• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides phenyl amidines of formula (1), tautomers thereof, stereoisomers thereof, mixtures thereof and salts thereof, in particular having pharmacological properties, preferably coagulation inhibitory effects, physiologically acceptable with inorganic acids or organic acids or bases It is about salt becoming. The present invention also relates to medicaments containing these compounds, their use and preparation methods thereof. Formula 1 In the above formula, R 1 to R 5 , X, Y and Z are as defined in claim 1.
    公开号:KR19990008011A
    申请号:KR1019970707535
    申请日:1996-04-18
    公开日:1999-01-25
    发明作者:힘멜스바흐프랑크；아우슈텔폴크하르트；린츠귄터；피퍼헬무트；구쓰브라이언；바이젠베르거요하네스
    申请人:슈노렌베르크；닥터칼토매게엠베하；
    IPC主号:
    专利说明:

    Substituted phenyl amidines, pharmaceutical compositions containing these compounds and methods of making the same
    The present invention relates to stereoisomers comprising phenylamidine of formula (1), tautomers thereof, mixtures thereof, and salts thereof, in particular inorganic or organic acids or bases, which have useful pharmacological properties, preferably coagulation-inhibiting properties, Tolerable salts, pharmaceutical compositions containing these compounds and methods for their preparation are provided.
    In the above formula,
    X and Z may be the same or different and each is unsubstituted or has one or two alkyl groups, alkenyl groups having 2 to 4 carbon atoms, alkynyl groups having 2 to 4 carbon atoms, aryl, arylmethyl, heteroaryl or heteroaryl A straight chain alkylene group which may be substituted by a methyl group,
    Y is a 5-7 membered cycloalkylene group unsubstituted or substituted by one or two alkyl groups; Pyrrolidinylene, piperidinylene or azacycloheptylene group, unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to the nitrogen atom may be substituted with a carbonyl group ; Or piperazinylene or 1,4-diazacycloheptylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to a nitrogen atom may be replaced by a carbonyl group Can be
    R 1 represents a hydrogen atom, an alkyl, 1,1,1-trifluoroethyl or alkyloxycarbonyl group, an arylalkyloxycarbonyl group having 1 to 3 carbon atoms in the alkyl moiety Wherein R a is a hydrogen atom or an alkyl group, R b is an alkyl group or a 3-7 membered cycloalkyl group,
    R 2 and R 3 may be the same or different and each is a hydrogen, fluorine, chlorine, bromine or iodine atom, alkyl, trifluoromethyl or alkoxy group,
    R 4 is a hydrogen atom, an alkyl, allylalkyl or heteroarylalkyl group,
    R 5 is a hydrogen atom, an alkyl group of 1 to 8 carbon atoms, a 4-7 membered cycloalkyl group, aryl or arylalkyl group, unsubstituted or substituted by one or two alkyl groups, or Wherein R c is a hydrogen atom or an alkyl group, R d is a hydrogen atom or an alkyl group, R e is an alkyl or alkoxy group, a 3-7 membered cycloalkyl group or a 5-7 membered cycloalkoxy group Is a group)
    Unless stated otherwise, the aryl moieties specified in the definitions of the above groups are monosubstituted by R 6 and monosubstituted, di-substituted or trisubstituted by R 7 or monosubstituted by R 6 and further added by R 7 . Is a phenyl group which may be mono- or di-substituted, wherein the substituents may be the same or different,
    R 6 is cyano, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphenyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, perfluor Roalkyl, trifluoromethoxy, nitro, amino, alkylamino, dialkylamino, alkylcarbonylamino, phenylalkylcarbonylamino, phenylcarbonylamino, alkylsulfonylamino, phenylalkylsulfonylamino, phenylsulfonylamino , N-alkyl-alkylcarbonylamino, N-alkyl-phenylalkylcarbonylamino, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonylamino, N-alkyl-phenylalkylsulfonylamino, N- Alkyl-phenylsulfonylamino, aminosulfonyl, alkylaminosulfonyl- or dialkylaminosulfonyl groups,
    R 7 is an alkyl, hydroxy or alkoxy group, a fluorine, chlorine, bromine or iodine atom (where two R 6 groups are bonded to adjacent carbons, these are alkylene groups of 3 to 6 carbon atoms, 1,3-butadiene May be a -1,4-diylene group or a methylenedioxy group),
    Heteroaryl moieties specified in the definition of the group may be an oxygen, sulfur or nitrogen atom; Nitrogen and oxygen atoms, sulfur or nitrogen atoms; Or a five-membered heteroaromatic ring containing two nitrogen atoms and an oxygen, sulfur or nitrogen atom, or one, two or three nitrogen atoms and further one or two -CH = N-groups are each -CO Is a 6-membered heteroaromatic ring which may be substituted by an —NR 8 -group where R 8 is a hydrogen atom or an alkyl group, wherein the heteroaromatic ring described above is further substituted by one or two alkyl groups or fluorine Can be substituted in the carbon skeleton by chlorine, bromine or iodine atoms or trifluoromethyl, hydroxy or alkyloxy groups,
    Unless stated otherwise, the alkyl, alkylene or alkoxy moieties described above may each contain 1 to 4 carbon atoms.
    However, preferred compounds of the compound of Formula 1
    X is one or two alkyl groups, alkenyl groups having 2 or 3 carbon atoms, alkynyl groups having 2 or 3 carbon atoms, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, 2 A straight chain alkylene group having 1 to 3 carbon atoms which may be substituted by an imidazolyl, 4-imidazolyl or 5-imidazolyl group, wherein the imidazolyl group is at one of the nitrogen atoms by an alkyl group May be further substituted),
    Z is one or two alkyl groups each, an alkenyl group having 2 or 3 carbon atoms, an alkynyl group having 2 or 3 carbon atoms, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, Methylene or ethylene groups, which may be substituted by 2-imidazolyl, 4-imidazolyl or 5-imidazolyl groups, wherein the imidazolyl group may be further substituted at one of the nitrogen atoms by an alkyl group. Can be)
    Y is a cyclohexylene group unsubstituted or substituted by one or two alkyl groups, a piperidinylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to a nitrogen atom May be substituted by a carbonyl group), a piperazinylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to the nitrogen atom are replaced by a carbonyl group Can be
    R 1 is a hydrogen atom, an alkyl group, an alkyloxycarbonyl group or a phenylmethoxycarbonyl group having 2 to 5 carbon atoms in total,
    R 2 is hydrogen, fluorine, chlorine, bromine or iodine atom, trifluoromethyl group, alkyl or alkoxy group,
    R 3 is a hydrogen atom,
    R 4 is a hydrogen atom or an alkyl group,
    R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a 5 or 7 membered cycloalkyl group or a phenylalkyl group,
    The phenyl groups mentioned in the definitions of the above groups may be mono- or di-substituted by fluorine, chlorine, bromine or iodine atoms, methyl, trifluoromethyl, hydroxy or methoxy groups, respectively, and the substituents may be the same or different. Wherein the pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or thiazolyl groups mentioned in the definitions of the above groups may be substituted by methyl or trifluoromethyl groups, respectively,
    Unless stated otherwise, the alkyl and alkoxy moieties mentioned above are compounds which may each contain 1 to 4 carbon atoms, tautomers thereof, stereoisomers comprising mixtures thereof and salts thereof.
