WO2001054726A1 - REMEDES DESTINES A UNE LESION PAR REPERFUSION CONTENANT UN ANTAGONISTE D'INTEGRINE αvβ3 - Google Patents
REMEDES DESTINES A UNE LESION PAR REPERFUSION CONTENANT UN ANTAGONISTE D'INTEGRINE αvβ3 Download PDFInfo
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- WO2001054726A1 WO2001054726A1 PCT/JP2001/000496 JP0100496W WO0154726A1 WO 2001054726 A1 WO2001054726 A1 WO 2001054726A1 JP 0100496 W JP0100496 W JP 0100496W WO 0154726 A1 WO0154726 A1 WO 0154726A1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention is used to prevent or treat reperfusion injury, to pharmaceutical compositions containing Integurinhi gamma 5 3 antagonist as an active ingredient.
- the medical system for ischemic disease has been rapidly improving in recent years, with guidance and measures in medical administration both inside and outside the country.
- the current trends in treatment are not always satisfactory in Japan and overseas.
- reperfusion injury has recently been one of the important issues in performing recanalization therapy.
- the occurrence of reperfusion injury leads to the expansion of myocardial infarcts, resulting in reduced cardiac function. Increased infarct size leads to death (T.D. Miller et al., Circulation, 92, 334, (1995)) and reduced cardiac function leading to death (R. Stevenson et al., Br. Med. J., 307, 349, (1993)).
- Various clinical preclinical studies have been conducted by various research institutions for the purpose of developing therapeutic agents for reperfusion injury.
- An object of the present invention is to provide a drug capable of effectively preventing or treating reperfusion injury in clinical practice.
- the present inventors have proposed that leukocyte adhesion 'suppresses infiltration and microthrombosis (M. Gawaz et al., Circulation, 96, 1809, (1997))' edema (H. Tsukada et al., Circ. Res., 77, 651, (1995)), and as a result of continued intensive research, a compound that antagonizes the adhesion molecule integrin ⁇ inhibits leukocyte adhesion and infiltration, resulting in reperfusion. For the first time found important scientific knowledge of suppressing disability
- the agent for treating or preventing reperfusion injury according to the present invention contains an integrin ⁇ - 3 antagonist, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
- microthrombus and edema are thought to be additional causes (M. Gawaz et al., Circulation, 96, 1809, (1997), H. Tsukada et al., Circ. Res., 77, 651, (1995)).
- the present inventors have found that an integrin v-3 antagonist inhibits adhesion of rat macrophages to vitronectin (Pharmacological Test Example 2).
- integrin v-3 antagonists inhibit adhesion of leukocytes to activated vascular endothelial cells (Pharmacological Test Example 6).
- Vitronectin receptor Yuichi is involved in the adhesion and infiltration of leukocytes, the development of microthrombi and edema, which cause reperfusion injury, and
- Integurin alpha [nu 3 antagonist that the material can treat and prevent the reperfusion injury by inhibiting the occurrence of adhesion and infiltration and fine thrombi and edema of leukocytes
- integrin ⁇ -3 antagonists inhibited infarction in rat, hamster, and dog models of myocardial infarction (Pharmacological Test Examples 3, 4, and 5).
- integrin ⁇ -3 antagonists are effective in treating or preventing reperfusion injury.
- reperfusion injury includes reperfusion injury associated with recanalization therapy during ischemic heart disease, reperfusion injury associated with recanalization therapy during cerebral ischemic disease, and organ transplantation. It can be reperfusion injury associated with blood transplantation or reperfusion injury associated with the use of artificial organs.
- an integrin ⁇ -3 antagonist for the manufacture of a medicament for treating or preventing reperfusion injury.
- the effective amount of Integurinhi V y5 3 antagonists, pharmaceutically Huh comprising administering an acceptable salt, or a solvate thereof, to a mammal together with a pharmaceutically acceptable carrier.
- Whether a substance has integrin v-3 antagonistic activity is determined, for example, by W099 / 38
- OnM or less Compounds having an IC 50 of 1 OnM or less, preferably 1. OnM or less can be referred to as “integrin v-3 antagonists”.
- the “integrin v / 5 3 antagonist” is not particularly limited as long as it is a substance that inhibits the binding of integrin v-5 to its ligand.
- Examples of integrin v-3 antagonists include small molecule compounds (eg, compounds with a molecular weight of 200-850), antibodies, cyclic peptides, and snake venom.
- “Integrin v-3 antagonists” can be selected, for example, from those described in the following literature: W095 / 32710 (Merck), W096 / 37 492 (Dupont-Merck), W097 / 01540 (Smith Klein Vehicle), W097 / 08145 (Searle), W097 / 23451 (Merck), W097 / 23480 (Dupont Merck), W097Z24119 (SKB), W097 / 26250 (Merck), W097 / 33887 (DuPont-Merck), W097 / 36858 (Searle), W097 / 36859 (Saar), W097 / 36860 (Searle), W097 / 36861 (Searle), W097 / 36862 (Searle) , W097 / 24336 (Smithklaine Beecham), W097 / 37655 (Merck), W098 / 0884 (Merck), W098 / 18460 (
- the integrin ⁇ -3 antagonist can preferably be a compound of formula (I).
- Saturated or unsaturated 5- to 7-membered heterocyclic group containing at least one nitrogen atom (this heterocyclic group is condensed with another saturated or unsaturated 5- to 7-membered carbocyclic or heterocyclic ring to form a bicyclic may form a Shikimoto, the heterocyclic group and bicyclic group, d-6 alkyl group, an amino group, C 2 - 6 alkenyl group, a hydroxyl group, a halogen atom, d-6 alkoxy group, d-6 alkoxycarbonyl group or Ararukiru group (this ⁇ I 6 alkyl group, an amino group, C 2 - 6 alkenyl group, hydroxyl group, C -!
