WO1998017625A1 - Nouveaux remedes pour des maladies infectieuses - Google Patents

Nouveaux remedes pour des maladies infectieuses Download PDF

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Publication number
WO1998017625A1
WO1998017625A1 PCT/JP1997/003812 JP9703812W WO9817625A1 WO 1998017625 A1 WO1998017625 A1 WO 1998017625A1 JP 9703812 W JP9703812 W JP 9703812W WO 9817625 A1 WO9817625 A1 WO 9817625A1
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Prior art keywords
group
carbon atoms
groups
alkoxyl
alkylthio
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PCT/JP1997/003812
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English (en)
Japanese (ja)
Inventor
Toshiharu Ohta
Kiyoshi Nakayama
Masami Ohtsuka
Hiroaki Inagaki
Toshiyuki Nishi
Yohhei Ishida
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Daiichi Pharmaceutical Co., Ltd.
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Priority to AU47221/97A priority Critical patent/AU4722197A/en
Priority to JP51922598A priority patent/JP4024309B2/ja
Publication of WO1998017625A1 publication Critical patent/WO1998017625A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • the present invention relates to a compound useful for the prevention and / or treatment of a microbial infection, or a medicament containing the compound as an active ingredient.
  • a number of antibacterial agents have been developed to date for the prevention and / or treatment of microbial infections, such as / 3-lactam, macrolide, tetracycline, chloramphenicol or quinolone.
  • microbial infections such as / 3-lactam, macrolide, tetracycline, chloramphenicol or quinolone.
  • antibiotics in clinical practice, the emergence of resistant bacteria to these antibiotics has become remarkable, which has become an important problem in the treatment of infectious diseases.
  • Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus are among the bacterial species that have been particularly problematic in recent infectious disease treatments.
  • Antimicrobial agents that are therapeutically effective against these bacterial species are currently limited, and there is no guarantee that therapeutic effects will be expected in the future with these effective agents.
  • infectious diseases caused by these bacteria are becoming a very serious problem in medical settings, especially in patients with reduced immunity. is there.
  • Pseudomonas aeruginosa drug efflux pumps are involved in the multidrug resistance of Pseudomonas aeruginosa because they pump / 3-lactam, tetracycline, chloramphenicol, or quinoline drugs.
  • antibacterial drugs with a new skeleton that can avoid resistance by a drug efflux pump, which is one of the factors of resistance, or existing antibacterial drugs by inhibiting the function of drug efflux pumps Providing a drug that restores the efficacy of the drug is considered to be an effective means. Disclosure of the invention
  • An object of the present invention is to provide a prophylactic and / or therapeutic agent for an infectious disease having an action of improving the antibacterial action of an antibacterial drug on pathogenic microorganisms. More specifically, it can inhibit the resistance mechanism of pathogenic microorganisms that have acquired resistance to an existing antimicrobial agent, and can prevent and / or prevent the antimicrobial agent against microbial infections caused by these microorganisms. Alternatively, it is an object of the present invention to provide a medicament capable of improving the therapeutic effect.
  • the present inventors have conducted intensive studies to find a compound having an effect of reducing the resistance to Pseudomonas aeruginosa which has acquired resistance, and the cyclic compound represented by the general formula (I) exerts this effect. And found to be useful as a medicament for the prevention and / or treatment of microbial infections. The present invention has been completed based on these findings.
  • the present invention provides a compound represented by the formula (1) having a substituent, R 2 and R 3 in a cyclic portion, a salt thereof, and a hydrate and a solvate thereof:
  • the cyclic structure portion is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom
  • a 5- to 7-membered ring which may contain 1 to 3 heteroatoms, wherein the ring is saturated (non-aromatic), partially unsaturated (non-aromatic), or fully unsaturated (aromatic) ) May be either;
  • This cyclic structure has another aromatic ring or 5- to 8-membered cycloalkane (the aromatic ring or 5- to 8-membered cycloalkane is selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Which may contain 1 to 3 heteroatoms) to form a bicyclic or tricyclic ring structure;
  • the ring may be 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.
  • Groups, alkanoyl groups having 2 to 6 carbon atoms include halogen atoms, hydroxyl groups, alkoxyl groups, amino groups, alkylamino groups, dialkylamino groups, and carboxyl groups).
  • R 1 has the formula:
  • a 11_ Q 11_ A 12_ C (R 11 ) (Q 12_ X 1L Y 1 ) _ Q 13_ N (R 12 ) represents a substituent represented by (R 13 ) ;
  • a 11 and A 12 each independently represent a single bond or an alkylene group having 1 or 2 carbon atoms, wherein the alkylene group is an alkyl group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms.
  • Groups, C1 to C6 alkylthio groups, C2 to C6 alkanoyl groups (these alkyl groups, alkoxyl groups, alkylthio groups, and alkanoyl groups include halogen atoms, hydroxyl groups, alkoxyl groups, and amino groups.
  • Q 11 represents a single bond, -CO-, or -N (R 14 ) -CO-;
  • Q 12 and Q 13 each independently represent a single bond, an alkylene group having 1 to 5 carbon atoms, or a cycloalkylene group having 3 to 6 carbon atoms;
  • the alkylene group includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanol group having 2 to 6 carbon atoms.
  • the alkyl group, the alkoxyl group, the alkylthio group, and the alkanol group include a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and It may have one or more substituents selected from the group consisting of thioxo groups.), Halogen atom, hydroxyl group, amino group, alkylamino group, alkylamino group, carboxyl group, thiol group, And one or more substituents selected from the group consisting of May contain one or more unsaturated bonds, and / or one or more carbonyl groups,
  • the cycloalkylene group includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanoyl group having 2 to 6 carbon atoms.
  • Group, alkoxyl group, alkylthio group, and alkanoyl group are formed from a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.
  • substituents selected from the group consisting of:), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, and a thiol group. It may have one or more selected substituents;
  • X 11 represents a single bond, -0-, -S-, or -N (R 15 )-;
  • R 12 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanol group having 2 to 6 carbon atoms, or an ⁇ -amino acid residue bonded at the C-terminus;
  • Q 12 or Q 13 is an alkylene group
  • R 12 includes Q 13 , or ⁇ ⁇ 1 so as to form a 5- or 6-membered ring including the nitrogen atom to which it is bonded. May be combined with;
  • R 11 , R 13 , R 14 , and 5 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkanoyl group having 2 to 6 carbon atoms;
  • the lucanyl group has one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, an alkylthio group, and a thiol group.
  • ⁇ 1 is a phenyl group or a 3- to 8-membered cycloalkyl group, or 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom A 5- or 6-membered aromatic heterocyclic group or a 3- to 8-membered cycloalkyl group;
  • phenyl, cycloalkyl, and heterocyclic groups are each an alkyl group having 1 to 6 carbon atoms (this alkyl group is a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, a dialkylamino group, an aminoalkyl group, It may have one or more substituents selected from the group consisting of a carboxyl group, an alkylthio group, a thiol group, an oxo group, and a thioxo group.), A halogen atom, a hydroxyl group, and a carbon number of 1 to 6 Alkoxyl groups, thiol groups, alkylthio groups having 1 to 6 carbon atoms, dialkylamino groups having alkyl groups having 1 to 6 carbon atoms (the two alkyl groups may be the same or different Good), alkylamino group having 1 to 6 carbon atoms, amino group, amino group, nitro group, carboxyl group, 2 to
  • the cyclic structure includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanoyl group having 2 to 6 carbon atoms.
  • Alkyl, alkoxyl, alkylthio, and alkanol groups are formed from halogen atom, hydroxyl group, alkoxyl group, amino group, alkylamino group, dialkylamino group, carboxyl group, thiol group, alkylthio group, oxo group, and thioxo group.
