WO2005037265A1 - Medicaments concurrents - Google Patents

Medicaments concurrents Download PDF

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Publication number
WO2005037265A1
WO2005037265A1 PCT/JP2004/015748 JP2004015748W WO2005037265A1 WO 2005037265 A1 WO2005037265 A1 WO 2005037265A1 JP 2004015748 W JP2004015748 W JP 2004015748W WO 2005037265 A1 WO2005037265 A1 WO 2005037265A1
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Prior art keywords
alkyl
integer
sulfo
hydrogen
formula
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PCT/JP2004/015748
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English (en)
Japanese (ja)
Inventor
Fujio Kobayashi
Kazuki Murakami
Naruyasu Komorita
Teruaki Imada
Masahiko Kajii
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Mitsubishi Pharma Corporation
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Priority to JP2005514881A priority Critical patent/JPWO2005037265A1/ja
Publication of WO2005037265A1 publication Critical patent/WO2005037265A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a combination drug containing an antibacterial drug and a hydroxamic acid derivative. More specifically, the present invention relates to the above concomitant drug useful for prevention and / or treatment of sepsis, a method for preventing and / or treating sepsis using the concomitant drug, and preventing and / or preventing sepsis. It relates to the use of a combination of an antimicrobial agent and a hydroxamic acid derivative for treatment.
  • Sepsis is a disease that causes bacteria to enter the blood from infected tracts such as the respiratory system, genitourinary system, gastrointestinal tract, central nervous system, bones, and skin. It is a systemic disease that presents symptoms, and may cause death due to shock symptoms accompanied by a decrease in body temperature, mental symptoms such as decreased blood pressure and confusion, and abnormal blood coagulation.
  • SIRS System emIc Inf 1 amm aTo ryResponse Syndrome; systemic inflammation fcfefc syndrome
  • the current treatment of sepsis is based on pharmacotherapy with antimicrobial agents that remove the infectious bacteria that cause sepsis. Based on this pharmacotherapy for removing infectious bacteria, other pharmacotherapy (cardiovascular drugs, DIC drugs, etc.), treatment with artificial organ assistance (respiratory management, plasma exchange / drainage, endotoxin removal column, etc.), infusion (
  • sepsis treatment with these treatments has not always been established, and is merely symptomatic treatment aimed at improving the condition by combining each treatment.
  • the therapeutic effects achieved with the treatment of sepsis based on these treatments have already reached their limits, and mortality from sepsis has changed little since the 1980s.
  • an antibacterial agent used for pharmacotherapy of sepsis it is known to use an antibacterial agent having a broad antibacterial spectrum having a broad antibacterial activity against various causative bacteria.
  • antimicrobials include penicillins, cefms, penems, Antibiotics such as pactams and other / 3-latatams, and tetracyclines, aminoglycosides, and macrolides are known.
  • sepsis is a very urgent disease, so antibiotics are administered based on the empirical judgment of a physician even before causative bacteria are detected and identified. Therefore, administration of this antibacterial drug may lead to a bacterial turnover phenomenon in some cases, promote the growth of specific infectious bacteria, prolong the disease state, and have many problems.
  • Sepsis is often accompanied by a rise in body temperature as a symptom in the early stages, but when it reaches a serious condition, it changes completely and shows a tendency to decrease body temperature, so a decrease in body temperature is one of the indicators for determining the severity of sepsis. I'm familiar. For this reason, suppressing this decrease in body temperature is thought to lead to the suppression of the deterioration of sepsis or prolonging the life. However, at present, no drug capable of effectively suppressing the decrease in body temperature in sepsis has been reported.
  • WO99 / 61414 and WO02 / 06214 include the formula (I):
  • X represents hydrogen or a protecting group for a hydroxyl group
  • R 1 represents hydrogen, alkyl, arylalkyl, heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl, phthalimidalkyl, alkenyl, Or — (CH 2 )!-A [1 is an integer of any one of 1 to 4, and A is (a) bonded by an N atom, and (b) at a position not adjacent to the bonded N atom.
  • hetero atom it may contain at least one atom selected from N, O and S, and (c) one or both C atoms adjacent to the bonding N atom are replaced by oxo. And (d) a benzo-fused or substituted force on one or more other C atoms by lower alkyl or oxo, and / or a reduced force on another N atom.
  • R 2 is hydrogen, alkyl, ⁇ reel alkyl, hetero Represents arylalkyl, cycloalkyl, cycloalkylalkyl or aryl, and R 3 is hydrogen, alkyl or a formula
  • Q 1 represents an aromatic hydrocarbon ring or an aromatic hetero ring
  • m represents an integer of 0 to 3
  • R 13 represents hydrogen, no, logen, Hydroxyl group, nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, COORa (Ra indicates lower alkyl, arylalkyl or aryl), carpamoyl , Guanidino, hydroxysulfonyl / reoxy, sulfo, arylalkyloxyalkyl or
  • n and q may be the same or different and each represents an integer of 1 to 5; r represents an integer of 0 to 2; 14 and R 15 may be the same or different, are each hydrogen, alkyl, Ari Ruarukiru represents a hetero ⁇ reel alkyl or Ariru, or R 14 and R 15 have been connexion substitutions together with the adjacent nitrogen atom Good heterocycle R 16 represents aryl, heteroaryl, hydroxysulferooxy or sulfo, R 17 represents a hydroxyl group, hydroxysulfonyloxy, sulfo, or sulfoxy)), Y represents alkyl Amino or formula
  • Q 2 represents an aromatic hydrocarbon ring or an aromatic hetero ring
  • R 18 is hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl.
