Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-09
2002-10-29
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S269000, C540S488000, C544S209000, C544S310000
Reexamination Certificate
active
06472384
ABSTRACT:
The present invention relates to a compound of formula (I), (XI), (XII), (XIII), (XIV), (XV) or (XVI) and a derivative of a compound of formula (Ia) which have excellent antibiotic activity or a pharmaceutically acceptable salt thereof.
FIELD OF THE INVENTION
The present invention is also a pharmaceutical composition comprising a compound described above as an active ingredient effective to treat or prevent infectious diseases.
The present invention includes a use of a compound described above in order to prepare a medicament effective to treat or prevent infectious diseases.
The present invention is concerned with a method effective to treat or prevent infectious diseases in warm-blooded animals comprising administering a pharmacologically effective amount of a compound described above to them.
The present invention includes a microorganism capable of producing a compound of formula (I), (XI), (XII), (XIV), (XV) or (XVI).
The present invention also includes a process for preparing a compound of formula (I), (XI), (XII), (XIV), (XV) or (XVI) using the said microorganism.
BACKGROUND OF THE INVENTION
A &bgr;-lactam antibiotic, an amino-glycoside, isoniazid or rifampicin has been conventionally used in treatment or prophylaxis of microbial infections including tubercule bacillus. Recently there have been a lot of bacteria resistant to these antibiotics. It is desirable to develop new compounds which are different type antimicrobial agents from conventional ones.
On the other hand it has been known that capuramycin having a formula shown below exhibits anti-tubercule bacillus activity (J. Antibiotics. 29. (8). 1047-1053 (1986)).
We found new compounds of formula (I), (XI), (XII), (XIV), (XV) or (XVI). which do not show any cross resistance to conventional medicaments, in the cultivation products of a microorganism. We prepared the derivatives of compounds described above and capuramycin. We studied the physiological activity of these derivatives for several years and found that these derivatives exhibit excellent antibiotic activity.
The compounds of the present invention can provide a method effective to treat and prevent infection diseases including ones arising from bacteria resistant to the conventional antibiotics. Compounds of formula (I), (XI), (XII), (XIV), (XV) or (XVI) are also useful starting materials for preparation of the compounds of the present invention having excellent antibiotic activity.
DISCLOSURE OF THE INVENTION
The present invention includes a compound of formula (I)
(wherein
R
1
is a methyl group, R
2
is a methyl group, R
4
is a hydroxy group, and X is a methylene group;
R
1
is a methyl group, R
2
is a hydrogen atom, R
4
is a hydroxy group, and X is a methylene group;
R
1
is a methyl group, R
2
is a methyl group, R
4
is a hydrogen atom, and X is a methylene group;
R
1
is a hydrogen atom, R
2
is a hydrogen atom, R
4
is a hydroxy group, and X is a methylene group; or
R
1
is a methyl group, R
2
is a methyl group, R
4
is a hydroxy group, and X is a sulfur atom) or a pharmaceutically acceptable salt thereof; or
a pharmaceutically acceptable ester, ether or N-alkylcarbamoyl derivative of a compound of formula (Ia)
(wherein R
1
is a hydrogen atom or a methyl group, R
2
a
is a hydrogen atom, a protecting group for a hydroxy group, or a methyl group, R
3
is a hydrogen atom or a protecting group for a hydroxy group, R
4
a
is a hydrogen atom, a hydroxy group or a protected hydroxy group, R
5
is a hydrogen atom or a protecting group for a hydroxy group, and X is a methylene group or a sulfur atom,
with the proviso that
when
X is a sulfur atom,
R
1
is a methyl group, R
2
a
is a methyl group, and R
4
a
is a hydroxy group or a protected hydroxy group;
when
X is a methylene group, R
1
is a methyl group, and R
2
a
is a hydrogen atom,
R
4
a
is a hydroxy group or a protected hydroxy group; or
when
X is a methylene group and R
1
is a hydrogen atom,
R
2
a
is a methyl group and R
4
a
is a hydroxy group or protected hydroxy group);
or a pharmaceutically acceptable salt thereof.
the term “N-alkylcarbamoyl” as used hereinafter in the specification includes N-alkylcarbamoyl, N-alkenylcarbamoyl and N-alkynylcarbamoyl.
The present invention is also a pharmaceutical composition comprising a compound described above as an active ingredient effective to treat or prevent infectious diseases.
The present invention includes the use of a compound described above in order to prepare a medicament effective to treat or prevent infectious diseases.
The present invention is concerned with a method effective to treat or prevent infectious diseases in warm-blooded animals comprising administering a pharmacologically effective amount of a compound described above to them.
The present invention includes a microorganism capable of producing a compound of formula (I).
The present invention also includes a process for preparing a compound of formula (I) using the said microorganism.
In the above formulae, the protecting group of “protecting group for a hydroxy group” and “protected hydroxy group” of R
2
a
and the like can be removed by a chemical procedure such as hydrogenolysis, hydrolysis, electrolysis or photolysis (hereinafter referred to as a general protecting group) or can be removed by biological method such as hydrolysis in vivo (with the proviso that it is not an ester residue group such as an acyl group). “The protecting group which can be removed by biological method such as hydrolysis in vivo” can be cleaved by biologically method such as hydrolysis in the human body to give a corresponding free acid or a salt thereof. Whether a compound has a protecting group removed in vivo is determined by detection of a corresponding parent compound or a pharmaceutically acceptable salt thereof in the body fluid of a rat or mouse to which it is administered by intravenous injection.
A general protecting group is selected from the group consisting of:
“tetrahydropyranyl and tetrahydrothiopyranyl group” such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl;
“tetrahydrofuranyl and tetrahydrothiofuranyl group” such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl;
“tri(lower alkyl)silyl group (hereinafter a lower alkyl moiety represents a group selected from the group consisting of C
1
-C
6
alkyl group such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group) such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, diisopropylmethylsilyl, di(tert-butyl)methylsilyl and triisopropylsilyl group;
“silyl group substituted with one or two aryl groups and two or one lower alkyl groups” such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and diisopropylphenylsilyl;
“lower alkoxymethyl group” (hereinafter an alkoxy moiety represents a group selected from the group consisting of C
1
-C
6
alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy), such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl;
“lower alkoxy-lower alkoxylmethyl group” such as the 2-methoxyethoxymethyl group;
“halogeno-lower-alkoxymethyl group” such as the 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl group;
“substituted ethyl group”, for example an ethyl group substituted with a lower alkoxy group such as the 1-ethoxyethyl or 1-(isopropoxy)ethyl group, and for example a halogenoethyl group such as the 2,2,2-trichloroethyl group;
“aralkyl group” (aryl moiety is selected from the group consisting of C
6
-C
14
aryl group such as phenyl, naphthyl, biphenyl, anthryl and phenanthryl group), for example a lower alkyl group substituted with 1 to 3 aryl groups such as benzyl, &agr;-naphthyl, &bgr;-naphthyl, diphenylmethyl, triphenylmethyl, &agr;-naphthyldiphenylmethyl and 9-anthrylmethyl, and for example a lower alkyl group substituted with 1 to 3 aryl groups, which are sub
Arai Masatoshi
Hotoda Hitoshi
Inukai Masatoshi
Kaneko Masakatsu
Kizuka Masaaki
Frishauf Holtz Goodman & Chick P.C.
Sankyo Company Limited
Shah Mukund J.
Truong Tamthom N.
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