CN1125051C - Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors - Google Patents
Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors Download PDFInfo
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- CN1125051C CN1125051C CN98812495A CN98812495A CN1125051C CN 1125051 C CN1125051 C CN 1125051C CN 98812495 A CN98812495 A CN 98812495A CN 98812495 A CN98812495 A CN 98812495A CN 1125051 C CN1125051 C CN 1125051C
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Abstract
Aminoguanidine and alkoxyguanidine compounds are described, including compounds of Formula (VII), wherein X is O or NR<9> and Het, R<1>, R<7>, R<8>, R<12>-R<15>, R<a>, R<b>, R<c>, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.
Description
The present invention relates to can be used as the new compound of proteolysis enzyme inhibitors, in particular to the new thrombin inhibitors of a class.
Proteolytic enzyme is can be at the enzyme of independent specific peptide bond place crack protein.Proteolytic enzyme can be divided into four classifications: serine protease, mercaptan or cysteinyl proteolytic enzyme, acidity or aspartyl proteolytic enzyme and metalloprotease (Cuypers etc., J.Biol.Chem.257:7086 (1982)).Proteolytic enzyme has various biological activitys, as digestion, formation and the dissolving to blood clot, to external cell and biological duplicating and immune response.The paraprotein hydrolysis is with human relevant with other mammiferous multiple disease.Human neutrophils proteolytic enzyme, elastoser and cathepsin G have shown can cause the disease for sign with disorganization.These diseases comprise: pulmonary emphysema, rheumatoid arthritis, keratohelcosis and glomerulonephritis (Barret, as the enzyme inhibitors of medicine, Sandler, ed., University Park Press, Baltimore, (1980)).Other proteolytic enzyme such as Tryptase, C-1 esterase, C-3 saccharase, urokinase, Profibrinolysin activator, acrosin and kallikrein are all playing an important role aspect the mammiferous normal physiological function.In many cases, when Mammals was treated, it was useful that the function of one or more proteases is destroyed.
Serine protease comprises such as elastoser (human leukocytes), cathepsin G, Tryptase, C-1 esterase, C-3 saccharase, urokinase, Profibrinolysin activator, acrosin, Quimotrase, trypsinase, zymoplasm, factor Xa and kallikrein.
The leukocyte elastase of human body is discharged in the inflammation site by polymorphonuclear leukocyte, thereby is the reason of many kinds of diseases.Cathepsin G is another kind of human body neutrophilia serine protease.The compound expection that can suppress these enzymic activitys can have antiphlogistic effects, can be used to treat gout, rheumatoid arthritis and other inflammatory diseases, and is used for treating pulmonary emphysema.Quimotrase and trypsinase are digestive ferment.The inhibitor of these enzymes can be used to treat pancreatitis.The inhibitor of urokinase and Profibrinolysin activator can be used to treat excessive cell growth property disease, as benign prostatauxe, prostate cancer and psoriasis.
Serine proteinases thrombin has vital role in hemostasis and thrombosis, and, as a kind of multifunctional protein, thrombocyte, endotheliocyte, smooth muscle cell, white corpuscle, heart and neurone are had very big effect.The activation of the coagulation cascade by endogenous approach (contact activation) or exogenous route (by blood plasma being placed non-inner skin surface, infringement tube wall or tissue factor discharge activation) causes a series of biological chemistry incidents that concentrate on zymoplasm.Zymoplasm cracking Fibrinogen finally causes hemostasis to stop up (grumeleuse formation), the decomposition of protein cracking of the uniqueness by the cell surface thrombin receptor and activated blood platelet (Coughlin effectively, Seminars inHematology 31 (4): 270-277 (1994)), amplify the production of himself automatically by feedback mechanism.Therefore, the zymoplasm depressant of functions has result of treatment to cardiovascular and host non-cardiovascular disease.
Factor Xa is another kind of serine protease in coagulation cascade.Factor Xa is relevant with factor Va and calcium on immobilized artificial membrane, thereby forms the prothrombinase title complex.Thereby this prothrombinase title complex can change into thrombogen zymoplasm (Claeson, blood coagulation and fibrinolysis 5:411-436 (1994); Harker, blood coagulation and fibrinolysis 5 (Suppl 1): S47-S58 (1994)).The inhibitor of factor Xa is considered to the reagent of direct Trombin inhibiting is had more advantage, its reason is, directly thrombin inhibitors still allow a large amount of new thrombin generation (Lefkovits and Topol, Circulation 90 (3): 1522-1536 (1994); Harker, blood coagulation and fibrinolysis 5 (Suppl 1): S47-S58 (1994)).
At present, reported in-vivo diagnostic formation method for thrombus in the blood vessel.These formation methods adopt the compound by radioactive atom or paramagnetic atom detectable label.For example, the thrombocyte with gamma ray radiator In-111 mark can be used as preparation (Thakur, M.L. etc., the Thromb R that detects thrombus
eS.9:345 (1976); Powers etc., neurological 32:938 (1982)).Also the someone proposes to use the thrombolytic enzyme streptokinase of Tc-99m mark as preparation (Wong, U.S. patent 4,418,052 (1983)).Having proposed a kind of material as preparation already is the fibrin binding domain by a-protein deutero-streptococcus aureus (Pang, U.S. patent 5,011,686 (1991)) of using gamma ray radiator I-125 and I-131 mark.To scleroproein have specificity (opposite) with Fibrinogen and with the Tc-99m mark monoclonal antibody also the someone propose to be used as preparation (Berger etc., U.S. patent 5,024,829 (1991); Dean etc., U.S. patent 4,980,148 (1990)).The somebody proposes, and uses paramagnetic contrast agent (diethylenetriamine pentaacetic acid gadolinium (De Roos, A. etc., Int.J.Card.Imaging 7:133 (1991)) in patient's mr of Acute Myocardial Infarction being carried out thrombolytic treatment.The somebody proposes to adopt the alpha-ketoamide derivative of radio-labeled and spin labeling as thrombus imaging agent (Abelman etc., U.S. patent 5,656,600).