- d -6 alkoxy group, an alkoxy force Ruponiru groups, and Ararukiru group is an alkyl group, d -6 may be substituted with an alkoxy group, a halogen atom, an amino group, or a hydroxyl group), or
- R 3 N C——
- R 3 -C C- or
- X represents one NH—, one CH 2 —, or a bond, preferably one NH—
- B represents C 6 alkylene chain which may have an unsaturated bond
- the methylene moiety at one or two arbitrary positions may be replaced by a group or atom selected from the group consisting of an oxygen atom, a sulfur atom, an optionally substituted imino group, or a carbonyl group d- 6 alkylene chains (this alkylene chain may have an unsaturated bond),
- d-6 alkyl groups C physician 6 alkoxy group, It may be substituted by a halogen atom, an amino group, a nitro group, a hydroxyl group, or an oxygen atom.
- the alkyl group and the d-6 alkoxy group are substituted by a halogen atom, a d-6 alkoxy group, an amino group, or a hydroxyl group. May be
- CONR 4 CHR 5 CHR 6 - group (R 4 represented by a hydrogen atom, C physician 6 alkyl le group, C 2 - 6 alkenyl group, C 2 - represents an alkynyl group or Ararukiru group, this d - 6 alkyl group, C 2 - 6 alkenyl group, C 2 - 6 alkynyl and Ararukiru group is a halogen atom, ⁇ I 6 alkoxy group, an amino group or may be substituted by hydroxyl, R 5 and R 6, may be the same or different, group (R 7 represented by a hydrogen atom, wherein one NR 7 COR 8 is hydrogen, d-6 straight chain alkyl or C 3, - it represents a 6 branched alkyl group, R 8 is a hydrogen atom, a linear alkyl group, C 26 Alkenyl group, C 3 - 6 branched alkyl group, C?
- - 6 alkyl group, ⁇ I 6 alkoxy group, C -! 6 alkoxycarbonyl group, Araruki group may be substituted by an amino group or hydroxyl group, Ararukiru group which may represented by R 8, carbocyclic group, and heterocyclic groups, hydroxyl group, an amino group, azido group, d-6 alkoxy groups, C physician 6 alkylamino group, di ⁇ - 6 alkylamino group, a nitro group, Shiano group, d-6 alkyl groups, C physician 6 may be substituted by an alkoxycarbonyl group, a carboxyl group, a halogen atom, or a d-6 alkylcarbonyl group), a group represented by the formula: NR 7 CO 2 R 8 (R 7 has the same meaning as described above.) means indicates, R 8 is as defined above), a group represented by the formula -NR 7 S0 2 R 8 (R 7 have the same meaning as described above, R 8 is as defined above), group
- Cycloprothrin building ring (this cyclopropyl group, a hydroxyl group, an amino group, azido group, d-6 alkoxy groups, C alkylamino group, di ⁇ have 6 alkylamino group, a nitro group, Shiano group, (Bok 6 alkyl group, C 6 may be substituted by an alkoxycarbonyl group, a carboxyl group, a halogen atom, or an alkylcarbonyl group), or
- Vinylene group (This vinylene group is a d-6 alkyl group, C! -6 alkylcarbonyl group, d-6 alkoxycarbonyl group, carboxyl group, halogen atom, azide group, A nitro group or a cyano group).
- C i may be substituted by an alkyl group or a phenyl group
- C t may be substituted by a thiol group, d alkyl group, d- 6 alkoxy group, C alkoxycarbonyl group, aralkyl group, amino group or hydroxyl group —
- R C is a hydrogen atom, d straight chain alkyl group, C 3 - 6 branched alkyl group,.
- Examples of the 57-membered monocyclic carbocyclic or heterocyclic group include cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, pyrimidyl, morpholinyl, piperazinyl , A biperidinyl group, a bilolidinyl group, a phenyl group, and a furyl group.
- C, - 6 alkyl as a group or part of a group
- C, - 6 alkoxy term, unless specifically mentioned, linear, branched, or cyclic Means alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
- C 2 - 6 alkenyl and - the term “C 2 6 Arukieru,” unless specifically mentioned, linear, branched, or cyclic And alkenyl and alkynyl having 2 to 6, preferably 2 to 4 carbon atoms.
- C 6 alkyl examples include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropyl methyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n -Hexyl and cyclohexyl.
- Examples of d-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
- Examples of C 2-6 alkenyl include an aryl group.
- alkynyl examples include 2-propynyl group and Echiniru group o
- Halogen atom represents a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
- the "Ararukiru group" as a group or part of a group C 7 - represents a 16 Ararukiru group, more specifically, Ri by the 5-7 membered carbocyclic group or heterocyclic ⁇ group a saturated or unsaturated Substituted Ci- 6 alkyl, preferably d- 4 alkyl.
- the aralkyl group include a benzyl group, a phenethyl group, and a naphthylmethyl group.
- the “saturated or unsaturated 5- to 7-membered heterocyclic group containing at least one nitrogen atom” represented by A is preferably a saturated or unsaturated 5- to 7-membered heterocyclic group containing 1 or 2 nitrogen atoms. It can be a formula group, more preferably a saturated or unsaturated 5- or 6-membered heterocyclic group containing one or two nitrogen atoms.
- the “bicyclic group” represented by A is preferably a 9 or 10-membered heterocyclic group, more preferably a 9 or 10-membered heterocyclic group containing 2 or 3 nitrogen atoms. Can be done.
- R 2 and R 3 ′ preferably represent a hydrogen atom.
- A preferably represents the following groups.
- Het represents a saturated or unsaturated 5- to 7-membered heterocyclic group containing at least one nitrogen atom, and the heterocyclic group is linked to another saturated or unsaturated 5- to 7-membered carbocyclic or heterocyclic ring.
