyl radicals.
Among the alkynyl radicals, one may cite the ethynyl or propargyl radicals. Among the acylamino radicals, one may cite the acetylamino [and] propionylamino radicals.
The lower alkoxy radicals may correspond to the alkyl radicals indicated above. The methoxy, ethoxy, or isopropyloxy radicals are preferred.
The saturated monocyclic cycloalkyls may be chosen from among the radicals having 3 to 7 carbon atoms such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl radicals.
The mono- or polysaturated cycloalkyl radicals may be chosen from among the cyclobutene, cyclopentene, cyclohexene, cyclopentanediene, cyclohexadiene.
Examples of the polycyclic cycloalkyl radical are bicyclo-[2,2,1]-heptyl or adamantyl.
The products of formula I may form addition salts with the acids, especially pharmacologically acceptable acids.
Examples of salts are given below in the experimental part.
A particular object of the invention is general formula I compounds such as are described above, characterized in that Ar represents a phenyl radical substituted by a substitute chosen from among the hydroxy, methoxy, —C(O)NHMe, —NHC(O)Me, —NHCO
2
R′
10
, with R′
10
representing a methyl or ethyl radical, —NHCONH
2
, —C(O)NHOH and R represents a cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, adamantyl, tertiary butyl, neopentyl, phenyl, [or] fluorophenyl radical.
The substitutes of the phenyl radical which may represent Ar are preferably situated in position 2 or 3.
More especially, the object of the invention are products described below in the examples, especially products responding to the following formulas:
N[4-{2-(2-methoxyphenoxy)ethyl}aminobutyl]benzamide;
N[4-{2-(2-methoxyphenoxy)ethyl}aminobutyl]adamantamide;
N[4-{2-(2-methylamino carbonyl phenoxy)ethyl]amino}butyl]benzamide;
N[4-{2-(2- hydroxyphenoxy)ethyl}aminobutyl]benzamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]cyclohexylamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]cycloheptylamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]2-bicyclo[2,2,1]heptylamide;
as well as the salts of these compounds with organic or mineral acids.
The object of the invention is likewise a preparation procedure for general formula I products as defined above, characterized in that:
A) Either it is a formula II product:
in which Ar has the meaning indicated above, with a product of formula III:
in which X represents a halogen or a pseudo-halogen to obtain a product of formula IV:
which formula IV product is subjected to a reaction for eliminating the phthalimide group to obtain a formula V product:
which formula V product is treated by an acylation reagent derived from RCO
2
H acid in which R has the meaning indicated above to obtain a product of formula VI:
B) or one causes a reaction of a product of formula VII:
with N-benzylethanolamine of formula:
to obtain a product of formula VIII:
which is converted into a product of formula IX:
in which Y represents a halogen or pseudo-halogen radical, a product of formula IX which is converted into a product of formula VI as previously defined, by causing a reaction of a phenol derivative of formula ArOH and formula VI products, which is converted into a product of formula I by splitting the benzyl function and formula I products which is converted, if desired, into acid salts by the action of the corresponding acid.
In this reaction diagram, Ar and R are as defined above and X represents a starting group such as chloro, bromo, iodo, methanesulphonyloxy, benzenesulphonyloxy, or p-toluenesulphonyloxy, in other words, a halogen or pseudo halogen group.
The reaction of a compound of general formula II with a compound of general formula III to obtain a compound of general formula IV can be readily accomplished by heating in a polar solvent, for example, acetonitrile or dimethylformamide in the presence of an acid acceptor such as potassium carbonate or sodium carbonate. Phthalimides of general formula IV may be converted into primary amines of general formula V according to conventional methods, for example by heating with hydrazine hydrate, preferably in a solvent such as ethanol. The primary amines of general formula V thus obtained may be converted into amides of general formula VI by reaction with a derivative of the acid RCO
2
H which may be the appropriate acid chloride or the acid anhydride or other activated acid derivatives such as those generally used in peptide coupling reactions. The reaction is carried out in an inert solvent such as ether, tetrahydrofurane, or dichloromethane and generally in the presence of an acid acceptor such as a tertiary amine, for example, triethy
Bigg Dennis
Defaux Jean Pierre
Defaux Jean-Baptiste
Martin Christiane
Pommier Jacques
Defaux Jean-Baptiste
Kumar Shailendra
Muserlian Lucas and Mercanti
Societe de Conseils de Recherches et D'Applications Scienti
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