Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-21
2004-08-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S312100, C548S314700, C548S315100, C548S338100, C514S399000
Reexamination Certificate
active
06770667
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel amide compounds and salts thereof. More particularly, it relates to novel amide compounds and salts thereof which have pharmacological activities such as 5-hydroxytryptarine (5-HT) antagonism and the like.
Said amide compounds and their salts are useful as a 5HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders, migraine,.anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse (e.g., with cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus in human being and animals.
BACKGROUND ART
With regard to the state of the art in this field, for example, the following amide compounds are disclosed in Japanese Patent Kokai No. Hei 11(1999)-130750.
wherein R
1
is quinolyl, quinazolinyl, isoquinolyl or pyridyl group, R
3
is phenyl, cyclo(lower)alkyl, indolyl, lower alkyl-indazolyl or 2,3-dihydroindolyl group, Y is single bond, lower alkylene or lower alkenylene group, and A is lower alkylene group.
DISCLOSURE OF INVENTION
As a result of an extensive study, the inventors of the present invention found some amide compounds which have strong pharmacological activities.
The amide compounds of the present invention are novel and can be represented by the formula (I):
wherein
R
1
is an N-containing heterocyclic group selected from an imidazolyl, a triazolyl, a pyridyl, a pyridazinyl, a pyrimidinyl and a pyrazinyl group, each of which may be substituted with one or more lower alkyl groups,
R
2
is a hydrogen atom or a lower alkyl group, and
R
3
is a phenyl group substituted with thienyl or halophenyl; a thienyl group substituted with thienyl, phenyl or halophenyl; a pyrrolyl group substituted with phenyl; a thiazolyl group substituted with phenyl; an indolyl group substituted with lower alkyl and/or halo(lower)alkyl; a fluorenyl group; or a carbazolyl group, provided that
(1) the imidazolyl group for R
1
is substituted with one or more alkyl groups, when R
3
is a phenyl group substituted thienyl; an indolyl group substituted with lower alkyl; or carbazolyl group,
(2) the imidazolyl group for R
1
is substituted with two lower alkyl groups, when R
3
is a phenyl group substituted with halophenyl, or
(3) R
1
is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, a 4-(lower alkyl)-imidazol-1-yl or a 4,5-di(power alkyl)-imidazol-1-yl group, when R
3
is fluorenyl group.
Suitable salts of the compounds (I) are conventional non-toxic pharmaceutically acceptable salts and may include salts with inorganic bases, for example, alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium or magnesium) or ammonia; salts with organic bases, for example, organic amines (e.g. triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine or N,N′-dibenzylethylenediamine); inorganic acid addition salts (e.g. hydrochloride, hydrobromide, hydriodide, sulfate or phosphate); organic carboxylic or sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate or p-toluenesulfonate); salts with basic or acidic amino acids (e.g. arginine, aspartate or glutamate); and the like, and preferable examples thereof are the inorganic or organic acid addition salts.
According to the present invention, the object compounds (I) can be prepared by the following process:
wherein R
1
, R
2
and R
3
are each as defined above.
In the above and subsequent descriptions of the present. specification, suitable examples and illustrations of the various definitions which the present invention include within the scope are explained in detail in the following.
The term “lower” is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable lower alkyl groups and lower alkyl moieties in the halo(lower)alkyl groups may include straight or branched ones, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl and hexyl, and preferably the ones having 1 to 4 carbon atom(s), among which the most preferred one is methyl.
Suitable halo(lower)alkyl groups may include lower alkyl groups substituted with one or more halogen atoms such as fluoromethyl, fluoroethyl, fluoropropyl, trifluoromethyl, chloromethyl, dichloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, iodomethyl, iodoethyl, iodopropyl, and the like.
Suitable halophenyl groups may include fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, tribromophenyl, iodophenyl, and the like.
When imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups for R
1
is substituted with two or more lower alkyl groups, said lower alkyl groups may be the same or different from each other.
And also, when indolyl group for R
3
is substituted with two or more lower alkyl groups and/or two or more halo(lower)alkyl groups, said lower alkyl groups and halo(lower)alkyl groups may be the same or different from each other.
The process for preparing the object compounds (I) is explained in detail in the following.
The object compound (I) and its salt can be prepared by reacting a compound (II) or its reactive derivative at the amino group or a salt thereof with a compound (III) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivatives at the amino group of the compound (II) may include Schiff's base type imine or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of a compound (II) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (II) and its reactive derivative can be referred to those as exemplified for the compound(l).
Suitable reactive derivatives at the carboxy group of the compound (III) may include the acid halides, acid anhydrides, activated amides, activated esters and the like.
Suitable examples of such reactive derivatives may be the acid chloride; the acid azide; the mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid] or aromatic carboxylic acid [e.g. benzoic acid]; symmetrical acid anhydride; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH
3
)
2
N*=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester or 8-quinolyl thioester], or ester with an N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinide, N-hydroxyphthaimide or 1-hydroxy-1H-benzotriazole], and the like.
The reactive derivative can optionally be selected from the above according to the kind of the compound (III) to be used.
Suitable salts of the compound (III) and its reactive derivative may be the base salts such as alkali m
Ito Kiyotaka
Miyake Hiroshi
Spears Glen W.
Takahashi Fumie
Tomishima Masaki
Fujisawa Pharmaceutical Co. Ltd.
Habte Kahsay
Shah Mukund J.
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