- condensation may form a bicyclic group, the heterocyclic group and bicyclic group d-6 alkyl group, amino group, C 2 - 6 alkenyl group, a hydroxyl group, a halogen atom,
- Alkoxy group, ⁇ I 6 alkoxycarbonyl alkylsulfonyl group or Ararukiru group (this - 6 alkyl group, amino group, C 2 - 6 alkenyl group, hydroxyl group, C] - 6 alkoxy group, d alkoxycarbonyl group and Ararukiru group, alkyl group, C, - 6 ⁇ alkoxy group, a halogen atom, may be substituted by an amino group or a but it may also be substituted by hydroxyl,)
- R 21 , R 22 , R 23 , and R 23 ′ may be the same or different and include a hydrogen atom, d alkyl group, C! -Alkoxy group, hydroxyl group, —alkoxycarbonyl group, Represents an alkenyl group or an aralkyl group; d- 6 alkyl group, C alkoxy group, hydroxyl group, d alkoxycarbonyl group, C alkenyl group or aralkyl group is a halogen atom, d-alkoxy group, amino group, d alkyl Group, Or may be substituted by a hydroxyl group, or
- Group - CHR 24 CH 2 CH 2 _ (R 24 is C -! Represents an alkyl group, an amino group or a hydroxyl group, the amino group and a hydroxyl group are alkyl groups, d-6 alkoxycarbonyl group, Ararukiru group or, May be substituted by an aralkyloxycarbonyl group),
- R 22 may represent a single bond between: 21 and the nitrogen atom to which it is attached)
- R 22 and R 23 ′ preferably represent a hydrogen atom.
- A is more preferably a hydrogen atom, an amidino group, an imidazolyl group, an imidazolidinyl group, a thiazolyl group, a thiazolidinyl group, a viridinyl group, a pyrimidinyl group, a tetrahydrovirimidinyl group, a triazinyl group, a benzimidazolyl group, or an azabenzo Represents an imidazolyl group; groups other than hydrogen atoms are C, 6 alkyl groups Amino group, C 2 - 6 alkenyl group, a hydroxyl group, a halogen atom, CI- 6 alkoxy group, alkoxycarbonyl group or Ararukiru group (this (: I 6 alkyl group, ⁇ amino group, C 2 - 6 alkenyl group, a hydroxyl group, d-6 alkoxy, Ci-6 alkoxycarbonyl, and aralkyl may be substitute
- X preferably represents 1 N H—.
- Examples of the d-6 alkylene chain in which a part of the chain represented by B may be optionally substituted include * —d-5 alkylene—0—, and more specifically, * —CH 2
- Examples of the piperazine ring that B may represent include:
- Examples of the pyrrolidine ring that B may represent include:
- Examples of the piperidine ring that B may represent include:
- bipyridine ring examples include:
- Examples of the pyrimidine ring that B may represent include:
- triazine rings that B may represent include:
- Examples of the substituted biperazine ring that B may represent include:
- Examples of the substituted bipyridine ring that B may represent include:
- D preferably represents a group of CONR 4 CHR 5 CHR 6 —, more preferably a group of CONHCH 2 C (—NHSO2E) 1 (E is the same as defined in the following formula (II) ).
- the integrin v- 3 antagonist can be a compound of formula (II). :
- A represents a hydrogen atom, an amidino group, an imidazolyl group, an imidazolidinyl group, a thiazolyl group, a thiazolidinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrimidinyl group, a triazinyl group, a benzoimidazolyl group, or an azabenzoimidazolyl group Represents
- Groups other than hydrogen atoms include C6 alkyl groups, amino groups, C2-6 alkenyl groups, hydroxyl groups, halogen atoms, alkoxy groups, C6 alkoxycarbonyl groups, and aralkyl groups (C6 alkyl groups).
- amino groups, C 2 - 6 alkenyl group, hydroxyl group, C physician 6 alkoxy groups, C physician 6 alkoxycarbonyl group and Ararukiru group is substituted d-6 alkyl group, an alkoxy group, a halogen atom, an amino group or a hydroxyl group, May be substituted by
- the methylene moiety at one or two arbitrary positions may be replaced by a group or atom selected from the group consisting of an oxygen atom, a sulfur atom, an optionally substituted imino group, or a carbonyl group d- 6 alkylene chains (this alkylene chain may have an unsaturated bond),
- One C 6 H 4 NHCO-, one C 6 H 4 S0 2 NH-, one C 6 H 4 NHS0 2 -, pyridine ring may be substituted by a C 6 alkyl group, a C 6 alkoxy group, a halogen atom, an amino group, a nitro group, a hydroxyl group, or an oxygen atom.
- E is a straight-chain alkyl groups, C 2-6 alkenyl groups, C 3 - 6 branched alkyl group,
- 6 alkyl group, a d-6 alkoxy group, d-6 may be substituted by an alkoxycarbonyl group, an aralkyl group, an amino group or a hydroxyl group, and an aralkyl group, a carbocyclic group and a heterocyclic group which may be represented by E include a hydroxyl group, an amino group group, azide groups, C physician 6 alkoxy group, d-6 Al Kiruamino group, di-0 had 6 alkylamino group, a nitro group, Shiano group, ⁇ I 6 alkyl group, d-6 alkoxycarbonyl group, a carboxyl group, a halogen atom , Or by d-6 alkylcarbonyl group
- Examples of the 5- to 7-membered monocyclic carbocyclic group or heterocyclic group which may be substituted and may be represented by E include a cyclopentyl group, a cyclohexyl group, a cycloheptyl
- d-2 a thiol group optionally substituted by an alkyl group or a phenyl group, d-6 alkyl group, C 6 alkoxy group, C ⁇ 6 alkoxycarbonyl group, aralkyl group, amino group or C 6 alkyl group which may be substituted by a hydroxyl group, or
- d-6 alkyl group d-6 alkoxy group, C-6 alkoxycarbonyl group, aralkyl group, amino group or d-6 alkoxy group which may be substituted by a hydroxyl group;
- RC is a hydrogen atom, d-6 straight chain alkyl group, C 3 - 6 branched alkyl group,.
- the integrin v33 antagonist can be a compound of formula (III).
- A represents a hydrogen atom, an amidino group, an imidazolyl group, an imidazolidinyl group, a thiazolyl group, a thiazolidinyl group, a pyridinyl group, a pyrimidinyl group, a tetrahydropyrimidinyl group, a triazinyl group, a benzimidazolyl group, or an azabenzoimidazolyl group.