  • U R represents a group selected from the following formulas, wherein s and t may be the same or different, and Represents an integer of 0 to 5, u represents an integer of 0 to 2, R 19 and R 2 Q may be the same or different, and each represents hydrogen, alkyl, arylalkyl, or heteroaryl.
  • R 19 and R 2 G may form a hetero cycle to which may be connexion substitutions together with the adjacent nitrogen atom
  • R 21 represents Ariru, Heteroariru, hydroxysulfonyl O key sheet, sulfo or carboxy
  • R 22 Represents a hydroxyl group, hydroxysulfonyloxy, sulfo or carboxy)]].
  • R 3 is the formula (A)
  • Q 1 represents a benzene ring
  • m represents an integer of 0 to 3
  • R 13 represents guanidino, hydroxysulfonyloxy, sulfo or
  • n represents an integer of 1 to 5
  • r represents an integer of 0 to 2
  • R 14 and R 15 may be the same or different, their respective hydrogen, alkyl, ⁇ reel alkyl, shows a hetero ⁇ reel alkyl or Ariru, or R 14 and R 15 may form a hetero cycle to which may be connexion substitutions together with the adjacent nitrogen atom
  • R 16 represents hydroxysulfo-loxy or sulfo.
  • R 19 and R 2 Q may be the same or different, and each represents hydrogen, alkyl, Le, ⁇ reel alkyl, to indicate the Teroari one Ruarukiru or ⁇ Li Ichiru, or R 1 9 and R 2 ° is also form a Terosa cycle to which may be connexion substitutions together with the adjacent nitrogen atom well
  • R 2 1 is Ariru, Heteroari Ichiru, hydroxy sulfo Niruokishi, or a group selected from showing a sulfo or force Rupokishi)
  • Q 2 represents a furan ring
  • R 1 8 is ⁇ Li one Ruarukiruo Kishiarukiru or 1 9, - (CH 2) S - (0- (CH 2) t -) U N and
  • R 19 and R 2 ° are the same or may be different, are each hydrogen, alkyl, ⁇ reel alkyl, Heteroari Ruarukiru or indicates ⁇ re Ichiru, or R 1 9 and R 2 0 is be connexion substitutions together with the adjacent nitrogen atom may form a hetero cycle to good, R 2 2 represents hydroxyl, hydroxysulfonyl O alkoxy, a group represented by a group selected from sulfo or an carboxy)).
  • Arylalkyl, heteroarylthioalkyl, arylthioalkyl , Arylalkylthioalkyl, phthalimidalkyl, aryl, heteroaryl and heteroarylalkyl may have a substituent.
  • hydroxamic acid derivative of the formula (I) represented by the formula: wherein the hydroxamic acid derivative is a tumor necrosis factor (TNF- ⁇ ) are described as useful as production inhibitors.
  • TNF- ⁇ tumor necrosis factor
  • the present invention has been made in view of the problems facing sepsis treatment using an antimicrobial agent as described above, and has as an object to provide a medicament for preventing and / or treating sepsis in which a higher therapeutic effect can be safely obtained.
  • the present inventors have also newly found that the hydroxamic acid derivative of the formula (I) effectively suppresses hypothermia in a sepsis model, but the suppression of hypothermia is associated with severe sepsis.
  • the effect of the combined use of the hydroxamic acid derivative of formula (I) and an antibacterial drug is one of It is estimated that there is.
  • the present invention is as follows.
  • X represents hydrogen or a protecting group for a hydroxyl group
  • R 1 represents hydrogen, alkyl, aryl, Alkyl, heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, or 1 (CH 2 ) -A (1 is an integer of 1 to 4
  • A contain (a) an atom bonded by an N atom, and (b) at least one heteroatom selected from N, O and S at a position not adjacent to the bonded N atom.
