Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-24
2001-11-27
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S384000, C548S250000, C548S251000, C548S253000, C548S254000, C548S262200, C548S264600
Reexamination Certificate
active
06323230
ABSTRACT:
OBJECT OF THE PRESENT INVENTION
Objects of the present invention is the use of nitrogen heterocyclic aromatic derivatives in the topical treatment of the diseases of the epithelial tissues.
Object of the present invention is also a chemical class of nitrogen heterocyclic aromatic derivatives and a procedure for their preparation.
Object of the present invention are pharmaceutical preparations which contains, as active principle, heterocyclic aromatic derivatives and their use in the topical treatment of the diseases of the epithelial tissues.
STATUS OF THE TECHNIQUE
Among all the diseases of the epithelial tissues, (epidermis, intestinal and bronchi mucosae), some of the more studied, because they large diffusion, are surely the psoriasis (epidermis) and the ulcerous cholitis (low intestine).
The psoriasis is a skin disease of genetic origin (phenotypes HLA with HLA-cw6 antigen) multi-factorial, characterised by inflammation and hyper-plasia of the epidermis with consequent plaques formation. In the psoriasis lesions, the rate of cell proliferation is of at least 10 times higher than normal. Different hypotheses exist on the origin of dermatological diseases like psoriasis; one of this suggests that a primary defect in keratinocyte growth regulation in the germinative stratum, may lead to epidermis hyper-proliferation. This hypothesis has been recently supported by finding showing the involvement of cytokines (interleukin, interferon, growth factors including EGF) in its pathogenesis.
The anti-proliferative and inflammatory components of psoriasis need for a therapeutic approach which can affect both or at least one of the two mechanisms; from a practical viewpoint, depending on the severity of the pathology, the pharmacological and/or physical treatment is strengthen while the therapeutic index is reduced and the untoward effects increased.
It is a fact that, by increasing the severity and recrudescence of the disease, the therapies at present considered more effective and of large use start with topical treatments by emollients and keratolytic, then with tars, topical corticosteroids, antralins, antimicrobics, UVB applications combined with Goeckmen Ingram, photochemio therapy PUVA, until to use systemic treatments like oral corticosteroids, retinoids, metotrexate, hydroxyurea, cyclosporine.
When both topical pharmacological and physical therapies, including the use of PUVA (induction of the covalent binding of psoralens with the pyrimidinic bases of DNA) result ineffective, the systemic therapies remain the only available. These are however performed by utilising drugs of high general toxicity but not always effective, like corticosteroids, retinoids, chemotherapics and cyclosporine.
When the therapeutic index is considered the results obtained are often poor whereas the recrudescence, of the illness is rapid.
Therefore, the compounds nowadays used in the therapy of psoriasis are scarcely effective and produce several and severe side-effects.
Similarly, about 20% of all the inflammatory diseases of the low intestine including the Crohn illness, do not improve by the most commonly used anti-inflammatory therapies with 5-amino-salycilic acid and cortico-steroids, while need of more aggressive treatments with immuno-suppressants. Among these latter, azathiopirine and methotrexate are used, in spite of their cytotoxic activity leading in the course of prolonged therapeutic cycles to serious adverse events as pancreatitis, bone marrow depression, hepatitis and allergic reactions.
Therefore, the availability of non-cytotoxic drugs, endowed with a high anti-proliferative activity attained locally on the epithelia of the intestinal mucosae, is to be regarded as an useful progress in the therapy of severe diseases of the low intestine.
OBJECTIVES OF THE INVENTION
Objective of the present invention is to make available nitrogen heterocyclic aromatic derivatives to be used in the topical pharmacological treatment of diseases of epithelial tissues..
Objective of the present invention is also to make. available nitrogen heterocyclic aromatic derivatives displaying their activity when topically administered by epicutaneous, oral or rectal route.
Objective of the present invention is also to make available pharmaceutical formulations, containing at least one nitrogen heterocyclic aromatic derivative as active principle, to be used in the treatment of diseases of the epithelial tissues, that display their activity when administered epicutaneously in the dermatological affections and by oral or rectal route in the diseases of the low intestine, that are well tolerated and able to allow a high therapeutic index.