- Groups other than a hydrogen atom include an alkyl group, an amino group, a C2-6 alkenyl group, a hydroxyl group, a halogen atom, a Ci-6 alkoxy group, a d-6 alkoxycarbonyl group, or an aralkyl group (the ( ⁇ 6 alkyl group) , amino group, C 2 -6 alkenyl group, a hydroxyl group, CI- 6 alkoxy group, d-6 alkoxycarbonyl group and Ararukiru groups d-6 alkyl group,, d-6 alkoxy group, a halogen atom, an amino group or a hydroxyl group, May be substituted by
- E is d-6 linear alkyl group, C2-6 alkenyl group, C3-6 branched alkyl group,
- a thiol group optionally substituted by a C 2 alkyl group or a phenyl group, a d-6 alkyl group,
- Hydroxyl group, d a thiol group optionally substituted by an alkyl group or a phenyl group, an alkyl group, a d-alkoxy group, a C-alkoxycarbonyl group, an aralkyl group, an amino group or a C alkyl group optionally substituted by a hydroxyl group; Or
- d represents an alkyl group, d alkoxy group, C alkoxycarbonyl group, aralkyl group, amino group or C alkoxy group which may be substituted by a hydroxyl group;
- R c is hydrogen atom, d - e straight chain alkyl group, C 3 - 6 branched alkyl group, C 7 - i.
- n 0, 1, or 2
- n 0, 1, or 2]
- Integurinhi / 5 3 antagonist can be a compound selected from the following 0
- B represents a piperazine ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, a pyrimidine ring or a triazine ring;
- Compounds of formula (V), formula (VII), formula (VIII), formula (IX), formula (X), and formula (XI) are compounds corresponding to group B (eg, 3-hydroxypiperidine, 4- (Hydroxypiperidine) and optionally substituted 4-fluorobenzoic acid to convert the hydroxyl group of the obtained compound to an amino group, and to give a compound corresponding to group A to a free primary amine (for example, 2 —Bromopyrimidine) is introduced into the deprotected carboxyl group via an amide bond to the group—D—COOR. Can be manufactured. These compounds can be produced, for example, according to the method described in W099 / 52872.
- B is a C 6 alkylene chain (1 or 2 methylene portions in the chain may be substituted by an oxygen atom or the like), a formula —C 6 H 4 CONH— group represented by group represented by the formula _C 6 H 4 NHCO-, wherein - C 6 H 4 S0 2 NH- group represented by the formula - C 6 H 4 NHS0 2 - compound represents a group represented by, and the formula
- the compound (VI) can be produced, for example, according to the method described in W095 / 32710.
- a compound (eg, 2-bromopyrimidine) corresponding to group A is introduced into group Q (eg, deprotected amino group) of (XX), and the group is further COORc (eg, deprotected carboxyl group). ) To the group via an amide bond —D—COOR. To build Can be manufactured more. Introduction of group A and construction of group-D-COORc can be performed according to the method described in W09952872.
- R 27 and R 28 may be the same or different and represent a hydrogen atom, a hydroxyl group, a d-4 alkoxy group, or a Ci-4 alkyl group
- Q is a hydroxyl group
- L represents an azide group or an amino group which may be protected
- L represents a leaving group
- R b and R e have the same meanings as defined in the formula (I)
- the nitrogen atom is an ortho group of the phenyl group.
- a compound of the formula (XIV) is obtained by reacting a compound of the formula (XII) with a compound of the formula (XIII).
- Compounds of formula (XII) are prepared by treating a natural organic compound, such as midecamycin, erythromycin or oleandomycin, with an acid in the presence of a lower alcohol to form a neutral sugar present in the structure. Specifically, it is isolated as a lower alkyl glycoside of mycalose, cladinose or oreandrose, and then, if necessary, is converted into an azide group while sterically inverting the free hydroxyl group present at the 4-position, and It can be obtained by converting to a reducing sugar by hydrolysis. Conversion to an azide group can be performed according to a conventional method.
- a natural organic compound such as midecamycin, erythromycin or oleandomycin
- the compound of the formula (XII) and the compound of the formula (XIII) can be reacted by a reductive amination reaction.
- the reductive amination reaction is carried out in the presence of a hydride reagent, for example, sodium cyanoborohydride, a reagent such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride, methanol, chloride, etc.
- a reaction solvent such as methylene, dimethylformamide, or dichloroethane or a mixed solvent thereof, the reaction can be performed at 0 ° C to 50 ° C (within the range not exceeding the boiling point of the reaction solvent), preferably at room temperature. it can.
- the timing of adding the hydride reagent depends on the substrate. It may be added immediately after the start of the reaction, or may be added after a certain period of time, for example, 24 hours, after the two substrates have been dissolved in the reaction solvent. At that time, certain organic acids, such as acetic acid, citric acid, formic acid, methanesulfonic acid, monochloroacetic acid, monofluoroacetic acid, or inorganic acids, for the purpose of improving the reaction selectivity of the hydride reagent, etc. For example, hydrochloric acid or sulfuric acid may be added.
- Conversion to the leaving group L can be carried out according to a known method, for example, by reacting methanesulfonyl chloride in methylene chloride at 0 ° C. to room temperature.
- the leaving group L include a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom) Are mentioned.
- the compound of the formula (XVI) can be obtained by cyclizing the compound of the formula (XV) in which the leaving group L is constructed by an intramolecular ring closure reaction.
- Bases for the intramolecular ring closure reaction include tertiary organic bases such as diisopropylethylamine, triethylamine and tribenzylamine, and inorganic bases such as sodium carbonate and potassium carbonate. It is preferable to use an organic base from the viewpoint of selectivity of the organic compound.
- the azide group can be reduced to an amino group, if necessary.
- the reduction reaction of the azide group can be performed according to a known method.
- reaction solvent used in the step of converting to a leaving group and the step of intramolecular ring closure reaction is not particularly limited.
- Q represents a hydroxyl group, an azido group, or an amino group which may be protected *
- L represents a leaving group
- R a and R ⁇ R e have the same meanings as defined in the above formula.