  • R 2 is indicates hydrogen, alkyl, ⁇ reel alkyl, heteroalkyl ⁇ reel alkyl, consequent opening alkyl, cycloalkylalkyl or ⁇ Li Ichiru
  • R 3 is hydrogen, alkyl or formula
  • Q 1 represents an aromatic hydrocarbon ring or an aromatic hetero ring
  • m represents an integer of 0 to 3
  • R 13 represents hydrogen, halogen, a hydroxyl group, Nitro, cyano, trifluoromethyl, lower alkyl, alkoxy, alkylthio, formyl, acyloxy, ferul, arylalkyl, carboxy, -COOR a (Ra indicates lower alkyl, arylalkyl or aryl), carpamoyl, Guanidino, hydroxys / lephonyloxy, sulfo, arylalkyloxyalkyl or 16
  • n and q may be the same or different and each represents an integer of 1 to 5; r represents an integer of 0 to 2; 14 and R 15 may be the same or different, are each hydrogen, alkyl, Ari Ruarukiru represents a hetero ⁇ reel alkyl or Ariru, or R 14 and R 15 have been connexion substitutions together with the adjacent nitrogen atom may form a hetero cycles to good, R 16 represents Ariru, Heteroariru shows a hydroxycarboxylic sulfonyl O key sheet or sulfo, R 17 is hydroxyl, hydroxysulfonyl O carboxymethyl, Suruhoma others carboxy)] , Y is alkylamino or formula
  • Q 2 represents an aromatic hydrocarbon ring or an aromatic hetero ring
  • R 18 represents hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, lower radical Alkyl, alkoxy, alkylthio, formyl, acyloxy, phenyl, arylalkyl, carboxy, -COORa (Ra indicates lower alkyl, arylalkyl or aryl), carpamoyl, guanidino, hydroxysulfonylox, sulfo, aryl Alkyloxyalkyl or R 19
  • S and t may be the same or different and each represents an integer of 1 to 5; u represents an integer of 0 to 2; 19 and R 2 ° may be the same or different and each is hydrogen, alkyl, Ari Ruarukiru represents a hetero ⁇ reel alkyl or Ariru, or R 19 and R 2G is substituted together with the adjacent nitrogen atom R 21 represents aryl, heteroaryl, hydroxysulfonyloxy, sulfo or carboxy, and R 22 represents hydroxyl, hydroxysulfonyloxyl, sulfo or carboxy.) .
  • R 3 is the formula (A)
  • Q 1 represents a benzene ring
  • m represents an integer of 0 to 3
  • R 13 represents guanidino, hydroxysulfonyloxy, sulfo or 16
  • n is an integer of 1 to 5
  • r is an integer of 0 to 2
  • R 14 and R 15 may be the same or different, their respective hydrogen, alkyl, ⁇ reel alkyl, shows a hetero ⁇ reel alkyl or Ariru, or R 14 and R 15 may form a hetero cycle to which may be connexion substitutions together with the adjacent nitrogen atom
  • R 16 represents hydroxysulfonyloxy or sulfo.
  • R 19 and R 2Q may be the same or different, and each represents hydrogen, alkyl, ⁇ reel alkyl, shows a hetero ⁇ reel alkyl or ⁇ Li Ichiru, or R 19 and R 2 ° is to be be connexion substitutions together with the adjacent nitrogen atom Terosa May form a cycle
  • R 2 1 is Ariru, Heteroariru, hydroxy sulfo Niruokishi, or a group selected from showing a sulfo or force Rupokishi)
  • Q 2 represents a furan ring
  • R 1 8 is ⁇ Li Monoalkyloxyalkyl or
  • arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, aryl, heteroaryl and heteroarylalkyl may have a substituent. And a pharmacologically acceptable salt or hydrate thereof.
  • Concomitant medications including.
  • the antibacterial agent is (5R, 6S) -3- [2- (formimidoylamino) ethyl-noresnolephaninole] 16-[(1R) -1-hydroxyethyl] 1-7-oxo-11-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid or a drug containing a pharmacologically acceptable salt or hydrate thereof, [1] or The concomitant drug according to [2].
  • the antibacterial drug is (5R, 6S) -1- [2- (formimidoylamino) ethylsulfanyl] -6-[(1R) -11-hydroxylexetil] _7-oxo-1_ Azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid or a pharmaceutically acceptable salt or hydrate thereof, and (+)-(Z) -7-[[(R) -2 Amino-12-carboxyethyl] thio] -12-[(S) -2,2-dimethylcyclopropanecarboxamide] sodium 2-heptanoate or a pharmacologically acceptable salt or hydrate thereof
  • the concomitant drug according to [1] which is a drug containing:
  • the hydroxamic acid derivative represented by the formula (I) is a 5-methyl-3 (R)
  • hydroxamic acid derivative of the formula (I) or a pharmacologically acceptable salt or hydrate thereof and an antibacterial agent are contained in the preparation, any of [1] to [5].
  • hydroxamic acid derivative of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof and an antibacterial agent are contained in separate preparations, respectively; [1] to [5] The concomitant drug described in any of the above.
  • the antibacterial agent and the hydroxamic acid derivative of the formula (I) or a pharmacologically acceptable salt or hydrate thereof are mixed at a ratio of 0.006 to 0.006 per unit weight per 1 kg of body weight to be administered.
  • Each symbol in the formula is as defined above. Characterized by administering an effective amount of a hydroxamic acid derivative or a pharmacologically acceptable salt or hydrate thereof, and an effective amount of at least one antibacterial agent, to prevent sepsis. Oops Z or how to treat.
  • the antibacterial agent is (5R, 6S) -13- [2- (formimidoinoleamino) ethylsulfanyl] —6 -— [(1R) 1-1-hydroxylexetil] 17-oxo-11-azabicyclo [ 3.2.0]
  • the method according to [12] or [13] which is a medicament comprising hept-2-ene-2-carboxylic acid or a pharmaceutically acceptable salt or hydrate thereof.
