Nitrate salts of antimicrobial agents

Details Nitrate salts of antimicrobial agents Nitrate salts of antimicrobial agents

2002-07-24

2004-09-21

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C546S112000, C546S113000

Reexamination Certificate

active

06794372

ABSTRACT:

The present invention relates to compounds, or their pharmaceutical compositions, for systemic use and non, to be used in the antimicrobial therapy.
It is known that the wide use of antimicrobial agents in the infection treatment has caused the development of strains resistant to these drugs, for example the case of antiviral, antifungal and antibacterial agents can be mentioned.
This resistance generally arises when microorganisms develop growth and reproduction mechanisms on which the antimicrobial therapy is ineffective, or when the microorganisms produce enzymes which neutralize the drug. The resistant microbial strain is then able to multiply, causing the illness prolongation and worsening, with possible diffusion of the infection in the communities. This fact, as known, can determine notable consequences at a social-economic and sanitary level.
A method to solve this problem is to increase the dosage of the antimicrobial drugs. In this way there is the drawback of an increased incidence of side effects both local and systemic. Besides, cases of microbial superinfection deriving from the antimicrobial agent itself due to the inbalance between pathogen and non pathogen microbial flora often occur. It is well known that antimicrobial agents must act on the pathogen agents which are responsible of the unhealthy process and leave unaltered the non pathogen microbes useful for the organism.
A widely followed approach for solving the problem of the microbial resistance, and/or of the diffusion of pharmaco-resistant strains, has been to introduce in therapy new molecules to be used as antimicrobial agents. The results so far obtained are not satisfactory.
The need was therefore felt to have available drugs able not only to be active on the microorganism but also to prevent and/or reduce the microbial resistance and therefore to allow a complete and effective antimicrobial therapy, said drugs being effective at the conventional minimum dosages to avoid the side toxic effects. Among the latter skin rash and the effects on the stomach, liver and kidney can for example be mentioned.
It has been surprisingly and unexpectedly found by the Applicant that it is possible to solve the above technical problem by using compounds which have shown to be able to effectively interact with microbes and to prevent or reduce the microbial resistance.
An object of the present invention is the use of nitrate salts of antimicrobial agents, or their pharmaceutical compositions, for the preparation of medicaments usable in the treatment of infectious diseases. Preferably the invention relates to the use of nitrate salts of antiviral, antifungal and antibacterial agents, or their pharmaceutical compositions; the antimicrobial agents usable for preparing the nitrate salts of the present invention must satisfy the following test: in the culture of specific pathogen microbes responsible for the single pathologies, the antimicrobial agent is inoculated at a concentration such as to result effective as antimicrobial agent and such as not to produce cytotoxicity in mammalian cells.
See for example the test of the dilution in vitro on medium reported in the Examples for the antibacterial agents.
More specifically the present invention relates to the use of nitrate salts of compounds, or their pharmaceutical compositions, for preparing medicaments usable in the treatment of infectious diseases as antimicrobial agents, said compounds preferably being selected from the following classes:
class I)
wherein:
R
1
=H, Cl or dimethylamino,
R
2
=H, OH, or free valence,
R
3
=H, CH
3
, when R
2
is free valence with the doublet of the C—R
3
bond it forms a double bond and R
3
is methylene,
R
4
=H, OH,
R
5
=H, CH
2