Edwards etc., J.A mer.Chem.Soc.114:1854-63 (1992) has described peptidyl site (P-site) α-ketone group benzoxazole, and it reversibly suppresses serine protease human leukocyte elastase and pig pancreas elastoser.
EP 363 284 has described the analogue of peptase zymolyte, and wherein, the nitrogen-atoms of the scissile amide group of peptide substrate is replaced by the carbonyl moiety of hydrogen or replacement.
Australian Patent publication number 86245677 has also been described peptidase inhibitors, and it has the electric ketone part of activatory parent, as fluorine methylene radical ketone or α-ketone group carboxy derivatives.
Brown etc., J.Med.Chem.37:1259-1261 (1994) has described the human leukocyte elastatinal of the non-peptide class of Orally active, and it comprises trifluorumethylketone and pyridone part.
H.Mack etc., J Enzyme Inhibition, 9:73-86 (1995) have described rigidity amidino groups phenylaniline thrombin inhibitors, and it comprises the pyridone part as division center.
WO 97/01338 has described the pyridinone compounds with following formula:
Wherein, W is R
1, R
1OCO, R
1CO, R
1SO
2Or (R
1)
m(CH
2)
nNH
qCO;
R
1Be R
2(CH
2)
n, (R
2) (OR
2) CH (CH
2)
p, (R
2)
2CH (CH
2)
nAnd R
2O (CH
2)
p
R
2Be hydrogen, replacement or unsubstituted phenyl, naphthyl, xenyl, list or bicyclic heterocycles base, COOR
6, C
1-4The alkyl of straight or branched, C
3-7Cycloalkyl or C
7-12Bicyclic alkyl; R
3Be hydrogen, C
1-4The alkyl of straight or branched, C
3-7Cycloalkyl or trifluoromethyl;
A is an one of the following:
Wherein, y is hydrogen, hydroxyl or CN; And R
6Be hydrogen or C
1-4The alkyl of straight or branched.WO97/30708 discloses the pyridone with following general formula:
This compound can be used for Trombin inhibiting and relevant thrombotic closure.WO96/18644 has described the compound that has with following formula:
Wherein Het is selected from:
With
R
3Be selected from:
With
It is a kind of specific coagulation enzyme inhibitors that this compound is described to.
People still place hope on to find and can be used as effectively and the non-peptide compound of proteinase inhibitor optionally, compare with the proteinase inhibitor of present employing, and this compound should have bigger bioavailability and side effect still less.Thereby the feature of new effective protein proteins enzyme inhibitors should be: having effective inhibition ability and lower to mammalian toxicity, should be to the potential valuable therapeutical agent of various illnesss, comprises the water-disintegrable disease of the multiple mammalian proteins of treatment.
The present invention relates to new aminoguanidine and alkoxyl group guanidine compound with following formula VII.The present invention also provides the preparation method of formula VII compound.New compound of the present invention is effective protein proteins enzyme inhibitors, particularly trypsin-like serine protease, as Quimotrase, trypsinase, zymoplasm, Tryptase and factor Xa.Some compound exhibits go out through to zymoplasm directly and the antithrombotic activity that optionally suppresses, or are used to form the intermediate of the compound with anti-thrombosis activity.The present invention also provide suppress or the treatment Mammals in the proteoclastic method of abnormality, the method for the compound of the formula VII by giving significant quantity with treatment thrombosis, local asphyxia, apoplexy, restenosis or inflammation is provided.
The present invention includes the composition that is used to suppress the loss of Mammals thrombocyte, platelet aggregation formation, scleroproein formation and embolus formation, it comprises compound of the present invention and pharmaceutically acceptable carrier.These compositions optionally comprise antithrombotics, anti-platelet agents and thrombolytic agent.Said composition can be added in blood, blood products or the mammalian organs to realize required restraining effect.The present invention also provides and has suppressed or the proteoclastic method of treatment Mammals abnormality the treatment myocardial infarction; Unstable angina; Apoplexy; Restenosis; Degree of depth venous thrombosis; Condense in the propagated blood vessel that causes by wound, sepsis or metastases; Hemodialysis; Cardiopulmonary bypass surgery; Adult respiratory distress syndrome; Ulcerative colitis; Endotoxin shock; Rheumatoid arthritis; Scleroma; Shift; Hypercoagulability during the chemotherapy; Presenile dementia; The Tang Shi innate stupid disease; The intraocular scleroproein forms and trauma care.Other effect of The compounds of this invention is with acting on embedding or the physical connection antithrombotics to the material of the device that is used for blood collecting, blood circulation and blood storage, and described device is conduit, haemodialysis control unit, blood collection unit, syringe, blood collection tube, blood line or support.
The present invention also comprises the thrombosed method in minimizing Mammals surface, comprises described surface is covalently or non-covalently adhered to compound of the present invention.
On the other hand, the present invention includes the composition that is used for carrying out in the mammalian body thrombus imaging, it comprises compound of the present invention, and this compound can detect in the health outside.Preferred said composition comprises compound of the present invention and a kind of detectable marker, as radioactivity or paramagnetic atom.
On the other hand, the invention provides and be used at the diagnosis composition of Mammals to thrombus imaging, it comprises the compound of the present invention or the composition of pharmaceutically acceptable carrier and diagnosis significant quantity.
On the other hand, the present invention includes and be used in the method for Mammals to the thrombus in-vivo imaging.