  • the antibacterial agent is (5R, 6 S) —3— [2- (honorelemmidinoleamino) etinoresnolefaninole] —6— [(1R) 1-1-droxicetil] — 7-oxo-1- 1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid or a pharmacologically acceptable salt or hydrate thereof, and (+) — (Z) — 7— [[ (R) 12-Amino-2-carboxyethyl] thio] 1-2-[(S) —2,2-Dimethinoresic Mouth propanecarboxamide] Sodium 2-heptanoate or a pharmaceutically acceptable salt thereof or The method according to [12], which is a drug containing a hydrate.
  • hydroxamic acid derivative of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof and an antibacterial agent are formulated in at least one injection, [12] to [: 18].
  • the antibacterial agent and the hydroxamic acid derivative of the formula (I) or a pharmacologically acceptable salt or hydrate thereof are mixed in a ratio of 1: 0.06 per unit time and per 1 kg of the subject's body weight.
  • [23] Includes the concomitant drug according to any one of [1] to [11], and documents stating that the concomitant drug can or should be used for the treatment of sepsis Commercial package.
  • FIG. 1 is a graph showing a survival rate-improving effect of the concomitant drug of the present invention in a CLP model.
  • FIG. 2 is a graph showing the effect of suppressing the decrease in body temperature of the concomitant drug of the present invention in a CLP model.
  • a concomitant drug containing the hydroxamic acid derivative of the formula (I) and an antibacterial drug (hereinafter, also simply referred to as “the concomitant drug of the present invention”) is useful for prevention or treatment of sepsis.
  • the use of the concomitant drug of the present invention can reduce the mortality of a subject suffering from sepsis. More specifically, it is possible to effectively suppress a decrease in body temperature in a subject suffering from sepsis that has fallen into a serious condition.
  • the alkyl in the above may have a carbon number of ⁇ to 10 and may be linear or branched.
  • the arylalkyl in R ⁇ R 2 , R 14 , R 15 , R 19 and 20 is preferably an alkyl moiety having 1 to 6 carbon atoms, which may be linear or branched.
  • the aryl moiety is preferably a phenyl, naphthyl, or ortho-fused bicyclic group having from 8 to 10 ring atoms and at least one ring being an aromatic ring (for example, an indole Etc.).
  • benzyl, phenethyl, 3-phenylpropyl 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphtinol) propyl , 3- (2-naphthyl) propyl and the like.
  • the heteroarylthioalkyl for R 1 is preferably such that the alkyl portion thereof may be linear or branched having 1 to 6 carbon atoms, and the heteroaryl portion preferably has 1 to 6 carbon atoms.
  • Heteroaryl parts include, for example, pyrroyl, pyrrolyl, furyl, chenyl, oxazolyl, isoxoxazolyl. Imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,2,4oxaziazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyranyl, pyrazyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,5 —Oxathiadiyl, 1,2,6-Oxathiazinyl ⁇ ⁇ Benzoxazolyl, Benzothiazolyl, Benzimid
  • heteroarylthioalkyl for R 1 examples include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl, 3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-chlorothiomethyl and the like.
  • the arylthioalkyl in R 1 preferably has an alkyl moiety of 1 to 6 carbon atoms and may be linear or branched, and the aryl moiety is the same as the aryl moiety of the above arylalkyl.
  • Specific examples include phenylthiomethyl, 1.1-naphthylthiomethyl, 2-naphthylthiomethyl and the like.
  • the alkyl portion of the alkylthio portion is the same as the above-mentioned alkyl, and the remaining alkyl portion preferably has 1 to 6 carbon atoms and may be linear or branched. Specific examples include methylthiomethyl, ethylthiomethyl, II-propylpyruthiomethyl, isopropylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, tert-butylthiomethyl and the like.
  • the arylalkylthioalkyl in R 1 has the same arylalkyl moiety as the above arylalkyl.
  • the remaining alkyl moiety preferably has 1 to 6 carbon atoms and may be linear or branched. Specifically, benzylthiomethyl, phenethylthiomethyl and the like can be mentioned.
  • the alkyl moiety of the phthalimidalkyl in R 1 is preferably a group having 1 to 6 carbon atoms. It may be linear or branched. Specific examples include phthalimidomethyl, 2-phthalimidethynole and the like.
  • the alkenyl in R 1 preferably has 2 to 6 carbon atoms and includes, for example, butyl, aryl, 3-butul, 5-hexenyl and the like.
  • the aryl in R 2 , R 14 , R 15 , R 19 , R 20 and R 21 is the same as the aryl moiety of the above-mentioned arylalkyl, and is preferably phenyl.
  • a of one (CH 2 ) A in R 1 is an N-heterocycle linked by an N atom, and examples thereof include the following groups.
  • R 8 and R 9 each represent hydrogen or together form another bond to form a double bond
  • R 10 represents hydrogen, lower alkyl or phenyl
  • X represents CO 1, 1 CH 2 —, —CH (lower alkyl) one, one C (lower alkyl) 2 —, —NH one, one N (lower alkyl) one or one 0—
  • Y are 1 ⁇ —, 1 ⁇ — Or one N (lower alkyl) represents one.
