WO2001034569A1 - Medicaments contre la pancreatite - Google Patents

Medicaments contre la pancreatite Download PDF

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Publication number
WO2001034569A1
WO2001034569A1 PCT/JP2000/007799 JP0007799W WO0134569A1 WO 2001034569 A1 WO2001034569 A1 WO 2001034569A1 JP 0007799 W JP0007799 W JP 0007799W WO 0134569 A1 WO0134569 A1 WO 0134569A1
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represent
piperazinyl
propan
hydrogen atom
aminophenoxy
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PCT/JP2000/007799
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English (en)
Japanese (ja)
Inventor
Kazumi Ogata
Shinya Ogino
Kazuhiko Ito
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Senju Pharmaceutical Co., Ltd.
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Priority to AU10574/01A priority Critical patent/AU1057401A/en
Publication of WO2001034569A1 publication Critical patent/WO2001034569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to a piperazine derivative and a pharmaceutically acceptable salt thereof useful as a therapeutic agent for knee inflammatory disease, their use for the manufacture of a therapeutic agent for therapeutic inflammatory disease, a therapeutic agent for osteoarthritis containing them as an active ingredient, and The method used for treating inflammation.
  • Knee inflammation is caused by injury to the acinar cells of the knee, extracellular extravasation of the knee fluid due to obstruction of the canal, etc., and autolysis of the knee parenchyma and interstitium by knee enzymes activated in the knee. It is mainly non-suppurative inflammation and is broadly divided into acute inflammation and chronic knee inflammation. The principle in treating acute knee inflammation is to keep the knees as restful as possible. For this purpose, it is necessary to suppress the secretion of acid in the stomach by fasting and to replenish electrolytes etc. with sufficient infusion to maintain circulatory dynamics. Moreover, H 2 receptor antagonists to inhibit the secretion of knee enzymes, and protease inhibitors to inhibit the activity of spilled knee enzymes, their respective administered. Chronic knee inflammation is divided into acute relapse, intermittent, and decompensated periods. The pathology of acute relapse is similar to acute knee inflammation. In the treatment of chronic inflammation, anti-enzyme drugs and the like are similarly administered.
  • Japanese Patent Application Laid-Open No. Hei 7-15757455, GB 1325 876, and Ind. m., 15B: 466-472 (1977) describes piperazine derivatives useful as antihypertensives and intraocular pressure lowering agents
  • JP-A 8-325241 describes piperazine derivatives having an antiallergic effect. Have been.
  • the present invention provides a compound represented by the general formula (I):
  • R 3 represents hydrogen or a lower alkyl group
  • R4, 13 ⁇ 45 and shaku 6 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom and the others are lower alkyl, lower alkoxy, halogen, amino or trifluoro.
  • R4, shaku 5 and! ⁇ 6 are all the same as each other, and represent a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, and
  • W1 and W2 are the same or different and represent a nitrogen atom or a carbon atom.
  • a pharmaceutically acceptable salt thereof both are referred to as “the present compound”.
  • the therapeutic agent for knee inflammation of the present invention is useful for treating acute symptoms of acute inflammation (acute knee inflammation including postoperative acute knee inflammation, acute tengitis after laparotomy, other traumatic knee inflammation), and acute knee inflammation. It is useful for remission of exacerbation.
  • the present invention also provides a method for treating inflammation in mammals, including humans, comprising administering an effective amount of the present compound to a patient with inflammation, and the use of the present compound for the manufacture of a therapeutic agent for osteoarthritis. Also provide use.
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent R 4, R 5, and R 6 each represent a lower alkoxy group
  • R 4, R 5, and R 6 each represent a lower alkoxy group
  • R 4, R 5, and R 6 each represent a lower alkoxy group
  • R 4, R 5, and R 6 Compounds or pharmaceutically acceptable salts thereof, one or two of which represent a lower alkoxy group and the other represent a hydrogen atom, are a group of compounds particularly suitable for use in the treatment of osteoarthritis. Is a compound of
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 Means that one, two or three of them represent a lower alkyl group, wherein one or two of R4, R5 and R6 represent a lower alkyl group and the others represent a hydrogen atom
  • Compounds or pharmaceutically acceptable salts thereof are another group of compounds that are particularly suitable for use in treating knee inflammation.