  • R 2 has the formula:
  • a 21 is a single bond, -CO-, or an alkylene group having 1 to 6 carbon atoms
  • the alkylene group is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, To 6 alkylthio groups, alkanoyl groups having 2 to 6 carbon atoms (these alkyl groups, alkoxyl groups, alkylthio groups, and alkanoyl groups include halogen atoms, hydroxyl groups, alkoxyl groups, amino groups, alkylamino groups, dialkyl It may have one or more substituents selected from the group consisting of an amino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.), A halogen atom, a hydroxyl group, One or more selected from the group consisting of an amino group, an alkylamino group, a dialkylamino group, a
  • Q 21 represents a single bond, an alkylene group having 1 to 5 carbon atoms, or a cycloalkylene group having 3 to 6 carbon atoms,
  • the alkylene group includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanol group having 2 to 6 carbon atoms.
  • Alkyl, alkoxyl, alkylthio, and alkanol groups include a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, And one or more substituents selected from the group consisting of: a thioxo group and a thioxo group.), A halogen atom, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, And may have from 1 to 3 substituents selected from the group consisting of
  • the alkylene group may contain one or more unsaturated bonds and / or one or more carbonyl groups at any position in the chain, and the cycloalkylene group Is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 2 to 6 carbon atoms (these alkyl groups, alkoxyl groups , An alkylthio group, and an alkanoyl group are selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.
  • Halogen atom may have one or more substituents.
  • Halogen atom may have one or more substituents.
  • Halogen atom may have one or more substituents selected from the group consisting of a lumino group, a carboxyl group, and a thiol group;
  • R 21 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanol group having 2 to 6 carbon atoms, or an ⁇ -amino acid residue bonded at the C-terminus.
  • the alkanoyl group has one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, an alkylthio group, and a thiol group.
  • R 22 and R 23 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkanoyl group having 2 to 6 carbon atoms, wherein the alkyl group and the alkanoyl group are a halogen atom, a hydroxyl group, It may have one or more substituents selected from the group consisting of an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, an alkylthio group, and a thiol group;
  • Q 21 is an alkylene group having 1 to 3 carbon atoms
  • ⁇ 1 is -N (R 23 )-
  • 3 is an alkyl group
  • R 2tJ is the nitrogen to which this is bonded. It may be bonded to R 21 or Q 21 to form a 4- to 7-membered ring including an atom.
  • R 3 has the formula:
  • Xi 1— Qi 1— represents a substituent represented by ⁇ 2 ;
  • Chi upsilon 1 is a single bond, -CO, -S0 2 -, - (CHo) n -0-, - (CH 2) n - S, or - (CH 2) n - N (R 31) - a represents (Where n represents an integer of 0 to 3, and R 31 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkanoyl group having 2 to 6 carbon atoms.
  • the group has one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, an alkylthio group, and a thiol group. );
  • Q 31 represents a single bond, an alkylene group having 1 to 5 carbon atoms, a cycloalkylene group having 3 to 6 carbon atoms, or -N (R 32 ) -Q 32- ,
  • the alkylene group includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanol group having 2 to 6 carbon atoms.
  • the alkyl group, the alkoxyl group, the alkylthio group, and the alkanol group include a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and It may have one or more substituents selected from the group consisting of thioxo groups.), Halogen atom, hydroxyl group, amino group, alkylamino group, alkylamino group, carboxyl group, thiol group, cyclo Propyl group, phenyl group, And one or more substituents selected from the group consisting of
  • the alkylene group may include one or more unsaturated bonds and / or one or more carboxy groups at any position in the chain, and the cycloalkylene group may be ,
  • An alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanoyl group having 2 to 6 carbon atoms (these alkyl groups, alkoxyl groups,
  • the alkylthio group and the alkanol group are selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.
  • a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a dial Arylamino group, a carboxyl group, a thiol group, phenyl group, and base Njiru may have one or more substituents selected from the group consisting of groups;
  • Q 32 represents a single bond, a carbon number of 1 Represents 5 alkylene groups or a cycloalkylene group having 3 to 6 carbon atoms,
  • the alkylene group includes an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanol group having 2 to 6 carbon atoms.
  • the alkyl group, the alkoxyl group, the alkylthio group, and the alkanol group include a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and It may have one or more substituents selected from the group consisting of thioxo groups.), Halogen atom, hydroxyl group, amino group, alkylamino group, alkylamino group, carboxyl group, thiol group Having one or more substituents selected from the group consisting of, a phenyl group, a benzyl group, and a cyclopropyl group At best,
  • the alkylene group may contain one or more unsaturated bonds and / or one or more carbonyl groups at any position in the chain, and the cycloalkylene group Is an alkyl group with 1 to 6 carbon atoms, 1 to 6 carbon atoms An alkoxyl group, an alkylthio group having 1 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms (these alkyl groups, alkoxyl groups, alkylthio groups, and alkanoyl groups are a halogen atom, a hydroxyl group, an alkoxyl group).
  • R " 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkanol group having 2 to 6 carbon atoms, wherein the alkyl group and the alkanol group are a halogen atom, a hydroxyl group, an alkoxyl group. , An amino group, an alkylamino group, a dialkylamino group, a propyloxyl group, a thiol group, a phenyl group, and a benzyl group, which may have one or more substituents;
  • R 32 may be bonded to Q 32 so as to form a 5- to 8-membered ring;
  • ⁇ is a phenyl group or a 3- to 8-membered cycloalkyl group, or a 5-membered ring containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom Or a 6-membered aromatic heterocyclic group or a 3- to 8-membered cycloalkyl group,
  • phenyl, cycloalkyl, and heterocyclic groups are each an alkyl group having 1 to 6 carbon atoms (this alkyl group is a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, a dialkylamino group, an aminoalkyl group, It may have one or two or more substituents selected from the group consisting of a carboxyl group, a thiol group, an oxo group, and a thioxo group.), A halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms Alkyl group having 1 to 6 carbon atoms, dialkylamino group having an alkyl group having 1 to 6 carbon atoms (the two alkyl groups may be the same or different ), An alkylamino group having an alkyl group having 1 to 6 carbon atoms, an amino group, a nitro group, a carboxyl group, and an alkoxycarbo
  • phenyl, cycloalkyl, and heterocyclic groups may be substituted with other aromatic rings or 5- to 8-membered cycloalkanes (these aromatic rings or 5- to 8-membered cycloalkanes may be nitrogen, oxygen, And may contain 1 to 3 heteroatoms selected from the group consisting of, and a sulfur atom) may be condensed to form a bicyclic or tricyclic ring structure,
  • This cyclic structure is composed of an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkanoyl group having 2 to 6 carbon atoms.
  • An alkoxyl group, an alkylthio group, and an alkanoyl group include a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.
  • a halogen atom selected from the group:), a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an oxo group, And one to three substituents selected from the group consisting of thioxo groups.
  • the cyclic moiety represented by the formula A is cyclopentane, cyclopentanone, pyrrolin, pyrrolidine, 2-pyrrolidinone, 3-pyrrolidinone, pyrrole, dihydrofuran, tetrahydrofuran.
  • R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms.
  • Canyl group, phenyl group (these are one selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, a thiol group, an alkylthio group, an oxo group, and a thioxo group.
  • substituent R 2 is a group of the following substituents: Is a substituent selected from the group of substituents that substituent R 3 shown below
  • (G) a medicament comprising as an active ingredient a substance selected from the group consisting of the compound of the above formula (I) and salts thereof, and hydrates and solvates thereof;
  • a prophylactic and / or therapeutic drug for infectious diseases containing as an active ingredient a substance selected from the group consisting of the compound of the above formula (I) and salts thereof, and hydrates and solvates thereof;
  • a pharmaceutical composition comprising as an active ingredient a substance selected from the group consisting of the compound of the formula (I) and salts thereof, and hydrates and solvates thereof, and at least one antibacterial agent;
  • the above antibacterial drugs are synthetic quinoline antibacterial drugs, penicillin antibiotics, cephalosporin antibiotics, rubavenem antibiotics, penem antibiotics, and tetracycline antibiotics.
