WO1997005107A1 - Derives de la serine - Google Patents

Derives de la serine Download PDF

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Publication number
WO1997005107A1
WO1997005107A1 PCT/JP1996/002026 JP9602026W WO9705107A1 WO 1997005107 A1 WO1997005107 A1 WO 1997005107A1 JP 9602026 W JP9602026 W JP 9602026W WO 9705107 A1 WO9705107 A1 WO 9705107A1
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WO
WIPO (PCT)
Prior art keywords
group
substituent
compound
optionally substituted
solvates
Prior art date
Application number
PCT/JP1996/002026
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English (en)
Japanese (ja)
Inventor
Masahiro Oshima
Norimichi Iwase
Koichi Sugawara
Misao Okitsu
Original Assignee
Mitsubishi Chemical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Chemical Corporation filed Critical Mitsubishi Chemical Corporation
Priority to AU64705/96A priority Critical patent/AU6470596A/en
Publication of WO1997005107A1 publication Critical patent/WO1997005107A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel serine derivatives. More specifically, the present invention relates to a serine derivative and a salt thereof having a protease inhibitory activity, in particular, an anti-thrombin action, and a protease inhibitor comprising them as an effective component.
  • a protease inhibitory activity in particular, an anti-thrombin action
  • a protease inhibitor comprising them as an effective component.
  • proteolytic enzymes exist in a living body. For example, thrombin, factor Xa, & factor, factor ⁇ 11a, trypsin, plasmin, tissue plasminogen activator, kallikrein, C1 enzyme in complement or C3ZC5 convertase, tripcusase
  • thrombin, factor Xa, & factor, factor ⁇ 11a trypsin, plasmin, tissue plasminogen activator, kallikrein, C1 enzyme in complement or C3ZC5 convertase, tripcusase
  • C1 enzyme in complement or C3ZC5 convertase
  • tripcusase tripcusase
  • an antithrombin agent is effective as a therapeutic agent for thrombosis, and a proteolytic enzyme inhibitor having an antithrombin action is being developed.
  • this inhibitor is problematic in several respects, including stability in vivo, selectivity between thrombin homologous serine proteases, and reduced antithrombin activity upon oral administration. Is not enough for practical use.
  • a tribeptide derivative containing an arginine derivative is known as a protease inhibitor.
  • D-Fenilara-Lu L-prolyl-L-arginal is known as a thrombin inhibitor (for example, Foiaia Haema tol., 109, 22 (1 982 )).
  • thrombin inhibitor for example, Foiaia Haema tol., 109, 22 (1 982 )
  • the present inventors have conducted a search to find a substance having sufficient enzyme selectivity, oral activity, and biostability for practical use, and having a new chemical structure.
  • the following serine derivative was found to have desired properties, and the present invention was completed.
  • n 1 or 2
  • R 1 may be substituted with a carboxyl group to C 1Q alkyl group, which may have a substituent c 6 to c 1 () aryl group, which may have a substituent c 3
  • To c 1 () represents an optionally substituted cycloalkyl group or an aralkyl group of c 7 to c
  • R 2 is a hydrogen atom, a C 1Q alkyl group, an optionally substituted C 7 C 12 aralkyl group, — C OR 3 (R ° is a hydrogen atom, and J 1 to C 1 () alkyl Group, an alkoxy group of c 1 (), an optionally substituted c 7 c 12 aralkyloxy group, an optionally substituted c 6 c 1Q aryl group and a substituent and even though good Ariruokishi group to c 1 (), a cycloalkyl group optionally c 3 c 1Q may have a substituent, cycloalkyl
  • R 4 is an alkyl group of ⁇ C 1 () , an aryl group of C thinkingC 1 () which may have a substituent, an aryl group of ⁇ C 1 () which may have a substituent ⁇ c 1 () . which. represents a) a cycloalkyl group, or may have a substituent group c 7 ⁇ E of Ararukiru group, provided that the following compounds are excluded:
  • R 1 represents a 4-carboxyphenyl group, R represents a methylsulfonyl group and n represents 1;
  • R 1 represents a 3- (benzyloxycarbonyl) phenyl group
  • R 2 represents a methylsulfonyl group
  • n represents 1;
  • R ⁇ represents a t-butyl group, represents a methylsulfonyl group, and n represents 1.
  • R 1 represents a 11-dimethylpyrazole group
  • R 2 represents a methylsulfonyl group
  • n represents 1.
  • R 1 represents a 1-methyl-1-ethyl loop pill group
  • R represents a methylsulfonyl group
  • n represents 1
  • R 1 represents a t-butyl group
  • R 2 represents an ethoxycarbonyl group
  • n 1.