  • 1 and! 12 each represent a lower alkyl group, or R 1 and R 2 together form one (CH 2 ) 2 -NH- ( CH 2 ) 2 —, R 3 represents a hydrogen atom, W 1 and W 2 both represent a carbon atom, and R 4, 15 and 1 ⁇ 6 represent one of them being a lower alkoxy group
  • Compounds or pharmaceutically acceptable salts thereof, the other two of which represent hydrogen atoms, are yet another group of compounds that are particularly suitable for use in treating spiritis.
  • R1, R2 and R3 all represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 Is it
  • R 1 and R 2 each represent a hydrogen atom
  • R 3 represents a lower alkyl group
  • W 1 and W 2 each represent a carbon atom
  • R 4 and R 4 5 and R 6 are compounds in which one or two of them represent a lower alkoxy group and the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof is used for the treatment of osteoarthritis
  • Rl, R2 and R3 each represent a hydrogen atom
  • W1 and W2 represent whether one of them represents a carbon atom and the other represents a nitrogen atom.
  • R4, shaku 5 and! ⁇ 6 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group
  • a compound or a pharmaceutically usable salt thereof, which represents a hydrogen atom and the other represents a hydrogen atom is yet another group of compounds which are particularly suitable for use in the treatment of osteoarthritis.
  • a compound selected from the following (1) to (23) or a pharmaceutically acceptable salt thereof is particularly suitable for use in the treatment of osteoarthritis.
  • the present invention provides a compound encompassed by the present compound, wherein the compound represented by the general formula (II):
  • 111 and 1 ⁇ 2 are the same or different and each represents a hydrogen atom or a lower alkyl group, or R 1 and R 2 together form one (CH 2 ) 2-NH- (CH 2 ) 2 —
  • R 3 represents hydrogen or a lower alkyl group
  • R4, scale 5 and! 3 ⁇ 46 each represent a hydrogen atom, or two of R4, R5 and R6 represent a hydrogen atom, and the others are lower alkyl, lower alkoxy, halogen, amino or trifyl.
  • R 4, 5 and! 3 ⁇ 4 6 are all the same and represent a lower alkyl group, a lower alkoxy group, a halogen, an amino group or a trifluoromethyl group, and
  • W1 and W2 are the same or different and represent a nitrogen atom or a carbon atom, However, when Rl, R2 and R3 are all hydrogen atoms and Wl and W2 are both carbon atoms:
  • R4, R5 and R6 do not all represent a hydrogen atom at the same time
  • R4, 13 ⁇ 45 and 16 are such that when one of them represents a methoxy group, the other two do not simultaneously represent a hydrogen atom,
  • R4, 115 and 16 are such that when one of them represents a chlorine atom at position 4, the other two do not represent a hydrogen atom, and
  • the novel compound Or a pharmaceutically acceptable salt thereof (hereinafter, referred to as “the novel compound”).
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof, in which two or three of them represent a lower alkoxy group and the other represents a hydrogen atom, is a group of compounds particularly suitable for use in the treatment of osteoarthritis.
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent , One, two or three of them represent a lower alkyl group, and when one or two of R4, R5 and R6 represent a lower alkyl group, the others represent a hydrogen atom
  • Compounds or pharmaceutically acceptable salts thereof are another group of compounds that are particularly suitable for use in treating knee osteoarthritis.
  • 13 ⁇ 41 and 13 ⁇ 42 each represent a lower alkyl group, or R 1 and R 2 together form — (CH 2 ) 2-NH— (CH 2 ) 2 —, R 3 represents a hydrogen atom, W 1 and W 2 each represent a carbon atom, and R 4, R 5 and R 6 each represent a lower alkoxy group.
  • Compounds wherein the other two represent a hydrogen atom or pharmaceutically acceptable salts thereof are yet another group of compounds which are particularly suitable for use in the treatment of osteoarthritis.