- p represents an integer of 0 to 3
- q represents an integer of 1 to 3
- the nitrogen atom is an ortho-position (), a meta-position (), or a para-position (and), preferably a phenyl group of the phenyl group. At the meta position, is bonded to the phenyl group.
- a compound of the formula (XX) is obtained by reacting a compound of the formula (XVII) with a compound of the formula (XIII).
- the compound of the formula (XVII) and the compound of the formula (XIII) can be reacted by a reductive amination reaction.
- the reductive amination reaction is carried out in the presence of a hydride reagent, for example, sodium cyanoborohydride, a reagent such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride, methanol, methylene chloride.
- a reaction solvent such as dimethylformamide or dichloroethane or a mixed solvent thereof, the reaction is carried out at 0 ° C to 50 ° C (within the range not exceeding the boiling point of the reaction solvent), preferably at room temperature. it can.
- the timing of adding the hydride reagent depends on the substrate. It may be added immediately after the start of the reaction, or may be added after a certain period of time has elapsed after dissolving the two kinds of substrates in the reaction solvent, for example, 24 hours later. At that time, certain organic acids, such as acetic acid, citric acid, formic acid, methanesulfonic acid, monochloroacetic acid, monofluoroacetic acid, or inorganic acids, for the purpose of improving the reaction selectivity of the hydride reagent, etc. For example, hydrochloric acid or sulfuric acid may be added.
- Conversion to the leaving group L can be performed according to a known method.
- a primary hydroxyl group can be converted to a bromine atom by reacting carbon tetrabromide with triphenylphosphine on the primary hydroxyl group.
- a halogen atom for example, a chlorine atom, a bromine atom, an iodine atom, and a sulfonate, for example, a methanesulfonyloxy group, p-toluenesulfonate
- a phonoxy group for example, a benzenesulfonyoxy group, and a trifluoromethyl sulfonyloxy group.
- the compound of the formula (XX) can be obtained by subjecting the compound of the formula (XIX) in which the leaving group L is constructed to an intramolecular ring closure reaction.
- the intramolecular ring closure proceeds spontaneously when the leaving group L is introduced.
- Examples of the base for the intramolecular ring closure reaction include tertiary organic bases such as diisoprovirethylamine, triethylamine and tribenzylamine, and inorganic bases such as sodium carbonate and potassium carbonate. It is preferable to use an organic base from the viewpoint of selectivity of the organic compound.
- the functional group represented by Q can be further chemically transformed if necessary.
- a hydroxyl group can be converted to an azide group, and the azide group can be reduced to an amino group.
- the reduction reaction of the azide group can be performed according to a known method.
- reaction solvent used in the step of converting to a leaving group and the step of intramolecular ring closure reaction is not particularly limited.
- the compound of formula (XVI I) can be selected from the group consisting of pentasaccharide, hexasaccharide, and heptasaccharide, and derivatives thereof.
- the derivative may, for example, hydroxyl groups other functional groups on the monosaccharide, e.g., d-4 alkyl group (e.g. methylation group), d 4 alkoxy group (e.g. methoxy group), an azide group, and amino group, Are converted.
- the compound of formula (XVI I) is more preferably a 2-doxy 11 report of formula (XVI I,):
- R b , R and L have the same meanings as defined in formula (I), and the nitrogen atom is in the ortho, meta or para position of the phenyl group, preferably in the meta position. And is bonded to a phenyl group.
- Integrin V ⁇ 3 antagonist can be a pharmacologically acceptable salt
- Such salts include non-toxic salts, with preferred salts being hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates
- Inorganic acid salts such as phosphates, lower alkyl sulfonates such as methanesulfonate, trifluoromethane sulfonate, ethanesulfonate, and salts such as benzene sulfonate and p-toluenesulfonate
- Organic acid salts such as monosulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.
- amino acid salts such as glutamate, aspartate, sodium salt Alkali metal or alkaline earth metal salts such as potassium or calcium salts, organic alkali salts such as pyridine salt, triethylamine salt, etc. Can be mentioned.
- Integrin V-3 antagonists can also form pharmacologically acceptable solvates.
- solvates are not limited, but include, for example, alcohols such as hydrates, methanol solvates and ethanol solvates, and ethers such as tetrahydrofuran.
- compositions containing as an active ingredient an integrin ⁇ - 3 antagonist, particularly a compound of formulas (I) to (XI), a pharmacologically acceptable salt thereof, or a solvate thereof are administered orally or non-orally. It can be administered orally (e.g., by inhalation, nasal, ophthalmic, subcutaneous, intravenous, intravenous, intramuscular, rectal and transdermal), and can be administered orally or parenterally as a drug.
- suitable dosage forms are used for humans and non-human animals.
- oral preparations such as tablets, capsules, chewables, granules, powders, pills, fine granules, troches, syrups, emulsions, suspensions, and solutions, inhalants , Nasal solution, ophthalmic solution, topical solution, patch, injection such as intravenous and intramuscular injection, intravenous drip, etc., rectal administration, oily suppository, water-soluble suppository, ointment, etc. It can be prepared in any formulation form such as an agent.
- Liquid preparations such as injections and infusions are provided as powdered pharmaceutical compositions, for example, in lyophilized form, which are dissolved or dissolved in water or other suitable medium (eg, saline, dextrose infusion, buffer, etc.) before use. It may be used after being suspended.
- suitable medium eg, saline, dextrose infusion, buffer, etc.
- These various formulations contain commonly used excipients, extenders, binders, wetting agents, It can be manufactured by a conventional method using a disintegrant, a surfactant, a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, a stabilizer and the like. .
- the non-toxic additives that can be used include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or salts thereof, Arabic Examples include rubber, olive oil, propylene glycol, polyethylene glycol, syrup, vaseline, glycerin, ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, ascorbic acid, and cyclodextrins.
- the content of the compound described in the present invention in a drug varies depending on its dosage form, but it is usually 1.0 to 100% (W / W), preferably 1.0 to 60% in the whole composition. (W / W) concentration.
- the dosage and the number of administrations of the medicament described in the present invention are not particularly limited, but may be appropriately determined according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, and symptoms of the patient. The number of doses can be determined.
