WO1999026925A1 - Inhibiteurs de tryptase comprenant des composants d'amide heterocycliques - Google Patents

Inhibiteurs de tryptase comprenant des composants d'amide heterocycliques Download PDF

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Publication number
WO1999026925A1
WO1999026925A1 PCT/JP1998/005280 JP9805280W WO9926925A1 WO 1999026925 A1 WO1999026925 A1 WO 1999026925A1 JP 9805280 W JP9805280 W JP 9805280W WO 9926925 A1 WO9926925 A1 WO 9926925A1
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optionally substituted
compound
hydrogen
integer
formula
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PCT/JP1998/005280
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English (en)
Japanese (ja)
Inventor
Masahiro Takeuchi
Hiroshi Sakashita
Shinichiro Ono
Shigeki Kuwahara
Koji Naito
Youichiro Naito
Takashi Imagawa
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Yoshitomi Pharmaceutical Industries, Ltd.
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Priority to AU11762/99A priority Critical patent/AU1176299A/en
Publication of WO1999026925A1 publication Critical patent/WO1999026925A1/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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention relates to novel tryptase inhibitors. Further, the present invention relates to a novel compound having low toxicity and having selective tryptase inhibitory activity, and its pharmaceutical use.
  • Immediate allergic inflammation involving IgE is caused by the reaction of allergen and IgE on cell surfaces such as mast cells and basophils.
  • Mast cells trigger this inflammation, and when an antigen-specific reaction occurs through the IgE receptor on the mast cell membrane, the intracellular signal transduction mechanism is activated, and intergranular and intercellular membranes interact with the granule membrane. Fusion is triggered and the granules are released out of the cell.
  • Mast cells that are released by degranulation include chemical mediators such as histamine, serotonin, leukotriene, thromboxane, and PAF, and intragranular proteases.
  • mediator release inhibitors have been developed and provided to the clinic.
  • immediate inflammation is a reaction involving a number of factors, and at present it has not been possible to obtain a sufficient therapeutic effect using only mediator release inhibitors.
  • Tryptase is a neutral serine protease present mainly in hisminin granules in mast cells, and is released into the extracellular fluid together with chemical mediators such as histamine by degranulation by antigen stimulation. .
  • chemical mediators such as histamine by degranulation by antigen stimulation.
  • tryptase it has been reported that very large amounts of tryptase are present in mast cells present in the lungs (airways and alveoli) and nasal mucosal tissues.
  • the physiological activities of tryptase include the release of histamine from mast cells / amplification of bronchoconstriction, the degradation of VIP (the most potent bronchodilator) and the promotion of conversion of complement C3 to C3a, and fiber.
  • VIP the most potent bronchodilator
  • the present inventors have conducted various studies to achieve the above-mentioned object, and based on a series of compounds disclosed as thrombin inhibitors in 97/01338, the inventors have found that they are selective for tryptase.
  • the present invention has been completed by finding a compound having excellent inhibitory activity.
  • the present invention is as follows.
  • A is the following formula (1), (2), (3), (4), (5), (6), (7) or (8)
  • E 1 , E, E 2 and E 3 are the same or different and each represents a hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, or a protecting group for amidino, guanidino or amino.
  • 1 NE 1 E may together form a heterocyclic ring which may further contain a heteroatom; 1 is an integer of 0-3, m is an integer of 0-2, n is Represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.
  • R 3 represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl.
  • R 1 represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. ⁇ Or a pharmacologically acceptable salt thereof as an active ingredient.
  • E 1 , E, E 2 and E 3 are the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, or amidino, guar A protecting group for nitro or amino;
  • _NE 1 E may together form a heterocyclic ring which may further contain a heteroatom; 1 is an integer of 0 to 3, m is Represents an integer of 0 to 2, n represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.
  • R 3 represents an aralkyl which may be represented by:
  • A is a compound of the formula (1) or a pharmacologically acceptable salt thereof.
  • A is a compound of the formula (2) or a pharmacologically acceptable compound thereof.
  • A is a compound of the formula (3) or a pharmacologically acceptable salt thereof.
  • A is a compound of the formula (4) or a pharmacologically acceptable salt thereof.
  • B is hydrogen are excluded.
  • A is a compound of the formula (5) or a pharmacologically acceptable salt thereof.
  • A is a compound of the formula (6) or a pharmacologically acceptable salt thereof.
  • B is hydrogen.
  • A is a compound of the formula (7) or a pharmacologically acceptable salt thereof.
  • B is hydrogen are excluded.
  • A is a compound of the formula (8) or a pharmacologically acceptable compound thereof.
  • a pharmaceutical composition comprising, as an active ingredient, the compound according to any of (2) to (11) or a pharmacologically acceptable salt thereof.