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof, in which one of them represents a halogen bonded to the 2- or 3-position of the phenyl group and the other two represent a hydrogen atom, or a pharmaceutically acceptable salt thereof, is used for treating knee inflammation
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof, in which one of them represents a halogen bonded to the 2- or 3-position of the phenyl group and the other two represent a hydrogen atom, or a pharmaceutically acceptable salt thereof, is used for treating knee inflammation
  • R1, R2 and R3 each represent a hydrogen atom
  • W1 and W2 each represent a carbon atom
  • R4, R5 and R6 represent A compound or a pharmaceutically acceptable salt thereof
  • R 1 and R 2 each represent a hydrogen atom
  • R 3 represents a lower alkyl group
  • W 1 and W 2 each represent a carbon atom
  • R 4 , R 5 and R 6 are compounds in which one or two of them represent a lower alkoxy group and the other represents a hydrogen atom, or a pharmaceutically acceptable salt thereof is used for the treatment of osteoarthritis
  • Rl, R2, and R3 in Formula (II) each represent a hydrogen atom
  • W1 and W2 represent whether one of them represents a carbon atom and the other represents a nitrogen atom.
  • R4 and R6 each represent a hydrogen atom, or one or two of R4, R5 and R6 represent a lower alkoxy group
  • a compound or a pharmaceutically acceptable salt thereof, which represents a hydrogen atom and the other represents a hydrogen atom is yet another group of compounds which are particularly suitable for use in treating osteoarthritis.
  • the following compounds (1) to (16) or pharmaceutically acceptable salts thereof are particularly suitable for use in treating knee osteoarthritis.
  • lower alkyl group refers to an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably an alkyl group having 1 or 2 carbon atoms, that is, methyl.
  • Group or ethyl group refers to an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably an alkyl group having 1 or 2 carbon atoms, that is, methyl.
  • Group or ethyl group refers to an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably an alkyl group having 1 or 2 carbon atoms, that is, methyl.
  • Group or ethyl group refers to an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably an alkyl group having 1 or 2 carbon
  • the “lower alkoxy group” refers to an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and particularly preferably an alkoxy group having 1 to 3 carbon atoms. Refers to an alkoxy group of Formula 1 or 2, that is, a methoxy group or an ethoxy group.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • one of the starting materials 2,3-epoxypropanol derivative
  • can be prepared according to a known method a method described in JP-A-8-325241
  • It can be obtained by heating a phenol having a nitro group and a substituent R 3 and a halogenated methyloxysilane in a solvent such as acetone or methyl ethyl ketone in the presence of an alkyl carbonate.
  • R 4, R 5, R 6 -substituted phenylbiperazine and R 4, R 5, R 6 -substituted pyridylpiperazine R 4, R 5, R 6 -substituted pyrimidylpi Perazine is commercially available or can be N-monobenzylpiperazine substituted with R 4, R 5, R 6 -substituted according to a known method (method described in JP-A-9-290570). A halogenated benzene having a group is heated in an organic solvent or in the absence of a solvent to obtain [1-benzyl 4- (R4, R5, R6, substituted) phenyl] piperazine.
  • R 4 R 5, R 6 -substituted pyridylpiperazine and R 4, R 5, R 6 -substituted pyrimidylpiperazine can also be synthesized in the same manner.
  • the compounds of formulas (III) and (IV) thus obtained are heated and stirred in a solvent such as dioxane or methanol for about 5 to 20 hours, then the solvent is distilled off and extracted with ethyl acetate or the like.
  • a solvent such as dioxane or methanol
  • the solvent is distilled off and extracted with ethyl acetate or the like.
  • the compound of formula (V) After reducing the nitro group with a metal such as zinc or Pd-C and adding 2N hydrochloric acid to form a hydrochloride, the alcohol (methanol, ethanol, propanol, etc.) noacetone, or alcohol (methanol, ethanol,
  • the desired compound can be obtained by recrystallization from ethyl acetate or the like. Further, the amino group of the target compound was replaced with ⁇ Ora. Chem., 37: 1 67 By dimethylation according to the method of 3 (1972), a dimethyl compound as another target compound can also
  • the present compound having a piperazylphenoxy group can be synthesized, for example, as follows. That is, commercially available 4-hydroxyphenylpyrazine (VI) is dissolved in ethanol or the like, and di-t-butyl dicarbonate or benzyloxycarbonyl chloride is added thereto to introduce a urethane-type protecting group to form an N-protected product. (VII).
  • the following reaction scheme shows the case where di-t-butyl dicarbonate is used.
  • a halogenated methyloxysilane is added to a solvent such as acetone or methylethylketone in the presence of alkali carbonate.