  • a pharmaceutical composition which is one or more antibacterial agents selected from the group consisting of rifamycin antibiotics, glycopeptide antibiotics, macrolide antibiotics, and chloramphenicol;
  • Antibacterial drugs include quinoline synthetic antibacterial drugs, benicillin antibiotics, cephalosporin antibiotics, rubavenem antibiotics, penem antibiotics, tetracycline antibiotics, The above-mentioned treatment or Z or prevention, which is one or two or more antibacterial agents selected from the group consisting of a mycin antibiotic, a glycopeptide antibiotic, a macrolide antibiotic, and lipoprotein Method;
  • (0) a method for producing a medicament, comprising compounding a substance selected from the group consisting of the compound of the above formula (I) and salts thereof, and hydrates and solvates thereof;
  • An agent for enhancing the sensitivity of a microorganism to an antibacterial drug which comprises, as an active ingredient, a substance selected from the group consisting of the compound of the formula (I) and a salt thereof, and a hydrate and a solvate thereof.
  • an “alkyl group” or one or more alkyl may be a straight or branched chain. And preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms.
  • the term “halogen atom” may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the number of substituents is not limited unless otherwise specified, but is preferably One to four, more preferably one to two, and even more preferably one.
  • alkylene and cycloalkylene may further contain a double bond in some cases.
  • the number of double bonds contained in these groups is not particularly limited, and includes, for example, one to three, more preferably one or two, and particularly preferably one double bond. You may go out.
  • the term “unsaturated bond” is used as a concept including both a double bond and a triple bond unless otherwise specified.
  • the compounds of the present invention have the formula (I):
  • the cyclic portion represented by the formula A means a hydrocarbon-based or complex ring-based cyclic structure.
  • This cyclic structure portion may be a 5-membered, 6-membered, or 7-membered ring.
  • examples of the cyclic moiety include cyclopentane, cyclopentanone, pyrroline, pyrrolidine, 2-pyrrolidinone, 3-pyrrolidinone, pyrrol, dihydrofuran, and Trahidrofuran, furan, tetrahydrodiothione, 3-thiophenone, thiophene, pyrazoline, virazolidin, and 3 pyrazones Lysinone, virazole, imidazoline, imidazolidin, --2-imidazolidinone, 4-imidazolidinone, hydantoin, imidazole, oxazolin, oxazolidin, oki / IN7 Sazo Use thiol, thiazolin, thiazolidin, thiazolidin-4-one, thiazolyl, isoxazoline, isoxazolidin, isoxazol, isothiazol
  • the resulting alpha [alpha] 1 - 2,) is converted to a substituent R 2 with I spoon compound alpha [alpha] 1 the same procedure described for the synthesis of one 4), and allows the introduction of R 1, compounds alpha [alpha] 1 _ 4 ,) can be synthesized.
  • Compound ⁇ 1 is obtained by converting the amino group of the compound ⁇ ⁇ ⁇ ⁇ ⁇ 1 into a substituent R 2 by reacting the amino group with a carboxylic acid or halide having a preferred substituent.
  • the compound of the formula ( 1A2 ) can be produced, for example, by the method shown in Reaction Scheme 12.
  • Reaction Scheme-2 the formulas (l A2 — 8 ), (1 A2 — u), (1 A2 — 12 ), and G A2 — 15 ) are compounds included in the formula G A2 ).
  • the compound (1 A2 — 6 ) converted to the substituent RA can be derived by using the above method. Then, - the carboxyl group of the ester group of (1 A9 6) obtained by hydrolyzing (l A o- 7), as R 2
  • tosyl derivative alpha .alpha.9 - can be guided to - 2) and azide derivatives alpha [alpha] 2 one 3) also has to the method shown in Scheme Therefore substituents 8 1, the R and ⁇ (i A9.
  • Compounds in which the cyclic moiety represented by Formula A is a six-membered ring include, for example, cyclohexane, cyclohexanone, benzene, piperidine, 2-pyridone, pyridine, and 2-hydroxypyridone.
  • examples of preferred substitution positions of the substituents R 1 R and ⁇ are represented by the following formulas ⁇ 1 ) to ⁇ ⁇ 2 () ), and ( ⁇ 1 ) and ⁇ 2 ) are, for example, a reaction formula — Can be manufactured by the method shown in 3.
  • Specific examples of the compound in which the cyclic moiety represented by the formula ⁇ is a 6-membered ring include, for example, N- (2,2-diphenylethyl) -3-glycylamino-5- (L-phenylarani) Rumino) benzamide, 3,5-bis (L-phenylalanylamino) - ⁇ - (2,2-diphenylethyl) benzamide, 3-amino-5- (refranylalanylamino) )- ⁇ - (2,2-diphenylethyl) benzamide, ⁇ - (2,2-diphenylethyl) -3- (3-aminopropionylamino) -5- (L-phenylaranilamyl) G) Benzamide, ⁇ - (3-phenylpropyl) -3-glycylamino-5- (L-phenylalanylamino) benzamide, 3,5-bis (L-phenylalanylamino),- ⁇
  • cyclic moiety represented by Formula A is a 7-membered ring, cycloheptane, cycloheptanone, homopiperidine, caprolactam, oxepane, 2-year-old xepanonone, hexamethylene sulfide, hexahi Dro-1,3-dazepine, hexahydra-1,3-dazepine-2-one, homopidazine, 1,4-dazepin-2-one, 1,4-dazepine-5,7-dione, 1,3,5-triazacycloheptane, 1,3,5-triazacycloheptane-2,
  • R 2 and R 3 examples of preferable substitution positions of the substituents, R 2 and R 3 are those represented by the formulas (i ei ) to (ie 6 ).
  • Specific compounds include 1,4-bis- ⁇ -homogenylalanyl) -6- (glycylamino) hexahydro-1H-1,4-dazepine, 1-((S) -2-amino- 4-phenylbutyl) -3-C3-aminopropyl) -5- (2-naphthylmethyl) -1,3,5-triazacycloheptane -2, 4-dione and the like.
  • ⁇ 1,4-bis- ⁇ -homogenylalanyl) -6- (glycylamino) hexahydro-1H-1,4-dazepine, 1-((S) -2-amino- 4-phenylbutyl) -3-C3-aminopropyl) -5- (2-naphthylmethyl) -1,3,5-triazacycloheptane -2, 4-dione and the like.
  • ⁇ 1,4-bis- ⁇ -homogen
  • the substituent R 1 of the compound of the present invention has the formula:
  • A11_ Q 1L A 12_ C (R 11 ) (Q 12_ X 11_ Y 1 ) _ Q 13_ N (R 12 ) (R 13 ) which is a group containing a nitrogen atom at the end of the structure Q ltJ It is based, also characterized in that the cyclic structure Y 1 end to hydrocarbon or heterocyclic ring system structure Q 12 -X 11 are attached. As can be seen from Reaction Schemes 1, 2, and 3, the structure:
  • -A 11 -Q 11 -A 12 is a functional group necessary for introducing the substituent R 1 on the ring, and various combinations depending on various functional groups substituted on the cyclic moiety represented by the formula A. Can be used.
  • a portion of this structural moiety A 11 -Q 11 -A 12 may be derived from a ring structure. Chi words, when constructing the R 1, may be part of the functional group which the compound of the cyclic moiety represented by the formula A used as a raw material has.
  • the method of constructing a substituent R 1 in the basic ring structure carbon one-carbon bond, Ami de bond, an ester bond, an ether bond, Chioe - ether bond, Amino bond, may be used and sulfonamide linkage thereof.