- the dosage for treatment and prevention of heart disease and the like is appropriately determined in consideration of the usage, the age, sex, and degree of symptoms of the patient, but is usually about 0.1 to 4000 mg per day for an adult, preferably 4 mg / day.
- the dose is preferably about 1000 mg, which can be administered once a day or several times or once a few days, and further continuously.
- the precipitated inorganic substance was separated by filtration through celite, and washed with tetrahydrofuran. The combined filtrate and washings were dried over anhydrous sodium sulfate. A 4.0 mol / 1 solution of hydrochloric acid in ethyl acetate (13.3 ml, 53.2 mol) was added to the filtrate, and the solvent was distilled off under reduced pressure. The obtained residue was azeotroped with methanol to give the dihydrochloride of the title compound (3.57 g, 78%).
- the reaction solution was filtered using celite, washed with dioxane and water, and the filtrate and the washing solution were combined and concentrated under reduced pressure.
- Tetrahydrofuran was added to and dissolved in Intermediate 8-1 (85 mg, 0.15 recited ol), 34% of 5% palladium carbon was added, and the mixture was vigorously stirred at room temperature under 1 atm of hydrogen for 12 hours.
- the reaction solution was filtered using celite, washed with tetrahydrofuran and ethanol, and the filtrate and the washing solution were combined and concentrated under reduced pressure.
- Oleandomycin phosphate (25.4 g, 32.4 ol) was dissolved by adding 200 ml of acetonitrile and 50 ml of ethanol, and toluene sulfonic acid (12.3 g, 64.9) was added. Stirred for hours. A saturated aqueous solution of sodium carbonate was added to the reaction solution, and the mixture was extracted three times with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing system: ethyl acetate) to obtain ethyl oleandroside (3.75 g, 61%).
- 1,4-Dioxane 1.0 ml and water (0.5 ml) were sequentially added to Intermediate 10-7 (11 mg, 0.039 tmol) and dissolved, and 10% palladium on carbon (3.0 m) was added. Stirred for hours. The insoluble material was filtered, washed with 20 ml of a solvent having the same composition as the mixed solvent used in the reaction, and the filtrate and the washing were combined. This was concentrated under reduced pressure to give the title compound (11 mg, 100).
- Pharmacological test example 1 Adhesion inhibitory activity test between vascular smooth muscle cells and vitronectin
- the adhesion of vascular smooth muscle cells to immobilized human vitronectin was measured with reference to the method of Liaw et al. (L. Liaw et al., Circ. Res., 74, 214, (1994)).
- a solution of vitronectin derived from human serum prepared in a concentration of 4 jug / ml in Dulbecco's PBS (Dulbecco's PBS (-)) is added to a microplate (Maxisorp) in 50 ⁇ 1 portions, and the mixture is allowed to react at 4 ° C and solidified. Phased.
- the human vascular smooth muscle cells cultured at 37 ° C under 5% carbon dioxide at 37 ° C were detached with Dulbecco's PBS (-) containing trypsin-EDTA, and washed with Dulbecco's PBS (-).
- the cells were suspended in Dulbecco's modified Eagle's medium at a concentration of 2 xlO 5 cells / ml.
- Drugs are added to Atsushi microplates coated with human vitronectin Add 50 jl of Dulbecco's Modified Eagle Medium containing 20 mg / ml Pseudoserum albumin, preculture at 37 ° C for 10 minutes in 5% carbon dioxide, and then suspend Dulbecco's Modified Eagle with human vascular smooth muscle cells. The medium was added at 50 ° C., stirred well, and reacted at 37 C under 5% carbon dioxide for 90 minutes. Next, after removing the reaction solution containing non-adherent cells, the cells were washed three times with Dulbecco's PBS (-).
- the adherent cells were fixed with 100% Dulbecco's PBS (-) containing 4% paraformaldehyde for 10 minutes at room temperature, and then Dulbecco's PBS containing 0.5% toluidine and 4% paraformaldehyde. (-) was added to 100 ⁇ l, stained at room temperature for 5 minutes, and washed thoroughly with distilled water. Next, after the inside of the well was air-dried, a 1% aqueous solution of sodium dodecyl sulfate was added to lyse the cells, and the absorbance at 595 nm of the obtained microplate was measured.
- Hamster and canine vascular smooth muscle cells were cultured in Dulbecco's modified Eagle's medium containing 10% fetal serum, and then cultured in Dulbecco's modified Eagle's medium at 3 ⁇ 10 5 cells / ml (rat) and 3X10 The cells were suspended at a concentration of 5 cells / ml (Hamus Yuichi) and 4xl0 5 cells / ml (dog).
- Rat and hamster adhesion systems used rat vitronectin, and dog adhesion systems used sibitronectin. .
- Pharmacological test example 2 Test for inhibiting adhesion of rat macrophages to vitronectin
- the plate was washed twice with PBS (-) of No. 1 to prepare an Atssay plate.
- Rat peritoneal macrophages were collected after inducing peritoneal thioglycolate.
- 3% thioglycolate medium was intraperitoneally administered to male Wistar rats (300-400 g) at 100 ml / kg, and 4 days later, intraperitoneal fluid and cold PBS (-) (100) ml / kg) and macrophages were collected.
- Macrophages were isolated by removing non-adherent cells. That is, cells obtained from the peritoneal cavity are washed twice with PBS (-), and cultured in Dulbecco's modified Eagle's medium containing 0.1% serum albumin for 30 minutes under carbon dioxide to allow adhesion.
- PBS PBS
- Dulbecco's modified Eagle's medium in which macrophage was suspended was added at 50/1, mixed well, and reacted at 37 ° C for 10 minutes under 5% carbon dioxide.
- the cells were washed three times with PBS (-).
- the adherent cells were fixed with 10% PBS (-) containing 4% paraformaldehyde for 10 minutes at room temperature, and then 100% PBS (-) containing 0.5% toluidine blue and 4% paraformaldehyde were added. 1 was added, and the mixture was stained at room temperature for 5 minutes, and washed sufficiently with distilled water.