  • a medicament comprising a substance selected from the above-mentioned serine derivatives and salts thereof, and hydrates and solvates thereof; the above-mentioned serine derivatives and salts thereof;
  • a pharmaceutical composition comprising a substance that is an active ingredient selected from hydrates and solvates of, and a pharmaceutically acceptable carrier.
  • the above medicines and doctors The drug composition is useful for the prevention and treatment of diseases caused by increased protease activity, and is useful, for example, as an antithrombin agent, that is, an oral anticoagulant.
  • a protease inhibitor comprising a substance selected from the above serine derivatives and salts thereof, and hydrates and solvates thereof is also provided as one embodiment of the present invention.
  • a method for treating a disease caused by hypertension comprising a step of administering to a patient a therapeutic and / or Z- or prophylactically effective amount of a substance selected from the above serine derivatives and salts thereof, and hydrates and solvates thereof.
  • a method is provided that includes: BEST MODE FOR CARRYING OUT THE INVENTION
  • the serine derivative of the present invention is represented by the above formula (I).
  • Examples of the alkyl group of the formula (1) to ( C 1) in the above definition include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, and a t-butyl group.
  • n-pentyl group 1, 1-dimethyl-open pill group, neopentyl group, n-hexynole group, 1-methyl-1-ethyl-open-mouth pill group, n-heptyl group, 1,1-ethyl-propyl, n-octyl Group, n-nonyl group, n-decyl group and the like.
  • cycloalkyl group of c 3 to c 1Q cyclopropyl group, Shikurubuchiru group, cyclopentyl group, cyclohexyl group, heptyl group cycloalkyl, shea Kurookuchiru group, cyclononyl group, cyclodecyl group, one one methyl one cyclopentyl Le group No.
  • Examples of the alkoxy group of c to 1Q include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butyloxy group, an s-butyloxy group, an i_butyloxy group, a t-butyloxy group, and an n-pentyloxy group. , Neopentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy and the like, and a C 3 -C 1 () cycloalkyloxy group.
  • the aryloxy group of c 6 to c 1Q include a phenyloxy group, a tolyloxy group, and a naphthyloxy group.
  • Can be as a Ararukiru group c 7 to c 12 are benzyl groups, Fuweniruechiru group, phenylpropyl group, etc. naphthylmethyl group.
  • the substituent when “may have a substituent (s)", the substituent may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group. , S-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group, etc.
  • chloromethyl group bromomethyl group, dichloromethyl group, 1-chloroethyl group ⁇ C such as 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group and trifluoromethyl group.
  • Haloalkyl groups methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, s-butyloxy, isobutyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy
  • a C i -C alkoxy group such as a group; a hydroxyl group; a carboxyl group; a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 5-carboxypentyl group, and a 6-carboxypentyl group. ?
  • C 2 ⁇ C carboxyalkyl groups such as a cyclohexyl group carboxy; carboxymethyl butoxy group, 2 - carboxy ethoxy, 3 - carboxypropoxy group, 4-Cal Bo carboxybutyl O alkoxy group, 5-carboxypentyl Ruo alkoxy group , carboxyalkyl O alkoxy group c 2 ⁇ c 7 such key Shiruokishi group to 6-carboxy; Asechiru group, Pro Oniru group, Puchiriru group, Isopuchiriru group, valeryl group, Isobareriru group, Pibaro I group, the Kisanoiru group, Ashiru groups c 2 to c 7 such Heputanoiru group; Asechiruo alkoxy group, a propionyloxy Ruo alkoxy group, Puchiriruokishi group, isopropoxy Chiriruokishi group, Bruno Reriruokishi group, isova
  • R 1 is an alkyl group of C 5 to C 1 () , or an aryl group of c 6 to c 1 () which may have a substituent. And may have a substituent c.
  • Cycloalkyl group to c 1 () compounds are Ararukiru group substituent good c 7 to c 12 have a.
  • R 1 is a C 5 to c 1Q alkyl group, an aryl group of c 6 to c 1 () which may have a substituent, A cycloalkyl group of c 3 to c 1 () , an optionally substituted c 7 to C 12 aralkyl group, R 2 is a hydrogen atom, and d to C 1 Examples of the compound include an alkyl group represented by () , an optionally substituted C 7 -C 19 aralkyl group, or —CO 3 (R 3 is the same as defined above).
  • the serine derivative represented by the general formula (I) can have various steric structures.
  • its absolute configuration may be either (S) or (R), and may be racemic.
  • the optical isomers or diastereoisomers in pure form, any mixtures of these isomers, racemates and the like are all included in the scope of the present invention.
  • Examples of the salt which the compound of the general formula (I) can form include, for example, hydrochloride, odor Inorganic acid salts such as hydrochloride, hydroiodide, sulfate, nitrate, phosphate, etc., succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate , Acetate, glycolate, methanesulfonate, and toluenesulfonate.
