Severe sepsis preventive therapeutic agent
The present invention provides an agent for the prophylaxis or treatment of severe sepsis, which contains a compound represented by the formula (I): or, the formula (II): , or a salt thereof or a prodrug thereof, a TLR signal inhibitor containing a non-peptide compound and an agent for the prophylaxis or treatment of organ dysfunction and the like, which contains a TLR signal inhibitory substance.
1 . An agent for the prophylaxis or treatment of severe sepsis, which comprises a cycloalkene compound as an active ingredient.
2 . An agent for the prophylaxis or treatment of severe sepsis, which comprises a compound represented by the formula (I):
wherein
R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1 wherein R 1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or a group represented by the formula:
wherein
R 1b and R 1c are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents,
R 0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination form a bond,
ring A 1 represents a cycloalkene optionally substituted by 1 to 4 substituents selected from the group consisting of
(1) an aliphatic hydrocarbon group optionally having substituents,
(2) an aromatic hydrocarbon group optionally having substituents,
(3) a group represented by the formula: —OR 11 wherein R 11 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents and
(4) a halogen atom,
Ar represents an aromatic hydrocarbon group optionally having substituents,
a group represented by the formula:
represents a group represented by the formula:
and
n represents an integer of 1 to 4,
or a salt thereof or a prodrug thereof, or a compound represented by the formula (II):
wherein R 1′ represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1a′ wherein R 1a′ represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or a group represented by the formula:
wherein R 1b′ and R 1c′ are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents,
X represents a methylene group, NH, a sulfur atom or an oxygen atom,
Y represents a methylene group optionally having substituents or NH optionally having substituents,
ring A′ represents a 5- to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of (1) an aliphatic hydrocarbon group optionally having substituents, (2) an aromatic hydrocarbon group optionally having substituents, (3) a group represented by the formula: —OR 2′ wherein R 2′ represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents and (4) a halogen atom,
Ar′ represents an aromatic hydrocarbon group optionally having substituents,
a group represented by the formula:
represents a group represented by the formula:
s represents an integer of 0 to 2,
t represents an integer of 1 to 3, and
the total of s and t is not more than 4;
provided that when X is a methylene group, Y represents a methylene group optionally having substituents, or a salt thereof or a prodrug thereof.
3 . The agent of claim 2 , wherein the formula (I) is the formula (Ia):
wherein R 1a represents a C 1-6 alkyl, R 2a represents a hydrogen atom or a C 1-6 alkyl and Ar a represents a phenyl group substituted by 1 or 2 halogen atoms, and the formula (II) is the formula (IIa):
wherein R 1a″ represents a C 1-6 alkyl, X a represents a methylene group or an oxygen atom, Y a represents a methylene group or —NH— and Ar a , represents a phenyl group optionally having 1 or 2 substituents selected from a halogen atom and a C 1-6 alkoxy group.
4 . The agent of claim 2 , further comprising at least one kind of drug selected from the group consisting of antibacterial agent, antifungal agent, non-steroidal antiinflammatory drug, steroid and anticoagulant.
5 . A method for the prophylaxis or treatment of severe sepsis, which comprises administration of an effective amount of a compound represented by the formula (I) or the formula (II) or a salt thereof or a prodrug thereof described in claim 2 to a mammal.
6 . Use of a compound represented by the formula (I) or the formula (II) or a salt thereof or a prodrug thereof described in claim 2 for the production of an agent for the prophylaxis or treatment of severe sepsis.
7 . A TLR signal inhibitor comprising a non-peptide compound as an active ingredient.
8 . The agent of claim 7 , wherein the non-peptide compound is a non-peptide compound having a molecular weight of not more than about 1000.
9 . The agent of claim 8 , wherein the non-peptide compound is a compound represented by the formula (I):
wherein R represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1 wherein R 1 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or a group represented by the formula:
wherein R 1b and R 1c are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents,
R 0 represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R 0 in combination form a bond,
ring A 1 represents a cycloalkene optionally substituted by 1 to 4 substituents selected from the group consisting of (1) an aliphatic hydrocarbon group optionally having substituents, (2) an aromatic hydrocarbon group optionally having substituents, (3) a group represented by the formula: —OR 11 wherein R 11 represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents and (4) a halogen atom,
Ar represents an aromatic hydrocarbon group optionally having substituents,
a group represented by the formula:
represents a group represented by the formula:
and
n represents an integer of 1 to 4, or a salt thereof or a prodrug thereof, or, a compound represented by the formula (II):
wherein R 1′ represents an aliphatic hydrocarbon group optionally having substituents, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a group represented by the formula: —OR 1a′ wherein R 1a′ represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents, or
a group represented by the formula:
wherein R 1b′ and R 1c′ are the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents,
X represents a methylene group, NH, sulfur atom or oxygen atom,
Y represents a methylene group optionally having substituents or NH optionally having substituents,
ring A′ represents a 5 to 8-membered ring optionally having 1 to 4 substituents selected from the group consisting of (1) an aliphatic hydrocarbon group optionally having substituents, (2) an aromatic hydrocarbon group optionally having substituents, (3) a group represented by the formula: —OR 2′ wherein R 2′ represents a hydrogen atom or an aliphatic hydrocarbon group optionally having substituents and (4) a halogen atom,
Ar′ represents an aromatic hydrocarbon group optionally having substituents,
a group represented by the formula:
represents a group represented by the formula:
s represents an integer of 0 to 2,
t represents an integer of 1 to 3,
the total of s and t is not more than 4;
provided that when X is a methylene group, Y represents a methylene group optionally having substituents, or a salt thereof or a prodrug thereof.
10 . The agent of claim 7 , wherein TLR is TLR4.
11 . An agent for the prophylaxis or treatment of a disease caused by a change in a TLR signal, which comprises the agent of claim 7 .
12 . The agent of claim 11 , wherein the disease caused by the changes in the TLR signal is organ dysfunction.
13 . The agent of claim 12 , wherein the organ is an organ of central nervous system, circulatory system, respiratory system, bone and joint system, digestive system or renal and urinary system.
14 . A method for the inhibition of TLR signal, which comprises administration of an effective amount of a non-peptide compound to a mammal.
15 . A method for the prophylaxis or treatment of a disease caused by a change in a TLR signal, which comprises administration of an effective amount of a non-peptide compound to a mammal.
16 . Use of a non-peptide compound for the production of a TLR signal inhibitor.
17 . Use of a non-peptide compound for the production of an agent for the prophylaxis or treatment of a disease caused by a change in a TLR signal.
18 . An agent for the prophylaxis or treatment of organ dysfunction, which comprises a TLR signal inhibitory substance.
19 . The agent of claim 18 , wherein the organ is an organ of central nervous system, circulatory system, respiratory system, bone and joint system, digestive system or renal and urinary system.
20 . A method for the prophylaxis or treatment of severe sepsis or organ dysfunction, which comprises inhibition of TLR signal.