Objective of the present invention is also to make available nitrogen heterocyclic aromatic derivatives to be used in the treatment of diseases of the epithelial tissues and displaying a high activity when administered topically, thus able to reduce the risk of systemic side-effects.
Objective of the present invention is also to make available nitrogen heterocyclic aromatic derivatives to be used in the treatment of diseases of the epithelial tissues in combination with other compounds also employed in the same therapeutic areas in order to achieve synergistic effects.
DESCRIPTION OF THE INVENTION
These and other objectives with further advantages which are clarified in the description below, are obtained by the nitrogen heterocyclic aromatic derivatives having the following general formula:
where
when X═Y, X, Y═N;
when X═Y, X, Y═N, C, CH;
R is chosen between:
hydrogen;
any group able to form a bond with a nitrogen atom,
—COR
8
where R
8
is C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkinyl, phenyl possibly substituted by 1 to 3 substituents, benzyl, C
1
-C
4
alkylamino, di-(C
1
-C
4
alkyl)amino, phenylamino possibly substituted by 1 to 3 substituents, C
1
-C
4
halolkyl, C
1
-C
4
alkoxy, benzyloxy. Each eventual substituent being independently chosen among: halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoro-methyl, CN, nitro, amino, di-(C
1
-C
4
alkyl)amino, acylaminoC
2
-C
4
and methylendioxy;
SO
2
R
12
, where R
12
is chosen among: C
1
-C
4
alkyl, phenyl, (C
1
-C
4
alkyl)phenyl, (C
1
-C
4
alkoxy)phenyl, acetylphenyl
R
1
has the following general formula:
where
R
3
and R
4
are independently chosen among:
hydrogen,
halogen,
C
1
-C
10
alkyl or alkoxyl C
1
-C
10
,
allyloxy, propergyloxy,
trifluoro-methyl,
phenyl,
di-methylamino,
or
R
3
and R
4
together form a methylendioxy group;
R
2
has the following general structure:
where
R
6
is chosen among:
hydrogen,
halogen,
C
1
-C
10
alkyl or alkoxyl C
1
-C
10
;
where
R
10
is chosen among:
hydrogen,
methyl;
where
R
11
is chosen among:
hydrogen,
C
1
-C
4
alkyl,
formyl,
OR
5
, where R
5
is chosen among hydrogen, C
1
-C
4
alkyl, SO
2
R
11
, where R
11
is defined as above, or R
5
is chosen among:
where Z═OR
7
with R
7
is chosen among a saturated or non-saturated, linear or branched C
1
-C
20
aliphatic hydrocarbon, or is chosen according to the following formula:
where R, R
1
, R
6
, X and Y are defined as above or Z is chosen among C
1
-C
20
linear or branched alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkinyl, phenyl possibly substituted by 1 to 3 substituents, benzyl, C
1
-C
4
alkylamino, di-(C
1
-C
4
alkyl)amino, phenyl-amino possibly substituted by 1 to 3 substituents, C
1
-C
4
halo-alkyl, C
1
-C
4
alkoxy, benzyloxy. Each eventual substituent being independently chosen among: halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoro-methyl, CN, nitro, amino, di-(C
1
-C
4
alkyl)amino, acyl-aminoC
2
-C
4
and methylendioxy;
or Z is chosen equal to NHR
9
where R
9
is a linear or branched C
1
-C
20
alkyl chain, or mentioned R
10
and R
11
, together form a further bond between the carbon atom and one oxygen atom;
mentioned R
1
and R
2
are never located on two adjacent atoms of the heterocyclic aromatic ring;
or by nitrogen heterocyclic aromatic derivatives of general formula as follows:
where:
R
15
and R
16
are chosen among:
hydrogen,
phenyl,
hydroxy,
C
1
-C
4
alkyl,
C
1
-C
4
D'Souza Andrea M
Geange Ltd.
Higel Floyd D.
Nixon & Vanderhye
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