Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-28
2001-12-25
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000, C548S269400, C548S343500
Reexamination Certificate
active
06333343
ABSTRACT:
OBJECT OF THE PRESENT INVENTION
Objects of the present invention are nitrogen heterocyclic aromatic derivatives and their use as anti-gestative, immunosuppressant and anti-tumoral agents. Object of the present invention is also a procedure for the preparation of nitrogen heterocyclic aromatic derivatives.
Object of the present invention is again a pharmaceutical composition which contains, as active principle, at least one heterocyclic aromatic according to the present invention.
STATUS OF THE TECHNIQUE
Chemical classes of compounds endowed with anti-gestative activity are known, more specifically BE 866,728 reports a class of 3,5-diphenyl-1H-1,2,4 triazoles of the
following general formula:
where R
1
is an alkyl group C
1
-C
4
.
EP11129 reports 1,2,4 triazoles derivatives of the following general structure:
where R is hydrogen or methyl and R
1
is hydrogen or an alkyl group C
1
-C
4
, or R
1
and R
2
together form an additional bond between the carbon and oxygen atoms.
BE 879,732 reports a class of compounds showing the following general structure:
where, among the other possible substitutions, R is an
hydrogen or a R
5
—CO group where R
5
is chosen among alkyl C
1
-C
4
, alkenyl C
2
-C
4
and alkinyl C
2
-C
4
, whereas R
2
is a —CH(R
7
)OR
8
where R
7
is an hydrogen or methyl and R
8
is like R
5
—CO.
In the above mentioned disclosed documents, the pharmacological data show how these compounds display a high anti-gestative activity after repeated parenteral administrations (daily up to 5 consecutive days). The literature describes the compound 3-(2-ethyl-phenyl)-5-(3-methoxy-phenyl)-1H-1,2,4-triazole, also identified by the code DL 111-IT (Reviews on Drug Metabolism & Drug Interactions,
Vol. IV,
N. 2&3, 1982, A. Assandri, A: Omodei-Sale', G. Galliani).
The mentioned DL 111-IT, reported in BE 879,732, did show an interesting anti-gestative activity in all the investigated animal species including the mouse, the rat, the hamster, the dog and monkeys. DL 111-IT has been proposed as anti-gestative agent for human use.
These previously disclosed anti-gestative compounds, including the compound DL 111-IT, when tested according to a protocol which foresee a single dose parenteral treatment, displayed their activity at doses much higher than those required by multiple dose regimens. EP0080053 describes 3,5 diphenyl-1H-1,2,4 triazole derivatives that, as compared to the previously reported derivatives, have been structurally modified in order to obtain a high anti-gestative activity after a single-dose parenteral administration by subcutaneous and intramuscular route.
The compounds described in EP0080053 have the following general structure:
where, R is chosen between hydrogen and R
5
CO—, where R
5
is a saturated or non-saturated aliphatic C
1
-C
20
hydrocarbon chain, R
1
, R
2
and R
3
are chosen among hydrogen and short-chain alkyl or alkoxyl, or R
1
and R
2
together form a methylendioxy group, R
4
is a saturated or non-saturated aliphatic C
1
-C
20
hydrocarbon group.
The above mentioned derivatives, when given by single dose to rodents, displayed a high anti-gestative activity. This activity was however shown to be highly species-specific. Actually, while in rodents it was very high, in the higher mammal species, like the dog, the anti-gestative activity markedly decreased, due to a too slow hydrolysis rate of the administered products that undergo metabolism before the active principle become bioavailable.
OBJECTIVES OF THE INVENTION
Objective of the present invention is to make available nitrogen heterocyclic aromatic derivatives endowed with high anti-gestative activity when administered as single dose to different animal species including higher mammals and man.
Objective of the present invention is also to make available nitrogen heterocyclic aromatic derivatives endowed with high immuno-suppressant activity.
Again, objective of the present invention is to make available nitrogen heterocyclic aromatic derivatives endowed with non species-specific anti-gestative, immuno-suppressant and anti-tumour activity.
Again, objective of the present invention is to make available nitrogen heterocyclic aromatic derivatives endowed with a sustained duration of action, thus able to display the desired activity by a single-dose treatment (anti-gesative activity) or by multiple dose treatments with wide inter-administration time intervals (immuno-suppressant and anti-tumor acitvities).
Objective of the present invention is also to make available a pharmaceutical formulations, containing at least one nitrogen heterocyclic aromatic derivative as active principle, easy to be administered, well tolerated and able to allow a high therapeutic index.
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 dervatives having the following general formula:
when X=Y, X, Y=N;
when X=Y, X, Y=N, C, CH;
—R is chosen between hydrogen, —COR
8
where R
8
is a saturated or non-saturated C
1
-C
10
aliphatic hydrocarbon,
or R represents any other group able to form a bond with nitrogen atom;
—R
1
has the following genera formula:
where R
3
is chosen among hydrogen, halogen, alkyl or alkoxyl C
1
-C
10
, R
4
is chosen among hydrogen, alkyl or alkoxyl C
1
-C
10
, or R
3
and R
4
together form a ethylendioxy group;
—R
2
has the following general structure:
where 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 hydroacarbon, or is chosen according to the following formula:
where R, R
1
, X, and Y are defined as above and R
6
is chosen among hydrogen, halogen, alkyl or alkoxyl C
1
-C
10
, or Z is chosen equal to NHR
8
where R
8
is a linear or branched C
1
-C
10
alkyl chain. Mentioned R
1
and R
2
are never located on two adjacent atoms of the heterocyclic aromatic ring.
Namely, the mentioned nitrogen heterocyclic aromatic derivative of formula (I) is a derivative of imidazole and 1H-1,2,4-triazole respectively:
According to the present invention, the mentioned derivative of formula (I) is a triazole derivative having the following general formula:
where X=Y=N, while the other substituents are defined as for the derivative of formula (I).
Of particular interest are those derivatives of formula (IV) where R
6
is hydrogen, R
4
is —OCH
3
or —OCH
2
CH
3
, R
3
is hydrogen, R
5
is chosen equal to COZ where Z=OR
7
with R
7
as a saturated linear aliphatic C
1
-C
12
hydrocarbon.
Always according to the present invention, of particular interest were those derivatives having the following formulas:
In addition according to the present invention, of particular interest were the two derivatives having the following formulas:
As reported in the literature, see Potts K. T, J: Chem. Soc. 3451, (1954) and Potts K. T., Chem. Rew. 61, 99 (1961), Kubota and Uda, Chem. Pharm. Bull. 23(5), 955 (1975), due to the high mobility of the hydrogen atoms of 1,2,4-triazoles, compounds of formula (I) of the present invention where X=Y=N, are to be regarded as a mixture of two tautomeric forms, i.e. those in which the hydrogen atom is located on one or the other of the two adjacent nitrogen atoms of the triazole ring. Depending on the nature of the substitutes at the 3 and 5 positions, a form may predominate on the other one. Consequently, both mentioned tautomeric forms must be considered as part of the present invention. It is known that tautomeric forms rapidly exchange in between and consequently behave as a dynamic equilibrium.
Anyway, throughout the whole description and claims relative to the present invention, 3,5 diphenyl-1H-1,2,4-triazoles according to the present invention, will be numbered as reported above for derivative (V).
The derivatives of the present invention are provided of anti-gestation, immuno-suppressive and anti-tumour activities. Particularly, the anti-gestative activity is displayed by a single dose
Geange Ltd.
Gerstl Robert
Nixon & Vanderhye
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