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Claims for Patent: 6,265,536

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Claims for Patent: 6,265,536

Title: Cyclic hexapeptides having antibiotic activity
Abstract:This invention relates to new polypeptide compounds represented by the following formula (I): ##STR1## wherein R.sup.1 is as defined in the description and pharmaceutically acceptable salt thereof which have antimicrobial activities (especially, antifungal activities), inhibitory activity on .beta.-1,3-glucan synthase, to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the prophylactic and/or therapeutic treatment of infectious diseases including Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal.
Inventor(s): Ohki; Hidenori (Takarazuka, JP), Tomishima; Masaki (Minoo, JP), Yamada; Akira (Fujiidera, JP), Takasugi; Hisashi (Sakai, JP)
Assignee: Fujisawa Pharmaceutical Co., Ltd. (Osaka, JP)
Application Number:09/248,267
Patent Claims: 1. A polypeptide compound of the following general formula (SEQ ID NO:1): ##STR133##

wherein R.sup.1 is lower alkanoyl substituted with unsaturated 6-membered heteromonocyclic group containing at least one nitrogen atom which may have one or more suitable substituent(s);

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing at least ore oxygen atom which may have one or more suitable substituent(s);

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing 1 to 3 sulfur atom(s) which may have one or more suitable substituent(s);

lower alkanoyl substituted with saturated 3 to 8 membered heteromonocyclic group containing at least one nitrogen atom which may have one or more suitable substituent(s);

ar(lower)alkenoyl substituted with aryl which may have one or more suitable substituent(s);

naphthyl(lower)alkenoyl which may have one or more higher alkoxy;

lower alkynoyl which may have one or more suitable substituent(s);

(C.sub.2 -C.sub.6)alkanoyl substituted with naphthyl having higher alkoxy;

ar(C.sub.2 -C.sub.6)alkanoyl substituted with aryl having one or more suitable substituent(s), in which, ar(C2-C6)alkanoyl may have one or more suitable substituent(s);

aroyl substituted with heterocyclic group which may have one or more suitable substituent(s), in which aroyl may have one or more suitable substituent(s);

aroyl substituted with aryl having lower alkoxy(higher)alkoxyl;

aroyl substituted with aryl having lower alkyl;

aroyl substituted with aryl having higher alkyl;

ar(lower)alkoxy(lower)alkanoyl which may have one or more suitable substituent(s);

arylamino(lower)alkanoyl which may have one or more suitable substituent(s);

lower alkanoyl substituted with pyrazolyl which has lower alkyl and aryl having higher alkoxy;

lower alkoxy(higher)alkanoyl, in which higher alkanoyl may have one or more suitable substituent(s);

aroyl substituted with cyclo(lower)alkyl having lower alkyl; indolylcarbonyl having higher alkyl;

naphthoyl having lower alkyl;

naphthoyl having higher alkyl;

naphthoyl having lower alkoxy(higher)alkoxy;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy(higher)alkoxy;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl which has aryl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl having heterocyclicoxy(higher)alkoxy;

aroyl substituted with aryl having aryloxy(lower)alkoxy;

lower alkanoyl substituted with oxazolyl which has aryl having higher alkoxy;

higher alkanoyl having hydroxy;

higher alkanoyl having ar(lower)alkyl and hydroxy; or 3-methyl-tridecenoyl; and a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

R.sup.1 is lower alkanoyl substituted with unsaturated 6-membered heteromonocyclic group containing at least one nitrogen atom which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, 3 to 8-membered saturated heteromonocyclic group containing at least one nitrogen atom which may have phenyl having higher alkoxy, phenyl substituted with phenyl having lower alkoxy, 3 to 8-membered saturated heteromonocyclic group containing at least one nitrogen atom which may have phenyl having lower alkoxy(higher)alkoxy, 3 to 8-membered saturated heteromonocyclic group containing at least one nitrogen atom which may have phenyl having lower alkoxy, and oxo;

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing at least one oxygen atom which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenol having; lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, unsaturated 6-membered heteromonocyclic group containing at least one nitrogen atom which may have higher alkoxy, and oxo;

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing 1 to 3 sulfur atom(s) which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, and oxo;

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing 2 or more nitrogen atoms which may have 1 to 3 substituent(s) selected from the group containing of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, and oxo; or

lower alkanoyl substituted with saturated 3 to 8-membered heteromonocyclic group containing at least one nitrogen atom which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, and oxo.