Compound of the present invention comprises compound or its solvate, hydrate or the pharmacologically acceptable salt of following formula VII:
Wherein:
R
1Be alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl group, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl, each group all optionally is substituted;
Z is-SO
2-,-OCO-,-CO-,-NR
2CO-or covalent linkage,
Wherein, R
2Be hydrogen, alkyl, aralkyl, aryl, hydroxyl (C
2-10) alkyl, ammonia
Base (C
2-10) alkyl, alkyl monosubstituted amino (C
2-10) alkyl, dialkyl amido (C
2-10) alkane
Base or carboxyalkyl; Het is selected from:
With
R wherein
3, R
4And R
5Be hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl group independently of one another,
Replace or unsubstituted aryl, replacement or unsubstituted aralkyl, replacement or
Unsubstituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano group, nitre
Base, formamido group ,-CO
2R
x,-CH
2OR
xOr-OR
x,
Wherein, under each situation, R
xBe hydrogen, alkyl or cycloalkyl independently of one another, its
In, described alkyl or cycloalkyl has optionally that one or more are unsaturated
Key;
R
6Be hydrogen, alkyl, aralkyl, aryl, cyano group (C
2-10) alkyl, hydroxyl (C
2-10) alkyl, alkoxyl group (C
2-10) alkyl, list and dialkyl amido (C
2-10) alkyl or carboxyalkyl;
R
7Be hydrogen, C
1-4Alkyl or C
2-4Alkenyl;
R
8Be hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl group, alkyl monosubstituted amino (C
2-10) alkyl, dialkyl amido (C
2-10) alkyl or carboxyalkyl;
R
12, R
13, R
14And R
15Be hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl group, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl or carboxyalkyl independently of one another;
Perhaps R
12And R
13Lump together formation-(CH
2)
y-, wherein, y is 2-7, preferred 2-5, and R
14And R
15As preceding definition;
Perhaps R
14And R
15Lump together formation-(CH
2)
q-, wherein, q is 2-7, preferred 2-5, and R
12And R
13As preceding definition;
Perhaps R
12And R
14Lump together formation-(CH
2)
r-, wherein, r is 0 (singly-bound) or 1-7, preferred 0-4, and R
13And R
15As preceding definition;
X is oxygen or NR
9,
Wherein, R
9Be hydrogen, alkyl, cycloalkyl or aryl, wherein, described alkyl,
Cycloalkyl or aryl can be replaced by following radicals or not be substituted: amino, monoalkyl ammonia
Base, dialkyl amido, alkoxyl group, hydroxyl, carboxyl, alkoxy carbonyl, fragrant oxygen
Base carbonyl, aromatic alkoxy carbonyl, aryl, heteroaryl, acyl amino, cyano group or
Trifluoromethyl;
R
a, R
bAnd R
cBe hydrogen, alkyl, hydroxyl, alkoxyl group, aryloxy, aralkoxy, alkoxy-carbonyl oxy, cyano group or CO independently of one another
2R
w, wherein
R
wBe alkyl, cycloalkyl, phenyl, benzyl,
Or
Wherein, R
dAnd R
eBe hydrogen, C independently of one another
1-6Alkyl, C
2-6Alkenyl or phenyl,
R
fBe hydrogen, C
1-6Alkyl, C
2-6Alkenyl or phenyl, R
gBe hydrogen, C
1-6Alkyl, C
2-6
Alkenyl or phenyl, R
hBe aralkyl or C
1-6Alkyl;
N is 0-8; With
M is 0-6.
Preferred compound within the scope of the present invention comprises following formula VII compound, wherein, and R
1Be C
6-10Aryl (C
1-4) alkyl, C
6-10Aryl, C
4-7Cycloalkyl (C
1-4) alkyl, heterocyclic radical or heterocycle C
1-4Alkyl, wherein heterocycle is the individual N that is selected from of the saturated or undersaturated 1-3 of containing, heteroatomic 5-to the 7-unit's list of O and S or 9-to 10 yuan of bicyclic heterocycle.Above-mentioned R
1Any group can be replaced by following 1-5 preferred 1,2 or 3 group or not be substituted: hydroxyl, nitro, trifluoromethyl, halogen, C
1-6Alkyl, C
2-6Alkenyl, C
6-10Aryl, C
1-6Alkoxyl group, C
6-10Aryl (C
1-6) alkoxyl group, C
1-6Aminoalkyl group, C
1-6Aminoalkoxy, amino, list (C
1-4) alkylamino, two (C
1-4) alkylamino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Hydroxyalkyl, C
2-6Hydroxy alkoxy base, (C
1-6) alkoxyl group (C
2-6) alkoxyl group, list and two C
1-4Alkylamino (C
2-6) alkoxyl group, C
2-10Single (carboxyalkyl) is amino, two (C
2-10Carboxyalkyl) amino, C
6-14Aryl (C
1-6) alkoxy carbonyl, C
2-6Alkynyl group carbonyl, C
1-6Alkyl sulphonyl, C
2-6Alkenyl alkylsulfonyl, C
2-6Alkynyl group alkylsulfonyl, C
6-10Aryl sulfonyl, C
6-10Aryl (C
1-6) alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulfonyl amino, C
6-10Arenesulfonyl amino, C
6-10Virtue (C
1-6) alkyl sulfonyl amino, amidino groups, guanidine radicals, C
1-6Alkyl imino amino, formyl radical imino-amino, C
2-6Carboxyl alkoxyl group, C
2-6Carboxyalkyl, C
2-6Carboxyalkyl amino, cyano group, trifluoromethoxy or perfluor oxyethyl group.
Particularly preferred one group of compound that compound is following formula VII, wherein, R
1Be phenyl, benzyl, naphthyl, naphthyl methyl, pyridyl, pyridylmethyl, thienyl, thienyl methyl, quinolyl or quinolyl methyl; its 1,2 or 3 selectivity substituting group can being listed later on replaces or is not substituted; described substituting group is halogen particularly; as chlorine or fluorine, methoxyl group, methyl, trifluoromethyl, cyano group, nitro, methyl sulphonyl, amino or dimethylamino.