  • the alkyl in R 1 to R 3 , E 1 , E 1 ′. E 2 and E 3 is lower alkyl having 1 to 6 carbon atoms and may be linear or branched. Specifically, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, 2-methylpropyl, 1,1-dimethylpropyl, 1, 2, 2-trimethylpropyl and the like. Preferred are methyl, ethyl, propyl, isopropyl, n-butyl and the like.
  • the alkyl is a halogen (fluorine, chlorine, bromine, or iodine), an amino group, a hydroxyl group, or an alkoxy (a lower alkoxy having 1 to 6 carbon atoms, which may be linear or branched. Specifically, it may be substituted with methoxy, ethoxy, propoxy, isopropoxy, etc.).
  • the alkyl moiety is the same as described above, and specifically, benzyl, phenyl, 3-phenylpropyl, 4 C- Alkyl is substituted with alkyl (same as above), halogen (same as above), amino group, hydroxyl group, nitro, cyano, alkoxy (same as above), etc. It may be.
  • the protecting group for amidino, guanidino or amino in E 1 , E, E 2 and E 3 may be an optionally substituted aralkyl (for example, benzyl, p-chlorobenzyl, p-fluorobenzyl).
  • Chloroacetyl, trifluoroacetyl, etc. piperidinyloxyalkanol (for example, 4-piberidinyloxyacetyl), alkenyloxycarbonyl (for example, aryloxycarbonyl), alkoxycarbonyl (for example, methoxycarbonyl) , Ethoxycarbonyl, t-butoxycarbonyl, hexyloxycarbonyl, etc.), acyloxyalkoxycarbonyl (eg, acetooxymethyloxycarbonyl, (1-acetoxitytyl) oxycarbonyl, propionyloxy Methyloxycarbonyl, bivaloyloxymethyloxycarbonyl, butyryloxymethyloxycarbonyl, isobutyryloxymethyloxycarbonyl, etc., haloalkoxycarbonyl (for example, chloromethoxycarbonyl, trichloroethoxycarbonyl) Phenyl), optionally substituted aroyl
  • phenoxycarboni Naphthyloxycarbonyl, etc.
  • phenyloxycarbonyl which may have a substituent
  • arylglyoxyloyl which may have a substituent
  • phenylalkoxycarbonyl which may have a substituent
  • alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, propylpyrusulfonyl, butylsulfonyl, pentylsulfonyl
  • the alkyl, alkanoyl, alkoxy, and acyl moieties in each group include lower ones having 1 to 6 carbon atoms, and the alkenyl moieties include lower ones having 2 to 6 carbon atoms.
  • arylsulfonyl examples include nitro, trifluoromethyl, alkyl (same as above), phenyl, alkoxy (same as above), halogen (same as above), alkanol (lower alkanol having 1 to 6 carbon atoms) Yes, it may be linear or branched, and specific examples include formyl, acetyl, propionyl, butyryl, valeryl, bivaloyl, hexanoyl, and the like.
  • aryl in R 1 to R 3 include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • the aryl may be substituted with alkyl (as described above), halogen (as described above), amino group, hydroxyl group, nitro, cyano, alkoxy (as described above) and the like.
  • Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) [hereinafter also referred to as compound (I)] include inorganic acid addition salts (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid) , Sulfuric acid, phosphoric acid, etc.), salts with amino acids (eg, salts with glutamic acid, aspartic acid, etc.), and organic acid addition salts (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, Acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, and salts with malic acid).
  • inorganic acid addition salts for example, hydrochloric acid, hydrobromic acid, hydroiodic acid
  • a ′ has the same meaning as the above A, or, when it contains amidino, it represents a substituent containing cyano as a precursor thereof, and B ′ has the same meaning as the above B, or When it contains a bonyl group, it represents a substituent containing a hydroxyl form which is a reduced form thereof, wherein W ′ has the same meaning as the above W, or a protecting group for hydrogen or amino, and R 1 , X, W, A, and B are as defined above.
  • compound (I) is a carboxylic acid represented by the formula ( ⁇ ) [hereinafter, compound ( ⁇ ) and ) And a compound represented by the formula (m) [hereinafter, also referred to as compound (m)] by a condensation reaction (amidation) or a precursor thereof [hereinafter, compound (IV) ).
  • the compound ( ⁇ ) is a compound described in the literature (JP-A-6-56785, JP-A-5-286946, Warner et al., J. Med. Chem., 1994, 37, p3090, Symbolwood J. Med. Chem., 1994, 37, p3303, Veale et al., J. Med. Chem., 1995, 38, p98, W093 / 21210, W096 / 33974, W096 / 18644, etc.), or Alternatively, it is prepared by a conventional method based on these documents.