  • Lower alkyl means alkyl having 1 to 6 carbon atoms, which may be linear or branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutynole, sec-butynole, tert- Petinole, n-pentinole, isopentinole, n-hexyl and the like.
  • N-hetero ring examples include, for example, 2-oxo-11-pyrrolidinyl, 1-oxoisoindoline-1-yl, 2-oxoindoline-11-yl, and 2,5-dioxo 1-Pyrrolidinyl, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidine-14-yl, 2,5-dioxo 3-methyl-1-imidazolidur, 2,5-dioxo 3,4,4 1-trimethyl-11-imidazolidinyl, 3,5-dioxo-2-methyl-1,2,4-oxadiazolidine-14-yl, 3-methyl-1,2,4,5-trioxo-11-imidazolidinyl, 2 , 5-dioxo-3-phenyl-1 -imidazolidinyl 2,2,6-dioxopiridino.
  • the heteroarylalkyl represented by R 2 , R 14 , R 15 , R 19 and R 20 is preferably such that the alkyl portion thereof has 1 to 6 carbon atoms and may be linear or branched.
  • the part is the same as the heteroaryl part of the above heteroarylthioalkyl.
  • the cycloalkyl for R 2 preferably has 3 to 7 carbon atoms and includes, for example, cyclopropyl pill, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and the like.
  • the cycloalkylalkyl for R 2 is preferably such that the alkyl portion thereof has 1 to 6 carbon atoms and may be linear or branched, and the cycloalkyl portion is the same as the above-mentioned cycloalkyl. Specifically, cyclopropylmethyl, 2-cyclobutylethyl, pen mouth pentinole methinole, 3-neck pentinole propinole, hexyl hexyl methinole,
  • the aromatic hydrocarbon ring for Q 1 and Q 2 is a benzene ring, a naphthalene ring, or an ortho-fused bicyclic hydrocarbon ring having from 8 to 10 ring atoms and at least one ring being an aromatic ring (For example, indene, etc.).
  • Preferred is a benzene ring.
  • the aromatic hetero ring in Q 1 and Q 2 includes a 5- to 6-membered ring having 1 to 4 hetero atoms (oxygen, sulfur or nitrogen) or 8 to 1 derived therefrom.
  • Examples include ortho-fused bicyclic aromatic heterocycles having 0 ring atoms, especially benzo derivatives fused to benzene rings.
  • aromatic hetero ring examples include pillow / le, furan, thiophene, oxazonole, isoxazonole, imidazonole, thiazole, isothiazol, pyrazole, 1,2,3-triazole, 1,2,4 Monotriazole, tetrazole, 1,3,4-oxadiazole, 1,2,4 monoxadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4 -Triazine, 1, 2,
  • arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidalkyl, aryl, heteroaryl and heteroarylalkyl are, for example, halogen (fluorine, chlorine, bromine, iodine) , Hydroxyl, nitro, cyano, trifluoromethyl, lower alkyl (however, the alkyl moiety of arylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthalimidalkyl is not substituted) , Alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, -COORa (Ra represents lower alkyl, arylalkyl or aryl) Le, Amino, lower alk Kiruamino, di-lower Ar
  • alkoxy preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
  • alkylthio the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be linear or branched, and examples thereof include methinorethio, ethylthio, n-propylthio, and isopropylthio.
  • the axyloxy is preferably an alkynyloxy having 2 to 6 carbon atoms which may be linear or branched, and includes, for example, acetyloxy, propionyloxy, petyryloxy, pareryloxy, piperoyloxy, hexanoyloxy and the like.
  • An arylalkyloxyalkyl is the same as the above-mentioned arylalkyl, and the remaining alkyl is preferably a straight-chain or branched chain having 1 to 6 carbon atoms. ,.
  • benzyloxymethyl, phenethyloxymethyl and the like can be mentioned.
  • lower alkyl moiety in lower alkylamino and di-lower alkylamino may have 1 to 6 carbon atoms and may be linear or branched.
  • Examples of lower alkylamino include methylamino, ethyl Examples include amino, propinoleamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino.
  • di-lower alkylamino examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutinoleamino, diisopropylamino, g-sec-butylamino, di-tert-butylamino, diethylamino, dihexylamino, and ethylmethylamino. And methylpropylamino, butylmethylamino, ethylpropylamino, ethylbutylamino and the like.
  • R 14 and R 15 may be formed together with the adjacent nitrogen atom, may be substituted, and may be substituted, and R 19 and R 2 ° may be formed together with the adjacent nitrogen atom.
  • An optionally substituted heterocycle has at least one carbon atom and at least one nitrogen atom, and further has at least one heteroatom in the ring selected from nitrogen and oxygen and sulfur.
  • a 4- to 7-membered ring group which may contain an atom and which may be substituted by oxo with respect to a carbon atom constituting a ring, and further comprising two adjacent carbon atoms constituting a heterocycle.
  • the aromatic ring such as a benzene ring may be condensed by utilizing.