R
1Useful group comprises; for example, benzyl; luorobenzyl; the benzyl chloride base; the iodine benzyl; dichloro benzyl; bromobenzyl; trifluoromethyl benzyl; the methyl sulphonyl benzyl; two (trifluoromethyl) benzyl; methyl-benzyl; tertiary butyl benzyl; methoxy-benzyl; dimethoxy-benzyl; hydroxybenzyl; the carboxyl benzyl; aminobenzyl; the methylamino benzyl; the normal-butyl aminobenzyl; amidino benzyl; the guanidine radicals benzyl; formyl radical imino-aminobenzyl; the acetimidoyl aminobenzyl; the methoxycarbonyl benzyl; the ethoxy carbonyl benzyl; the carboxyl methoxy-benzyl; naphthyl methyl; the hydroxyl naphthyl methyl; cyclohexyl methyl; cyclopentyl-methyl; phenyl; chloro-phenyl-; iodophenyl; dichlorophenyl; bromophenyl; trifluoromethyl; the methyl sulphonyl phenyl; two (trifluoromethyl) phenyl; aminomethyl phenyl; tert-butyl-phenyl; p-methoxy-phenyl; Dimethoxyphenyl; hydroxy phenyl; carboxyl phenyl; aminophenyl; the methylamino phenyl; the normal-butyl aminophenyl; the amidino groups phenyl; guanidino phenyl; formyl radical imino-aminophenyl; the acetimidoyl aminophenyl; the methoxycarbonyl phenyl; the ethoxy carbonyl phenyl; the carboxyl p-methoxy-phenyl; naphthyl; the hydroxyl naphthyl; cyclohexyl and cyclopentyl.The R that other is useful
1Comprise pyridyl, thienyl, isoquinolyl, pyridylmethyl, isoquinolyl methyl, tetrahydric quinoline group and tetrahydroquinoline ylmethyl.
R
1More preferably comprise phenyl; the 2-chloro-phenyl-; the 3-chloro-phenyl-; the 4-chloro-phenyl-; the 4-bromophenyl; the 4-iodophenyl; the 4-p-methoxy-phenyl; the 4-aminomethyl phenyl; the 2-trifluoromethyl; the 4-trifluoromethyl; the 2-fluorophenyl; the 3-fluorophenyl; the 4-fluorophenyl; 3; the 4-dichlorophenyl; 3-chloro-4-fluorophenyl; 3; the 5-dichlorophenyl; the 2-aminomethyl phenyl; the 3-aminomethyl phenyl; the 4-ethylphenyl; 2-methyl sulphonyl phenyl; the 4-isopropyl phenyl; 3; the 4-Dimethoxyphenyl; 2; 4; the 6-trimethylphenyl; 2; the 5-3,5-dimethylphenyl; the 4-ethenylphenyl; 2-chloro-6 aminomethyl phenyls; 3-bromo-6-p-methoxy-phenyl; 3-chloro-2-aminomethyl phenyl; 2-chloro-5 trifluoromethyls; 2; the 4-dichlorophenyl; 2-butoxy-5-(1; the 1-dimethyl propyl) phenyl; the 3-nitrophenyl; 4-chloro-3-nitrophenyl; 4-methyl carbonylamino phenyl; the 4-tert-butyl-phenyl; the 3-cyano-phenyl; 4-methyl sulphonyl phenyl; pentafluorophenyl group; 2; the 5-dichlorophenyl; 2; the 4-Dimethoxyphenyl; 2-methyl-5-nitro phenyl; 3-chloro-2-cyano-benzene oxygen) phenyl; 2-chloro-4-fluorophenyl; 3-chloro-6-p-methoxy-phenyl; 2-methoxyl group-5-aminomethyl phenyl; the 4-phenyl; 2-propyl group butyl; 5-chloro-2-p-methoxy-phenyl; the 2-cyano-phenyl; 2-(N-hydroxyl) aminophenyl; 2-(4-xenyl methoxyl group) phenyl; 2-(3-xenyl methoxyl group) phenyl; benzyl; 2-(phenyl sulfonyl) phenyl; 2; 4-two (methyl sulphonyl) phenyl; 2-chloro-4-methyl sulphonyl phenyl; benzyl; 3-benzyl chloride base; the 3-trifluoromethyl benzyl; the 2-trifluoromethyl benzyl; 2-iodine benzyl; 2-benzyl chloride base; the 2-bromobenzyl; the 3-luorobenzyl; 4-benzyl chloride base; 2-chloro-6-luorobenzyl; the 2-luorobenzyl; 2; the 3-dichloro benzyl; 3; the 4-difluorobenzyl; 2; the 4-dichloro benzyl; 2; the 5-dichloro benzyl; 3; the 4-dichloro benzyl; the 2-methyl-benzyl; 5-chloro-2-methoxy-benzyl; 2-cyano group benzyl; 2-(4-xenyl methoxyl group) benzyl; 2-(3-xenyl methoxyl group) benzyl; 2-(phenyl sulfonyl) benzyl; 2,4-two (methyl sulphonyl) benzyl; 3-methyl sulphonyl benzyl; 2-chloro-4-methyl sulphonyl benzyl; the 1-naphthyl methyl; 2-naphthyl methyl and 2-naphthyl.
Other preferred R
1Comprise dansyl, thiophene-2-base, pyridine-2-base, 3-toluquinoline-1-base, 1-Methylimidazole-4-base, quinoline-5-base, quinoline-8-base, 6-bromonaphthalene-2-base, 6-chloronaphthalene-2-base, 5-chlorothiophene-2-base, 5-methyl-8-quinolyl, 8-quinolyl methyl, 5-methyl-8-quinolyl methyl, 4-benzo-2; 1; 3-thiadiazolyl group and 5-chloro-1,3-dimethyl-4-pyrazolyl.