  • Compound (m) is a compound described in the literature (MR ffiley et al., Bioorg. Med. Chem. Lett., 1996, 6, p2387, JD Prugh et al., Synthetic Communications, 1992, 22, p2357, TA Lyle et al., Bioorg. Med. Chem. Lett., 1997, 7, p67, US5498779, 6/30396, I096 / 1949U W096 / 19483, etc.) or prepared by a conventional method based on these documents. .
  • a compound converted to a reactive derivative such as an acid anhydride, an active ester, or an acid halide by a conventional method may be used.
  • the acid anhydride for example, an anhydride with pivalic acid, an anhydride with isobutyl carbonate and the like are used.
  • the active ester include p-nitrophenyl ester, 2,4,5-trichloromethyl phenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimid ester, N-hydroxy-5-norbornene 2,3-Dicarboxyimid ester is used.
  • the acid halide for example, carboxylic acid chloride, carboxylic acid bromide or the like is used.
  • the reaction solvent for the amidation reaction is N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethoxetane, benzene, ethyl acetate, sulfolane, etc. Is used.
  • Preferred solvents include N, N-dimethylformamide, methylene chloride, tetrahydrofuran, and acetonitrile.
  • the compound (H) or the reactive derivative thereof and the compound (EI) are usually charged in an amount of at least one equivalent of the compound (II) or the reactive derivative thereof relative to the compound (II).
  • the reaction temperature of this amidation reaction is about 0 to 100, and the reaction time is several hours to 3 days.
  • reaction aids such as dimethylaminopyridine can be used.
  • reaction auxiliary such as 4-dimethylaminopyridine and 1-hydroxybenzotriazole can be used.
  • the reaction is preferably performed in the presence of a hydrogen halide scavenger such as triethylamine, pyridine, picoline, or sodium hydrogen carbonate.
  • a hydrogen halide scavenger such as triethylamine, pyridine, picoline, or sodium hydrogen carbonate.
  • the group represented by A ′ in compound (m) includes amino, amidino, guanidino, and the like. However, in this amidation reaction, these groups are preferably subjected to the reaction in a protected form. Examples of the protecting group include those which can be easily removed after the reaction and led to amino, amidino or guanidino, for example, a t-butoxycarbonyl group
  • Boc group benzyloxycarbonyl group
  • Z group benzyloxycarbonyl group
  • the amidation reaction may be carried out in a form having a substituent convertible to amidino or guanidino (for example, cyano as a substituent convertible to amidino), and after the reaction, may be converted to amidino or guanidino. .
  • a substituent convertible to amidino or guanidino for example, cyano as a substituent convertible to amidino
  • the conditions for deprotection include those based on hydrogenolysis and those based on an acid.
  • the conditions for deprotection by hydrogenolysis are as follows: under hydrogen atmosphere, use palladium-carbon or palladium-black as a catalyst, and use methanol, ethanol, acetic acid, chloroform, dioxane, etc. as a solvent.
  • An acid such as hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid is used in an amount of 1 to 10 equivalents to the substrate.
  • the reaction temperature is about 0 to 100, and the reaction time is several hours to 3 days.
  • the conditions for deprotection with an acid when the Z group is used can be carried out according to a known method using trifluoromethanesulfonic acid or the like (Japanese Patent Application Laid-Open No. 5-2866946). No.)
  • the conditions for deprotection are as follows: 5- to 40-fold equivalent of hydrogen chloride is used, and ethyl acetate, benzene, ethanol, and acetic acid are used as solvents. And dioxane.
  • the reaction temperature is about 0 ° C. to room temperature, and the reaction time is about 30 minutes to 24 hours.
  • Scheme H shows a method of converting piperidine, which may be protected at A ′, into N-amidinopiperidine of A in the process from compound (IV) to compound (I).
  • E la, E 2a, E 3a are the same or different Amino protecting groups against Guanijino (8 0 (; Arui represents a 2 group), B ', W', X, R 1 is the First, deprotection of the amino-protecting group can be carried out by a conventional method as shown in method 1).
  • the guanidination is carried out by N, N, 1-bis- (t-butyloxycarbonyl) 1 1-guanylvirazole, N, N, 1-bis-1 (benzyloxycarbonyl) 1-guanylvirazole or N, N '' It can be carried out according to a known method using mono-bis- (t-butyloxycarbonyl) -S-methylisothiourea (MS Bernatowicz et al., ⁇ ⁇ L., 1993, 34, pp 3389-3392; Y. fu et al., Synthetic Communications, 1993, 23, pp 3055-3060, US 5498779).
  • a guanidino compound protected by a Z group is obtained by reacting N, N, -bis- (benzyloxycarbonyl) -1-guanylvirazole with an amine compound as a raw material
  • a solvent such as methanol or ethanol may be used.