  • a nitrogen atom in the terminal, the position of the terminal to a ⁇ ring structure 2 -X 11 is preferably in the range of constant in terms of number of carbon atoms. That is, the structure one A 11 -Q 11 - A 12 - C - Q 13 moiety is preferably in the range of 1 to 8 as the number of carbon atoms in total length, also the structure - A 11 - Q 11 -A 12 one C -Q 12 - X 11 — also preferably has a carbon number in the range of 3 to 8.
  • the substituent R 2 of the compound of the present invention has the formula:
  • the structure: -A 21 -X 21 -Q 21 - is a structural part required to introduce a substituent R 2 on the ring, and is represented by the formula A
  • Various combinations can be used depending on various functional groups to be substituted for the compound having a cyclic moiety. That is, a part of the structure: -A 21 -X 21 -Q 21- may be derived from a ring structure. That is, in constructing ⁇ , it may be a part of the functional group of the compound of the cyclic portion represented by the formula A used as a raw material.
  • a nitrogen atom is directly introduced on the ring, or a carbon-carbon bond, an amide bond, an ester bond, an ether bond, a ether bond, an amide bond, or an amide.
  • the substituent R 2 can be constructed by using a method such as a bond or a sulfonamide bond.
  • the position of the nitrogen atom at the terminal of the structure 1 from the ring is preferably a position having the following length in terms of the number of carbon atoms. That is, the structure: -A 21 -X 21 -Q ⁇ 1 -is preferably, as the total length, a bond (0 in carbon number) or a range of 1 to 7 carbon atoms. Examples of the substituent R 2 are shown below c
  • the substituent R 3 of the compound of the present invention has the formula:
  • X 31 -Q 31 - is a functional group necessary for constructing a substituent R 3 on the ring, and a cyclic moiety represented by the formula ⁇
  • R 3 it may be a part of the functional group of the compound of the cyclic portion represented by the formula (1) used as a raw material.
  • the method of constructing a substituent R 3 in the ring structure, carbon one-carbon bond, Ami de bond, an ester bond, an ether bond, Chioeteru bond, ⁇ Mi Roh bond, the substituents R 3 using a method such as sulfonamide linkage thereof Can be built.
  • the position of Y 2 from the cyclic structure is preferably converted to the number of carbon atoms and the next length is within a certain range. That is, the structure X UL -Q 31- preferably has 1 to 8 carbon atoms. Examples of the substituent ⁇ are shown below.
  • the compound of the present invention represented by the formula (I) may have one or more asymmetric carbons, and various optical isomers or diastereoisomers exist. Encompasses all these isomeric compounds and any mixtures of the isomeric compounds.
  • the compound of the present invention may exist in a free form, or may exist as an acid addition salt with a basic moiety, or in the case where a carboxyl group is present, as a salt thereof.
  • acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; or acetate, methanesulfonic acid Organic salts such as salts, benzenesulfonate, toluenesulfonate, quesate, maleate, fumarate, and lactate can be given.
  • Examples of the salt of a carboxyl group include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, and triethylamine salt N-methylglucamine salt. Tris- (hydroxylmethyl) aminomethane salt and the like can be mentioned.
  • compounds of formula (I) in free or salt form may exist as hydrates or solvates.
  • the solvent that forms the solvate include acetone, ethanol, and the like.
  • the compounds of the present invention detolerize microorganisms that have become resistant to antimicrobial drugs, primarily by inhibiting the function of the drug efflux pump of resistant bacteria. It has the effect of increasing sensitivity to antibacterial drugs. Therefore, the compound of the present invention is useful as an active ingredient of a medicament, in particular, an active ingredient of a medicament for preventing and / or treating infectious diseases.
  • the type of microbial infectious disease to which the medicament of the present invention is applied is not particularly limited.
  • it can be applied to aerobic or anaerobic gram-positive and / or gram-negative bacterial infections.
  • an excellent therapeutic effect can be expected for infectious diseases caused by single-drug resistant bacteria or multidrug-resistant bacteria (for example, methicillin-resistant Staphylococcus aureus, resistant Pseudomonas aeruginosa, and resistant tuberculosis bacteria).
  • the active ingredient of the medicament provided by the present invention is selected from the group consisting of the above compounds and physiologically acceptable salts thereof, and hydrates and physiologically acceptable solvates thereof. Substances can be used, and two or more of these substances may be used in combination.
  • the administration form of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally.
  • the above-mentioned substance as an active ingredient may be used as it is, but in the form of a pharmaceutical composition containing a compound of the active ingredient and a pharmacologically and pharmaceutically acceptable additive for a pharmaceutical preparation.
  • a pharmaceutical composition containing a compound of the active ingredient and a pharmacologically and pharmaceutically acceptable additive for a pharmaceutical preparation.
  • the above-mentioned substances may be blended together with one or more kinds of antibacterial agents, and used as a so-called pharmaceutical composition in the form of a mixture.
  • compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, syrups and the like.
  • formulations suitable for parenteral administration include, for example, injections, drops, suppositories, inhalants, transdermal absorbers, eye drops, ear drops, ointments, creams, patches, and the like.
  • the dose of the medicament of the present invention is not particularly limited, and an appropriate dose is selected depending on various conditions such as the purpose of treatment or prevention, the type of microorganism causing the infectious disease, the age and symptoms of the patient, and the administration route. It is possible to The medicament of the present invention is usually used together with an antibacterial drug, but the number of times and period of administration may be appropriately selected according to the number of times and period of administration of the antibacterial drug. Examples-The present invention will be described in more detail with reference to the following Reference Examples, Examples, and Experimental Examples, which are merely illustrative and should not be construed as limiting the present invention.
  • amino acids and their derivatives used in the examples amino acids and their derivatives whose absolute configuration is not described are rare amino acids.
  • 0D deuterated methanol
  • D 2 0 heavy water
  • MS0 heavy dimethyl sulfoxide
  • s Shinguretsu Bok (singlet); d: Daburetsu Bok (doublet); dd: Daburudabure' Doo (double doublet); t: triplets (triplet ); Q: quartet; m: multiplet; br: broad; J: coupling constant; Hz: Herz; FAB-MS: fast atom bombardment Mass spectrometry.
  • trans-4-Hydroxyproline 2-naphthylamide (240 mg, 0.936 nunol) and N-tert-butoxycarbinyl dilanalanine (248 mg, 0.936 IMO1) were dissolved in methylene chloride (10 ml), and the mixture was cooled under ice-cooling.
  • Isopropylethylamine (0.36 ml) and N, N-bis- (2-oxo-3-oxazolidinyl) phosphinic chloride (263 mg) were added, and the mixture was stirred at room temperature for 3.5 hours.
  • reaction solution was partitioned between ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel chromatography (chloroform) to give the title compound (313 mg, 77%) as a colorless amorphous.
  • N-tert-butoxycarbonylphenylalanyl-trans-4- (p-toluenesulfonyloxy) proline 2-naphthylamide (a50mg, 0.228mniol) obtained in (B) was treated with DMF.
  • N-tert-butoxycarbonylphenylalanyl trans-4-hydroxypropyl-2-naphthylamide (150 mg) obtained in Example KA) was dissolved in THF (3 ml), and the mixture was treated with triphenylphosphine (3 ml). 94 mg) and formic acid (0.012 ml) were added. Zodicarboxylate (0.056 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 20 hours. Triphenylphosphine (94 mg), formic acid (0.012 ml) and getyl azodicarboxylate (0.056 ml) were added, and the mixture was further stirred for 6 hours.