    Particularly preferred compounds are the stereoisomers comprising the compounds of formula 1a, tautomers thereof, mixtures thereof and salts thereof.
    In the above formula,
    X is one or two alkyl groups of 1 to 3 carbon atoms, vinyl, allyl, ethynyl, propargyl, phenyl, wherein the phenyl group is a fluorine, chlorine, bromine or iodine atom, methyl, trifluoromethyl, May be further substituted by oxy or methoxy group), pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group, and a straight alkylene group having 1 to 3 carbon atoms,
    Z is one or two alkyl groups of 1 to 3 carbon atoms, vinyl, allyl, ethynyl, propargyl, phenyl, wherein the phenyl group is a fluorine, chlorine, bromine or iodine atom, methyl, trifluoromethyl, Methylene or ethylene group which may be further substituted by oxy or methoxy), pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group,
    Y is 1,4-cyclohexylene, 1,4-piperidinylene, 2-oxo-1,4-piperidinylene, 1,4-piperazinylene, 2-oxo-1,4-piperazinyl Ethylene, 2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group, wherein the groups described above are each one or two carbon atoms of 1 to 3 May be substituted by four alkyl groups),
    R 1 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkyloxycarbonyl group or benzyloxycarbonyl group having 2 or 3 carbon atoms in total,
    R 2 and R 3 are each a hydrogen atom,
    R 4 is a hydrogen atom or a methyl group,
    R 5 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a cyclohexyl group,
    Particularly preferably,
    X is an ethylene group which may be substituted by one or two methyl groups,
    Z is substituted by one or two methyl groups, pyridyl or phenyl groups, wherein the phenyl groups may be further substituted by fluorine, chlorine or bromine atoms, methyl, methoxy or trifluoromethyl groups Methylene group,
    Y is 1,4-cyclohexylene, 1,4-piperidinylene, 2-oxo-1,4-piperidinylene, 1,4-piperidinylene, 2-oxo-1,4-piperazinylene , 2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group,
    R 1 is a hydrogen atom, an alkyloxycarbonyl group or benzyloxycarbonyl group having 2 or 3 carbon atoms in total,
    R 2 , R 3 and R 4 are each a hydrogen atom,
    R 5 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a cyclohexyl group.
    Particularly preferred of the compounds of formula 1a are
    X is an ethylene group,
    Z is a methylene group,
    Y is a 1,4-piperidinylene group,
    R 1 , R 2 , R 3 and R 4 are each hydrogen atoms,
    R 5 is a hydrogen atom, a compound having 1 or 2 alkyl groups or cyclohexyl groups, stereoisomers thereof, mixtures thereof and salts thereof.
    According to the invention, the novel compounds of formula (1) are for example reacted with a compound of formula (2) with a compound of formula (3) or a reactive derivative thereof,
    Continuously, optionally, it can be obtained by a process of continuously converting group R 5 to a hydrogen atom.

    In the above formula,
    R 1 to R 5 , X, Y and Z are as defined above.
    Examples of reactive derivatives in compounds of formula 3 are acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or monocarboxylic acids, imidazolides thereof and esters thereof such as alkyl, aryl and ar Alkyl esters such as methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl esters.
    The reaction is typically a solvent or a mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, pyridine / dimethylformamide, benzene / tetrahydrofuran or dioxane Dehydrating agents (e.g. isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphoxide, N, N'-dicyclohexylka) Bodyimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, 2- (1H-benzotriazolyl) -1,1,3,3-tetramethyl-uronium salt, N Dimethylaminopyridine or 1-hydroxy-benzotriazole and / or base (with or without N'-carbonyldiimidazole, N, N'- thionyldiimidazole or triphenylphosphine / carbon tetrachloride) Examples: triethylamine, N-ethyl-diisoph Peel-amine, pyridine, or N- methyl-morpholine is carried out in), typically from -10 to a temperature of 180 ℃ in the presence or absence of, preferably in the range from 0 to a temperature of 120 ℃.
    Continuous conversion of the group R 5 to a hydrogen atom is usually in the presence of an acid (eg hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof) or a base (eg lithium hydroxide, sodium hydroxide). Or a temperature of −10 to 120 ° C. in a suitable solvent (eg water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane) in the presence of potassium hydroxide, For example at ambient temperature to boiling temperature of the reaction mixture.
    In the reactions described above, all the reactive groups present, such as carboxy, amino, alkylamino, imino or amidino groups, can be protected during the reaction by conventional reactive groups which are separated again after the reaction.
    For example, the protecting group for the carboxyl group can be a trimethylsilyl, methyl, ethyl, tertiary butyl, benzyl or tetrahydropyranyl group and the protecting group for any alkyl-substituted amidino group is benzyloxycarbo The protecting group for an amino, alkylamino or imino group may be formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy Benzyl or 2,4-dimethoxybenzyl groups, methyl groups may be considered further for imino groups and phthalyl groups are also possible for amino groups.
    Any successive separation of all protecting groups used may, for example, include acids (eg trifluoroacetic acid in an aqueous solvent such as water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water). Hydrochloric acid or sulfuric acid) or an alkali metal base (e.g. sodium hydroxide or potassium oxalate), or by hydrolysis in the presence of iodotrimethylsilane, for example from 0 to 120 캜, preferably from 10 to It can be separated by ether at a temperature of 100 ° C.
