Imidazole compounds and their therapeutic applications

Details Imidazole compounds and their therapeutic applications Imidazole compounds and their therapeutic applications

2000-04-06

2001-07-31

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S255030, C514S272000, C514S341000, C514S365000, C514S397000, C514S398000, C514S399000, C514S400000, C544S324000, C544S370000, C546S272700, C546S275100, C546S270400, C546S274100, C548S311100, C548S312400, C548S314400, C548S315100, C548S315400, C548S326100, C548S335500, C548S339100, C548S171000

Reissue Patent

active

RE037303

ABSTRACT:

The present invention relates to novel imidazole derivatives, to their preparation and to their therapeutic applications.
The imidazole derivatives in accordance with the invention show useful antagonist properties for histamine H
3
receptors which control the release and synthesis of histamine. Their antagonist activity on the H
3
receptors makes them useful in therapeutics, in particular as a medicament possessing sedative, sleep regulating, anticonvulsant, psychostimulating, cerebral circulation modulating and anti-ulcer effects.
The derivatives in accordance with the invention correspond to the general formula IA or IB
in which
the chain A represents a saturated or unsaturated, straight or branched hydrocarbon chain containing 1 to 6 carbon atoms, it being possible for the saturated hydrocarbon chain to be interrupted by a hetero atom such as a sulphur atom,
X represents an oxygen or sulphur atom, —NH—, —NHCO—, —N(alkyl)CO—, —NHCONH—, —NH—CS—NH—, —NHCS—, —O—CO—, —CO—O—, —OCONH—, —OCON(alkyl)—, —OCONH—CO—, —CONH—, —CON(alkyl)—, —SO—, —CO—, —CHOH— or —NR—C(═NR″)—NR′—, R and R′ denoting a hydrogen atom or a lower alkyl radical and R″ a hydrogen atom or another powerful electronegative group, such as a cyano or COY
1
group, Y
1
denoting an alkoxy group,
the chain B represents a straight alkylene chain —(CH
2
)
n
—, n being an integer which can vary between 0 and 5 or a branched alkylene chain containing from 2 to 8 carbon atoms, it being possible for the alkylene chain to be interrupted by one or a number of oxygen or sulphur atoms, or a group —(CH
2
)
n
—O— or —(CH
2
)
n
—S— where n is an integer equal to 1 or 2,
Y represents a straight or branched alkyl group containing 1 to 8 carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms, a bicycloalkyl group, a cycloalkenyl group, an aryl group such as an optionally substituted phenyl group, a 5- or 6-membered heterocyclic radical containing one or two heteroatoms chosen from nitrogen and sulphur atoms, the said heterocyclic radical optionally being substituted, or also a bicyclic radical resulting from the fusion of a benzene ring to a heterocycle as defined above.
The chain A can be a straight alkylene chain —(CH
2
)
n
—, n representing an integer between 0 and 6 carbon atoms, preferably between 1 and 4 carbon atoms, or a branched alkylene chain, preferably a chain substituted by one or a number of methyl or ethyl radicals.
The chain A can also be a straight or branched alkylene chain, and can be, for example, the allyl group.
When Y represents a cycloalkyl group, the latter can be, for example, cyclopentyl, cyclohexyl or a bicycloalkyl group.
When Y represents a substituted phenyl group, the phenyl group can be mono- or polysubstituted, for example, by a halogen, by a lower alkyl, for example CH
3
, by CF
3
, CN, COCH
3
, COOR
1
or OR
1
, R
1
representing a lower alkyl, for example COOCH
3
, the NO
2
group or the group NR
2
R
3
, R
2
and R
3
representing a hydrogen atom and/or a lower alkyl radical (“lower alkyl” means an alkyl radical containing at most 6 carbon atoms).
When Y represents a heterocyclic radical, the latter can be, for example, the pyridyl radical, the pyridyl N-oxide radical or the pyrazinyl radical, optionally mono- or polysubstituted by NO
2
, CF
3
, CH
3
, NH
2
, a halogen such as Cl, the COOCH
3
group or also the imidazolyl or thiazolyl radical.
When Y represents a bicyclic radical resulting from the fusion of a benzene ring to a heterocycle, the radical can be, for example, the benzothiazyle radical.
The compounds which correspond to the formula IA or IB are novel compounds, with the exception, however:
a) of the compounds in which X represents —NH—, the chain A the —(CH
2
)
2
— group, the chain B the —(CH
2
)
2