  • N-tert-butoxycarbonylphenylalanyl cis-4-hydroxyproline 2-naphthylamide (80 mg) obtained in (A) was dissolved in methylene chloride (3 ml), and 4 (dimethylamino) pyridine (70 mg) was dissolved. ) And p-toluenesulfonyl chloride (89 mg) were added, and the mixture was stirred for 4 hours. P-Toluenesulfonyl chloride (90 mg) was added, and the mixture was further stirred for 16 hours.
  • reaction solution was partitioned between ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound as a colorless amorphous. (105 mg, quantitative).
  • N-tert-butoxycarbonyldivinyl cis-4- (p-toluenesulfonyloxy) proline 2-naphthylamide (105 mg) obtained in (B) was converted to DMF (4 ml) -water (0. 5 ml), sodium azide (17 mg) was added, and the mixture was stirred at 80 ° C for 5 hours.
  • the reaction solution was partitioned between hexane-ethyl acetate (1: 1, v / v) and water, the organic layer was washed with water, dried over magnesium sulfate, and the desiccant was removed by filtration.
  • Example 3 In the same manner as in Example 1 from homophenylanilar-cis-4-aminoproline 2-naphthylamide N-tert-butoxycarbonylhomophenylanilanine and trans-4-hydroxyproline 2-naphthylamide Obtained as the dihydrochloride salt by the method.
  • Example 4 Homophenylanilanyl-trans-4-aminoproline 2-naphthylamide N-tert-butoxycarbonylhomophenylanilanine and trans-4 hydroxypro N-tert-Butoxycarbonyl homophenylanilanyl-trans-4-hydroxy-4-hydroxyproline 2-naphthylamide was synthesized from phosphorus 2-naphthylamide in the same manner as in Example 1. Then, it was obtained as a dihydrochloride in the same manner as in Example 2.
  • Triethylamine (0.03 ml) and WSCD'HC1 25 mg were added under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was partitioned between 1N aqueous hydrochloric acid and 1N hydrochloric acid, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, dried over magnesium sulfate, and the desiccant was removed by filtration.
  • the residue was purified by preparative silica gel thin layer chromatography (chloroform-methanol, 97: 3, v / v) to give the title compound (59 mg, 83%) as a colorless amorphous.
  • dihydrochloride was prepared from N-tert-butoxycarbonyl homophenylvinyl-2-cis-4-aminoproline 2-naphthylamide and Ntert-butoxycarbonylalanine. As obtained.
  • Example 7 In the same manner as in Example 7, it was obtained as a dihydrochloride from N-tert-butoxycarbonylhomophenylalanyl-trans-4-aminoproline 2-naphthylamide and N-tert-butoxycarbonylalanan.
  • N-tert-butoxycarbonyl-trans-4-hydroxyproline (4.89 g, 21.lmmol) and 5-aminoindan (3.0 g, 22.5 tmol) were dissolved in methylene chloride (200 ml), and HOBt (2.9 g) was dissolved.
  • Triethylamine (3 ml) and WSCD.HC1 (4.6 g) were added under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
  • reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and the desiccant was removed by filtration.
  • the solvent was evaporated under reduced pressure to give a colorless oil (3.80 g). Further, this was dissolved in methylene chloride (50 ml), and 4- (dimethylamino) pyridine (3.0 g) and p-toluenesulfonyl chloride (3.3 g) were added under ice-cooling, followed by stirring at room temperature for 24 hours. did.
  • the solvent was distilled off under reduced pressure, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the desiccant was removed by filtration. Was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (chloroform) to give the title compound (3.87 g, 87%) as a colorless amorphous.
  • N-tert-butoxycarbonyl-cis-4- (p-toluenesulfonyloxy) proline 5 indanylamide (1.85 g, 3.70 mmol) obtained in (B) was treated with methylene chloride (20 ml). Then, trifluoroacetic acid (10 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. After the solvent was distilled off under reduced pressure, toluene and methanol were added to the residue, and the solvent was distilled off. The residue was partitioned between aqueous solution of formaldehyde monosaturated sodium bicarbonate and the organic layer was dried over magnesium sulfate.
  • N-tert-butoxycarbonyl-trans-4- (p-toluenesulfonyloxy) proline 5-indanilamide The N-tert-butoxycarbonyl trans-4 hydroxyproline 5 indanylamide (2.0 g, 5.77 mmol) obtained in Example 9 (A) was dissolved in methylene chloride (50 ml), and the solution was cooled under ice-cooling. (Dimethylamino) pyridine (1.41 g) and p-toluenesulfonyl chloride (1.65 g) were added, and the mixture was stirred at room temperature for 23 hours. P-toluenesulfonyl chloride (825mg),
  • Example 1 The same procedure as in Example 1 was carried out from the N-tert-butoxycarbonyl-trans-4- (p-toluenesulfonyloxy) proline 5-indanylamide and N-tert-butoxycarbonyl homophenylalanine obtained in (A). Obtained as the dihydrochloride using the method.
  • Example 12 D-homophenylalanil trans-4- (daricylamino) proline 5 -Indanilamide-N tert-butoxycarbonyl-cis-4- (p-toluenesulfonyloxy) proline 5-indanylamide and!)-Tert-butoxycarbonyl homo obtained in Example 9 (B) From the phenylalanine, DN-tert-butoxycarbonyl homophenyl-2-alan-4-trans-4-aminoproline 5-indanylamide was synthesized in the same manner as in Example 9. Then got!
  • N-tert-butoxycarbonylhomophonylanalanyl-D-trans 4-aminophenol was obtained from D-cis-4-hydroxyproline obtained by the method described in the literature in the same manner as in Example 9. Lin-5-indanylamide was synthesized.
  • Example 5 a method similar to that of Example 5 was carried out from the obtained N-tert-butoxycarbonylhomophonylanalyl-D-trans-4-aminopropylin-5 indanilamide and N-tert-butoxycarponyldaricin. To give the title compound as the dihydrochloride salt.
  • the dihydrochloride was obtained from the N-tert-butoxycarbyl trans-4- 4-amino-prolin 5-indanylamide and N-tert-butoxycarbonylalanine obtained in Example 9 using the same method as in Example 5. As obtained.
  • the dihydrochloride was obtained from N-tert-butoxycarbonyl-trans 4-aminoproline 5-indanylamide and DN-tert-butoxycarbonylalanine obtained in Example 9 using the same method as in Example 5. As obtained.
  • Example 5 was obtained from the N-tert-butoxycarbonyl homophenylanilanyl-trans-4-aminoproline 5-indanilamide and tri-N-tert-butoxycarbonylaminocyclopropanecarboxylic acid obtained in Example 9. Obtained as dihydrochloride using a similar method. Was. -
  • Example 5 The same procedure as in Example 5 was carried out from the N-tert-butoxycarbonylhomophenylanilanyl-trans-4-aminoprolin 5-indandanilamide and N-tert-butoxycarbonylserine obtained in Example 9. Obtained as the dihydrochloride using the method.
  • Example 9 Same as Example 5 from N-tert-butoxycarbonylhomophenylanilanyl-trans-4-amino-prolin 5-indanylamide and N-tert-butoxycarbonyl- ⁇ -fluoroalanine obtained in Example 9.
  • the isomers ⁇ ⁇ ⁇ and B according to the configuration of the fluoromethyl group were separated by high performance liquid chromatography to obtain the respective dihydrochlorides.
  • N-tert-butoxycarbonyl-trans-4-amino-prolin-5 indanylamide 100 mg, 0.197 mmol
  • N-tert-butoxycarbonylphenylanilanyl 60 mg obtained in Example 9 were added.
  • Example 5 was obtained from N-tert-butoxycarbonyl-trans-4-aminoaminolin-5-indanylamide and N-tert-butoxycarbonyldiphenylalanine obtained in Example 9. was obtained as the dihydrochloride using a method similar to -
  • Example 9 Performed from N-tert-butoxycarbonyl-trans-4-amino-prolin-5-indanilamide obtained in Example 9 and N (D-tert-butoxycarbonyl-N (5) -tert-butoxycarbonylornitine). Obtained as a trihydrochloride using the same method as in Example 5.
