&agr;1-adrenergic receptor antagonists

Details &agr;1-adrenergic receptor antagonists &agr;1-adrenergic receptor antagonists

1998-09-28

2001-10-09

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S402000, C514S252120

Reexamination Certificate

active

06300499

ABSTRACT:

Neuroreceptors are considered as dynamic entities which constitute an accessible means of clinical manipulation. The norepinephrine sympathic neurotransmitter and the epinephrine surrenal hormone regulate numerous physiological activities through interactions with the &agr;- and &bgr;-adrenergic receptors. The &agr;
1
-adrenergic receptors are mediators of a number of the physiological effects of catecholamines, in particular glycogenolysis, contraction of the vascular and genito-urinary smooth muscle, hyperpolarisation of the intestinal smooth muscle, the contractile force and cardiac arythmia.
In one of its aspects, the invention relates to a compound of formula I:
in which:
R
1
represents a hydrogen, a lower alkyl, or an aryl-lower alkyl;
R
2
represents a hydrogen, a lower alkyl, OR
6
, S(O)
m
R
6
(in which m is 0, 1, or 2), NHS(O)
n
R
6
(in which n is 1 or 2), OC(O)R
6
, CONR
6
R
7
, NR
6
R
7
, or N(R
7
)C(O)R
6
;
R
3
and R
4
, independent of each other, represent hydrogen, or one of the following substituted compounds (i.e., one to four times on the carbon or nitrogen atoms) or non-substituted: a lower alkyl, a cycloalkyl, an aryl, a lower aryl-alkyl, a heterocycle, or a heterocycle-lower alkyl, in which said substituent is a lower alkyl, a halogen, OR
6
, SR
6
, NR
6
R
7
, CN, NO
2
, CF
3
, a heterocycle, or an aryl, or R
3
and R
4
constitute, together with the carbon atom to which they are jointly linked, an aryl or a substituted heterocycle (i.e. in one to four locations) or non-substituted, in which said substituent is a lower alkyl, OH, or a hydroxyl-lower alkyl;
R
5
is a substituted aryl (i.e., on one to four carbon atoms) or non-substituted, in which said substituent is a lower alkyl, a cycloalkyl, a hydroxyl-lower alkyl, a hydroxyl-cycloalkyl, a alkoxy-lower alkyl, an alkoxy-cycloalkyl, a halogen, OR
6
, SR
6
, NR
6
R
7
, or CN; and
R
6
and R
7
, independent of each other, represent a hydrogen or one of the following compounds substituted (i.e., on one to four carbon atoms) or non-substituted: lower alkyl, aryl or aryl-lower alkyl, in which said substituent is a lower alkyl, a halogen, or a lower alkoxy; in which if R
3
or R
4
represents a hydrogen, R
2
does not represent OH; or one of its pharmaceutically acceptable salts.
In one of the embodiments, R
1
represents hydrogen or a lower alkyl, R
2
represents a hydrogen, a lower alkyl, OR
6
(in which R
6
represents a hydrogen or an aryl-lower alkyl), SR
6
(in which R
6
is a lower alkyl), NH
2
, NHSO
2
R
6
(in which R
6
is a lower alkyl or an aryl-lower alkyl), OC(O)R
6
(in which R
6
is an aryl-lower alkyl) or CONR
6
R
7
or N(R
7
)C(O)R
6
(in which R
7
represents a hydrogen and R
6
represents an aryl-lower alkyl); R
5
represents a substituted or non-substituted phenyl, in which said substituent is a lower alkyl, CN, a halogen, a hydroxy-lower alkyl, a hydroxy-cycloalkyl, a lower alkoxy-lower alkyl, or OR
6
(in which R
6
is a lower alkyl); and R
3
and R
4
, independent of one another, represent a hydrogen or one of the following substituted or non-substituted compounds: a lower alkyl, a cycloalkyl, or an aryl, in which said substituent is a halogen, OR
6
(in which R
6
is a lower alkyl), or an aryl.
In another embodiment, R
1
represents a hydrogen and R
5
represents 2,5-dimethyl-phenyl; R
2
represents OR
6
(in which R
6
represents a hydrogen, a lower alkyl, or an aryl-lower alkyl); and R
3
represents a lower alkyl and R
4
represents a phenyl.
In another embodiment, R
3
and R
4
, together with the carbon atom to which they are jointly linked, constitute an aryl or a heterocycle; R
1