  • the reaction temperature is from room temperature to 100 ° C, and the reaction time is from several hours to three days.
  • Deprotection of the obtained guanidino form can be carried out by a conventional method as described in method 1).
  • scheme m shows a method of converting cyanophenyl of A ′ to amidinofenyl of A in the process from compound (IV) to compound (I).
  • Amidination can be carried out according to a known method via an imidated or thiocarbamoyl form (T. Nakayama et al., Chem. Pharm. Bull., 1993, 41 (1), ppl 17-125, Organic Functional (See Group Preparations, III, Academic, Chapter 6> or Leo Alig et al., Journal of Medicinal Chemistry 1992, 35 (23), pp4393-44 07) o
  • the nitrile form is reacted with 1 equivalent to a large excess of hydrogen sulfide in a solvent such as pyridine, triethylamine, N, N-dimethylformamide, or a mixed solvent thereof, Obtain the thiocarbamoyl form.
  • Reaction temperature is ice Under cooling to room temperature, the reaction time is about 5 hours to 1 day, preferably about 10 to 20 hours at room temperature.
  • the obtained thiocarbamoyl compound is reacted with 1 equivalent to a large excess of an alkyl halide such as methyl iodide or butyl bromide in a solvent such as acetone, dioxane or tetrahydrofuran.
  • the reaction temperature is about 50 to 100 ° C, and the reaction time is about 0.5 to 10 hours.
  • the intermediate thus obtained is isolated or not isolated, and is reacted with 1 to 50 equivalents of ammonia or an ammonia derivative such as ammonium acetate or ammonium chloride to obtain amidine.
  • alcohol such as methanol, ethanol and propanol, N, N-dimethylformamide and the like are used.
  • the reaction is preferably carried out by reacting with ammonium sulfate in a methanol or ethanol solvent.
  • the reaction temperature is about 50 to 100, and the reaction time is several hours to 10 hours.
  • the nitrile form is reacted with an equivalent to a large excess of an alcohol such as methanol, ethanol, propanol or butanol in the presence of hydrogen halide such as hydrogen chloride or hydrogen bromide.
  • an imidate body is obtained.
  • aliphatic ethers such as ethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, and aprotic solvents such as benzene may be used.
  • the reaction temperature is about -10 to 130 ° C, and the reaction time is several hours to two days. It is preferably for about 8 to 15 hours under ice cooling to room temperature.
  • an amidine compound is obtained by reacting 1 to 50 equivalents of ammonia with the obtained imidate compound.
  • Solvents include alcohols such as methanol, ethanol, and propanol; aliphatic ethers such as dimethyl ether; halogenated hydrocarbons such as chloroform and methylene chloride; aprotic solvents such as benzene; N, N-dimethylformamide And dimethyl sulfoxide. It is preferable that ammonium chloride coexist in the reaction with ammonia.
  • the reaction temperature is about -10 to + 100 ° C, and the reaction time is 0.5 to 20 hours.
  • the reaction is preferably carried out in a methanol, ethanol or propanol solvent at about 50 to 80 ° C for several hours.
  • the group represented by B ′ in compounds ( ⁇ ) and (IV) includes trifluoromethylketone or benzothiazo-1-yl-2-ylketone, etc.
  • ketones other groups that can be easily converted to ketone
  • the hydroxyl form ⁇ 2,2,2-trifluoro-1-hydroxyethyl or 1- (benzothiazoyl-2-yl) -1-hydroxymethyl etc. ⁇ can also be used.
  • the desired compound can be derived by using an oxidation reaction in the conversion reaction from compound (IV) to compound (I) in Scheme I.
  • a preferred method of this oxidation reaction is, for example, a method in which an excess of dimethyl sulfoxide and water-soluble rubodiimide are used at about room temperature in an inert solvent such as toluene, using dichloroacetic acid as a catalyst.
  • Other useful methods include, for example, the use of aqueous potassium permanganate solutions, the use of oxalyl chloride, dimethyl sulfoxide and tertiary amines, the use of acetic anhydride and dimethyl sulfoxide.
  • the amine present in A 'of the compound (IV), the amino, amidino or guanidino, and the amine present in the pyridone or pyrimidone skeleton are optionally substituted with a Z group or Boc Protection with a protecting group such as a group. Deprotection of these protecting groups can be carried out by a conventional method as shown in method 1). Conversion of A, from the A, B, from the conversion to B, various E 1, E, conversion of E 2, E 3 of does not mean that only possible when the above process, affecting other reaction It can be performed at various stages of the synthesis to the extent that it does not exist. Also, W to W conversion, each The same applies to the conversion between species w.