—O— group or the group —(CH
2
)
n
—S— and Y the phenyl or p-chloro phenyl group,
b) of the compounds in which X represents the —NHCO— group, the chain A the —(CH
2
)
2
— group and Y the methyl group (formula IB) or the chain B and Y (formula IA) represent a straight alkylene chain —(CH
2
)
n
—, n being between 1 and 4, the —CH
2
—O— or —CH
2
—S—CH
2
— groups and a phenyl group, or also the —CH
2
—CH
2
— or —CH
2
—S—CH
2
— groups and the diphenyl group, or also the —(CH
2
)
3
— or —CH
2
—S—CH
2
— groups and the pyridyl group, or also the —CH
2
—CH
2
— or —CH
2
—S— groups and the diphenyl group, or else the —(CH
2
)
3
— group and the imidazolyl or cyclohexyl group,
c) of the compounds in which X represents —NHCO—, the chain A the —CH
2
—CH(CH
3
)— group, the chain B the —(CH
2
)
3
— group and Y the phenyl group,
d) of the compounds in which X represents —NHCSNH— or —NHCONH—, the chain A the —(CH
2
)
2
— group, the chain B the —(CH
2
)
2
— group and Y the phenyl group,
e) of the compounds in which the chain A represents a straight saturated hydrocarbon chain containing 1 to 6 carbon atoms, X represents —NH—, the chain B represents an alkylene chain as defined above and Y represents a phenyl group or an imidazolyl radical, as well as those in which A represents a straight saturated hydrocarbon chain containing 1 to 6 carbon atoms, X represents the —NHCONH— group, the chain B and/or Y represent an alkyl and Y represents an aryl radical;
f) of the compounds in which X represents an oxygen atom, the chain A a —CH
2
— group and Y a substituted phenyl group (formula IB);
g) of the compounds in which X represents the —NHCO— group, the chain A the —(CH
2
)
2
— group and Y a substituted cyclohexyl group (formula IB);
h) of the compounds in which X represents the —NH—CS—NH— group, the chain A the group —(CH
2
)
n
— (n=3 to 6) and Y an alkyl, aryl and aralkyl group (formula IB);
i) of the compounds in which X represents the —CO— group, the chain A the —(CH
2
)
2
— group and Y an optionally substituted aryl radical, a 5-membered heterocyclic radical containing sulphur as heteroatom and optionally substituted, or a bicyclic radical resulting from the fusion of a benzene ring to a 5- or 6-membered heterocycle containing nitrogen and/or sulphur atoms as hetero atoms (formula IB);
j) of the compounds in which X represents the —CONH— group, the chain A the —(CH
2
)
2
— group and Y the optionally substituted phenyl group (formula IB);
k) of the compounds in which X represents the —NH—C(═NCN)—NH— group, the chain A a hydrocarbon chain containing 2 to 4 C atoms interrupted by an S atom and Y a 5- or 6-membered heterocycle containing one or two nitrogen and sulphur atoms (formula IB);
l) of the compounds in which X represents the —NH—C(═NCN)—NH— group, the chain A a —CH
2
—S—(CH
2
)
2
— group and Y a methyl radical (formula IB);
m) of the compounds in which X represents the —NH—C(═NH)—NH— group, the chain A and chain B have the abovementioned meaning and Y represents an alkyl group, an aryl group, or a 5- or 6-membered heterocyclic radical containing one or two heteroatoms which can be nitrogen and/or sulphur.
The compounds set out under a) to d) were disclosed during a symposium which was held at Budapest in August 1988 (“10th International Symposium on Medicinal Chemistry”) and more recently at Noordwijkerhout (July 1990).
The compounds set out under e) have been described in Patent GB 1,341,375; the compounds set out under f) in French patent No. 1,220,002; the compounds set out under g) in U.S. Pat. Nos. 2,301,532 and 2,376,424; the compounds set out under h) in Patent GB 1,305,547; the compounds set out under i) in European Patent Application EP-A-0,291,172; the compounds set out under j) in European Patent Application EP-A-315,316; the compounds set out under k) in Patent GB 1,531,221 and the compounds set out under l) in Australian Patent AU-A-514,574; the compounds set out under m) in European Patent Applications EP-A-0,199,845 and EP-A-0,262,448.
The present invention also relates to the addition salts which the compounds of formula IA or IB form with pharmaceutically acceptable acids. The pharmaceutically acceptable salts comprise the nontoxic salts of inorganic or organic acids such as the hydrochloride, the hydrobromide or the maleate.
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