  • the serine derivative represented by the general formula (I) has a free hydroxyl group, it can form a salt with a pharmaceutically acceptable base.
  • Examples of such salts include alkali metal salts, alkaline earth metal salts, ammonium and alkyl ammonium salts, and the like.
  • the serine derivative represented by the general formula (I) and a salt thereof may form a hydrate, and form a solvate with methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, and the like. In some cases, these are also included in the scope of the present invention.
  • specific examples of the compound of the present invention will be shown.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Ph represents a phenyl group
  • n Pr represents an n-propyl group
  • ipr represents an i-propyl group
  • Bu represents a butyl group
  • i-Bu is an i-butyl group
  • s—Bu is an s-butyl group
  • eye 1 o—Hex is a cyclohexyl group
  • 4-F-Ph and 4-OMe — Ph represents a 4-fluorophenyl group and a 4-methoxyphenyl group, respectively.
  • the compound of the present invention can be produced by a combination of reactions suitable for the target compound.
  • a typical reaction scheme is illustrated below, but it is not limited to only the methods described below.
  • R 1 , R 2 and n are the same as defined above, and P and Q represent amino-protecting groups such as benzyloxycarbonyl group and tert-butyloxycarbonyl group.
  • the reaction is carried out according to a conventional method, using an inert solvent such as tetrahydrofuran, getyl ether, dichloromethane or the like under cooling or at room temperature or warming.
  • an inert solvent such as tetrahydrofuran, getyl ether, dichloromethane or the like under cooling or at room temperature or warming.
  • the compounds (V) and (I) are synthesized by performing a deprotection reaction by a method known in peptide chemistry (for example, see Nobuo Izumiya et al., “Basic and Experimental Peptide Synthesis” Maruzen). You.
  • Each compound obtained as described above is isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization, and various types of chromatography.
  • the compound of the present invention When the compound of the present invention is used as a medicament, it may be used per se, but it is usually preferable to use it in the form of a pharmaceutical composition containing the compound of the present invention, which is an active ingredient, and a pharmaceutically acceptable additive.
  • the ratio of active ingredient to pharmaceutically acceptable excipients can vary, for example, from 1% to 90% by weight.
  • an oral composition such as granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids is administered. It may be administered intravenously, intramuscularly or subcutaneously as an injection. It can also be used as a suppository. It may be used as a powder for injection and prepared at the time of use.
  • compositions may include pharmaceutical or organic, solid or liquid carriers or diluents suitable for oral, enteral and parenteral use.
  • excipient used for producing a solid pharmaceutical composition for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used.
  • Liquid compositions for oral administration ie, emulsions, syrups, suspensions, solutions and the like, may contain commonly used inert diluents, such as water or vegetable oils.
  • the liquid composition may contain, in addition to the inert diluent, adjuvants such as wetting agents, suspending aids, sweetening agents, flavoring agents, coloring agents or preservatives.
  • the composition may be included in a capsule of absorbable material such as gelatin.
  • the solvent or suspending agent used for the production of parenterally administered pharmaceutical compositions include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.
  • the method for preparing the pharmaceutical composition may be a conventional method.
  • the clinical dosage when used by oral administration, is as follows: for adults, the compound of the present invention generally ranges from 0.01 to LOOO mg daily, preferably from 10 to 100 Omg daily. However, it is more preferable to increase or decrease as appropriate depending on age, disease state and symptoms.
  • the daily dose of the agent of the present invention may be administered once a day, divided into two or three times a day at appropriate intervals, or may be administered intermittently.
  • NMR in physical properties means a nuclear magnetic resonance spectrum, and the number is a 5 (delta) value usually used to indicate a chemical shift, and its unit is ppm.
  • TMS tetramethylsilane
  • the numbers in katzko following the value indicate the number of hydrogen atoms, followed by s for a single line, d for a double line, t for a triple line, q for a quadruple line, and m for multiple lines.
  • the line and br indicate broad absorption peaks.
  • IR infrared absorption spectrum, unless otherwise specified, as potassium bromide tablets It was measured. The number indicates the wave number, and the unit is cm- 1 . Only the main absorption peak was shown. mp means melting point, unit is. C, indicating an uncorrected value.