  • the formula (VIII) By heating in the solution, the formula (VIII) can be obtained.
  • the acid for deprotection include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as acetic acid and trifluoroacetic acid.
  • the present compounds can be used in free form or in the form of a pharmaceutically acceptable salt as a therapeutic agent for osteoarthritis.
  • pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, lead sulfate, and nitrate or salts of organic acids such as acetate, maleate, and tartrate. Not done.
  • the compound of the present invention can be formulated into a form for oral administration or for injection as a therapeutic agent for knee inflammation.
  • the “agent for oral administration” means various forms to be taken, and examples thereof include appropriate solid preparations such as tablets, granules, powders, and capsules.
  • injection preparations also include those in the form of injection preparations for normal intravenous injection, intramuscular injection, subcutaneous injection, and infusion for intravenous drip infusion.
  • compositions include commonly used excipients, binders, disintegrants, dispersants, lubricants, diluents, absorption enhancers, buffers, surfactants, solubilizing agents, preservatives, Various additives such as an emulsifier, an isotonic agent, a stabilizing agent, a dissolving agent for injection, and a pH adjuster may be appropriately used.
  • the dosage of the therapeutic agent for knee inflammation of the present invention varies depending on the age, body weight, symptoms, and dosage form of the patient.
  • an adult is usually administered at a dose of about 1 to 200 mg once daily, orally
  • the dosage is usually about 10 to 1000 mg per adult, several times a day.
  • FIG. 1 shows the IR spectrum of the compound of Example 10.
  • the obtained residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate, and the solvent was distilled off.
  • Methyl phenyl) piperazinyl] — 1- (4-nitrophenoxy) propane-2-ol 7.0 g was obtained 3.3 g of this compound was dissolved in methanol 80 mL. It was dissolved and catalytically reduced using palladium on carbon (Pd-C). Then, after filtering off Pd-C, the solvent was distilled off. The obtained residue was extracted with ethyl acetate, washed with water, and then the solvent was distilled off. The obtained residue was added with 2N hydrochloric acid to form a hydrochloride, and then recrystallized from methanol-isopropanol to give 3.1 g of the target compound (decomposed) as white crystals, melting point 280-284.
  • Pd-C palladium on carbon
  • the residual oil was extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and water in that order, and the ethyl acetate was distilled off.
  • the obtained residue was dissolved in 100 mL of methanol, and thereto was added 5.8 g of 11- (2-methoxyphenyl) piperazine, and the mixture was refluxed for 8 hours.
  • the test was performed according to the method of Martin GR, Humphrey PPA: Neuropharmacol., 33: 261-273 (1993). That using human recombinant CHO-K1 cells, 50mM Tris-H C 1, 10mM Mg S_ ⁇ 4, 0.5 mM EDTA, 0.1% acetic acid, in a buffer of pH 7.4, at 25, at incubation conditions of 60 minutes, The effect of 5 nM of 3H-8-OH-DPAT on the specific binding was determined. The effect was judged by IC 50 , K t , and n H. IC 5. Represents the concentration of the gonist which inhibits the reaction of the agonist alone by 50%, and represents the dissociation constant of the inhibitor. ⁇ ⁇ represents the ⁇ counting. (Test results)
  • the compounds of Examples 1 and 2 and the mesilate power moststat as a positive control were It was used by dissolving in distilled water to a concentration of mg / lOm1.
  • Test II Lombard! B., Estes L.W., Longnecker D.S., Am. J. Pathol., 79: 465-480 (1975), was performed as follows. That is, 9-week-old female BALB / c mice purchased from Japan SLC were used. Mice fasted for 48 hours before were fed a choline-deficient 0.5% DL-ethionine-supplemented diet (prepared by CLEA Japan) to induce severe etionine knee inflammation. The normal group received normal feeding. Blood was collected 54 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine supplemented diet, and serum amylase levels were measured.
  • test substances of the compounds of Examples 1 and 2 were orally administered at a total of three times (30 mgZl0m1 / kg) at 0, 24, and 48 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine-supplemented diet.
  • a mesylate-powered maststat was orally administered 5 times at 0, 12, 24, 36, and 48 hours after the start of feeding with a choline-deficient 0.5% DL-ethionine supplemented diet (30 m 10 m 1 Zk g).