  • Example 5 A method similar to that of Example 5 was carried out from N-tert-butoxycarbonyl-trans-4-aminoprolin 5-indanylamide and N-tert-butoxycarbonylglutamate tert-butyl ester obtained in Example 9. To give the dihydrochloride.
  • Example 26 Homophenylalan-trans-4- (3-aminopropionylamino) proline 5-indanilamide A method similar to that of Example 5 from N-tert-butoxycarbonyl homophenylalanyl trans-4-amino-proline 5-indanilamide and N-tert-butoxycarbonyl- ⁇ -alanine obtained in Example 9. To give the dihydrochloride.
  • Example 9 Performed from N-tert-butoxycarbonylhomophenylanilanyl-trans-4-aminoproline 5-indanilamide and 4- (N-tert-butoxycarbonylamino) butyric acid obtained in Example 9. Obtained as the dihydrochloride using a method similar to Example 5.
  • N-tert-butoxycarbonylhomophonylanalyl-trans-4-aminoproline 3-quinolinolamine was prepared from trans-4-hydroxyproline and 3-aminoquinoline in the same manner as in Example 9. Was synthesized.
  • the title compound was obtained from the obtained N-tert-butoxycarbonylhomofenylalanyl-trans-4-amino-l-aminolin 3-quinolylamide and N-tert-butoxycarbonylglycine using the same method as in Example 5.
  • the compound was obtained as trihydrochloride.
  • HOBt 135 mg, 0.999 mmol
  • WSCD * HC1 1.15 g, 5.99 mmol
  • reaction solution was diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline.
  • organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography (form: chloroform) to obtain the title compound (91.8 mg, 58%).
  • the reaction solution was diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (118 mg, 56%).
  • chloroform silica gel column chromatography
  • the catalyst was filtered off, the catalyst was dissolved again in methanol (3 ml), 5% palladium on carbon (lOmg) and a 1N aqueous hydrochloric acid solution (0.411 ml) were added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for one hour. After filtering off the catalyst, the solvent was concentrated under reduced pressure and lyophilized to give the title compound (76.2 mg, 75%) as the dihydrochloride.
  • the catalyst was filtered off, the catalyst was dissolved again in methanol (3 ml), 5% palladium on carbon (10 mg) and a 1N aqueous hydrochloric acid solution (0.412 ml) were added, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). After filtering off the catalyst, the solvent was concentrated under reduced pressure, and lyophilized to give the title compound (63.5 mg, 69%) as the dihydrochloride.
  • reaction solution was diluted with a black hole form and washed with an aqueous solution of citric acid, an aqueous solution of saturated sodium bicarbonate, and a saturated saline solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to give the title compound (2.63 g, quantitative).
  • (2S, 4S) -2_ (N-tert-butoxycarbonylamino) methyl-4- (N-tert-butoxycarbonylhomophenylanilanylamino) -N- (2 -Hydroxy-3-phenylpropyl) pyrrolidine (isomer A, 155 mg, 0.254 mmol) was dissolved in a 4.2N methanolic hydrochloric acid solution (4 ml) and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, azeotropically dried with methanol several times, and dried. The residue was solidified using getyl ether to obtain the title compound (83.2 mg, 62 mg) as a trihydrochloride.
  • the reaction solution was diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the resulting residue was purified by silica gel gel chromatography (methanol chloroform, 1: 100, v / v). The title compound (131 mg, 32%) was obtained.
  • N- (2,2-diphenylethyl) cis-4-aminoproline methyl ester (266 mg, 0.820 mmol) obtained in Example 35 (B) and N-tert-butoxycarbonyldaricin (172 mg, 0.984 mmol) was dissolved in methylene chloride (8 ml), HOBt (22.2 mg. 0.164 mmol) and WSCD'HC1 (189 mg, 0.984 mmol) were added at 0 ° C., and the mixture was heated to room temperature and stirred for a while. The reaction solution was diluted with chloroform and washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution.
  • reaction solution was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline.
  • organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the resulting residue was subjected to preparative silica gel thin layer chromatography (ethyl acetate-toluene, 1: 1, v / v). Purification gave the title compound (42.3 mg, 40%).
  • N- (2,2-diphenylethyl) -3,5-diaminonovenamide 3,5-Diaminobenzoic acid (1.53 g) was suspended in THF (20 ml), 2,2-diphenylethylamine (1.98 g) was added, and WSCD * HC1 (2.42 g), HOBt (0.27 g) were added under ice cooling. g) and triethylamine (1.02 g) were added, and the mixture was stirred at room temperature for 5 days.
  • reaction solution was concentrated under reduced pressure, chloroform was added, and the mixture was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and the solid precipitated from the organic layer was collected by filtration to obtain the title compound (1.04 g).
  • the mother liquor was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (form-methanol, 24: 1, v / v) to give the title compound (0.88 g).
  • N- (2,2-diphenylethyl) -3,5-diaminobenzamide (0.824 g) obtained in (A) was dissolved in methylene chloride (15 ml), and N-benzyloxycarbonyl was dissolved. Phenylalanine (1.12 g) was added, and WSCD * HC1 (0.524 g) and HOBt (0.067 g) were added under ice-cooling, followed by stirring at room temperature for 21 hours.
  • Methyl formacetone 99: 1 to 19: 1, v / v) to give the title compound 3,5-bis (N-benzyloxycarbonyldiphenylvinylanilano) -N- (2,2- Diphenylethyl benzamide (0.488 g) and 3-amino-5- (N-benzyloxycarbonylphenylalanylamino) -N- (2,2-diphenylethyl) benzamide (0.919 g) were obtained. .
  • Example 52 The 3,5-bis (N-benzyloxycarbonyldivinylaramino) -N- (2,2-diphenylethyl) benzamide (0.448 g) obtained in Example 52 (B) was dissolved in ethanol. (12 ml), 5% palladium on carbon (0.1 lg) and 1N aqueous hydrochloric acid (1.07 ml) were added, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 22 hours. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, dimethyl ether was added, and the solid was collected by filtration to obtain the title compound (0.330 g) as a dihydrochloride.
  • 3,5-Dinitrobenzoic acid (2.13 g) was suspended in THF (20 ml), 3-phenylpropylamine (1.36 g) was added, and WSCD'HC1 (2.50 g) and HOBt (0. 27g) and stirred at room temperature for 17 hours. After concentrating the reaction solution under reduced pressure, add chloroform and wash with water and saturated aqueous sodium hydrogencarbonate solution, dry over anhydrous sodium sulfate, concentrate the solvent under reduced pressure, purify by silylation gel column chromatography (chloroform). A compound (3.26 g) was obtained.
  • N- (3-Phenylpropyl) -3,5-diaminobenzamide (0.81 g) obtained in (B) was dissolved in methylene chloride (20 ml) to give N-benzyloxycarbonylphenylalanine.
  • N- (3-Phenylpropyl) -3,5-diaminobenzamide (0.81 g) obtained in Example 56 (B) was dissolved in methylene chloride (20 ml) to give N-benzyloxycarbonyl homophene.
  • Dilulanin (l.41 g) was added, and under ice cooling, WSCD * HC1 (0.634 g) and HOBt (0.081 g) were added, followed by stirring at room temperature for 17 hours.
  • N-benzyloxycarbonylglycine (0.143 g) was added, WSCD-HC1 (0.131 g) and HOBt (0.014 g) were added under ice cooling, and the mixture was stirred at room temperature for 21 hours. The precipitated solid was collected by filtration to give the title compound (0.189 g). Further, the mother liquor was diluted with chloroform, washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Purification from 9: 1, v. V) gave the title compound (0.186 g).