Among the formula VII, R
2Preferably include hydrogen, C
1-6Alkyl, C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl, C
2-10Hydroxyalkyl, C
2-10Aminoalkyl group, C
2-7Carboxyalkyl, list (C
1-4Alkyl) amino (C
1-8) alkyl, two (C
1-4Alkyl) amino (C
1-8) alkyl.Suitable R
2Comprise: hydrogen, methyl, ethyl, propyl group, normal-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-amino-ethyl, 2-carboxyl methyl, 3-carboxy ethyl, 4-carboxyl propyl group and 2-(dimethylamino) ethyl, first-selected hydrogen.
Preferred Het group comprises:
With
Preferably compound is following those: wherein, and R
3, R
4And R
5Be hydrogen, C independently of one another
1-4Alkyl, C
3-7Cycloalkyl, C
6-14Aryl, particularly C
6-10Aryl, C
6-10Aryl (C
1-4) alkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano group, nitro, formamido group, carboxyl, alkoxy carbonyl, carboxyl methyl, alkoxy carbonyl methyl or cyclo alkoxy carbonyl.
Useful R
3, R
4And R
5Comprise: hydrogen, methyl, ethyl, propyl group, chlorine, bromine, trifluoromethyl, hydroxymethyl, methoxyl group, oxyethyl group, formamido group, nitro, phenyl, cyclopropyl, hydroxyl, sec.-propyl, methoxycarbonyl, ethoxy carbonyl and benzyl.
Preferred R
3And R
4Comprise: hydrogen, C
1-2Alkyl and C
2-6Alkenyl.R
3And R
4First-selected hydrogen.
Preferred R
5Comprise: hydrogen, halogen, C
1-5Alkyl, C
3-6Alkenyl, C
3-5Cycloalkyl, trifluoromethyl and C
1-4Alkoxyl group, more preferably C
1-4Alkyl is as methyl, ethyl, propyl group or sec.-propyl.
Work as R
3And R
4When being independently from each other hydrogen or methyl, particularly preferred Het is:
Wherein, R
5Be selected from hydrogen, methyl, ethyl, propenyl, allyl group, propyl group, sec.-propyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl-, 1-amyl group, R-2-amyl group, S-2-amyl group, 3-amyl group, S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl, R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrryl, 3-pyrryl, 1-hexyl, S-2-hexyl, R-2-hexyl, R-3-hexyl and S-3-hexyl.Particularly preferred Het is R
5Be hydrogen, methyl, ethyl, propyl group or sec.-propyl.
Z preferably includes :-SO
2-and covalent linkage.
R
7Be preferably hydrogen.
Preferred compound is following formula VII compound, wherein, and R
8Be hydrogen, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl.
When X is NR
9The time, preferred compound is following compound, wherein, and R
9Be hydrogen or C
1-6Alkyl; can be replaced by following radicals 1,2 or 3 or not be substituted; preferably replaced by 1 substituting group, described substituting group is amino, alkyl monosubstituted amino, dialkyl amido, alkoxyl group, hydroxyl, alkoxy carbonyl, aryloxycarbonyl, aromatic alkoxy carbonyl, carbalkoxy, phenyl, cyano group, trifluoromethyl, acetylamino, pyridyl, thienyl, furyl, pyrryl or imidazolyl.
Suitable R
9Comprise: hydrogen, methyl, ethyl, propyl group, normal-butyl, benzyl, styroyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxyl methyl and carboxy ethyl.X is an oxygen in the first-selected compound.
Preferred compound is following formula VII compound, wherein, and R
12, R
13, R
14And R
15Be hydrogen, C independently of one another
1-6Alkyl, C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl, C
2-10Hydroxyalkyl or C
2-7Carboxyalkyl.Useful R
12, R
13, R
14And R
15Comprise: hydrogen, methyl, ethyl, propyl group, normal-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-carboxyl methyl, 3-carboxy ethyl and 4-carboxyl propyl group.Other preferred compound is following compound, wherein, and R
12And R
13Lump together formation-(CH
2)
y-, wherein, y is 2.
Among the formula VII, preferred R
a, R
bAnd R
cBe hydrogen, hydroxyl, C independently of one another
1-6Alkyl, C
1-6Alkoxyl group, cyano group or-CO
2R
w, wherein, under each situation, R
wBe preferably C
1-4Alkyl, C
4-7Cycloalkyl or benzyloxycarbonyl.Suitable R
a, R
bAnd R
cComprise: hydrogen, methyl, ethyl, propyl group, normal-butyl, hydroxyl, methoxyl group, oxyethyl group, cyano group ,-CO
2CH
3,-CO
2CH
2CH
3With-CO
2CH
2CH
2CH
3In the most preferred embodiment, R
a, R
bAnd R
cBe hydrogen.
Same preferred R
a, R
bAnd R
cBe group-CO
2R
w, wherein, R
wBe one of the following
Or
Wherein, R
d-R
hAs preceding definition.Work as R
a, R
bAnd R
cFor-CO
2R
w, wherein, R
wDuring for one of these parts, the compound of formation is the prodrug with required prescription and bioavailability feature.Preferred R
d, R
eAnd R
gBe hydrogen, R
fBe methyl, preferred R
hComprise: the benzyl and the tertiary butyl.
N is preferably 0-6 among the formula VII, more preferably 0-4, first-selected 0,1 or 2.
The preferred 0-4 of m, first-selected 0,1 or 2.
In most preferred, m and n are 0.
According to particularly preferred aspect, the invention provides following formula VII compound, wherein, Z is-SO
2-, R
1For replacing or unsubstituted aryl or aralkyl, Het is
X is O, R
8Be hydrogen, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl, R
a, R
bAnd R
cBe hydrogen.More preferred aspect relates to following compound, wherein, and R
1For replacing or unsubstituted benzyl or phenyl, X is O, R
8Be hydrogen, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl, R
a, R
bAnd R
cBe hydrogen.