  • the serum amylase level in the group to which the compound of Example 1 was administered was lower than that of the positive control, mesylic acid moss, and the compound of Example 1 was less effective in suppressing knee inflammation. It turned out to be stronger than the acid power statistics.
  • the serum amylase level in the group to which the compound of Example 2 was administered was equivalent to that in the group to which mesylate-powered statat was administered. Considering that the number of administrations of the compound of Example 2 is smaller than that of the mesylate-powered mosquito, it is presumed that the compound of Example 2 also has a stronger inhibitory action on phlegmitis than the mesylate-based mosquito.
  • the test was performed on Tani S. e.a. in accordance with the method described in International Journal of Pancreatology, 2: 337-348 (1987), as follows. That is, Wistar rats weighing about 200 g were fasted for 12 hours, and then cellulane (20 g / m 1 kg) was injected subcutaneously four times every hour to induce acute edema inflammation. Blood was collected 6 hours after the first injection of caerulein, and the amylase and lipase levels in the serum were measured. The test substance was orally administered 1 hour before the first injection of caerulein.
  • the value indicates mean soil SD, (n 8): p ⁇ 0.001, significant difference from control group
  • the amylase value of the control group was 56593 ⁇ 7404 IU / L by injection of caerulein, The level significantly increased from 623 IU / L in the normal group.
  • the amylase value was 31529 ⁇ 10019 IU / L and 34528 ⁇ 1281 ⁇ IU / L, respectively, which was lower than that in the control group. It was significantly lower.
  • the lipase level was significantly increased to 2884 ⁇ 418 IU / L in the control group, compared to 5.7 ⁇ 5. ⁇ IU / L in the normal group.
  • the lipase value was 1150 ⁇ 382 IU / L and 1440 ⁇ 708 IU / L, respectively, which were significantly lower than the values in the control group.
  • the mesylate-powered monstat-administered group showed a slight suppression tendency of 2506 ⁇ 530 IU / L, but no significant difference from the control group.
  • the compounds of Examples 1 and 2 exhibited a significant inhibitory effect on knee inflammation induced by injection of caerulein, and were clearly superior to mesylate power statistics.
  • CDLj Closed Duodenal Loop
  • the compounds of Examples 1 and 2 and the mesylate-based power state were each dissolved in distilled water so as to have a concentration of 30 mg / 5 ml.
  • Ferrie M.M.e.a. was performed as follows according to the method described in Digestion, 18: 280-285 (1978). That is, using a male SD rat weighing about 200 g, after fasting for 12 hours, laparotomy was performed under anesthesia with chloral hydrate SSOmgZSm 1 / kg, and both sides of the duodenum were ligated around the opening of the common bile duct. After creating a 1 cm blind loop, the abdomen was closed. Blood was collected 6 hours after the blind loop was prepared, and the amylase and lipase levels in the serum were measured. The test substance was orally administered one hour before the preparation of the bride loop.
  • the lipase value was 477 ⁇ 169 IU / L and 483 ⁇ 164 IU / L in the group to which the compound of Example 1 or 2 was administered, compared to 630 ⁇ 231 IU / L in the control group. And the tendency to suppress slightly compared to the control group. On the other hand, the group receiving mesilate-powered statat showed a tendency to further increase to 801 ⁇ 2851 l / l compared to the control group.
  • the mesylate power test showed no effect and showed a tendency to worsen, whereas the compounds of Examples 1 and 2 showed a tendency to suppress the rhoutitis. Was done.
  • the compounds of Examples 1 and 2 and the mesylate-based power state were each dissolved in distilled water so as to have a concentration of 30 mg / 5 ml.
  • Mizama et al. Modified the method described in Nikkei Gaijikai, 11: 822-828 (1978) as follows. That is, male SD rats weighing about 200 g were used, and after fasting for 12 hours, the abdomen was opened under anesthesia with hydrochloride hydrochloride 300 m 2 m 1 / kg, and the liver side of the common bile duct was closed with a temporary clip. 0.1 ml of an endotoxin solution (10 / z gZml) was retrogradely injected with a continuous syringe through a polyethylene tube (1 minute: at a flow rate of 6 ml), and after ligation of the common bile duct, the abdomen was sutured. . Blood was collected 7 hours after ligation of the common bile duct, and the amylase and lipase levels in the serum were measured. The test substance was administered 1 hour before ligation of the common bile duct. (Test results)
  • the serum lipase level was remarkably increased from 58.7 ⁇ 35.3 IU / L in the normal group to 1430 ⁇ 797 IU / L, whereas in the group to which the compound of Example 1 was administered, 701 ⁇ 240 IU / L L and the magnitude of the rise were significantly less.