- a 1% aqueous solution of sodium dodecyl sulfate was added to lyse the cells, and the absorbance of the obtained microplate at 595 nm was measured.
- the total binding was the absorbance in the wells containing no test substance, and the non-specific binding (100% inhibition) was the absorbance in the wells without vitronectin and booked with serum albumin.
- Pharmacological test example 3 Infarction inhibition test of integrin V ⁇ antagonist on rat acute myocardial infarction model
- Male Wis type 1 rats (330-420 g) were subjected to controlled respiration with a ventilator under pentoparbital anesthesia (60 mg / kg, i.p.), and blood pressure and heart rate were measured via a blood pressure amplifier and heart rate unit. The number was measured.
- myocardial bleeding was confirmed via a bioelectric amplifier via a monitor for an increase in R in the lead II of the electrocardiogram.
- the rat closed the coronary artery and myocardium with a suture with a needle. After 3 minutes of ischemia and 5 minutes of reperfusion, 45 minutes of ischemia and 45 minutes of reperfusion were performed.
- the drug used and the concentration of the drug preparation were 3 mg / kg + 3 mg / kg / hr (bolus + infusion) (L; low dose group) and 6 mg / kg + 3 ing / kg of the compound represented by the formula (V). / hr
- the control group (Group C) was administered a 10% (v / v) dimethyl sulfoxide / 5% glucose solution, and each drug was dissolved in the same solvent.
- the dose volume was 3 ml / kg + 3 ml / kg / h (bolus + infusion).
- the drug was continuously administered by an infusion pump from 1 minute before ischemia to the end of the experiment. After 45 minutes of reperfusion, the rats were sacrificed with pentobarbital overdose and the hearts were removed. After perfusion with Ringer's solution, perfusion staining with 1.5% triphenyltetrazolium chloride was performed to quantify the infarcted area in the left ventricle. The experiment was performed with 5 animals in each group.
- the blood pressure was measured via a blood pressure pump, and the heart rate was measured using a heart rate unit triggered by blood pressure.
- the animals underwent chest surgery and the coronary arteries were occluded together with the myocardium with a suture with a needle. After 90 minutes of ischemia, reperfusion was performed for 2 hours to determine myocardial infarction.
- the sodium salt of the compound represented by the formula (IV) was mixed with 2 equivalents of arginine and dissolved in a 5% glucose solution.
- the dose volume was 2 ml / kg + 2 ml / kg / h (bolus + infusion).
- the vehicle administration group used a 0.64 mg / ml arginine 5% glucose solution.
- Drugs were administered continuously using an infusion pump from 1 minute before ischemia to the end of the experiment. Two hours after reperfusion, 1,000 U / kg heparin and an excessive amount of pentobarbi were killed intravenously and the heart was removed. The isolated heart was perfused with Ringer's solution, the blood was washed, and the coronary artery was occluded again.
- Blood is collected from the abdominal aorta using a syringe containing 3.8% sodium citrate solution (final concentration 0.38 » centrifuged at 900 rpm (approximately 80 x g ) for 10 minutes, and another 3,000 platelet plasma is collected.
- the ischemic platelet plasma was collected by centrifugation at rpm (about 880 ⁇ g) for 10 minutes, and the agglutination was measured using an aggregometer ADP (final concentration: 5 iM) was used as the aggregation-inducing agent.
- the inhibitory rate of platelet aggregation by this dose of the compound represented by formula (IV) (in both the H group and the L group) was 20% or less.
- the test of each treatment group was performed by Dunnett's multiple comparison test.
- the integrin cn-3 antagonist significantly suppressed infarct size and suppressed reperfusion injury.
- the compound represented by formula (IV) used in the evaluation system also has an antiplatelet effect, but at the drug dose in this experiment, the platelet aggregation inhibitory effect was about 20%, It was confirmed that the size-suppressing effect was mainly due to integrin vL antagonism, not to the antiplatelet effect.
- Example Pharmacological Test 5 infarction suppression test Integurin g 3 antagonists on I j model of myocardial infarction
- Another dog species which has been shown to inhibit adhesion of vascular smooth muscle cells to vitronectin, was selected as another animal species, and integrin was used in a myocardial infarction model using this animal. It was investigated.
- the low dose was an amount that hardly inhibited platelet aggregation, specifically, an amount that inhibited platelet aggregation by about 30% to about 40%.
- the control group (C:) received the solvent used for drug administration.
- an antiplatelet effect is not necessarily required.
- the integrin-3 antagonist described in the present invention is not limited by the presence or absence of an antiplatelet effect, but has no antiplatelet effect and has an integrin- 3 antagonistic activity; And any substance having an integrin ⁇ - 3 anti-antagonistic action.
- Pharmacological test example 6 Adhesion inhibition test of human monocytes to human activated vascular endothelial cells
- integrin and ⁇ - 3 antagonists show leukocyte inhibitory effects using human blood cells.
- Adhesion to human monocytes was determined by the method of Murphy et al. (J. F. Murphy et al., Biochem.
- the cells were cultured for 5 minutes in PBS (-) containing 1 U / ml of ⁇ citrombin, 5 mM CaCL, and 5 mM MgCL, and 1 ( ⁇ -D-phenylalanyl-
- PBS (-) containing L-prolyl-L-argininechloromethane and PBS (-).
- U937 cells cultured in RPMI1640 medium containing 10% fetal serum were cultured in the above medium containing 6M of 2 ', 7, -bis (carboxy eth 1) carboxyfluorecene and tetraacetoxymethyl ester.
- the cells were cultured at 37 ° C for 1 hour under% carbon dioxide, washed with PBS (-), and fluorescently labeled.
- Labeled 2 x 10 s cell Nowell U937 cells, RPM11640 medium 100 1 containing drug and 1 fetal serum were added to the endothelial cell layer, and the adhesion reaction was performed at 37 ° C for 10 minutes in 5% carbon dioxide.
- RPM11640 medium 100 1 containing drug and 1 fetal serum were added to the endothelial cell layer, and the adhesion reaction was performed at 37 ° C for 10 minutes in 5% carbon dioxide.