    However, benzyl, methoxybenzyl or benzyloxycarbonyl groups are preferably solvents (eg methanol, ethanol, ethyl acetate or glacial acetic acid) in the presence of a catalyst (eg palladium / charcoal), for example by hydrolysis with hydrogen. ) Is optionally added with an acid (e.g. hydrochloric acid) and separated under hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar, at a temperature of 0 to 100 ° C, preferably 20 to 60 ° C. However, the 2,4-dimethoxybenzyl group is preferably separated in the presence of anisole in trifluoroacetic acid.
    However, tertiary butyl or tertiary butyloxycarbonyl groups are preferably solvents (eg methylene chloride, dioxane) by treatment with acids (eg trifluoroacetic acid or hydrochloric acid) or treatment with iodotrimethylsilane. , Methanol or ether).
    However, the trifluoroacetyl group is preferably separated at a temperature of 50 to 120 ° C. in the presence or absence of a solvent (eg acetic acid or methanol) by treatment with an acid (eg hydrochloric acid) or a solvent (eg tetra Hydrofuran or methanol) and separated by treatment with sodium hydroxide solution at a temperature of 0-50 ° C.
    The phthalyl group is preferably 20 to 50 in a solvent (eg methanol, ethanol, isopropanol, toluene / water or dioxane) in the presence of hydrazine or primary amines such as methylamine, ethylamine or n-butylamine. At a temperature of < RTI ID = 0.0 >
    In addition, as already described above, the obtained compound of formula 1 can be optionally separated into its enantiomers and / or stereoisomers. Thus, for example, cis / trans mixtures can be separated into their cis and trans isomers, and compounds with one or more optically active carbon atoms can be separated into their enantiomers.
    Thus, for example, the cis / trans mixtures obtained can be separated into their cis and trans isomers by chromatography, and the compounds of formula 1 obtained as racemates are described in Allinger NL and Eliel EL in Topics. in Stereochemistry, Vol. 6, Wiley Interscience, 1971, which can be separated into their optical symmetries, wherein compounds of formula 1 having two or more asymmetric carbon atoms are known per se, for example by chromatography and / or fractional crystallization. The method can be used to separate these diastereomers based on their physical / chemical differences. If these diastereomers are present in racemic form, they can be subsequently degraded into enantiomers as described above.
    Separation of enantiomers preferably comprises column separation on chiral or recrystallization from an optically active solvent or for example racemic compounds, in particular acids and activated derivatives thereof or salts or derivatives of alcohols and esters or amides thereof. By reaction with an optically active material to form, and by separation of the diastereomeric mixtures of the salts or derivatives thus obtained based on, for example, differences in solubility, while the glass symmetry is obtained by the action of a suitable formulation. It may be released from stereoisomeric salts or derivatives. Particularly typical examples of optically active acids include the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include (+) or (-)-menthol, and examples of optically active acyl groups in amides include (+)-or (-)-methyloxycarbonyl.
    In addition, the compounds of formula 1 obtained can be converted to their salts, more particularly inorganic or organic acids and their physiologically acceptable salts for pharmaceutical purposes. Examples of suitable acids include hydrochloric acid, boric acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
    In addition, the novel compounds of formula (1) obtained can be converted, if desired, to salts with inorganic or organic bases, in particular their physiologically acceptable salts for pharmaceutical use, if they contain carboxyl groups. Examples of bases include sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
    The compounds used as starting compounds are in some cases known from the literature or can be obtained by methods known from the literature (see Examples).
    As already mentioned above, the novel phenylamidines and their salts, in particular inorganic or organic acids or bases and their physiologically acceptable salts, have useful properties. Thus, the novel compounds of formula 1 have useful physiological properties and, in addition to the anti-inflammatory effect and the inhibitory effect of bone degeneration, they especially have antithrombotic effect, anticoagulant effect and tumor- and metastatic-inhibitory effect.
    For example, compounds of formula 1 are investigated for their biological activity as follows.
    1. for a person light bulb 3Inhibition of H-BIBU 52 Binding
    Human precursor suspensions in plasma were prepared using 3 H-BIBU 52 [= (3S, 5S) -5-[(4'-amidino-) instead of the ligand 125 I-fibrinogen known from DE-A-4,214.245. 4-biphenylyl) oxymethyl] -3-[(carboxy) methyl] -2-pyrrolidinone [3- 3 H-4-biphenylyl]] and various concentrations of test substance are incubated. Free and bound ligands are separated by centrifugation and quantitatively determined by scintillation counting. From the results obtained, inhibition of 3 H-BIBU 52 binding by the test substance is measured.
    To do this, donor blood is taken from the anti-elbow vein and anticoagulated with trisodium citrate (final concentration 13 mM). Blood is centrifuged at 170 × g for 10 minutes and supernatant platelet-rich plasma (PRP) is removed. Residual blood is centrifuged one more time to obtain plasma. PRP is diluted 1:10 with autologous plasma. 750 μl are incubated for 20 minutes at ambient temperature with 50 μl of physiological saline, 100 μl of test substance solution, 50 μl of 14 C sucrose (3.700 Bq) and 50 μl of 3 H-BIBU 52 (final concentration: 5 nM). To measure non-specific binding, 5 μl of BIBU 52 (final concentration: 30 μM) is used instead of the test substance. Samples are centrifuged at 10,000 × g for 20 seconds and the supernatant is removed. 100 μl of this is measured to determine the free ligand. The pellet is dissolved in 500 μl of 0.2 N NaOH and 450 μl is mixed with 2 ml of scintillator to measure 25 μl of 5N HCl. Residual plasma remaining in the pellet is measured from 14 C content and bound ligand is measured from 3 H. After excluding non-specific binding, the pellet activity is graphed against the concentration of the test substance and the concentration for 50% binding inhibition is measured.
    2. Antithrombotic Activity:
    Way
    Progenitor coagulation was performed in platelet-rich plasma from healthy test subjects using the Born and Cross method [J. Physiol. 170, 397 (1964). To inhibit coagulation, the blood is mixed with 3.14% sodium citrate in a volume ratio of 1:10.
    Collagen-Induced Coagulation
    The process of increasing optical density of platelet suspensions is measured and recorded by photometry after the addition of coagulation-inducing substances. The solidification rate is calculated from the slope angle of the density curve. The optical density is calculated using the point on the curve with the highest light transmittance.
    The amount of collagen is chosen as little as possible, but enough to produce a constant response curve. Commercial standard collagen manufactured by Hormonchemie of Munich is used.
    Before adding collagen, plasma is incubated with the material for 10 minutes at 37 ° C.