  • Example 61 3,5-bis (homophenylalanilamino) -N- (3-phenylpropyl) benzamide 3,5-Bis (N-benzyloxycarbonylhomophenylanilanylamino) -N- (3-phenylpropyl) benzamide (0.276 g) obtained in Example 60 (A) was added to ethanol (10 ml). After dissolution, 5% palladium on carbon (0.15 g) and a 1N aqueous hydrochloric acid solution (0.67 ml) were added, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 21 hours. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, getyl ether was added, and the solid was collected by filtration to obtain the title compound (0.206 g) as a dihydrochloride.
  • Example 56 N- (3-phenylpropyl) -3,5-diaminobenzamide obtained in Example 56 (B) and N-benzyloxycarbonylhomophenylalanine, D-N-benzyloxycarbonylhomophane was used.
  • the same reaction as in Example 60 was carried out using penylalanine and 3- (N-benzyloxycarbonylamino) propionic acid in place of N-benzyloxycarbonylglycine, to give the title compound. Obtained as the dihydrochloride.
  • N- (2,2-diphenylethyl) -2,4-diaminobenzamide (0.45 g) obtained in (B) is suspended in THF (20 ml), and N-benzyloxycarbonylglycine ( 0.284 g), WSCD'HC1 (0.338 g) and HOBt (0.037 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, add chloroform to the solution, wash with water, dry over anhydrous sodium sulfate, concentrate the solvent under reduced pressure, silica gel column chromatography (chloroform moosetone, 24: 1, V / V). Further purification gave the title compound (0.295 g).
  • N- (2,2-diphenylethyl) -2,4-diaminobenzamide (0.265 g) obtained in Example 68 (B) was suspended in THF (10 ml), and N-benzyloxycarbonyl disulfide was added.
  • Dilulanine (0.622 g) was added, and under ice-cooling, WSCD'HC1 (0.399 g) and HOBt (0.022 g) were added, followed by stirring for 15 hours.
  • the reaction mixture was concentrated under reduced pressure, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then added with chloroform. The solid was collected by filtration to give the title compound (0.412 g). ).
  • the precipitate was washed with a pore-form, and the filtrate and the washing solution were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the title compound (3.76 g) was obtained as a pale yellow oil. The obtained crude product was used for the next reaction without further purification.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (80 ml) and a saturated aqueous solution of sodium chloride (80 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was purified by silica gel gel chromatography (methylene chloride monoethyl acetate, 1: 1, v / v) to give the title compound (199 mg, 59.9%) as a colorless amorphous substance. .
  • N-benzyloxycarbonyl homophenylalanine (1.57 g, 5 mmol)
  • N-benzylglycine ethyl ester (1.12 ml, 6 mmol)
  • HOBt 810 mg, 6 mmol
  • triethylamine 0.7 ml, 5mmol
  • methylene chloride 20ml
  • WSCD-HC1 (1.15g, 6mmol) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours.
  • the reaction solution was diluted with ethyl acetate, washed sequentially with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the resulting oil was purified by silica gel column chromatography (chloroform-formanol, 100: 2, v / v) to give the title compound ( 540 mg, 36%).
  • the reaction solution was diluted with ethyl acetate, washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride in that order, and dried over anhydrous sodium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the resulting oil was purified by silica gel column chromatography (chloroform-methanol, 100: 1, v / v) to give the title compound (296 mg, 85%).
  • the reaction solution was diluted with ethyl acetate, washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride in that order, and dried over anhydrous sodium sulfate.
  • the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the resulting oil was purified by silica gel column chromatography (chloroform / methanol, 100: 1, v / v) to give the title compound. (136 mg, 87%).
  • 6-Hydroxyhexahydro-1H-1,4-dazepine dihydrobromide 100 mg
  • N-tert-butoxycarbonylhomophonylanalanine 201 mg, 0.72 mraol
  • HOBt 97 mg, 0.72 mmol
  • triethylamine 0.28 ral, 2 mmol
  • methylene chloride 8 ml
  • DMF 4 ml
  • WSCD'HC1 138 mg, 0.72 rec.ol
  • the reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in that order, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting oil was purified by silica gel column chromatography (chloroform-methanol, 100: 3, v / v) to give the title compound ( 102 mg, 37%).
  • 1,4-Bis N-tert-butoxycarbonylhomophenylalanil-obtained in (D) 6-Hydroxyhexahydro-1H-1,4-diazepine (100 mg, 0.156 mmol) and triethylamine (0.13 ml, 0.932 mmol) are added to methylene chloride (9 ml), and methane chloride is added under ice-cooling. Sulfonyl (0.072 ml, 0.93 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 hours.
  • the reaction solution was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, and a saturated saline solution in that order, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 1,4-bis (N-tert-butoxycarbonylhomophenylalanyl) -6 (methanesulfonyloxy) hexahydro-1H-1,4-dazepine.
  • 6-Azido-1,4-bis (N-tert-butoxycarbonylhomophenylanilanyl) hexahydro-1H-1,4-dazepine 80 mg, 0.12 mmol obtained in (E), 5 % Palladium on carbon (37 mg) and methanol (9 ml) were mixed, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 18 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 6-amino-1,4-bis (N-tert-butoxycarbonylhomophenylalanil) hexahydro-1H-1,4-dazepine. .
  • the N-benzyloxycarbonyl homophenylalanine methyl ester (2.09 g, 6.38 mmol) obtained in (A) was dissolved in toluene (30 ml), and the system was replaced with nitrogen. The solution was cooled to ⁇ 50 ° C. in a ton bath, and a 1.0 M solution of diisobutylaluminum hydride in hexane (12.8 ml, 12.8 mmol) was added dropwise over 10 minutes. After stirring at the same temperature for 3 hours, a 1N aqueous hydrochloric acid solution was added, the temperature was raised to room temperature, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, and combined with the organic layer.
  • N-tert-butoxycarbonyl N '-(2naphthylmethyl) ethylenediamine (0.56 g, 1.86 mmol) obtained in (C) is dissolved in methylene chloride (20 ml), and the mixture is cooled under ice-cooling. Acetic acid (10 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. After evaporating the solvent and excess reagent under reduced pressure, the residue was azeotroped with toluene and methanol to obtain N- (2 naphthylmethyl) ethylenediamine as trifluoroacetate.
  • N- (2-naphthylmethyl) ethylenediamine trifluoroacetate and the N-benzyloxycarbonylhomophenylalananil (665.2 mg, 2.24 mmol) obtained in (B) were added to methanol (40 ml). After dissolving, sodium cyanoborohydride (140.6 mg, 2.24 mmol) was added little by little under ice-cooling, and the mixture was stirred at the same temperature for 2 hours and then at room temperature overnight.
  • 3-Amino-1-propanol (3.00 g, 39.9 mmol) was dissolved in chloroform (100 ml), and triethylamine (6.13 ml, 43.9 mmol) was added dropwise under ice cooling.
  • benzyloxycarbonyl chloride (6.37 ml, 39.9 mraol) was added dropwise in small amounts over 10 minutes, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 30 minutes.
  • reaction solution was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the residue was powdered, filtered, washed with hexane and dried under reduced pressure to give the title compound (8.07 g, 96.6%) as a white powder. Melting point: 39.0-42.0 ° C.
  • the reaction solution was diluted with ethyl acetate, washed with a 5% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. .
  • the residue was purified by silica gel column chromatography— (black-mouthed form) to give the title compound (4.58 g, 76.2%) as a pale-yellow oil.