- integrin v-3 antagonists can prevent or treat reperfusion injury in clinical practice.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01946792A EP1250935A1 (en) | 2000-01-25 | 2001-01-25 | REMEDIES FOR REPERFUSION INJURY CONTAINING INTEGRIN ALPHAvBETA3 ANTAGONIST |
AU28819/01A AU782393B2 (en) | 2000-01-25 | 2001-01-25 | Remedies for reperfusion injury containing integrin alphavbeta3 antagonist |
CA002398186A CA2398186A1 (en) | 2000-01-25 | 2001-01-25 | Therapeutic agent for reperfusion injury comprising integrin .alpha.v.beta.3 antagonists |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2000-16342 | 2000-01-25 | ||
JP2000016342 | 2000-01-25 |
Publications (1)
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WO2001054726A1 true WO2001054726A1 (fr) | 2001-08-02 |
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PCT/JP2001/000496 WO2001054726A1 (fr) | 2000-01-25 | 2001-01-25 | REMEDES DESTINES A UNE LESION PAR REPERFUSION CONTENANT UN ANTAGONISTE D'INTEGRINE αvβ3 |
Country Status (5)
Country | Link |
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US (1) | US20030040531A1 (ja) |
EP (1) | EP1250935A1 (ja) |
AU (1) | AU782393B2 (ja) |
CA (1) | CA2398186A1 (ja) |
WO (1) | WO2001054726A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1227083A1 (en) * | 1999-10-08 | 2002-07-31 | Meiji Seika Kaisha Ltd. | 3-AMINOPIPERIDINE DERIVATIVES AS INTEGRIN $g(a)v$g(b)3 ANTAGONISTS |
AU782393B2 (en) * | 2000-01-25 | 2005-07-21 | Meiji Seika Kaisha Ltd. | Remedies for reperfusion injury containing integrin alphavbeta3 antagonist |
WO2024024915A1 (ja) * | 2022-07-28 | 2024-02-01 | 国立大学法人佐賀大学 | ペリオスチン介在性疾患及び該疾患に伴うそう痒の予防又は治療剤 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2002336650B2 (en) | 2001-10-25 | 2008-06-05 | Emory University | Catheter for modified perfusion |
US20070160645A1 (en) * | 2001-10-25 | 2007-07-12 | Jakob Vinten-Johansen | PostConditioning System And Method For The Reduction Of Ischemic-Reperfusion Injury In The Heart And Other Organs |
JPWO2006016637A1 (ja) * | 2004-08-11 | 2008-05-01 | 杏林製薬株式会社 | 新規環状アミノ安息香酸誘導体 |
JP2008525468A (ja) * | 2004-12-22 | 2008-07-17 | エモリー・ユニバーシティ | ポストコンディショニング臓器保護作用を増強する治療補助薬 |
EP1862464A4 (en) * | 2005-03-23 | 2010-08-25 | Kyorin Seiyaku Kk | NEW CYCLIC AMINOPHENYL ALKANIC ACID DERIVATIVE |
EP1911743B8 (en) * | 2005-08-01 | 2013-01-16 | Takeda Pharmaceutical Company Limited | Cyclic amine compound |
WO2013082458A1 (en) | 2011-12-02 | 2013-06-06 | The Regents Of The University Of California | Reperfusion protection solution and uses thereof |
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WO1995032710A1 (en) * | 1994-05-27 | 1995-12-07 | Merck & Co., Inc. | Compounds for inhibiting osteoclast-mediated bone resorption |
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WO1997036860A1 (en) * | 1996-03-29 | 1997-10-09 | G.D. Searle & Co. | Cinnamic acid derivatives and their use as integrin antagonists |
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WO1999038849A1 (fr) * | 1998-01-30 | 1999-08-05 | Meiji Seika Kaisha, Ltd. | DERIVES DE PHENYLPIPERAZINE UTILISES COMME ANTAGONISTES DE L'INTEGRINE αvβ3 |
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GB9313330D0 (en) * | 1993-06-28 | 1993-08-11 | Fujisawa Pharmaceutical Co | New compound and its preparation |
AU782393B2 (en) * | 2000-01-25 | 2005-07-21 | Meiji Seika Kaisha Ltd. | Remedies for reperfusion injury containing integrin alphavbeta3 antagonist |
-
2001
- 2001-01-25 AU AU28819/01A patent/AU782393B2/en not_active Ceased
- 2001-01-25 EP EP01946792A patent/EP1250935A1/en not_active Withdrawn
- 2001-01-25 US US10/182,035 patent/US20030040531A1/en not_active Abandoned
- 2001-01-25 WO PCT/JP2001/000496 patent/WO2001054726A1/ja active IP Right Grant
- 2001-01-25 CA CA002398186A patent/CA2398186A1/en not_active Abandoned
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1227083A1 (en) * | 1999-10-08 | 2002-07-31 | Meiji Seika Kaisha Ltd. | 3-AMINOPIPERIDINE DERIVATIVES AS INTEGRIN $g(a)v$g(b)3 ANTAGONISTS |
EP1227083A4 (en) * | 1999-10-08 | 2002-11-20 | Meiji Seika Kaisha | 3-AMINOPIPERIDE DERIVATIVES AS INTEGRIN- $ g (a) v $ g (b) 3-ANTAGONISTS |
AU782393B2 (en) * | 2000-01-25 | 2005-07-21 | Meiji Seika Kaisha Ltd. | Remedies for reperfusion injury containing integrin alphavbeta3 antagonist |
WO2024024915A1 (ja) * | 2022-07-28 | 2024-02-01 | 国立大学法人佐賀大学 | ペリオスチン介在性疾患及び該疾患に伴うそう痒の予防又は治療剤 |
Also Published As
Publication number | Publication date |
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EP1250935A1 (en) | 2002-10-23 |
AU782393B2 (en) | 2005-07-21 |
US20030040531A1 (en) | 2003-02-27 |
AU2881901A (en) | 2001-08-07 |
CA2398186A1 (en) | 2001-08-02 |
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