  • azetidino, 1-pyrrolidur, piperidino, 1-pidazur, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxo-11-quinazolidiel and the like can be mentioned.
  • heterocycle contains a nitrogen atom as a further hetero atom in the ring, such as 1-piperazinyl, lower alkyl (as above), arylalkyl (as above), Heteroarylalkyl (same as above), aryl (same as above), heteroaryl (same as above), one COOR a (R a is the same as above) Good.
  • the acyl is represented by one CORa, and Ra is the same as described above.
  • Preferred examples of the optionally substituted heterocycle include 1-pyrrolidinyl, piperidino, morpholino and those in which the nitrogen atom at the 4-position is substituted with lower alkyl. Good 1-piperazir.
  • the protecting group for the hydroxyl group in X includes, for example, arylalkyl (same as above), aryl (same as above), heteroaryl (same as above), silyl (eg, trimethylsilyl, tert-butyldimethylsilyl, tert-butyl) Diphenylsilyl), 2-tetrahydroviranyl, p-methoxybenzyl, tert-butyl and the like.
  • the arylalkyl, aryl and heteroaryl may have one or more substituents as exemplified above.
  • the protecting group for the hydroxyl group silyl, 2-tetrahydrovillael, benzyl and the like are preferable.
  • the alkylamino in Y means that the alkyl portion thereof preferably has 1 to 6 carbon atoms and may be linear or branched. Specific examples include methylamino, ethylamino, n-propyl pyramino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, II-hexylamino and the like.
  • a preferable example of X is hydrogen.
  • Preferred examples of R 1 include phthalimidoalkyl, and more preferred examples include phthalimidomethyl.
  • Preferred examples of R 2 include lower alkyl, more preferred examples include alkyl having 1 to 4 carbon atoms, and still more preferred examples include isoptyl.
  • Preferred examples of R 3 include the formula
  • preferred examples of Q 1 include an aromatic hydrocarbon ring, and more preferred examples include phenol.
  • R 3 there may be mentioned 1 Preferred examples of m, 3 Preferred examples of n can and Ageruko.
  • the R 3, can be sulfo Preferred examples of R 1 6.
  • Preferred examples of Y include alkylamino, more preferred examples include alkylamino having 1 to 4 carbon atoms, and still more preferred examples include methylamino.
  • the hydroxamic acid derivative represented by the formula (I) or a pharmacologically acceptable salt thereof may have an asymmetric carbon, it may exist as an optically active isomer and a racemate.
  • the body can be separated into each optically active substance by a method known per se.
  • the hydroxamic acid derivative or a pharmacologically acceptable salt thereof further has an additional asymmetric carbon, the compound must exist as a diastereomer mixture or as a single diastereomer. These can also be separated from each other by a method known per se.
  • hydroxamic acid derivative or a pharmaceutically acceptable salt thereof can exhibit polymorphism, can exist as more than one tautomer, and It can exist as a hydrate (eg, hydrate, etc.).
  • the present invention includes any stereoisomers, optical isomers, polymorphs, tautomers, solvates, and any mixtures thereof as described above.
  • Optically active, racemic and diastereomers are also included within the scope of the present invention.
  • Examples of pharmacologically acceptable salts of the hydroxamic acid derivatives include, for example, alkali metal salts (for example, salts with lithium, sodium, potassium, etc.) and alkaline earth metal salts (for example, salts with calcium, magnesium, etc.) , Aluminum salts, ammonium salts, salts with organic bases (eg, salts with triethylamine, morpholine, piperidine, triethanolamine, etc.).
  • salts include, for example, inorganic acid addition salts (eg, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts Salts (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid , Succinic acid, mandelic acid, malic acid, etc.), amino acid salts (eg, glutamic acid, aspartic acid, histidine, Gin, salts with arginine, etc.). Further, it can be converted into a salt using oxalic acid for crystallization.
  • inorganic acid addition salts eg, salts with hydrochloric acid, hydrobromic acid
  • hydroxamic acid derivatives of the formula (I) 5-methyl-13 (R)- ⁇ 1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl ⁇ -2 (R)
  • Monophthalimidomethylhexanohydroxamic acid and its pharmaceutically acceptable salts are preferred.
  • hydroxamic acid derivative of the formula (I) or a pharmaceutically acceptable salt thereof used in the present invention can be prepared according to the method described in WO 99/61412 or WO 2/06214.
  • the hydroxamic acid derivative of the formula (I) may be a pharmacologically acceptable acid addition salt, which includes inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, methanesulfonic acid, fumaric acid and maleic acid. And organic acids such as mandelic acid, citric acid, tartaric acid and salicylic acid.
  • a salt with a metal such as sodium, potassium, calcium, magnesium, or aluminum, or a salt with an amino acid such as lysine can be used.
  • their monohydrate, dihydrate, mono-dihydrate, 1/3 hydrate, 14 tetrahydrate, 2/3 trihydrate, 3 no dihydrate, 6 / Pentahydrate and the like are also included in the present invention.