  • the value was 914 ⁇ 601 IU / L, which was also smaller than that in the control group.
  • the lipase level in the serum of the mesylate-powered monstat administration group was 1105 ⁇ 647 IU / L, indicating a tendency toward suppression compared to the control group.
  • the compounds of Examples 1 and 2 have a stronger inhibitory effect on osteoarthritis than the mesilic acid power test Rukoto has been shown.
  • the compound of Example 3 is similar to the compounds of Examples 1 and 2 in serum. It showed a significant inhibitory effect on the increase in amylase level.
  • the compounds of the examples used in the test were dissolved in physiological saline to make each lOmgZlOmL. Their dose was lOmgZkg.
  • the test was performed according to the method of Lombardi II, Estes LW, Longnecker DS, Am. J. Pathol., 79: 465-480 (1975).
  • a test animal a 3 week-old female R strain mouse purchased from Nippon Chars River Co., Ltd. was used. Choline deficiency in mice 0.5% Feeding a diet supplemented with DL-ethionine (prepared by CLEA Japan) induced severe knee inflammation of etionine. The normal group was given a normal diet (MF: Oriental yeast) ad libitum. Blood was collected 72 hours after the start of the choline-deficient 0.5% DL-ethionine supplemented diet, and the amylase level in the serum was measured.
  • MF Oriental yeast
  • test substance was administered intravenously a total of 6 times 0, 6, 24, 30, 48, and 54 hours after the start of the choline-deficient 0.5% DL-ethionine supplementation diet.
  • the compounds of the examples used in the test were dissolved in physiological saline to make 0.3 mL, 1, 3, 10, or 30 mg Z5 mL, and their doses were 0.3, 1, 3, 10, or 30 mg / kg, respectively. did.
  • Nafamostat mesilate was dissolved in physiological saline to a concentration of 10 mg and 5 mL, and the dose was 10 mg / kg.
  • the test was performed according to the method of ⁇ S., Otsuki M., Ke oh H., Fujii I., Nakamura I., Oka I., Baba S., International Journal of Pancreatology, 2: 337-348 (1987).
  • test animals male Wistar rats (body weight: about 200 g) purchased from SLC Japan were used. Acute edematous knee inflammation was induced by subcutaneously injecting cerulein (20 gZlmL / kg) four times every 2 hours into rats that had been fasted for 2 hours. Blood was collected 6 hours after the initial administration of caerulein, and the amylase, lipase, and trypsin-like activities in serum were measured. In addition, the wet weight of the knee was measured. The test substance was administered intravenously 0, 1, and 2 hours after the initial administration of caerulein.
  • the compounds of the examples used in the test were dissolved in physiological saline to give a concentration of 3, 10 or SOmg / ZSmL, and the dose was 3, 10, or SOmg / kg.
  • Nafamostat mesilate was dissolved in physiological saline to a concentration of 10 mg / 5 mL, and the dose was 10 mg / kg.
  • the amylase, lipase, and trypsin-like activities in serum were significantly increased in the control group compared to the sham-operated group, and in the knee.
  • the wet weight of the offal increased significantly.
  • the increase in amylase level was significantly suppressed in a dose-dependent manner.
  • the nafamostat mesilate administration group the amylase level tended to be further enhanced rather than increased.
  • the increase in the lipase level was suppressed in both the group administered with the compound of Example 10 and the group administered with nafamostat mesilate.
  • the increase in trypsin-like activity was significantly suppressed in a dose-dependent manner by administration of the compound of Example 10. Also, in the nafamos mesylate evening administration group, the increase in tribcine-like activity was significantly suppressed. The increase in wet weight of the knee tended to be suppressed in a dose-dependent manner by the compound of Example 10. In contrast, in the nafamostat mesilate group, the increase in the wet weight of the knee tended to be further enhanced.
  • the compound of Example 10 is considered to have a stronger inhibitory effect on osteoarthritis than nafamosid mesylate.