  • the compound (I) thus synthesized can be collected as an arbitrary pure substance by appropriately performing known separation and purification means such as concentration, extraction, chromatography, reprecipitation, and recrystallization.
  • a pharmacologically acceptable salt of the compound (I) can be produced by a known method.
  • the compound of the present invention has an excellent inhibitory activity on a mammal, such as a human, a dog, a mouse, a mouse, a rat, or the like. Therefore, it is useful for the above animals for various diseases such as allergic rhinitis, irritable pneumonia, pulmonary fibrosis, and bronchial asthma.
  • a pharmacologically acceptable carrier in the form of powders, granules, tablets, capsules, syrups, injections, ointments, creams and the like, which can be administered orally or parenterally.
  • An effective amount of compound (I) or a pharmacologically acceptable salt thereof is compounded in the above pharmaceutical composition.
  • the dose of the compound (I) of the present invention and the pharmacologically acceptable salt thereof will vary depending on the type and degree of the disease, the compound to be administered, the administration route, the patient's condition, body weight or age, etc.
  • the amount of compound (I) is usually 0.01 to 10 when orally administered to an adult. It is preferable to administer 0 O mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, in 1 to several times a day.
  • the organic layer was washed with water, a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, concentrated and purified by silica gel column chromatography (silica gel, methanol / chloroform). The desired compound (1.60 g, 62%) was obtained.
  • step (4) To the compound (100 mg, 0.141 mmol) obtained in step (4) was added a 4 N solution of dioxane hydrochloride (4.0 mL, 16 mmol) at room temperature, and the mixture was stirred for 6 hours. The residue obtained by concentrating the reaction mixture was dissolved in water. This was freeze-dried to give the title compound as a pale yellow powder (57 mg, 74%).
  • Example 11 The compound obtained in item (2), which is a compound described in W096 / 33974, 2-(5- Using benzyloxycarbonylamino-1,6-dihydro-2-methyl-16-oxo-1-pyrimidinyl) acetic acid, the reaction was carried out in the same manner as in Example 1_ (3) to obtain the desired compound. (Yield 77%).
  • Example 11 2- (5-benzyloxycarbonylamino-1,6-dihydro-16-oxo-1-2-phenyl-2-pyrimidinyl 2- (5-benzyloxycarbonylamino-1,6-benzyl), which is the compound obtained in one of (2) and described in W096 / 33974 The reaction was carried out using acetic acid and in the same manner as in Example 11- (3) to obtain the desired compound (yield 78%).
  • step (2) The compound obtained in step (2) was reacted in the same manner as in Example 11- (5) to give a pale yellow powder as the title compound (yield 95%).
  • Example 1 A compound (144 mg, 0.202 mmol) obtained in (4).
  • a suspension of palladium black (20 mg) in ethanol (2.0 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. .
  • the catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired compound (115 mg, 99%).
  • Trifluoroacetic acid (2.0 mL, 26.0 mmol) was added to the compound (115 mg, 0.199 mmol) obtained in the step (1) at room temperature, and the mixture was stirred for 30 minutes.
  • a 4 N dioxane hydrochloride solution (10 mL, 40 ol) at room temperature, and the mixture was stirred for 30 minutes. This The residue obtained by concentrating the mixture was dissolved in water (10 mL). This was lyophilized to give the title compound, a brown powder (62.6 mg, 70%).
  • Example 2- (2) Using the compound obtained in Example 2- (2), the reaction was carried out in the same manner as in Example 4- (1) to quantitatively obtain the target compound.
  • Example 3- (2) Using the compound obtained in Example 3- (2), a reaction was carried out in the same manner as in Example 4- (1) to quantitatively obtain the target compound.
  • reaction solution was diluted with ethyl acetate, and this was washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
  • the organic layer was dried and concentrated to obtain a dark green oil residue (8.1 g). This was subjected to silica gel column chromatography (ethyl ethyl hexane acetate) to obtain a pale green solid (4.8 g, 71%).
  • a 1 N aqueous sodium hydroxide solution (36.0 mL, 36.0 mmol) was added dropwise to the solution at room temperature, and the mixture was stirred for 3 hours.
  • the precipitate was collected by filtration and dissolved in water (200 mL) while heating.
  • This aqueous solution was acidified with concentrated hydrochloric acid, and the suspension was stirred for 1 hour under ice cooling.
  • the white precipitate was collected by filtration and dried to give the target compound (4.0 g, 93%).
  • step (4) To the compound (129 mg, 0.182 mmol) obtained in step (4) was added a 4 N solution of dioxane hydrochloride (15 mL, 60 mmol) at room temperature, and the mixture was stirred for 41 hours. The residue obtained by concentrating the reaction mixture was dissolved in water (20 mL). This was freeze-dried to give the title compound as a brown solid (89 mg, 89%).