Abstract

Nouveaux composés comportant trois substituants dans leur structure cyclique partielle, tels qu'une pyrrolidine ou un noyau benzénique, par exemple homophénylalanyl-trans-4-((S)-3-amino-2-hydroxypropionylamino)proline 5-indanylamide et N-(3-phénylpropyl)-3-((S)-2-hydroxy-3-aminopropionylamino)-5-(D- homophénylalanylamino)-benzamide. Ces composés ont une action sur des micro-organismes pathogènes qui ont développé une tolérance aux agents antimicrobiens existants et augmentent la sensibilité aux agents antimicrobiens, les rendant ainsi non tolérants. Lorsqu'ils sont utilisés avec les antimicrobiens, lesdits composés peuvent efficacement servir à la prévention et/ou au traitement de maladies infectieuses d'origine microbienne.
PCT/JP1997/003812 1996-10-22 1997-10-22 Nouveaux remedes pour des maladies infectieuses WO1998017625A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU47221/97A AU4722197A (en) 1996-10-22 1997-10-22 Novel remedies for infectious diseases
JP51922598A JP4024309B2 (ja) 1996-10-22 1997-10-22 新規な感染症治療薬

Applications Claiming Priority (4)

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JP8/279172 1996-10-22
JP27917296 1996-10-22
JP8/287203 1996-10-30
JP28720396 1996-10-30

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WO1998046569A1 (fr) * 1997-04-11 1998-10-22 Sumitomo Pharmaceuticals Co., Ltd. Derives de benzene
WO2000001714A1 (fr) * 1998-07-01 2000-01-13 Microcide Pharmaceuticals, Inc. Inhibiteurs de pompes d'ecoulement
WO2001030757A1 (fr) * 1999-10-28 2001-05-03 Microcide Pharmaceuticals, Inc. Inhibiteurs de la pompe par liberation de medicaments
WO2001056987A1 (fr) * 2000-02-02 2001-08-09 Sunesis Pharmaceuticals, Inc. Analogues de tosylproline utilises comme inhibiteurs de la thymidylate synthase
WO2002087589A1 (fr) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicament permettant d'inhiber une pompe d'elimination de medicament
JP2002322054A (ja) * 2001-04-26 2002-11-08 Dai Ichi Seiyaku Co Ltd 薬剤排出ポンプ阻害薬
EP1425029A1 (fr) * 2001-08-10 2004-06-09 Palatin Technologies, Inc. Peptidomimetiques de metallopeptides biologiquement actifs
WO2005070919A1 (fr) * 2004-01-22 2005-08-04 Neuromed Pharmaceuticals Ltd. Bloqueurs de canal calcique de type n
JP2005523899A (ja) * 2002-02-01 2005-08-11 ノボ　ノルディスク　アクティーゼルスカブ アミノアルキル置換されたアゼチジン、ピロリジン、ピペリジン、およびアゼパンのアミド
WO2004082634A3 (fr) * 2003-03-17 2005-11-10 Univ Pennsylvania Polymeres et oligomeres a surface amphiphile et leurs utilisations
US7056917B2 (en) * 2001-04-26 2006-06-06 Daiichi Pharmaceutical Co., Ltd. Drug efflux pump inhibitor
WO2006067862A1 (fr) * 2004-12-22 2006-06-29 The Kitasato Institute Substances actives k03-0132 et procédé de production de celles-ci
WO2006075395A1 (fr) * 2005-01-11 2006-07-20 The Kitasato Institute RENFORCATEUR D'ACTIVITE D'ANTIBIOTIQUE A BASE DE β-LACTAME ET PROCEDE POUR LE PRODUIRE
US7173102B2 (en) 2001-03-08 2007-02-06 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers as anti-infective agents
JP2009521467A (ja) * 2005-12-23 2009-06-04 ジーランド ファーマ アクティーゼルスカブ 修飾リジン模倣化合物
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US8093249B2 (en) 2008-07-17 2012-01-10 Convergence Pharmaceuticals Limited Pyrazolo[1,5-A]pyrimidine-carbonyl-piperazine derivatives
US8222456B2 (en) 2004-01-23 2012-07-17 The Trustees Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
US8288388B2 (en) 2008-07-17 2012-10-16 Convergence Pharmaceuticals Limited 3-pyridylcarbonyl-piperazinylsulfonyl derivatives
US8299098B2 (en) 2008-06-25 2012-10-30 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
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US8889632B2 (en) 2007-01-31 2014-11-18 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US8927500B2 (en) 2012-02-15 2015-01-06 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US8987414B2 (en) 2012-02-15 2015-03-24 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof

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Cited By (55)

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WO1998046569A1 (fr) * 1997-04-11 1998-10-22 Sumitomo Pharmaceuticals Co., Ltd. Derives de benzene
US6399629B1 (en) 1998-06-01 2002-06-04 Microcide Pharmaceuticals, Inc. Efflux pump inhibitors
WO2000001714A1 (fr) * 1998-07-01 2000-01-13 Microcide Pharmaceuticals, Inc. Inhibiteurs de pompes d'ecoulement
EP1652839A2 (fr) * 1999-10-28 2006-05-03 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs de la pompe par liberation de medicaments
WO2001030757A1 (fr) * 1999-10-28 2001-05-03 Microcide Pharmaceuticals, Inc. Inhibiteurs de la pompe par liberation de medicaments
EP1652839A3 (fr) * 1999-10-28 2006-07-05 Daiichi Pharmaceutical Co., Ltd. Inhibiteurs de la pompe par liberation de medicaments
WO2001056987A1 (fr) * 2000-02-02 2001-08-09 Sunesis Pharmaceuticals, Inc. Analogues de tosylproline utilises comme inhibiteurs de la thymidylate synthase
US7173102B2 (en) 2001-03-08 2007-02-06 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers as anti-infective agents
WO2002087589A1 (fr) * 2001-04-26 2002-11-07 Daiichi Pharmaceutical Co., Ltd. Medicament permettant d'inhiber une pompe d'elimination de medicament
US7056917B2 (en) * 2001-04-26 2006-06-06 Daiichi Pharmaceutical Co., Ltd. Drug efflux pump inhibitor
JP2002322054A (ja) * 2001-04-26 2002-11-08 Dai Ichi Seiyaku Co Ltd 薬剤排出ポンプ阻害薬
EP1425029A4 (fr) * 2001-08-10 2006-06-07 Palatin Technologies Inc Peptidomimetiques de metallopeptides biologiquement actifs
EP1425029A1 (fr) * 2001-08-10 2004-06-09 Palatin Technologies, Inc. Peptidomimetiques de metallopeptides biologiquement actifs
JP2005523899A (ja) * 2002-02-01 2005-08-11 ノボ　ノルディスク　アクティーゼルスカブ アミノアルキル置換されたアゼチジン、ピロリジン、ピペリジン、およびアゼパンのアミド
WO2004082634A3 (fr) * 2003-03-17 2005-11-10 Univ Pennsylvania Polymeres et oligomeres a surface amphiphile et leurs utilisations
US9241917B2 (en) 2003-03-17 2016-01-26 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
US8455490B2 (en) 2003-03-17 2013-06-04 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
US8236800B2 (en) 2003-03-17 2012-08-07 The Trustees Of The University Of Pennsylvania Facially amphiphilic polymers and oligomers and uses thereof
WO2005070919A1 (fr) * 2004-01-22 2005-08-04 Neuromed Pharmaceuticals Ltd. Bloqueurs de canal calcique de type n
JP2007518742A (ja) * 2004-01-22 2007-07-12 ニューロメド ファーマスーティカルズ リミテド Ｎ型カルシウムチャネル遮断薬としての３−アミノピロリジン誘導体
US7507760B2 (en) 2004-01-22 2009-03-24 Neuromed Pharmaceuticals Ltd. N-type calcium channel blockers
US8222456B2 (en) 2004-01-23 2012-07-17 The Trustees Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
US8716530B2 (en) 2004-01-23 2014-05-06 The Trustess Of The University Of Pennsylvania Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof
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