    From the measurements obtained, the EC 50 corresponding to the 50% change in optical density for the inhibition of coagulation is measured graphically.
    Table 1 below contains the results found:
    Substance (Example Number) 3 H-BIBU-52-Binding Test IC 50 [nM]Platelet coagulation inhibition EC 50 [nM] One3.737 1 (1)51310
    With regard to their inhibitory effects on cell-to-cell and cell-to-matrix interactions, the novel cyclic urea derivatives of Formula 1 and their physiologically acceptable salts are associated with smaller or larger cell coagulation or Eradication or prevention of diseases in which cell-to-matrix interactions partially act, eg, prevention and prevention of venous and arterial thrombosis, cerebrovascular disease, pulmonary embolism, myocardial infarction, atherosclerosis, osteoporosis and tumor metastasis, and It is suitable for the treatment of genetically induced diseases or acquired diseases due to the interaction of cells with each other or with solid structures and cells. In addition, they are suitable for the combination of embolism and fibrinolysis or for the treatment of vascular adjustment or shock, psoriasis, diabetes and inflammation, such as interstitial angiogenesis.
    The dose for combating or preventing the above-mentioned diseases is 0.1 μg to 30 mg per kg body weight, preferably 1 μg to 15 mg per day, up to 4 times per day. One or more conventional inert carriers and / or diluents for this purpose, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, Water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances (e.g. hard fats or suitable mixtures thereof)], as well as other active substances (e.g. thromboxane-receptor antagonists) And thromboxane synthesis inhibitors or combinations thereof), serotonin antagonists, α-receptor antagonists, alkyl nitrates (such as glycerol trinitrate), phosphodiesterase inhibitors, prostacyclins and their analogs, fibrinolytics (such as tPA , Prourokinase, urokinase, streptokinase), or anticoagulants such as heparin, dermatan sulfate, activated protein C, a vitamin K antagonist, hirudin, thrombin or other activated coagulation factor inhibitors), optionally comprising a compound of formula (1) prepared according to the invention in conventional herbal preparations, e.g. It can be incorporated into powders, suspensions, solutions, sprays or suppositories.
    The following examples are intended to illustrate the invention in more detail:
    Example I
    4- [2- (chlorocarbonyl) ethyl] -1-[(ethoxycarbonyl) methyl] -piperidine-hydrochloride
    1.46 g of 4- (2-carboxyethyl] -1-[(ethoxycarbonyl) methyl] -piperidine in 10 ml of methylene chloride are added to 1 ml of saturated ether hydrochloric acid 1.2 g of thionyl chloride are added and the mixture is added to 3 Stir for hours at ambient temperature The reaction mixture is concentrated by evaporation, the residue is mixed twice with toluene and evaporated again The crude product is reacted further in Examples 1 and 2 without purification.
    The following compounds are obtained analogously to Example I:
    (1) 1- [2- (chlorocarbonyl) ethyl] -4-[(methoxycarbonyl) methyl] -piperidine-hydrochloride
    (2) 4- [2- (chlorocarbonyl) ethyl] -1-[(cyclohexyloxycarbonyl) -methyl] -piperidine-hydrochloride
    Example II
    4- [2- (carboxy) ethyl] -1-[(ethoxycarbonyl) methyl] -piperidine
    10 g of 4- [2- (benzyloxycarbonyl) ethyl] -1-[(ethoxycarbonyl) methyl] -piperidine in 150 ml of tetrahydrofuran under hydrogen pressure of 50 psi in the presence of 1.3 g of palladium on activated charcoal , Hydrogenate at ambient temperature for 4 hours. The reaction mixture is evaporated and crystallized from diethyl ether and a small amount of acetone.
    Yield: 5.8 g (79% of theory)
    Melting point: 65-67 ° C
    The following compounds are obtained analogously to Example II:
    (1) 4- (2-carboxyethyl) -1-[(cyclohexyloxycarbonyl) -methyl] -piperidine
    Melting point: 85-88 ° C
    Example III
    4- [2- (benzyloxycarbonyl) ethyl] -1-[(ethoxycarbonyl) methyl] -piperidine
    To 9.0 g of 4- [2- (benzyloxycarbonyl) ethyl] -piperidine and 5.2 g of N-ethyl-diisopropylamine in 70 ml of acetonitrile, 6.35 g of ethyl bromoacetate in 20 ml of acetonitrile in an ice bath It is added dropwise with stirring and the mixture is stirred at ambient temperature for 18 hours. The reaction mixture is evaporated to concentration and the residue is rapidly bisected into 10 ml of tertiary butyl-methylether, ice water and 2N sodium hydroxide solution. The organic phase is separated, washed with ice water and saturated salt solution and concentrated by evaporation.
    Yield: 10.05 g (83% of theory)
    R f value: 0.84 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 95: 5: 1)
    The following compounds are obtained in analogy to Example III:
    (1) 4- [2- (benzyloxycarbonyl) ethyl] -1-[(cyclohexyloxycarbonyl) methyl] -piperidine
    R f value: 0.47 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 98: 2: 0.5)
    Example IV
    4- [2- (benzyloxycarbonyl) ethyl] -piperidine
    4- (2-carboxyethyl) piperidine-hydrochloride [melting point: 240-250 ° C., prepared by hydrogenating 3- (4-pyridyl) -acrylic acid in glacial acetic acid in the presence of platinum oxide and then treating with hydrochloric acid 9.7 g, 30 ml of benzyl alcohol, 3 g of p-toluenesulfonic acid and 50 ml of toluene are heated using a water separator for 75 minutes. The reaction mixture is concentrated by evaporation in vacuo, the residue is mixed with 50 ml of ice water and extracted three times with tertiary butyl-methylether. The aqueous phase is alkaline and washed with tertiary butyl-methylether. The extract is washed with brine solution, dried and concentrated by evaporation.
    Yield: 9.0 g (73% of theory)
    R f value: 0.18 (silica gel; methylene chloride / methanol / concentrated aqueous ammonia = 95: 5: 1)
    Example Ⅴ
    1- (2-carboxyethyl) -4-[(methoxycarbonyl) methyl] -piperidine-hydrochloride
    To 2.9 g of 1- [2- (tert-butoxycarbonyl) ethyl] -4-[(methoxycarbonyl) -methyl] -piperidine in 20 ml of methylene chloride, 10 ml of trifluoroacetic acid is added and the mixture is brought to ambient temperature. Stir overnight at. The reaction mixture is concentrated by evaporation, dissolved in acetone, mixed with etheric hydrochloric acid and again concentrated by evaporation. It is once more dissolved in acetone, mixed with etheric hydrochloric acid and concentrated by evaporation. The residue is stirred with a little acetone added tert butyl-methylether, suction filtered and dried.
