Substituted aminocycloalkylpyrrolidine derivatives and...

Details Substituted aminocycloalkylpyrrolidine derivatives and... Substituted aminocycloalkylpyrrolidine derivatives and...

1999-09-17

2001-02-06

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S530000, C548S541000

Reexamination Certificate

active

06184388

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to antibacterial and antimicrobial compounds useful for pharmaceutical preparations, veterinary drugs, drugs for fisheries use and antibacterial and antimicrobial preservatives. This invention also relates to antibacterial and antimicrobial drugs and antibacterial and antimicrobial preparations containing these compounds.
BACKGROUND OF THE INVENTION
Since the discovery of norfloxacin, attempts have been made to improve the antimicrobial activity and pharmacokinetics of synthetic quinolone antimicrobial agents. As a result, a number of compounds are clinically available today as chemotherapeutic drugs efficacious in treating systemic infectious diseases.
In recent years, however, bacteria hyposensitive to these drugs have been increasing in the field of clinical medicine. Moreover, some bacteria tolerant to drugs other than these synthetic quinolone antimicrobial agents have also become hyposensitive thereto.
Staphylococcus aureus
(MRSA) is an example of such bacteria having no sensitivity to &bgr;-lactam antibiotics. Therefore, there is an urgent need to develop highly efficacious drugs in the field of clinical medicine.
In addition, it is reported that these antimicrobial agents sometimes induce convulsions when administered together with nonsteroidal anti-inflammatory drugs and exhibit other side effects such as phototoxicity. Thus, there is also a need to develop safer quinolone drugs.
SUMMARY OF THE INVENTION
In view of the above, the present inventors have conducted extensive studies with the aim of providing compounds which satisfy the aforementioned requirements.
As a result, the present inventors have discovered that substituted aminomethylpyrrolidine derivatives represented by the following formulae (I) and (XI), their salts and hydrates thereof have a broad antibacterial spectrum, exhibit potent antibacterial activity against quinolone-resistant bacteria including Gram positive bacteria, particularly MRSA, and also have favorable pharmacokinetics and high safety. The present invention has been accomplished on the basis of these findings.
Accordingly, a first aspect of the present invention relates to a compound represented by the following formula (I), its salts and hydrates thereof:
{wherein R
1
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R
2
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
wherein the alkyl group represented by R
2
may have at least one substituent selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms;
R
3
represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, wherein the alkyl group represented by R
3
may have at least one substituent selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms;
R
4
and R
5
each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms,
wherein the alkyl group represented by R
4
and R
5
may have at least one substituent selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms, and
R
4
and R
5
may be combined to form a hydroxyimino group, a poly-methylene chain having 3 to 6 carbon atoms (so as to form a spiro cyclic structure together with the pyrrolidine ring) or an alkyloxyimino group having 1 to 6 carbon atoms;
R
6
and R
7
each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
n is an integer of 1 to 3; and
Q is a partial structure represented by the following formula (II):
[wherein R
8
represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have one or more substituents, an aryl group which may have one or more substituents, a heteroaryl group which may have one or more substituents, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;
R
9
represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R
8
and R
9
may be combined to form a cyclic structure including a part of the mother nucleus, and the ring may contain a sulfur atom as a ring constituting atom and may further have an alkyl group having 1 to 6 carbon atoms as a substituent;
X1 represents a halogen atom or a hydrogen atom;
R
10
represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group represented by R
10
may have at least one substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms;
A
1
represents a nitrogen atom, or a partial structure represented by the following formula (III):
(wherein X
2
represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group represented by X
2
may have at least one substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and
X
2
and R
8
may be combined to form a cyclic structure including a part of the mother nucleus, and the ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituting atom and may further have an alkyl group having 1 to 6 carbon atoms as a substituent); and
Y
1
represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group] or Q is a partial structure represented by the following formula (IV):
(wherein R
11
represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms which may have one or more substituents, an aryl group which may have one or more substituents, a heteroaryl group which may have one or more substituents, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;
R
12
represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group represented by R
12
may have at least one substituent selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms;
X
3
represents a halogen atom or a hydrogen atom;
A
2
represents a nitrogen atom or a partial structure represented by the following formula (V):
(wherein X
4
represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an

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