  • hydroxamic acid derivative of the formula (I) has an optical isomer, a racemate or a cis-trans isomer, all of these can be used in the present invention, and these isomers can be obtained by a conventional method. It can be produced by using an isolating power and each isomer raw material.
  • the antibacterial agent used in the present invention which is used in combination with the hydroxamic acid derivative of the formula (I) or a pharmacologically acceptable salt thereof, has a significantly better prevention of sepsis than the antibacterial agent alone.
  • the mechanism of action is not particularly limited as long as it shows a therapeutic effect and / or any antibacterial agent can be used as long as it exhibits significantly better sepsis prevention and / or therapeutic effect than used alone. Can be used.
  • those that are clinically usable including those under development and those that will be developed in the future, can be used in the present invention.
  • antibacterial agents include penicillins, cefms, penems, monopactams, and other j3-latatams, and tetracyclines, which are conventionally used to prevent or treat sepsis.
  • antibiotics such as aminoglycosides and macrolides.
  • antibacterial antibiotics are preferred, and in particular, (5R, 6S) -13- [2- (formimidoylamino) ethylsulfanyl] -6-[(1) 1-Hydroxyethyl] 1 7 1-oxo-1 1-azabicyclo [3.2.0] heptose 2-ene-2-carboxylic acid.
  • the administration method of the concomitant drug containing the hydroxamic acid derivative of the formula (I) and the antibacterial drug is not particularly limited as long as the drug of the present invention can be used in combination.
  • the drug of the present invention may be administered as a single composition containing both of the drugs of the present invention, or may be administered as a formulation (kit) to which each drug can be separately administered by different administration methods.
  • excipients such as sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tran gum , Gum arabic, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvierpyrrolidone, hydroxypropinoresenolerose, hydroxypropylmethylcellulose, glycerin, polyethylene glycol, carbonate Sodium hydrogen, magnesium stearate, talc and the like are used.
  • tablets may be coated with normal skin as needed, such as sugar-coated tablets, Enteric-coated tablets, film-coated tablets, bi
  • animal and vegetable oils oil, corn oil, castor oil, etc.
  • mineral oils vaseline, white petrolatum, solid paraffin, etc.
  • waxes hohopa oil, carnapa wax, beeswax, etc.
  • a partially or totally synthesized glycerin fatty acid ester eg, lauric acid, myristic acid, or palmitic acid
  • additives such as sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol and the like can be mentioned.
  • a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used.
  • a suitable suspending agent such as sodium carboxymethylcellulose, a nonionic surfactant, and a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination.
  • an aqueous solution or an aqueous solution is used, and particularly, a sterile injectable aqueous solution is used.
  • Buffers preferably borate buffers, acetate buffers, carbonate buffers, etc. for reducing irritation
  • isotonic agents preferably borate buffers, acetate buffers, carbonate buffers, etc. for reducing irritation
  • solubilizing agents e.g., solubilizing agents
  • preservatives e.g., thickeners
  • chelates PH adjuster pH is usually preferably adjusted to about 6 to 8.5
  • various additives such as fragrance may be appropriately added.
  • the daily dose of the concomitant drug of the present invention varies depending on the severity of symptoms, age, sex, weight, sensitivity difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc.
  • the side effect is not particularly limited as long as the side effect is not a problem, but usually about 0.01 to about 2000 mg, preferably about 0.02 mg / kg of the mammal's body weight by i.V. administration. It is 1 to about 50 Omg, and more preferably about 0.3 to about 30 Omg.
  • the amount of each active ingredient in the concomitant drug of the present invention is not particularly limited as long as side effects do not pose a problem and does not adversely affect the effect of the concomitant administration.
  • the daily dose of each active ingredient in the concomitant drug of the present invention is based on the severity of symptoms, age, gender, body weight, sensitivity difference, administration timing, interval, nature of pharmaceutical preparation, preparation, type, efficacy, etc.
  • the hydroxamic acid derivative of the formula (I) and about 1 to about 1000 mg of the antibacterial agent per kg of the body weight and about 0.1 to about 10 of the hydroxamic acid derivative of the formula (I) Omg and about 2 to about 50 Omg are more preferred, and about 0.3 to about 3 Omg of the hydroxamic acid derivative of Formula (I) and about 5 to about 200 mg of the antibacterial are even more preferred.
  • each active ingredient may be administered simultaneously, or one ingredient may be administered first, and then the other ingredient may be administered. May be. Therefore, when formulating, each active ingredient may be contained in one preparation, or may be contained in separate preparations.
  • the concomitant drug of the present invention into a single injection containing each active ingredient or separate injections containing each separately.
  • the amount of the hydroxamic acid derivative of the formula (I) or the pharmacologically acceptable salt or hydrate thereof of 0.001 to 0.001 for the antibacterial drug 1 per unit time and per kg of the body weight of the administration subject. 2, preferably continuous infusion at a weight ratio of 0.006 to 0.02.
  • the concomitant drug of the present invention only needs to contain at least one active ingredient, and two or more formulas (I) as long as the administration of the concomitant drug of the present invention does not adversely affect the effect to be achieved.