    Yield: 2.45 g (92% of theory)
    Rf value: 0.73 (reverse phase silica gel; methanol / 5% aqueous salt solution = 6: 4)
    Example VI
    1- [2- (tert-butoxycarbonyl) ethyl] -4-[(methoxycarbonyl) methyl] -piperidine
    A mixture of 9 ml of tertiary butyl acrylate, 10 g of 4-[(methoxycarbonyl) methyl] -piperidine-hydrochloride and 7.2 ml of triethylamine in 150 ml of methanol was refluxed overnight. The reaction mixture is evaporated to concentration, dissolved in methylene chloride and washed twice with saturated sodium hydrogen carbonate solution. The organic phase is separated off, concentrated by evaporation and the residue is purified by chromatography on a silica gel column of methylene chloride / methanol (35: 5).
    Yield: 12.6 g (86% of theory)
    Rf value: 0.68 (silica gel; methylene chloride / methanol = 9: 1)
    Example 1
    4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl-1-carbonylmethyl-piperidine × 0.2H 2O
    To 420 mg of 4-aminobenzamidine-dihydrochloride and 20 mg of 4-dimethylaminopyridine in a mixture of 1.5 ml of dimethylformamide and 1.5 ml of pyridine, 4- [2- (chlorocarbonyl) ethyl] -1- [ 720 mg of oxycarbonyl) methyl] -piperidine-hydrochloride are added and the mixture is stirred at 100 ° C. for 1.3 h. The reaction mixture is cooled, mixed with ice water, alkaline with sodium hydroxide solution and extracted with tertiary butyl-methylether and methylene chloride. The aqueous phase is adjusted with hydrochloric acid so that the pH value is 3-4 and evaporated to dryness at a bath temperature of 70 ° C. The residue is heated until it is boiled with 100 ml of ethanol, cooled and filtered and the filtrate is concentrated by evaporation. The evaporation residue is heated with 30 ml of ethanol, it is cooled and the solid is filtered off with suction. The solid is stirred with 15 ml of tetrahydrofuran and 4.5 ml of 1N sodium hydroxide solution. The mixture is combined with 2.75 ml of 1N hydrochloric acid and stirred in an ice bath. The precipitate is washed with water and tetrahydrofuran and dried under vacuum.
    Yield: 144 mg (21% of theory)
    Melting Point: 283 ° C (Decomposition)
    Rf value: 0.76 (reverse phase silica gel; methanol / 5% aqueous salt solution = 6: 4)
    Calculated: C 60.77 H 7.32 N 16.67
    Found: 60.55 7.26 16.83
    Mass spectrum: (M + H) + = 333.
    The following compounds are obtained similarly to Example 1:
    (1) 1- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -4-carboxy-methyl-piperidine x 2 H 2 O
    Melting point: 192 to 200 ° C. (by sintering and decomposition)
    Rf value: 0.77 (reverse phase silica gel; methanol / 5% aqueous salt solution = 6: 4)
    Calculated: C 55.42 H 7.66 N 15.21
    Found: 55.02 7.38 14.95
    (2) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-piperazine
    (3) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-2-oxo-piperidine
    (4) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-2-oxo-piperazine
    (5) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-3-methyl-2-oxo-piperazine
    (6) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-2,3-dioxo-piperazine
    (7) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-2,5-dioxo-piperazine
    (8) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-3-oxo-piperazine
    (9) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-cyclohexane
    (10) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1- (1-carboxy-ethyl-piperidine
    (11) α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl] -phenylacetic acid
    (12) α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(3-pyridyl) acetic acid
    (13) 4- [2-[(4-amidinophenyl) aminocarbonyl] propyl] -1-carboxy-methyl-piperidine
    (14) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxy-methyl-3,3-dimethyl-2-oxo-piperazine
    (15) α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(4-fluorophenyl) acetic acid
    (16) α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(4-methoxyphenyl) acetic acid
    (17) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1- (2-carboxy-ethyl) -piperidine
    Example 2
    4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1- [ethoxycarbonyl) methyl] -piperidine × 2.15HCl × 0.7H 2O
    950 mg of 4- [2- (chlorocarbonyl) ethyl] -1-[(ethoxycarbonyl) methyl] -piperidine-hydrochloride was added to 625 mg of 4-aminobenzamidine and 30 mg of dimethylaminopyridine in 5 ml of pyridine. The mixture is stirred at 100 ° C. for 1 hour. 2 ml of dimethylformamide are added and the mixture is stirred at 100 ° C. for a further 1.2 h. The reaction mixture is evaporated to concentration and the residue is stirred twice with tertiary butyl-methylether, in which case the solvent is decanted off and discarded. The residue is purified by chromatography on aluminum oxide with ethanol. The product is dissolved in ethanol, slightly acidified with etheric hydrochloric acid and concentrated by evaporation. The residue is triturated with acetone and the solids are suction filtered and dried.
    Yield: 335 mg (25% of theory)
    Rf value: 0.35 (aluminum oxide; ethanol / concentrated aqueous ammonia = 99: 1)
    Calculated: C 50.55 H 7.04 N 12.41 Cl 16.88
    Found: 50.02 6.96 12.51 17.27
    Mass spectrum: (M + H) + = 361.
    Hydrochlorides of the following compounds are obtained similarly to Example 2:
    (1) 1- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -4-[(ethoxy-carbonyl) methyl] -piperidine
    (2) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -piperazine
    (3) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -2-oxo-piperidine
    (4) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -2-oxo-piperazine
    (5) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -3-methyl-2-oxo-piperazine
    (6) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -2,3-dioxo-piperazine
    (7) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -2,5-dioxo-piperazine
    (8) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -3-oxo-piperazine
    (9) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -cyclohexane
    (10) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1- [1- (ethoxy-carbonyl) ethyl] -piperidine
    (11) ethyl α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl] -phenylacetate
    (12) ethyl α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(3-pyridyl) acetate
    (13) 4- [2-[(4-amidinophenyl) aminocarbonyl] propyl] -1-[(ethoxy-carbonyl) methyl] -piperidine
    (14) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(ethoxy-carbonyl) methyl] -3,3-dimethyl-2-oxo-piperazine
    (15) ethyl α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(4-fluorophenyl) acetate
    (16) ethyl α- [4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-piperidinyl]-(4-methoxyphenyl) acetate
    (17) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1- [2- (ethoxy-carbonyl) ethyl] -piperidine
    (18) 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(cyclohexyloxycarbonyl) methyl] -piperidine × 2,3HCl × 2H 2 O
    Melting Point: 170 ° C (Decomposition)
    Rf value: 0.58 (reverse phase silica gel; methanol / 5% aqueous salt solution = 6: 4)
    Calculated: C 51.69 H 7.60 N 10.48 Cl 15.26
    Found: 51.69 7.46 10.44 15.17
    Example 3
    Anhydrous ampoule containing 2.5 mg of active substance per 1 ml
    Furtherance:
    Active substance: 2.5mg
    Mannitol 50.0mg
    Add 1.0 ml water for injection.