  • Example 7- (4) A suspension of the compound (444 mg, 0.625 mmol) obtained in Example 7- (4) and palladium-carbon (95 mg) in ethanol (6.0 mL) was stirred at room temperature for 17 hours under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated to quantitatively obtain the target compound.
  • Example 9 2- (3-Acetylamino-1,2-dihydro-2-oxo-1-pyridyl) 1 N— [4- (1-amino-1 1-iminomethylamino) 1-1— (2, Synthesis of 2,2-trifluoro-1-one-year-old oxoethyl) butyl] acetamide hydrochloride (1) Synthesis of ethyl ester of 2- (3-acetylamino-1,2-dihydro-1-2-oxo-one-pyridyl) acetate
  • the reaction solution was diluted with ethyl acetate, and a 10% aqueous solution of citric acid was added. Ethyl acetate was added to the mixture, and the mixture was separated. The organic layer was washed with water and saturated saline. After concentration, the residue was subjected to silica gel column chromatography (methanol / ethyl acetate Z-cloth form) to obtain the desired compound (269 mg, 21%).
  • step (4) The compound obtained in step (4) was reacted in the same manner as in Example 4- (2) to give a light brown solid as the title compound (yield 68%).
  • Example 7 The compound (350 mg, 1.16 mmol) obtained in (2) was dissolved in tetrahydrofuran (15 mL) in WSCI (270 mg, 1.4 mmol), H0Bt (213 mg, 1.4 mmol) and diisopropyl. Ethylamine (1.0 mL, 5.7 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The compound described in W096 / 30396, 2- [2-amino-1-hydroxy-5-
  • Manganese dioxide (4 g, 46 mmol) was added to dichloromethane (40 mL) of the compound (410 mg, 0.55 mmol) obtained in step (1), and the mixture was stirred at room temperature for 1.5 hours. After the reaction, manganese dioxide was removed by filtration and the filtrate was concentrated. After concentration, the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain a red-white solid (310 mg, 76%).
  • step (1) To a suspension of the compound (5.95 g, 22.7 mmol) obtained in step (1) in ethanol (150 mL) was added hydrazine monohydrate (1.14 g, 22.7 mmol), and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool, and ether (200 mL) was added. The precipitated white powder was filtered off, and a 4 N hydrogen chloride dioxane solution (6.24 mL, 25.0 mmol) was added to the filtrate. The precipitated white powder was collected by filtration to obtain the desired compound (2.88 g, 75%). .
  • step (4) To a suspension of the compound (0.576 g, 1.28 mmol) obtained in step (4) in acetone (30 mL) was added methyl iodide (10 mL), and the mixture was heated under reflux for 1 hour. After cooling, ether (50 mL) was added, and the insoluble powder was collected by filtration to obtain the target compound as a yellow powder (0.648 g, 86%).
  • step (5) To a suspension of the compound (0.593 g, 1.00 mmol) obtained in step (5) in methanol (15 mL) was added ammonium acetate (0.116 g, 1.50 mmol), and the mixture was heated under reflux for 1 hour. Release After cooling, add 10% aqueous potassium carbonate solution (20 mL), and add
  • Example 12 To a solution of the compound obtained in 2- (6) (0.092 g, 0.196 mmol) in ethanol (4 mL) was added a 4 N hydrogen chloride dioxane solution (0.5 mL) and 10% palladium-carbon catalyst, and hydrogen was added. The mixture was stirred at room temperature under an atmosphere for 5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a light brown powder. This powder was recrystallized from methanol-ether to give the title compound (0.060 g, 82%) as a pale brown powder.
  • Trifluorophenylphosphine (24.9 g, 95 mmol) was added to tetrahydrofuran (150 mL) and water (45 mL) of the compound (21.8 g, 79 mmol) obtained in step (1), and the mixture was brought to room temperature. And stirred for 15 hours. After the reaction, tetrahydrofuran was distilled off, water (100 mL) was added to the resulting aqueous layer, and the mixture was ice-cooled. After cooling on ice, the pH was adjusted to 4 by adding 10% citric acid, and the mixture was washed with a black hole form. After washing, the mixture was ice-cooled again, adjusted to pH 9-10 with potassium carbonate, and extracted with chloroform. The extract was dried over potassium carbonate and concentrated to give a white solid (18.2 g, 92%).
  • step (1) A suspension of the compound (976 mg, 1.83 mmol) obtained in step (1) and 10% palladium-carbon catalyst (390 mg) in methanol (70 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours.
  • the reaction solution was filtered, concentrated, and purified by silica gel column chromatography (silica gel, methanol / chloroform) to obtain the desired compound (528 mg, 72%).