One group of preferred compound or its solvate, hydrate or pharmacologically acceptable salt have formula VIII:
Wherein
Z ' is-OCO-,-CO-,-SO
2-,-NHCO-or covalent linkage;
R
21Be R
22(CH
2)
k, wherein, k is 0-4, (R
22) (OR
22) CH (CH
2)
p, wherein, p is 1-4, (R
22)
2CH (CH
2)
k, wherein, k is 0-4 and R
22Can be identical or different, wherein, (R
22)
2Also can be a ring substituents on CH, by C
3-7Cycloalkyl, C
7-12Dialkyl group or 5-7 unit's monocycle or 9-10 unit bicyclic heterocycle, it can be saturated or undersaturated, and it comprises 1-3 heteroatoms that is selected from N, O and S, expression; And R
22O (CH
2)
p, wherein, p is 1-4;
R
22Be hydrogen; Phenyl can be replaced by following one or more substituting groups or not be substituted: C
1-4Alkyl, C
1-4Alkoxyl group, halogen, trifluoromethyl, hydroxyl, COOH or CONH
2Naphthyl; Xenyl; 5-7 unit's monocycle or 9-10 unit bicyclic heterocycle, it can be saturated or undersaturated, and it comprises 1-3 heteroatoms that is selected from N, O and S; C
1-4Alkyl; C
3-7Cycloalkyl or C
7-12Bicyclic alkyl;
R
25Be hydrogen; C
1-4Alkyl; C
3-7Cycloalkyl or trifluoromethyl;
Or
Wherein, R
dAnd R
cBe hydrogen, C independently of one another
1-6Alkyl, C
2-6Alkenyl or phenyl, R
fBe hydrogen, C
1-6Alkyl, C
1-6Alkenyl or phenyl, R
gBe hydrogen, C
1-6Alkyl, C
2-6Alkenyl or phenyl, R
hBe aralkyl or C
1-6Alkyl;
R
32, R
33, R
34And R
35Be hydrogen, C independently of one another
1-6Alkyl, C
2-10Carboxyalkyl or C
2-10Hydroxyalkyl, perhaps R
32And R
33Lump together formation-(CH
2)
y-, wherein, y is 2-5, and R
34And R
35As preceding definition; Or R
34And R
35Lump together formation-(CH
2)
q-, wherein, q is 2-5, and R
32And R
33As preceding definition; Or R
32And R
34Lump together formation-(CH
2)
h-, wherein, r is 0 (singly-bound) or 1-4, and R
33And R
35As preceding definition;
R
28Be hydrogen, C
1-4Alkyl or C
6-10Aryl (C
1-4) alkyl; X ' is O;
N is 0-4; With
M is 0-2.
Useful compound is following compound, wherein, Z ' be covalent linkage or-SO
2-.Further useful compound is following compound, wherein, and R
21Be R
22(CH
2)
k, (R
22)
2CH (CH
2)
k, phenyl or (phenyl)
2-CH.
Another kind of useful compound is following compound, wherein, and R
25Be C
1-4Alkyl, particularly R
25Be methyl, ethyl, propyl group or sec.-propyl.
Another kind of useful compound is following compound, wherein, and R
28Be hydrogen or C
1-4Alkyl and X ' are O.
The illustrative structure of compound within the scope of the present invention and pharmacologically acceptable salt example hydrochloric acid salt and acetate comprises following:
The example of concrete new compound within the scope of the present invention comprises:
3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-benzyl sulfuryl amino-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(carbobenzoxy-(Cbz)) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(1-(1-guanidine radicals oxygen ylmethyl) cyclopropyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(4-guanidine radicals oxygen base) piperidino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-trifluoromethyl benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-trifluoromethyl benzyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-iodine benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-bromobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-chloro-6-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,3-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,4-difluorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,5-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(1-naphthyl methyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-naphthyl methyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-methyl-benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-benzyl chloride base alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,4-dichloro benzyl alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-methyl sulphonyl phenyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-naphthyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-bromophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-iodophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,4-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-chloro-4-fluorophenyl alkylsulfonyl) amino-6-methyl-[1-(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-isopropyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,5-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3,4-Dimethoxyphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-thienyl sulphonyl base) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(1-naphthyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,4,6-trimethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,5-3,5-dimethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-chloro-6-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-bromo-6-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-chloro-2-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-chloro-5-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,4 dichloro benzene base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-ethenylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-butoxy-5-(1, the 1-dimethyl propyl) phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-chloro-3-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-methyl carbonylamino phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-tert-butyl-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-cyano-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-methyl sulphonyl phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-dansyl amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(pentafluorophenyl group alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,5-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-two (4-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,5-Dimethoxyphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-propyl group phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-methyl-5-nitro phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2,3-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-Trifluoromethoxyphen-l alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-(3-chloro-2-cyano-benzene oxygen) phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-chloro-4-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-chloro-6-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-methoxyl group-5-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(5-chlorothiophene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(6-chloronaphthalene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(6-bromonaphthalene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-bromophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(quinoline-8-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(quinoline-5-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(1-Methylimidazole-4-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-toluquinoline-8-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(2-pyridyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-pyridyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(4-ethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl)-N-methylamino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-ethyl-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-propyl group-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N "-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N "-ethyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N "-benzyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-N " butyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N-methoxycarbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N, N ', N " the trimethoxy carbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N, N '-dimethoxycarbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone; With
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N-ethoxycarbonyl) guanidine radicals oxygen base ethyl] amino carbonyl methyl]-the 2-pyridone.
Be appreciated that to the present invention includes steric isomer and optically active isomer, for example mixture of enantiomorph and one enantiomorph and diastereomer, they be since in the compound that the present invention selectes the asymmetry of structure cause.
The compound of formula VII also can be by solvation, particularly by aquation.Aquation can occur in compound or comprise in the production process of described compound compositions, and perhaps, aquation may be because the water absorbability that compound had takes place.