    Manufacturing method:
    The active substance and mannitol are dissolved in water. After being bottled, the solution is freeze-dried. In use, the solution is combined with water for injection.
    Example 4
    Anhydrous Alfoll containing 35 mg of active substance per 2 ml
    Furtherance:
    Active substance: 35.0mg
    Mannitol 100.0mg
    Add 2.0 ml water for injection
    Manufacturing method:
    The active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. In use, the solution is combined with water for injection.
    Example 5
    Tablets containing 50 mg of active substance
    Furtherance:
    (1) active substance: 50.0mg
    (2) 98.0mg lactose
    (3) 50.0mg corn starch
    (4) 15.0 mg of polyvinylpyrrolidone
    (5) Magnesium Stearate 2.0mg
    215.0 mg
    Manufacturing method:
    (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granules. Compressed tablets are prepared from the mixture, which is double flat with small sides on both sides and graduation gold on one side.
    Diameter of the tablets: 9mm
    Example 6
    Tablets containing 350 mg of active substance
    Furtherance:
    (1) active substance: 350.0mg
    (2) Lactose 136.0mg
    (3) corn starch 80.0mg
    (4) 30.0 mg of polyvinylpyrrolidone
    (5) magnesium stearate 4.0mg
    600.0mg
    Manufacturing method:
    (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granules. Compressed tablets are prepared from the mixture, which is double flat with small sides on both sides and graduation gold on one side.
    Diameter of the tablets: 12mm
    Example 7
    Capsules containing 50 mg of active substance
    Furtherance:
    (1) active substance: 50.0mg
    (2) 58.0 mg anhydrous corn starch
    (3) 50.0mg powdered lactose
    (4) Magnesium Stearate 2.0mg
    160.0 mg
    Manufacturing method:
    (1) is polished to (3). The polished mixture is added to the blend of (2) and (4) with vigorous mixing.
    Using a capsule filling device, the powdered mixture is packaged into size 3 hard gelatin capsules.
    Example 8
    Capsules containing 350 mg of active substance
    Furtherance:
    (1) active substance: 350.0mg
    (2) 46.0 mg corn starch anhydrous
    (3) 30.0mg powdered lactose
    (4) 4.0 mg magnesium stearate
    430.0mg
    Manufacturing method:
    (1) is polished to (3). The polished mixture is added to the blend of (2) and (4) with vigorous mixing.
    Using a capsule filling device, the powdered mixture is packaged into size 0 hard gelatin capsules.
    权利要求:
    Claims (11)
    [1" claim-type="Currently amended] Phenylamidine of formula (1).
    Formula 1

    In the above formula,
    X and Z may be the same or different and each is unsubstituted or has one or two alkyl groups, alkenyl groups having 2 to 4 carbon atoms, alkynyl groups having 2 to 4 carbon atoms, aryl, arylmethyl, heteroaryl or heteroaryl A straight chain alkylene group which may be substituted by a methyl group,
    Y is a 5-7 membered cycloalkylene group unsubstituted or substituted by one or two alkyl groups; Pyrrolidinylene, piperidinylene or azacycloheptylene group, unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to the nitrogen atom may be substituted with a carbonyl group ; Or piperazinylene or 1,4-diazacycloheptylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to a nitrogen atom may be replaced by a carbonyl group Can be
    R 1 represents a hydrogen atom, an alkyl, 1,1,1-trifluoroethyl or alkyloxycarbonyl group, an arylalkyloxycarbonyl group having 1 to 3 carbon atoms in the alkyl moiety Wherein R a is a hydrogen atom or an alkyl group, R b is an alkyl group or a 3-7 membered cycloalkyl group,
    R 2 and R 3 may be the same or different and each is a hydrogen, fluorine, chlorine, bromine or iodine atom, alkyl, trifluoromethyl or alkoxy group,
    R 4 is a hydrogen atom, an alkyl, allylalkyl or heteroarylalkyl group,
    R 5 is a hydrogen atom, an alkyl group of 1 to 8 carbon atoms, a 4-7 membered cycloalkyl group, aryl or arylalkyl group, unsubstituted or substituted by one or two alkyl groups, or Wherein R c is a hydrogen atom or an alkyl group, R d is a hydrogen atom or an alkyl group, R e is an alkyl or alkoxy group, a 3-7 membered cycloalkyl group or a 5-7 membered cycloalkoxy group Is a group)
    Unless stated otherwise, the aryl moieties specified in the definitions of the above groups are monosubstituted by R 6 and monosubstituted, di-substituted or trisubstituted by R 7 or monosubstituted by R 6 and further added by R 7 . Is a phenyl group which may be mono- or di-substituted, wherein the substituents may be the same or different,
    R 6 is cyano, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, alkylcarbonyl, alkylsulphenyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, perfluor Roalkyl, trifluoromethoxy, nitro, amino, alkylamino, dialkylamino, alkylcarbonylamino, phenylalkylcarbonylamino, phenylcarbonylamino, alkylsulfonylamino, phenylalkylsulfonylamino, phenylsulfonylamino , N-alkyl-alkylcarbonylamino, N-alkyl-phenylalkylcarbonylamino, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonylamino, N-alkyl-phenylalkylsulfonylamino, N- Alkyl-phenylsulfonylamino, aminosulfonyl, alkylaminosulfonyl- or dialkylaminosulfonyl groups,
    R 7 is an alkyl, hydroxy or alkoxy group, a fluorine, chlorine, bromine or iodine atom (where two R 6 groups are bonded to adjacent carbons, these are alkylene groups of 3 to 6 carbon atoms, 1,3-butadiene May be a -1,4-diylene group or a methylenedioxy group),
    Heteroaryl moieties specified in the definition of the group may be an oxygen, sulfur or nitrogen atom; Nitrogen and oxygen atoms, sulfur or nitrogen atoms; Or a five-membered heteroaromatic ring containing two nitrogen atoms and an oxygen, sulfur or nitrogen atom, or one, two or three nitrogen atoms and further one or two -CH = N-groups are each -CO Is a 6-membered heteroaromatic ring which may be substituted by an —NR 8 -group where R 8 is a hydrogen atom or an alkyl group, wherein the heteroaromatic ring described above is further substituted by one or two alkyl groups or fluorine Can be substituted in the carbon skeleton by chlorine, bromine or iodine atoms or trifluoromethyl, hydroxy or alkyloxy groups,
    Unless stated otherwise, the alkyl, alkylene or alkoxy moieties described above may each contain 1 to 4 carbon atoms.