  • Examples of subjects to which the concomitant drug of the present invention is administered include various mammals such as humans, monkeys, mice, rats, puppies, puta, dogs, puppies, puppies, and the like. Shows preventive and therapeutic effects.
  • CLP model rats were prepared according to the method of Wicht erman, et al. (J. Surg. Res., 29, 189-201, 1980).
  • the rats were continuously administered to the tail vein of rats at a rate of 2.5 mL // kg / hr for 24 hours using an intravenous needle with a 23 G wing. Drugs or saline were replenished to the syringe at any time (about every 8 hours). The survival rate of each group was observed and compared every hour from immediately after surgery to 24 hours.
  • Table 1 shows the dose, administration route, administration time, and number of subjects in each experimental group. The concomitant effects were determined by continuous administration of a mixture of both drugs (mixtures prepared with the respective drugs at the doses shown in the table) and comparison with the single drug. table 1
  • the combined administration group of I PMZC S and Compound A showed a significant life-prolonging effect at the doses of 0.03 and 0.1 mg / kg / hr compared to the single administration group of IPM / CS.
  • the survival rate after 24 hours in each group was 0% in the control group, IPM / CS 5 mg / kg 37.5% in the compound A / hr group and 6.3% in the compound A 0.3 mg / kg / hr group, compared to 81 in the compound AO.03 mg / kg / hr group. 3%, and 75.0% in the compound A 0.1 mg / kg / hr combination administration group.
  • the body temperature (rectal temperature) was measured by inserting a thermistor probe SXN-64 into the anus of the rectum of the rat at a depth of about 4.0 cm and using a hybrid recorder K-382 (Technol S even Co.). , J apan).
  • the difference between the body temperature before ether anesthesia for CLP treatment and the body temperature 6 hours after CLP treatment was defined as the change in body temperature (A ° C).
  • the combined dose of IPM / CS and Compound A was about 2 at a dose of 0.03 mg / kg ghr compared to the control group.
  • C about 3 at a dose of 0.1 mgZk gZhr.
  • C The effect of suppressing body temperature decrease was demonstrated.
  • the concomitant drug of this invention sepsis can be prevented and / or treated more effectively than the conventional drug therapy only with an antimicrobial agent. Furthermore, the concomitant drug of the present invention can effectively suppress the decrease in body temperature observed when sepsis becomes severe. While certain embodiments of the invention have been described in detail, those skilled in the art will recognize that certain embodiments illustrated therein can have various modifications and alterations without departing substantially from the teachings and advantages of the invention. It is possible to do Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims.

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Abstract

Des médicaments concurrents comprennent une combinaison d'au moins un dérivé d'oxyde hydroxamique représenté par la formule (I) (les symboles étant définis dans la description) ou un sel pharmaceutiquement acceptable ou un hydrate de celui-ci, avec au moins un médicament antibactérien, qui a un effet sensiblement plus puissant en matière de prévention de la septicémie et/ou de traitement que les médicaments individuels utilisés séparément. L'invention concerne aussi un procédé de prévention et/ou de traitement de la septicémie, qui consiste à utiliser des médicaments concurrents, et une utilisation d'une combinaison d'au moins un dérivé d'acide hydroxamique représenté par la formule (I) ou d'un sel pharmaceutiquement acceptable ou d'un hydrate de celui-ci avec au moins un médicament antibactérien destiné à la prévention ou au traitement de la septicémie.
PCT/JP2004/015748 2003-10-17 2004-10-18 Medicaments concurrents WO2005037265A1 (fr)

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JP2019525954A (ja) * 2016-06-24 2019-09-12 フンダシオン パラ ラ インベスティガシオン ビオメディカ デル オスピタル グレゴリオ マラニョン 敗血症の処置のために用いられるシラスタチン

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WO1999061412A1 (fr) * 1998-05-22 1999-12-02 Welfide Corporation Derives d'acide hydroxamique et utilisation medicinale de ces derives
WO2002006214A1 (fr) * 2000-07-19 2002-01-24 Mitsubishi Pharma Corporation Derives a l'acide sulfonique d'acides hydroxamiques et leur utilisation comme produits medicaux
JP2002234850A (ja) * 2000-12-08 2002-08-23 Takeda Chem Ind Ltd 併用薬

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WO1999061412A1 (fr) * 1998-05-22 1999-12-02 Welfide Corporation Derives d'acide hydroxamique et utilisation medicinale de ces derives
WO2002006214A1 (fr) * 2000-07-19 2002-01-24 Mitsubishi Pharma Corporation Derives a l'acide sulfonique d'acides hydroxamiques et leur utilisation comme produits medicaux
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Publication number Priority date Publication date Assignee Title
JP2019525954A (ja) * 2016-06-24 2019-09-12 フンダシオン パラ ラ インベスティガシオン ビオメディカ デル オスピタル グレゴリオ マラニョン 敗血症の処置のために用いられるシラスタチン
JP7109791B2 (ja) 2016-06-24 2022-08-01 フンダシオン パラ ラ インベスティガシオン ビオメディカ デル オスピタル グレゴリオ マラニョン 敗血症の処置のために用いられるシラスタチン

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