represents a hydrogen and R
5
represents 2-methoxy-phenyl or 2,5-dimethyl-phenyl; and R
2
represents OR
6
(in which R
6
represents a hydrogen, a lower alkyl, or an aryl-lower alkyl).
In yet another embodiment, R
3
and R
4
, together with the carbon atom to which they are jointly linked, constitute 9-xanthenyl or 9-fluorenyl.
The following examples are examples of compounds according to the present invention:
According to another aspect, the present invention relates to the use as medicaments of products of general formula I as described above, as well as a pharmaceutical composition containing a compound of formula I
in which:
R
1
represents a hydrogen, a lower alkyl, or an aryl-lower alkyl;
R
2
represents a hydrogen, a lower alkyl, OR
6
, S(O)
m
R
6
(in which m is 0, 1, or 2), NHS(O)
n
R
6
(in which n is 1 or 2), CONR
6
R
7
, NR
6
R
7
, or N(R
7
)C(O)R
6
;
R
3
and R
4
, independent of one another, represent hydrogen or one of the following substituted or non-substituted compounds: a lower alkyl, a cycloalkyl, an aryl, an aryl-lower alkyl, a heterocyle, or a heterocycle-lower alkyl, in which said substituent is a lower alkyl, a halogen OR
6
, SR
6
, NR
6
R
7
, CN, NO
2
, CF
3
, a heterocycle, or an aryl, or R
3
and R
4
constitute, together with the carbon atom to which they are jointly linked, a heterocycle;
R
5
is a substituted or non-substituted aryl, in which said substituent is a lower alkyl, a hydroxyl-lower alkyl, an alkoxy-lower alkyl, a halogen, OR
6
, SR
6
, NR
6
R
7
or CN; and
R
6
and R
7
, independent of one another represent a hydrogen or one of the following substituted or non-substituted compounds: lower alkyl, aryl or aryl-lower alkyl, in which said substituent is a lower alkyl, a halogen, or a lower alkoxy; or one of its pharmaceutically acceptable salts.
According to one embodiment, R
1
represents a hydrogen, R
5
represents 2,5-dimethyl-phenyl; R
2
represents OR
6
(in which R
6
represents a hydrogen, a lower alkyl, or an aryl-lower alkyl); R
3
represents a lower alkyl, and R
4
represents a phenyl.
As used here, a “lower alkyl” includes saturated aliphatic hydrocarbon groups at the same time linear, branched, or straight chain, having from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and similar.
As used here, a “cyclo-alkyl” includes any cyclic non-aromatic hydrocarbon fragment having from 3 to 10 carbon atoms in which 3 to 8 of the carbon atoms constitute a cycle. Examples of such fragments include, but are not limited to, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-methyl, cyclopropyl-ethyl, and cyclohexyl-ethyl.
As used here, an “aryl” includes any stable monocyclic, bicyclic, or tricyclic carbon nucleus (nuclei) or cycle(s) containing up to 7 members in each cycle, in which at least one cycle is aromatic. Examples of such aryl groups include phenyl, the naphthyl, anthracenyl, biphenyl, tetrahydronaphthhyl, indanyl, phenanthrenyl, and similar.
As used here, a “lower alkoxy” includes saturated aliphatic hydrocarbon groups at the same time linear, branched, and straight chain, having form 1 to 6 carbon atoms and an oxygen atom. Examples of lower alkoxys include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and similar.
The term heterocycle, as used here, represents a heterocyclic nucleus or cycle containing a stable monocycle with 5 to 7 members or a stable bicycle with 8 to 11 members or a tricycle stable with 11 to 15 members, which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 4 heteroatoms chosen from the group consisting of N, O, and S, and including any bicyclic group in which any one of the heterocyclic cycles defined above is linked to the benzene nucleus. The heterocyclic cycle can be linked to any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulphone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthhyri

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