  • step (2) To the compound (2.16 g, 5.39 mmol) obtained in step (2) was added a 4N hydrochloric acid-dioxane solution (50 mL, 200 mmol) at room temperature, and the mixture was stirred for 21.5 hours. The precipitated solid was collected by filtration, washed with getyl ether (100 ml), dissolved in water and lyophilized to give a pale yellow powder (1.6
  • the enzyme was dissolved in a 10 mM MES (2- [N-morphorino] ethansulfonic acid, pH 6.1) solution containing 2 mM CaCl 2 , 20% glycerol, and 50 mg / mL heparin.
  • Assay buffer used was 0.1 M NaCl, 0.1% Triton X-100, and a 0.05 M Tris-HCl buffer (pH 8.0) containing 50 mg / mL of parin. .
  • Each test compound was dissolved in a 20% DMS0 solution.
  • Each test compound or a 20% DMS0 solution, Atsushi buffer (140 ⁇ ) and an enzyme solution (20 ywL) were added to a 96-well microplate, and the mixture was pre-incubated at 37 ° C. for 10 minutes. Further, 20 ⁇ M of a 5 mM substrate (N-p-Tosyl-Gly-Pro-Lys-pNA, Sigma) was added thereto, and a Thermo-Max (registered trademark, manufactured by Molecular Devices) microplate reader Using one, the change in absorption at 405 nm was measured.
  • the Ki 'values of the compounds were determined from the inhibition rates at various concentrations.
  • the value means the inhibitor constant of the enzyme-substrate-inhibitor (here, the test compound) complex. The smaller the value, the higher the affinity and the stronger the inhibitory activity. Table 1 shows the results.
  • the enzyme used was prepared from thrombin-green (manufactured by Green Cross) at a concentration of 0.04 U / mL in 20 mM CaCl 2 and 10 mM acetate buffer (pH 6.5) containing 0.1% Triton X-100. Was. In addition, a 0.1 M Tris-HCl buffer (pH 8.0) containing 20 mH CaCl 2 and 0.1% Triton X-100 was used as an Atsushi buffer. The test compounds were each dissolved in a 20% DMS0 solution.
  • (1), (3), (4) and (2) were each dried and reduced to a constant water content, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder of uniform quality and mixed for a short time (30 seconds).
  • the mixed powder is tableted (punch: 6.3mm0, 6.0mmR) and 1 tablet of 85mg Tablets.
  • the tablet may be coated with a commonly used gastrosoluble film coating agent (for example, polyvinylacetate-l-jetylaminoacetate) or an edible colorant.
  • a commonly used gastrosoluble film coating agent for example, polyvinylacetate-l-jetylaminoacetate
  • an edible colorant for example, polyvinylacetate-l-jetylaminoacetate
  • novel tryptase inhibitor of the present invention has excellent tryptase inhibitory activity and can provide an antiallergic agent having a new mechanism of action. Furthermore, the novel compounds of the present invention have excellent tryptase inhibitory activity and are effective as tryptase inhibitors.

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Abstract

Cette invention se rapporte à des inhibiteurs de tryptase contenant comme principe actif des composés représentés par la formule générale (I) ou des sels de ces composés acceptables sur le plan pharmacologique; à des nouveaux composés contenus dans le groupe des composés représentés par la formule générale (I) ou à des sels de ces nouveaux composés acceptables sur le plan pharmacologique; et à des compositions de médicaments contenant ces composés comme principe actif. Dans cette formule, chaque symbole a la même signification que celle spécifiée dans les pièces descriptives de l'invention. Ces nouveaux inhibiteurs de tryptase ont une excellente action inhibitrice de la tryptase, ce qui les rend utiles pour prévenir et traiter des maladies allergiques, notamment. Les nouveaux composés mentionnés ci-dessus ont une excellente activité inhibitrice de la tryptase, ce qui les rend utiles comme inhibiteurs de la tryptase.