OH, or one of the following substituents:
class II)
wherein:
X and Y, different the one from the other, are C or N,
R
6
=ciclopropyl, C
2
H
5
, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoroethyl,
R
7
=H, amino, CH
3
,
R
8
=H or F, when Y=N, R
8
is free valence and it is the free doublet on the nitrogen atom,
R
9
=H, CH
3
or one of the following substituents:
wherein M=H, CH
3
, C
2
H
5
, OH,
wherein T
1
is H, OH
R
8
and R
9
taken together form the bivalent radical having formula: —O—CH
2
—O— (IIP),
R
10
=H, Cl, F, when X=N, R
10
is free valence and it is the free doublet on the nitrogen atom, R
6
and R
10
taken together form the following bivalent radicals:
when X in the formula (II)=N, R
10
is free valence and it forms a double bond with the carbon atom adjacent to the nitrogen;
class IIIa):
wherein:
Z=S, C,
R
11
=H, pivaloyloxymethylene of formula (IIIaF) wherein T
2
is the tert-butyl group,
R
12
=Cl, CH
3
, acetyloxymethylene of formula (IIIaF) wherein T
2
is CH
3
, 2-propenyl or one of the following substituents:
R
13
=amino, OH, or the substituent (IIIaD):
R
14
is phenyl, 4-hydroxyphenyl, or the radical (IIIaE);
class IIIb)
wherein:
X=CH, N.
Y=C, N,
R
15
=COOH, COO
−
, (CH
3
)
3
CCOOCH
2
OCO— or (CH
3
)
2
CHOCOOCH(CH
3
)OCO—,
R
16
=H, CH
3
, C
2
H
5
, —CH═CH
2
, NH
2
COOCH
2
—, CH
3
COOCH
2
—, or one of the following substituents:
when R
15
is carboxylated anion R
16
is a radical selected from the following: (IIIbL), (IIIbM) or (IIIbN)
R
17
=OH, OCH
3
, C
2
CH
5
, —OCH
2
COOH, —CH
2
COOH;
class IIIc)
wherein:
R
18
is one of the following substituents:
R
19
=H, CH
3
COOCH
2
—, or one of the following groups:
class IVa:
wherein:
R
20
is one of the following substituents:
R
21
=H, the radical (IIIaF) with T
2
=tert-butyl, CH(CH
3
)OCOOC
2
H
5
or one of the following substituents:
—CH
2
CH
2
N(CH
2
CH
3
)
2
.HI  (IVaR),
class IVb)
wherein:
R
22
=H, CH
3
,
R
23
is selected from the following groups:
—CH
2
CH
2
NHCH═NH  (IVbD),
class IVc)
wherein:
R
33
, R
34
, R
36
, equal to or different from each other, are H, CH
3
;
R
35
=H, —CH
2
OCONH
2
,
class V)
wherein
R
24
=H, Br, OCH
3
, CH
3
OCH
2
CH
2
O—;
class VI)
wherein:
R
25
is one of the following substituents:
class VII)
wherein
R
26
=H, or one of the following substituents: benzoyl, acetyl, 3-methyl-2-butenoyl, carbamoyl, aminothioxo NH
2
C(S)— 2-pyridinyl, pyrazinyl, 2-pyrimidinyl, 2-thiazolyl, salicyl-4-yl, 6-chloro-pyridazine-3-yl, 1-ethyl-1,2-dihydro-2-oxo-pyrimidin-4-yl, 5,6-dimethoxy-pyrimidin-4-yl, 2,6-dimethoxy-Pyrimidin-4-yl, 4-methyl-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl, 6-methoxy-2-methyl-pyrimidin-4-yl, 5-methyl-pyrimidin-2-yl, 2,6-dimethyl pyrimidin-4-yl, 3-methoxy-pyrazine-2-yl, 6-methoxy-pyridazin-3-yl, 4,6-diethyl-1,3,5-triazin-2-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-methoxy-1,2,5-thiadiazol-3-yl, 4-methyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4,5-dimethyl-oxazol-2-yl, 3,4-dimethyl-isooxazol-5-yl, 4,5-dimethyl-2-oxazolylaminoiminomethyl, 5-methyl-isooxazol-3-yl, 1-phenyl-1H-pyrazol-5-yl, 4-methylamino sulphonylphenyl, 4-amino-sulphonylphenyl, 3,4-dimethylbenzoyl, 4-isopropoxy benzoyl;
class VIII)
wherein:
R
27
=H, 4,6-dimethyl-pyrimidin-2-yl;
R
28
=2,4-diamino-6-carboxyphenyl, 2,4-diaminophenyl, 3-car-boxy-4-hydroxyphenyl;
class IX)
wherein:
R
29
=H, OH,
R
30
=COOH, phenoxycarbonyl, 4-(amino)phenylsulphinyl, hydra-zinecarbonyl;
class X)
wherein:
R
31
=amino, NH
2
—CH
2
—, benzylamino,
R
32
=amino, 4-(hydroxyethylamino)phenyl, —N═C(NH
2
)
2
, 4-(amino)phenyl, 4-(aminomethyl) phenyl, 4-(carboxymethyl amino)phenyl, 4-(carboxypropionyl amino)phenyl, 2-amino-thiazol-5-yl;
class XI)
wherein:
M=O, S,
R
52
=H, C
2
H
5
, C
3
H
7
,
R
53
=amino, —NHNH
2
, or one of the following substituents:
class XII)
wherein:
R
37
=Cl, OH;
class XIIIa)
wherein:
R
38
=H, acetyl, COC
2
H
5
(propionyl),
R
39
=H, propionyl, COC
3
H
7
(butyryl), COCH
2
CH(CH
3
)
2
(isovaleryl),
R
40
=H, propionyl,
R
41
=H, or:

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