  • Example 1 trans-4-monoamino [(S) -N-[(R) -2-isopropoxycarbonylamino-3-3- (1 ', 1'-dimethylpropoxy) -propanoyl] prolyl] aminomethylcyclo Synthesis of hexane (Compound N 0.80 in Table 1) hydrochloride
  • Example 2 trans-1-amino-1-((S) -N-[(R) -2-isopropoxycarbonylamino-3-3-t-butoxypropanol] prolyl] aminomethylcyclohexane (Table 1 Compound of No. 53) Hydrochloride
  • Example 4 Transformer 4-amino — [(S) -N-[(R)] 2-isopropoxycarbonylamino-3- (1 ', 1'-dimethylbutoxy) propanol] propyl] aminomethylcyclohexane (Compound N o in Table 1) 14 1) Hydrochloride NMR (CDC 1): 8.33 (br, 3H), 7.24 (m, 1 1), 5.36
  • Marauder R (CDC 1): 8.29 (br, 3H), 7.25 (m, 1H), 5.50 (m, 1H), 4.84 (m, 1H), 4 7 0—4.40 (m, 2H), 4.00-3.70 (m, 2H), 3.60-3.40 (m, 2H), 3.25 -2.90 (m, 4H), 2.50 -1.40 (m, 14H), 1.24 (d, 6H), 1.04 (s, 3H), 0.79 (dt, 6 H), 1.10-0.90 (m, 2 H).
  • Example 9 Trans-Amino [(S) -N-[(R ) — 2-Propoxy power Luponylamino-3-(1 ', 1'-Dimethylpropoxy) propanol] Prolyl] aminomethylcyclohexane (Compound No. 79 in Table 1) Hydrochloride NMR (CDC 1): 8.31 (br, 3H), 7.19 (t, 1H), 5.59
  • S-2238 (Kabi) was dissolved in a Tris-HCl buffer (pH 8.3) to prepare a S-2238 0.4 M Tris-HCl solution having a concentration of 80 / M.
  • An aqueous solution of the compound of the present invention (5 ⁇ ⁇ ⁇ ) was added to the 1751, incubated at 37 ° C for 1 minute, and then a beef thrombin (Mochida) 4.4 units / ml solution was added to 101.
  • a measure of the hydrolysis reaction of the substrate was determined. 1/2 absorption when no inhibitor (compound of the present invention) is added The concentration of the inhibitor showing the luminosity was determined as I 5 ⁇ ( ⁇ ).
  • the compound of the present invention was dissolved in water or physiological saline to make a total volume of 0.1 ml, to which 0.1 ml of rat plasma was added, and incubated at 37 ° C for 30 seconds. To this was added 0.1 ml of an 8 unit / ml solution of beef thrombin (Mochida), and the coagulation time was measured at 37 ° C. The concentration of the inhibitor that prolonged the clotting time by two times without the addition of the inhibitor (the compound of the present invention) was determined as I 5Q ( ⁇ ).
  • Table 2 summarizes the results of Test Examples 1 and 2.
  • the serine derivative or a salt thereof of the present invention has a strong inhibitory activity against thrombin and is also excellent in oral absorbability, so that it is useful as an orally administrable antithrombin agent, that is, an anticoagulant.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pyrrole Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne les dérivés représentés par la formule générale (I). Dans cette formule, n est 1 ou 2, R1 est un alkyle en C¿1-10? éventuellement carboxylé, un aryle en C6-10 éventuellement substitué, etc; et R?2¿ est un hydrogène, un alkyle en C¿1-10?, un aralkyle en C7-12 éventuellement substitué, etc. Le trans-4-amino [(S)-N-[(R)-2-propoxycarbonylamino-3-(1',1'-diméthylpropoxy)propanoyl]prolyl]aminométhylcyclohexane constitue un composé typique de l'invention. Ces dérivés sont de puissants inhibiteurs de la thrombine et sont donc utiles comme anticoagulants.
PCT/JP1996/002026 1995-07-26 1996-07-19 Derives de la serine WO1997005107A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64705/96A AU6470596A (en) 1995-07-26 1996-07-19 Serine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/190650 1995-07-26
JP19065095 1995-07-26

Publications (1)

Publication Number Publication Date
WO1997005107A1 true WO1997005107A1 (fr) 1997-02-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008024720A (ja) * 1995-07-26 2008-02-07 Mitsubishi Chemicals Corp ペニシラミンアミド誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07252217A (ja) * 1994-01-27 1995-10-03 Mitsubishi Chem Corp プロリンアミド誘導体
WO1996003374A1 (fr) * 1994-07-22 1996-02-08 Merck & Co., Inc. Inhibiteurs de la thrombine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07252217A (ja) * 1994-01-27 1995-10-03 Mitsubishi Chem Corp プロリンアミド誘導体
WO1996003374A1 (fr) * 1994-07-22 1996-02-08 Merck & Co., Inc. Inhibiteurs de la thrombine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008024720A (ja) * 1995-07-26 2008-02-07 Mitsubishi Chemicals Corp ペニシラミンアミド誘導体

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