PCT/JP1998/005280 1997-11-26 1998-11-24 Inhibiteurs de tryptase comprenant des composants d'amide heterocycliques WO1999026925A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1062949A1 (fr) * 1998-03-11 2000-12-27 Welfide Corporation INHIBITEURS DE PRODUCTION D'ANTICORPS IgE ET INHIBITEURS DE MALADIES AUTO-IMMUNES
US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
US6469036B1 (en) 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
JP2004503538A (ja) * 2000-06-13 2004-02-05 テュラリク・リミテッド セリンプロテアーゼインヒビター
JP2004526721A (ja) * 2001-03-02 2004-09-02 エフ．ホフマン−ラ　ロシュ　アーゲー Ｉｐアンタゴニストとしてのアルコキシカルボニルアミノヘテロアリールカルボン酸誘導体
US20140086936A1 (en) * 2011-06-02 2014-03-27 SOCPRA Sciences Sante et Humaines S.E.C. Matriptase inhibitors and uses thereof against orthomyxoviridae infections
US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US10730826B2 (en) 2016-09-16 2020-08-04 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US10906881B2 (en) 2015-11-09 2021-02-02 Cortexyme, Inc. Inhibitors of arginine gingipain

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WO1994020527A1 (fr) * 1993-03-12 1994-09-15 Arris Pharmaceutical Corporation Compositions et procedes pour le traitement d'affections inflammatoires immunoresultantes
WO1995032945A1 (fr) * 1994-06-01 1995-12-07 Arris Pharmaceutical Corporation Compositions et procedes de traitement d'etats induits par des mastocytes
US5525623A (en) * 1993-03-12 1996-06-11 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1996030396A1 (fr) * 1995-03-24 1996-10-03 Molecumetics Ltd. IMITATEURS DE FEUILLETS β ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PROTEASE

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WO1994020527A1 (fr) * 1993-03-12 1994-09-15 Arris Pharmaceutical Corporation Compositions et procedes pour le traitement d'affections inflammatoires immunoresultantes
US5525623A (en) * 1993-03-12 1996-06-11 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1995032945A1 (fr) * 1994-06-01 1995-12-07 Arris Pharmaceutical Corporation Compositions et procedes de traitement d'etats induits par des mastocytes
US5656660A (en) * 1994-06-01 1997-08-12 Arris Pharmaceutical Corporation Compositions and methods for treating mast-cell mediated conditions
WO1996030396A1 (fr) * 1995-03-24 1996-10-03 Molecumetics Ltd. IMITATEURS DE FEUILLETS β ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PROTEASE

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6221914B1 (en) 1997-11-10 2001-04-24 Array Biopharma Inc. Sulfonamide bridging compounds that inhibit tryptase activity
EP1062949A1 (fr) * 1998-03-11 2000-12-27 Welfide Corporation INHIBITEURS DE PRODUCTION D'ANTICORPS IgE ET INHIBITEURS DE MALADIES AUTO-IMMUNES
EP1062949A4 (fr) * 1998-03-11 2002-10-09 Mitsubishi Pharma Corp INHIBITEURS DE PRODUCTION D'ANTICORPS IgE ET INHIBITEURS DE MALADIES AUTO-IMMUNES
US6528514B1 (en) 1998-03-11 2003-03-04 Welfide Corporation IgE antibody production inhibitors and autoimmune diseases inhibitors
US6469036B1 (en) 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
US7132418B2 (en) 1999-01-27 2006-11-07 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
JP2004503538A (ja) * 2000-06-13 2004-02-05 テュラリク・リミテッド セリンプロテアーゼインヒビター
JP2004526721A (ja) * 2001-03-02 2004-09-02 エフ．ホフマン−ラ　ロシュ　アーゲー Ｉｐアンタゴニストとしてのアルコキシカルボニルアミノヘテロアリールカルボン酸誘導体
US9752149B2 (en) 2011-06-02 2017-09-05 SOCPRA Sciences Sante et Humaines S.E.C. Matriptase inhibitors and uses thereof against orthomyxoviridae infections
US9365853B2 (en) * 2011-06-02 2016-06-14 SOCPRA Sciences Sante et Humaines S.E.C. Matriptase inhibitors and uses thereof against orthomyxoviridae infections
US20140086936A1 (en) * 2011-06-02 2014-03-27 SOCPRA Sciences Sante et Humaines S.E.C. Matriptase inhibitors and uses thereof against orthomyxoviridae infections
US10208308B2 (en) 2011-06-02 2019-02-19 SOCPRA Sciences Sante et Humaines S.E.C. Matriptase inhibitors and uses thereof against orthomyxoviridae infections
US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US9988375B2 (en) 2014-10-06 2018-06-05 Cortexyme, Inc. Inhibitors of lysine gingipain
US10301301B2 (en) 2014-10-06 2019-05-28 Cortexyme, Inc. Inhibitors of lysine gingipain
US10676470B2 (en) 2014-10-06 2020-06-09 Cortexyme, Inc. Inhibitors of lysine gingipain
US11332464B2 (en) 2014-10-06 2022-05-17 Cortexyme, Inc. Inhibitors of lysine gingipain
US10906881B2 (en) 2015-11-09 2021-02-02 Cortexyme, Inc. Inhibitors of arginine gingipain
US10730826B2 (en) 2016-09-16 2020-08-04 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US11325884B2 (en) 2016-09-16 2022-05-10 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US12110263B2 (en) 2016-09-16 2024-10-08 Lighthouse Pharmaceuticals, Inc. Ketone inhibitors of lysine gingipain

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