  • the above ingredients are mixed by a conventional method to make one tablet.
  • Sugar coating may be applied if desired.
  • the present invention is intended for remission of acute symptoms of knee inflammation (acute knee inflammation after surgery, acute knee inflammation after angiography, other acute inflammation including traumatic knee inflammation, and acute exacerbation of chronic knee inflammation). It enables the manufacture of useful, therapeutic agents for knee inflammation.

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Abstract

La présente invention concerne des médicaments contre la pancréatite et dont le principe actif est un composé tel que ceux représentés par la formule générale (I) ou l'un de ses sels pharmaceutiquement admis. Dans cette formule, R1 et R2, qui sont généralement chacun indépendamment hydrogène ou alkyle inférieur, peuvent également former ensemble un -(CH2)2-NH-(CH2)2-. R3 est hydrogène ou alkyle inférieur. R4, R5 et R6 sont chacun indépendamment hydrogène, alkyle inférieur, alcoxy inférieur, halogéno, amino, ou trifluorométhyle. Enfin W1 et W2 sont chacun indépendamment azote ou carbone.
PCT/JP2000/007799 1999-11-11 2000-11-06 Medicaments contre la pancreatite WO2001034569A1 (fr)

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AU10574/01A AU1057401A (en) 1999-11-11 2000-11-06 Pancreatitis remedies

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044160A1 (fr) * 2000-11-30 2002-06-06 Senju Pharmaceutical Co., Ltd. Medicaments pour lutter contre la pancreatite et produits medicinaux pour prevenir et traiter l'oesophagite peptique
JP2009534291A (ja) * 2007-05-08 2009-09-24 大塚製薬株式会社 エポキシ化合物及びその製造方法

Citations (4)

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Publication number Priority date Publication date Assignee Title
GB1332008A (en) * 1971-09-28 1973-10-03 Pfizer Ltd Piperazine derivatives their preparation and pharmaceutical compositions containing them
EP0031925A1 (fr) * 1979-12-28 1981-07-15 Tanabe Seiyaku Co., Ltd. Composition pharmaceutique pour le traitement de l'hypertension intracrânienne
US4642307A (en) * 1982-03-18 1987-02-10 Nippon Shinyaku Co., Ltd. 1-phenoxy-3-(4-phenylpiperidino)-2-propand having both alpha- and beta-adrenergic action
WO1999055672A2 (fr) * 1998-04-29 1999-11-04 American Home Products Corporation Derives d'indolyl psychotiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1332008A (en) * 1971-09-28 1973-10-03 Pfizer Ltd Piperazine derivatives their preparation and pharmaceutical compositions containing them
EP0031925A1 (fr) * 1979-12-28 1981-07-15 Tanabe Seiyaku Co., Ltd. Composition pharmaceutique pour le traitement de l'hypertension intracrânienne
US4642307A (en) * 1982-03-18 1987-02-10 Nippon Shinyaku Co., Ltd. 1-phenoxy-3-(4-phenylpiperidino)-2-propand having both alpha- and beta-adrenergic action
WO1999055672A2 (fr) * 1998-04-29 1999-11-04 American Home Products Corporation Derives d'indolyl psychotiques

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Title
GUPTA S.P. ET AL.: "Synthesis and structure-activity relationship in 3-(o-, m- and p-nitro/amino/acetamido/methanesulfonamidophenoxy)-2-hydroxy-1-tert-amino propanes - a class of CNS depressants and hypotensive agents", INDIAN J. CHEM., SECT. B, vol. 15B, no. 5, 1977, pages 466 - 472, XP002936526 *
YOSHINO T., YAMAGUCHI I.: "Possible involvement of 5-HT2 receptor activation in aggravation of diet-induced acute pancreatitis in mice", J. PHARMACOL. EXP. THER., vol. 283, no. 3, 1997, pages 1495 - 1502, XP002936527 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044160A1 (fr) * 2000-11-30 2002-06-06 Senju Pharmaceutical Co., Ltd. Medicaments pour lutter contre la pancreatite et produits medicinaux pour prevenir et traiter l'oesophagite peptique
JP2009534291A (ja) * 2007-05-08 2009-09-24 大塚製薬株式会社 エポキシ化合物及びその製造方法

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