Some compound among the formula VII is the derivative that is referred to as prodrug.Term " prodrug " is meant the derivative of known direct acting medicine, compares with medicine, and described derivative has the transmission characteristics of enhancing and therapeutic value, and changes into active medicine by the zymochemistry process.Useful prodrug is those wherein R
a, R
bAnd/or R
cFor-CO
2R
wCompound, R
wAs preceding definition, referring to US patent 5,466,811, and Saulnier etc., Bioorg.Med.chem.Lett.4:1985-1990 (1994).
When any variable group in any composition or formula VII takes place to surpass one time, irrelevant with definition under other situation to it to the definition of each situation.Equally, the combination of substituting group and/or variable group only allows when this combination causes stable compound.
On the other hand, the present invention includes the composition that is used for Mammals is carried out the thrombus in vivo imaging, said composition comprise of the present invention those can be at the detected compound of external sight.Preferred compositions comprises compound of the present invention and detectable marker, as radioactive atom or paramagnetic atom.
On the other hand, the present invention includes the method that is used for thrombus imaging in mammalian body.
According to preferred aspect, useful compound is those R
1Substituting group is with detectable marker such as radioiodine atom such as I-125, I-131 or compound that I-123 is replaced.Under this kind situation, R
1Be preferably phenyl, have to I-123, to I-125 or to the I-131 substituting group, or benzyl, it has an I-123, an I-125 or-131 substituting group.
Detectable marker also can be radioactivity Chinese blister beetle compound or paramagnetism inner complex, wherein, and suitable part (L) and R
1Substituting group links to each other, and can directly connect, and perhaps passes through divalent linker A " connect, perhaps, and in formula VII, group-A " L substituted radical-Z-R
1Suitable part is meant can chelating radiation metal ion or the organic moiety of paramagnetic metal ion.
In these compounds, divalent linker A " comprise can with the group of free ammonia group covalent bonding and chelating.For example, A " can be-C (=S)-,-C (=O)-,-C (=NH)-(CH
2)
6-C (=NH)-,-C (=O)-(CH
2)
6-C (=O)-,
Equally, in the compound that formula VII shows, chelating ligand L comprise can covalent bonding or non covalent bond be bonded to group on radioactive atom or the paramagnetic atom.Chelating is meant and comprises that those routines are used to cooperate the group of radioactive atom or paramagnetic atom.Chelating is meant and comprises 3-12, preferred 3-8 methylene phosphate group, methylene radical hydroxamic acid group, carboxyl ethylidene group, and perhaps carboxyl methylene group particularly, they link to each other with nitrogen-atoms.If acidic group only 1 or 2 links to each other with nitrogen-atoms, the ethylidene that those described nitrogen replace by selectivity or link to each other with the nitrogen-atoms that another has this group by 4 ethylidene unit that separated by nitrogen or oxygen or sulphur atom at the most.Preferably finishing agent (completing means) is diethylidene three imines-N, N, N ', N ", N " pentaacetic acid (DTPA).DTPA is the sequestrant to radioactive atom indium-111 (I positive 111), technetium-99m (Tc-99m) and paramagnetic atom gadolinium (Gd) as known in the art, Khaw etc., Science209:295 (1980); Paik C.H. etc., US patent 4,652,440 (1987); Gries, H etc., US patent 4,957,939 (1990).Preferred chelating ligand L is 1-(PAB)-diethylene triaminepentaacetic acid(DTPA).Sequestrant also comprises the compound that comprises sulfydryl or amine moiety, and its sum is at least 4 in any component.These sulfydryls or amine moiety are opened by at least two atom separates that can be carbon, nitrogen, oxygen or sulphur each other.Particularly preferred sequestrant L is a metallothionein(MT), and it is the sequestrant to Tc-99m as known in the art.
Term " alkyl " as self or an another kind of group part is meant straight chain and the branched group that has 12 carbon atoms at the most herein, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl.
Term " alkenyl " is meant the straight or branched group with 2-20 carbon atom herein, unless chain length is limited, it includes but not limited to vinyl, 1-propenyl, 2-propenyl, 2-methyl isophthalic acid-propenyl, 1-butylene base, crotyl etc.The alkenyl that preferably has 2-10 carbon atom, the more preferably alkenyl of 2-8 carbon atom, the alkenyl of a first-selected 2-4 carbon atom.
Term " alkynyl group " is meant the straight or branched group with 2-20 carbon atom herein, unless chain length is limited, wherein at least one triple bond is before two carbon atoms of chain, and it includes but not limited to ethynyl, 1-proyl, 2-propynyl etc.The alkynyl group that preferably has 2-10 carbon atom, the more preferably alkynyl group of 2-8 carbon atom, the alkynyl group of a first-selected 2-4 carbon atom.
All alkenyls or alkynyl group part as substituent situation under, unsaturated link(age) is that ethylene linkage or acetylene bond preferably directly do not link to each other with nitrogen, oxygen or sulphur.
Term " alkoxyl group " is meant that the straight or branched group of 1-20 carbon atom links to each other with Sauerstoffatom herein, unless chain length is limited, it includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy etc.Preferred alkoxyl group has 1-10 carbon atom, more preferably has 1-8 carbon atom.
Term " aryl " as self or an another kind of group part is meant monocycle or the bicyclic radicals that comprises 6-12 carbon atom in loop section herein, preferably has 6-10 carbon atom on loop section, as phenyl, naphthyl or tetralyl.
Term " heteroaryl " is meant the group with 5-14 annular atoms herein; 6,10 or 14 πDian Zis are shared the ring arrangement; And comprise 1,2 or 3 oxygen, (example of heteroaryl is: thienyl for nitrogen or sulfur heteroatom, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuran-base benzoxazolyl, benzopyranyl, oxa-anthryl; phenoxazinyl, the 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolinyl, pseudoindoyl, the 3H-indyl, indyl, indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolyl, the cinnolines base, pteridyl, 4 α H-carbazyls, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, the phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl isoxazolyl, the furazan base is with phenoxazinyl).