    [2" claim-type="Currently amended] The compound of claim 1, wherein X is one or two alkyl groups, alkenyl groups having 2 or 3 carbon atoms, alkynyl groups having 2 or 3 carbon atoms, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxa Straight chain alkylene groups of 1 to 3 carbon atoms which may be substituted by a zolyl, thiazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl group, wherein the imidazolyl group is May be further substituted at one of the nitrogen atoms),
    Z is one or two alkyl groups each, an alkenyl group having 2 or 3 carbon atoms, an alkynyl group having 2 or 3 carbon atoms, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, Methylene or ethylene groups, which may be substituted by 2-imidazolyl, 4-imidazolyl or 5-imidazolyl groups, wherein the imidazolyl group may be further substituted at one of the nitrogen atoms by an alkyl group. Can be)
    Y is a cyclohexylene group unsubstituted or substituted by one or two alkyl groups, a piperidinylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to a nitrogen atom May be substituted by a carbonyl group), a piperazinylene group unsubstituted or substituted by one or two alkyl groups, wherein one or two methylene groups adjacent to the nitrogen atom are replaced by a carbonyl group Can be
    R 1 is a hydrogen atom, an alkyl group, an alkyloxycarbonyl group or a phenylmethoxycarbonyl group having 2 to 5 carbon atoms in total,
    R 2 is hydrogen, fluorine, chlorine, bromine or iodine atom, trifluoromethyl group, alkyl or alkoxy group,
    R 3 is a hydrogen atom,
    R 4 is a hydrogen atom or an alkyl group,
    R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a 5 or 7 membered cycloalkyl group or a phenylalkyl group,
    The phenyl groups mentioned in the definitions of the above groups may be mono- or di-substituted by fluorine, chlorine, bromine or iodine atoms, methyl, trifluoromethyl, hydroxy or methoxy groups, respectively, and the substituents may be the same or different. Wherein the pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl or thiazolyl groups mentioned in the definitions of the above groups may be substituted by methyl or trifluoromethyl groups, respectively,
    Unless stated otherwise, the alkyl and alkoxy moieties mentioned above may each contain 1 to 4 carbon atoms, including the phenylamidine of Formula 1, tautomers thereof, mixtures thereof, and salts thereof.
    [3" claim-type="Currently amended] Stereoisomers and salts thereof, including phenylamidine of Formula 1a, tautomers thereof, mixtures thereof.
    Formula 1a

    In the above formula,
    X is one or two alkyl groups of 1 to 3 carbon atoms, vinyl, allyl, ethynyl, propargyl, phenyl, wherein the phenyl group is a fluorine, chlorine, bromine or iodine atom, methyl, trifluoromethyl, May be further substituted by oxy or methoxy group), pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group, and a straight alkylene group having 1 to 3 carbon atoms,
    Z is one or two alkyl groups of 1 to 3 carbon atoms, vinyl, allyl, ethynyl, propargyl, phenyl, wherein the phenyl group is a fluorine, chlorine, bromine or iodine atom, methyl, trifluoromethyl, Methylene or ethylene group which may be further substituted by oxy or methoxy), pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl group,
    Y is 1,4-cyclohexylene, 1,4-piperidinylene, 2-oxo-1,4-piperidinylene, 1,4-piperazinylene, 2-oxo-1,4-piperazinyl Ethylene, 2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group, wherein the groups described above are each one or two carbon atoms of 1 to 3 May be substituted by four alkyl groups),
    R 1 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkyloxycarbonyl group or benzyloxycarbonyl group having 2 or 3 carbon atoms in total,
    R 2 and R 3 are each a hydrogen atom,
    R 4 is a hydrogen atom or a methyl group,
    R 5 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a cyclohexyl group.
    [4" claim-type="Currently amended] The compound of claim 3, wherein X is an ethylene group which may be substituted by one or two methyl groups,
    Z is substituted by one or two methyl groups, pyridyl or phenyl groups, wherein the phenyl groups may be further substituted by fluorine, chlorine or bromine atoms, methyl, methoxy or trifluoromethyl groups Methylene group,
    Y is 1,4-cyclohexylene, 1,4-piperidinylene, 2-oxo-1,4-piperidinylene, 1,4-piperidinylene, 2-oxo-1,4-piperazinylene , 2,3-dioxo-1,4-piperazinylene or 2,5-dioxo-1,4-piperazinylene group,
    R 1 is a hydrogen atom, an alkyloxycarbonyl group or benzyloxycarbonyl group having 2 or 3 carbon atoms in total,
    R 2 , R 3 and R 4 are each a hydrogen atom,
    R 5 is a hydrogen atom, a phenylamidine of Formula 1a, a tautomer thereof, a mixture thereof, and a salt thereof, wherein the phenylamidine of Formula 1a is an alkyl group having 1 to 4 carbon atoms or a cyclohexyl group.
    [5" claim-type="Currently amended] The compound of claim 3, wherein X is an ethylene group,
    Z is a methylene group,
    Y is a 1,4-piperidinylene group,
    R 1 , R 2 , R 3 and R 4 are each hydrogen atoms,
    R 5 is a hydrogen atom, an alkyl group having 1 or 2 carbon atoms or a cyclohexyl group, a stereoisomer comprising a tautomer thereof, a mixture thereof and a salt thereof.