3. A compound of claim 1, wherein

R.sup.1 is ar(lower)alkenoyl substituted with aryl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, lower alkoxy(lower)alkyl, halo(lower)alkoxy, lower alkenyloxy, halo(higher)alkoxy, lower alkoxy(higher)alkoxy, and oxo;

naphthyl(lower)alkenoyl which may have 1 to 1 higher alkoxy;

lower alkynoyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, and oxo;

ar(C.sub.2 -C.sub.6)alkanoyl substituted with aryl having 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, phenyl having lower alkoxy(lower)alkoxy, and oxo, in which ar(C.sub.2 -C.sub.6)-alkanoyl may have hydroxy, oxo, protected amino or amino; or

(C.sub.2 -C.sub.6)alkanoyl substituted with naphthyl having higher alkoxy.

4. A compound of claim 1, wherein

R.sup.1 is aroyl substituted with heterocyclic group which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, naphthoyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, phenyl having lower alkoxy(higher)alkoxy, phenyl having higher alkenyloxy, heterocyclic group substituted with phenyl having lower alkoxy, heterocyclic group, cyclo(lower)alkyl having phenyl, phenyl having cyclo(lower)alkyl, phenyl substituted with heterocyclic group having lower alkyl and oxo, cyclo(lower)alkyl having lower alkyl, phenyl substituted with phenyl having lower alkoxy, phenyl having heterocyclic group and oxo, in which aroyl may have halogen;

aroyl substituted with aryl having lower alkoxy(higher)alkoxy;

aroyl substituted with aryl having lower alkyl; or aroyl substituted with aryl having higher alkyl.

5. A compound of claim 1, wherein

R.sup.1

ar(lower)alkoxy(lower)alkanoyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, higher alkoxy(lower)alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, naphthyl having lower alkoxy, naphthyl having higher alkoxy, phenyl having lower alkyl, phenyl having higher alkyl, phenyl having higher alkoxy, phenyl substituted with phenyl having lower alkyl, and oxo; or.

6. A compound of claim 1, wherein

R.sup.1 is lower alkanoyl substituted with pyrazolyl which has lower alkyl and aryl having higher alkoxy;

lower alkoxy(higher)alkanoyl, in which higher alkanoyl may have amino or protected amino;

aroyl substituted with cyclo(lower)alkyl having lower alkyl;

indolylcarbonyl having higher alkyl;

naphthoyl having lower alkyl;

naphthoyl having higher alkyl;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy(higher)alkoxy;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl which has phenyl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl having heterocyclicoxy(higher)alkoxy;

aroyl substituted with aryl having phenoxy(lower)alkoxy;

lower alkanoyl substituted with oxazolyl which has aryl having higher alkoxy;

higher alkanoyl having hydroxy;

higher alkenoyl having benzyl and hydroxy; or

3-methyl-tridecenoyl.

7. A compound of claim 2, wherein

R.sup.1 is lower alkanoyl substituted with pyridyl or pyridazinyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of higher alkoxy, higher alkoxy(lower)alkyl, phenyl having higher alkoxy, phenyl substituted with phenyl having lower alkoxy, piperazinyl substituted with phenyl having higher alkoxy, piperazinyl substituted with phenyl having lower alkoxy(higher)alkoxy, and piperazinyl substituted with phenyl having lower alkoxy;

lower alkanoyl substituted with coumarin which may have 1 to 3 substituent(s) selected from the group consisting of higher alkoxy, and oxo;

lower alkanoyl substituted with benzothiophenyl which may have 1 to 3 higher alkoxy;

lower alkanoyl substituted with benzofuranyl which may have 1 to 3 substituent(s) selected from the group consisting of higher alkoxy and lower alkyl;

lower alkanoyl substituted with benzooxazolyl which may have 1 to 3 substituent(s) selected from the group consisting of higher alkyl, phenyl having lower alkoxy, phenyl substituted with phenyl having lower alkyl, and pyridyl having higher alkoxy;

lower alkanoyl substituted with benzimidazolyl which may have 1 to 3 substituent(s) selected from the group consisting of higher alkyl, and phenyl having lower alkoxy; or

lower alkanoyl substituted with piperidyl or pierazinyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having higher alkoxy, and naphthoyl having higher alkoxy.