    [6" claim-type="Currently amended] A 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-carboxymethyl-piperidine, 4- [2-[(4-amidinophenyl) aminocarbo Yl] ethyl] -1-ethoxycarbonyl) methyl] -piperidine and 4- [2-[(4-amidinophenyl) aminocarbonyl] ethyl] -1-[(cyclohexyloxycarbonyl) methyl ] -Piperidine and salts thereof, phenylamidine of formula (I).
    [7" claim-type="Currently amended] A physiologically acceptable salt of a compound according to any one of claims 1 to 6 with an inorganic acid or an organic acid or base.
    [8" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to claim 1 or a physiologically acceptable salt according to claim 7 and optionally one or more inert carriers and / or diluents.
    [9" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 7 for the manufacture of a pharmaceutical composition suitable for the treatment or prevention of diseases in which small or large cell aggregation occurs or cell-substrate interactions.
    [10" claim-type="Currently amended] A process for preparing a pharmaceutical composition according to claim 8, characterized in that the compound according to claim 1 is incorporated into at least one inert carrier and / or diluent in a non-chemical manner.
    [11" claim-type="Currently amended] Reacting a compound of formula 2 with a compound of formula 3 or a reactive derivative thereof,
    Subsequently, if necessary, the thus obtained R 5 Conversion of a compound of formula 1 other than hydrogen atoms of a compound of formula (I) R 5 is a hydrogen atom and / or,
    If necessary, the cleavage of the protecting group used in the above-mentioned reaction is repeated
    If necessary, the compound of formula 1 thus obtained is separated into its stereoisomer and / or
    A compound of formula (1) according to any one of claims 1 to 7, characterized in that the compound of formula (1) thus obtained is converted to its salt, in particular its physiologically acceptable salt for pharmaceutically use. How to prepare.
    Formula 2

    Formula 3

    In the above formula,
    R 1 to R 5 , X, Y and Z are as defined in claim 1.
    类似技术:
    公开号 | 公开日 | 专利标题
    US10640534B2|2020-05-05|Therapeutically active compositions and their methods of use
    US9901572B2|2018-02-27|Aryl dihydropyridinones and piperidinone MGAT2 inhibitors
    JP4736043B2|2011-07-27|Nitrogen-containing heterocyclic derivatives and drugs containing them as active ingredients
    EP0542059B1|1996-03-20|Substituted biphenylpyridinones as angiotensin II antagonists
    JP2018021072A|2018-02-08|Therapeutically active compounds and their methods of use
    CN100496490C|2009-06-10|Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-II receptor blockers for the treatment of cardiovascular diseases
    US5650424A|1997-07-22|Cyclic urea derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
    KR100322319B1|2002-06-26|Cyclic derivatives and pharmaceutical compositions containing them
    US20170057994A1|2017-03-02|Therapeutically active compounds and their methods of use
    EP1757582B1|2015-12-30|Arylalkylamines and process for production thereof
    EP1445253B1|2009-08-05|4,4-difluoro-1, 2, 3, 4-tetrahydro-5h-1-benzazepine derivatives or salts thereof
    DE60300021T2|2005-09-08|que-
    US5880284A|1999-03-09|Cyclic urea derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
    RU2073676C1|1997-02-20|5-fluoro-2-{[|methyl]sulfinyl}-1h-benzimidazole or its physiologically acceptable salt, pharmcomposition based on thereof and intermediate compounds
    DE69912379T2|2004-05-06|Antithrombotic agents
    AU660930B2|1995-07-13|-2-ethoxy-4-|-3-methyl-1- butyl)aminocarbonylmethyl)benzoic acid
    EP1587795B1|2009-05-13|N- | ethyl) -1-piperidincarboxamid-derivatives and related compounds use as cgrp-antagonists for treating a headache
    JP4939401B2|2012-05-23|Imidazole derivatives used as TAFIa inhibitors
    DK171349B1|1996-09-16|Tetrahydronaphthalane derivatives, process for their preparation, medicaments containing the compounds and use of the compounds for the manufacture of medicaments
    RU2257381C2|2005-07-27|Diazepane derivative, pharmaceutical composition comprising thereof and inhibitor of blood coagulation activated factor x
    DK2686310T3|2018-02-26|Benzodioxan-INHIBITORERAFLEUKOTRIEN PRODUCTION
    TWI426070B|2014-02-11|Piperidine/piperazine derivatives
    JP5424256B2|2014-02-26|Derivatives of azabicyclooctane, process for producing the same and use thereof as inhibitors of dipeptidyl peptidase IV
    EP1095025B1|2002-12-11|Benzimidazoles, production thereof and use thereof as medicaments
    JP4053597B2|2008-02-27|Substituted N-[| phenyl] propylamide
    同族专利:
    公开号 | 公开日
    SK144397A3|1998-05-06|
    NO974945D0|1997-10-24|
    CA2219337A1|1996-10-31|
    GR3036023T3|2001-09-28|
    HU9801228A2|1998-08-28|
    RU2167857C2|2001-05-27|
    DK824515T3|
    AT200277T|2001-04-15|
    CZ288764B6|2001-08-15|
    EE9700292A|1998-06-15|
    SK282232B6|2001-12-03|
    BR9608038A|1999-01-12|
    DE19515500A1|1996-10-31|
    HU9801228A3|1998-09-28|
    WO1996033970A1|1996-10-31|
    EP0824515A1|1998-02-25|
    MX9708021A|1998-03-31|
    EE03919B1|2002-12-16|
    ES2158309T3|2001-09-01|
    NO974945L|1997-10-24|
    JPH11504630A|1999-04-27|
    AU5500896A|1996-11-18|
    PL322969A1|1998-03-02|
    TR199701258T1|1998-03-21|
    PT824515E|2001-09-28|
    HU222050B1|2003-04-28|
    PL184276B1|2002-09-30|
    BG101983A|1998-04-30|
    US5958952A|1999-09-28|
    DK0824515T3|2001-07-09|
    NO309422B1|2001-01-29|
    NZ306451A|1999-05-28|
    EP0824515B1|2001-04-04|
    AU703946B2|1999-04-01|
    BG63385B1|2001-12-31|
    CZ340697A3|1998-04-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-04-27|Priority to DE19515500.9
    1995-04-27|Priority to DE19515500A
    1996-04-18|Application filed by 슈노렌베르크, 닥터칼토매게엠베하
    1999-01-25|Publication of KR19990008011A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19515500.9|1995-04-27|
    DE19515500A|DE19515500A1|1995-04-27|1995-04-27|Substituted phenylamidines, pharmaceutical compositions containing these compounds and processes for their preparation|
    [返回顶部]