8. A compound of claim 3, wherein

R.sup.1 is phenyl(lower)alkenoyl substituted with phenyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, lower alkyl, higher alkyl, lower alkoxy(lower)alkyl, halo(lower)alkoxy, lower alkenyloxy, halo(higher)alkoxy, and lower alkoxy(higher)alkoxy;

naphthyl(lower)alkenoyl which may have 1 to 3 higher alkoxy;

lower alkynoyl which may have 1 to 3 substituent(s) selected from the group consisting of naphthyl having higher alkoxy, and phenyl substituted with phenyl having lower alkyl;

phenyl(C.sub.2 -C.sub.6)alkanoyl substituted with phenyl which has 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, higher alkoxy, lower alkyl, higher alkyl, and phenyl having lower alkoxy(lower)alkyl,

in which phenyl (C.sub.2 -C.sub.6)alkanoyl may have hydroxy, oxo, protected amino or amino; or

(C.sub.2 -C.sub.6)alkanoyl substituted with naphthyl having higher alkoxy.

9. A compound claim 4, wherein

R.sup.1 is benzoyl substituted with saturated 6-membered heteromonocyclic group containing at least one nitrogen atom which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having lower alkoxy, phenyl having higher alkoxy, phenyl having lower alkyl, phenyl having lower alkoxy(higher)alkoxy, phenyl having higher alkenyloxy, piperidyl substituted with phenyl having lower alkoxy, piperidyl, cyclo(lower)alkyl having phenyl, phenyl having cyclo(lower)alkyl, and phenyl substituted with triazolyl having oxo and lower alkyl,

in which benzoyl may have halogen;

benzoyl substituted with unsaturated 5-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) which may have 1 to 3 substituent(s) selected from the group consisting of higher alkyl, phenyl having lower alkoxy, phenyl having higher alkoxy, phenyl having lower alkoxy(higher)alkoxy, and phenyl substituted with phenyl having lower alkoxy;

benzoyl substituted with 5 or 6-membered heteromonoccyclic group containing 1 or 2 nitrogen atom(s) which may have 1 to 3 substituent(s) selected from the group consisting of higher alkyl and phenol having lower alkoxy;

benzoyl substituted with 5-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) and 1 to 2 sulfur atom(s) which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having lower alkoxy, phenyl having higher alkoxy, cyclo(lower)alkyl having lower alkyl, phenyl substituted with phenyl having lower alkoxy, phenyl having cyclo(lower)alkyl, phenyl having piperidine, and phenyl having lower alkoxy(higher)alkoxy;

benzoyl substituted with phenyl having lower alkoxy(higher)alkoxy;

benzoyl substituted with phenol having lower alkyl; or

benzoyl substituted with phenyl having higher alkyl.

10. A compound of claim 5, wherein

R.sup.1 is phenyl(lower)alkoxy(lower)alkanoyl which may have 1 to 3 higher alkoxy.

11. A compound of claim 1, wherein

R.sup.1 is benzoyl substituted with piperazinyl which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having lower alkoxy, phenyl having higher alkoxy, phenyl having lower alkyl, phenyl having lower alkoxy(higher)alkoxy, phenyl having higher alkenyloxy, piperidyl substituted with phenyl having lower alkoxy, cyclo(lower)alkyl having phenyl, phenyl having cyclo(lower)alkyl, and phenyl substituted with triazolyl having oxo and lower alkyl, in which benzoyl may have halogen;

benzoyl substituted with isoxazolyl which may have 1 to 3 substituent(s) selected from the group consisting of higher alkyl, phenyl having higher alkoxy, phenyl having lower alkoxy(higher)alkoxy, and phenyl substituted with phenyl having lower alkoxy;

benzoyl substituted with phenyl having lower alkoxy(higher)alkoxy;

benzoyl substituted with phenyl having lower alkyl;

benzoyl substituted with phenyl having higher alkyl;

phenyl(lower)alkenoyl substituted with phenyl which may have 1 to 3 substituent(s) selected from the group consisting of lower alkoxy, lower alkyl, higher alkyl, lower alkoxy(lower)alkyl, halo(lower)alkoxy, lower alkenyloxy, halo(higher)alkoxy and lower alkoxy(higher)alkoxy;

benzoyl substituted with thiadiazolyl which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having lower alkoxy, phenyl having higher alkoxy, cyclo(lower)alkyl having lower alkyl, phenyl substituted with phenyl having lower alkoxy, phenyl having cyclo(lower)alkyl, phenyl having piperidyl, and phenyl having lower alkoxy(higher)alkoxy; or

benzoyl substituted with oxadiazolyl which may have 1 to 3 substituent(s) selected from the group consisting of phenyl having lower alkoxy, phenyl having higher alkoxy, phenyl having lower alkoxy(higher)alkoxy, higher alkyl and phenyl substituted with phenyl having lower alkoxy.

12. A compound of claim 11, wherein

R.sup.1 is benzoyl substituted with phenyl having lower alkoxy(higher)alkoxy; or

benzoyl substituted with phenyl having lower alkyl.

13. A compound of claim 11, wherein,

R.sup.1 is benzoyl substituted with piperazinyl which may have phenyl having lower alkoxy;

benzoyl substituted with thiadiazolyl which may have phenyl having lower alkoxy(higher)alkoxy; or

benzoyl substituted with oxadiazolyl which may have phenyl having lower alkoxy.

14. A compound of claim 11, wherein

R.sup.1 is phenyl(lower)alkenoyl substituted with phenyl which may have lower alkoxy.

15. A process for the preparation of a polypeptide compound of the formula (SEQ ID NO:1): ##STR134##

wherein

R.sup.1 is lower alkanoyl substituted with unsaturated 6-membered heteromonocyclic group containing at least one nitrogen atom which may have one or more suitable substituent(s);

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing at least one oxygen atom which may have one or more suitable substituent(s);

lower alkanoyl substituted with unsaturated condensed heterocyclic group containing 1 to 3 sulfur atom(s) which may have one or more suitable substituent(s);

lower alkanoyl substituted with saturated 3 to 8-membered heteromonocyclic group containing at least one nitrogen atom which may have one or more suitable substituent(s);

ar(lower)alkenoyl substituted with aryl which may have one or more suitable substituent(s);

naphthyl(lower)alkenoyl which may have one or more higher alkoxy;

lower alkynoyl which may have one or more suitable substituent(s);

(C.sub.2 -C.sub.6)alkanoyl substituted with naphthyl having higher alkoxy;

ar(C.sub.2 -C.sub.6)alkanoyl substituted with aryl having one or more suitable substituent(s), in which ar(C.sub.2 -C.sub.6) alkanoyl may have one or more suitable substituent(s);

aroyl substituted with heterocyclic group which may have one or more suitable substituent(s), in which aroyl may have one or more suitable substituent(s);

aroyl substituted with aryl having lower alkoxy(higher)alkoxy;

aroyl substituted with 2 lower alkoxy;

aroyl substituted with aryl having lower vinyl;

aroyl substituted with aryl having higher alkyl;

ar(lower)alkoxy(lower)alkanoyl which may have one or more suitable substituent(s);

lower alkanoyl substituted with pyrazolyl which has lower alkyl and aryl having higher alkoxy;

lower alkoxy(higher)alkanoyl, in which higher alkanoyl may have one or more suitable substituent(s);

aroyl substituted with cyclo(lower)alkyl having lower alkyl;

indolylcarbonyl having higher alkyl;

naphthoyl having lower alkyl;

naphthoyl having higher alkyl;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy(higher)alkoxy;

aroyl substituted with aryl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl which has aryl having lower alkoxy(lower)alkoxy;

aroyl substituted with aryl having heterocyclicoxy(higher)alkoxy;

aroyl substituted with aryl having aryloxy(lower)alkoxy;

lower alkanoyl substituted with oxazolyl which has aryl having higher alkoxy;

higher alkanoyl having hydroxy;

higher alkanoyl having ar(lower)alkyl and hydroxy; or

3-methyl-tridecenoyl; and

a pharmaceutically acceptable salt thereof,

which comprises

1) reacting a compound of the formula: ##STR135##

or its reactive derivative at the amino group or a salt thereof, with a compound of the formula:

wherein R.sup.1 is defined above,

or its reactive derivative at the carboxy group or a salt thereof, to give a compound of the formula: ##STR136##

wherein R.sup.1 is defined above, or a salt thereof.

16. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.

17. A method for the prophylactic and/or the therapeutic treatment of infectious diseases caused by pathogenic microorganisms which may comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
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