Term " aralkyl " as self or an another kind of group part is meant the foregoing C with aryl substituent herein
1-6Alkyl is as benzyl, styroyl or 2-naphthyl methyl.
Term " cycloalkyl " as self or an another kind of group part is meant the cycloalkyl that comprises 3-9 carbon atom herein.Its representative instance is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group and ring nonyl.
Term " C
1-7Bicyclic alkyl " be meant and comprise two ring [2.2.1] heptyl (norborneol alkyl), two ring [2.2.2] octyl groups, 1,1,3-trimethylammonium two ring [2.2.1] heptyl (bornyl) etc.
Term " alkoxyl group " is meant above-mentioned any alkyl that links to each other with a Sauerstoffatom.
Term term " halogen " as self or an another kind of group part is meant chlorine, bromine, fluorine or iodine herein, preferred chlorine.
Term " monoalkylamine " as self or an another kind of group part is meant the amino that is replaced by the alkyl of a 1-6 carbon atom herein.
Term " dialkylamine " as self or an another kind of group part is meant the amino that is replaced by two alkyl herein, and each alkyl has 1-6 carbon atom.
Term " hydroxyalkyl " is meant above-mentioned any alkyl that is replaced by one or more hydroxyls herein.
Term " carboxyalkyl " is meant by above-mentioned any alkyl of one or more carboxyl substituted herein.
Term " heterocyclic radical " shows stable 5 to 7 yuan of lists or two ring or 7 to 10 yuan of stable bicyclic heterocycles systems except specified herein, any ring can be saturated or undersaturated, ring is formed and is contained 1-3 heteroatoms that is selected from N, O and S by carbon atom, wherein, nitrogen and sulfur heteroatom are optionally oxidized, and nitrogen heteroatom comprises any wherein above-mentioned heterocycle and phenyl ring condensed bicyclic groups optionally by quaternized.Useful especially is the ring that comprises an oxygen or sulphur atom, a 1-3 nitrogen-atoms, and perhaps 1 oxygen or sulphur atom are in conjunction with 1 or 2 nitrogen-atoms.Heterocycle can link to each other at any heteroatoms or carbon atom place that causes producing rock steady structure.The example of this heterocyclic group comprises piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepines base, the azepines base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzothienyl, the parathiazan base, parathiazan base sulfone, parathiazan base sulfoxide is with the oxadiazole base.
Term " heteroatoms " is meant Sauerstoffatom (" O "), sulphur atom (" S ") or nitrogen-atoms (" N ") herein.Be appreciated that when heteroatoms was nitrogen, it can form NR
aR
bPart, wherein, R
aAnd R
bBe hydrogen or C independently of one another
1-C
8-alkyl, or coupled nitrogen-atoms forms saturated or undersaturated 5,6 or 7 yuan of rings together.
Reaction scheme 1 and 2 shows the synthetic route of The compounds of this invention, wherein, and R
1-Z-is R
1-SO
2-.
Wherein, R
12-R
15, R
aR
bR
c, n and m be all as preceding definition.
In reaction scheme 1, amino alcohol 1 adopts the amino protecting group such as the carbobenzoxy-(Cbz) (Cbz) of standard to protect to obtain compound 2.Adopt Mitsunobu couling process (Mitsunobu, O., Synthesis, 1 (1981)) that the amino alcohol of protecting 2 is coupled to and obtain compound 3 on the N-hydroxyphthalimide.Preferred coupling condition comprises: adopt solvent, as tetrahydrofuran (THF) or methylene dichloride; Adopt the azodicarbonic acid dialkyl, as the azodicarbonic acid diethyl ester.Adopt standard conditions commonly known in the art to remove the phthalic imidine protecting group to form alkoxylamine 4 (Greene; T.W.; Wuts, P.G.W., Protecting Groups in Organicsynthesis; the 2nd edition; John Wiley and Sons, Inc.New, York; (1991)), described standard conditions methylamine or the hydrazine in suitable solvent such as ethanol or Virahol for example.Adopt the guanidine radicals reagent such as the N that replace, N-two (tertbutyloxycarbonyl)-S-methylthiourea (Bergeron, R.J. and McManis, J.S, J.Org.Chem., 52:1700 (1987) or N-R
a, N-R
b, B-R
c-1H-pyrazoles-1-carbonamidine (Bernatowicz, M.S. etc., Tetrahedron LetteR
34: 3389 (1993)) alkylamine 4 guanidine radicals that form are changed into 5.Adopt standard procedure commonly known in the art (Greene, T.W., Wuts; P.G.W.; Protecting Groups inOrganic synthesis, the 2nd edition, John Wiley and Sons; Inc.New; York, (1991)), as palladium/charcoal; in the methyl alcohol or ethanolic soln of The suitable solvent such as chloroform, make the group deprotection of amido protecting obtain intermediate 6.In some cases, preferred acid, the example hydrochloric acid of adding.Reaction scheme 2
Wherein, R
1, R
3-R
5, R
12-R
15, R
8, R
a, R
b, R
c, n and m such as preceding definition.
In reaction scheme 2,2 hydroxy pyrimidine formic acid 7 reacts in The suitable solvent such as diox with diphenyl phosphoryl azide (DPPA), triethylamine and benzylalcohol, and amino pyridone 8 has been protected.With the glycine Equivalent such as the monobromo-acetic acid tert-butyl ester it is carried out alkylation, adopt alkali such as hexamethyl two silicon lithium nitrides, Strontium carbonate powder or sodium hydride, in The suitable solvent, as tetrahydrofuran (THF) or N, dinethylformamide obtains compound 9.Then, adopt standard conditions commonly known in the art (Greene, T.W., Wuts, P.G.W., Protecting Groupsin Organic synthesis, the 2nd edition, John Wiley and Sons, Inc.New, York, (1991)), as the ethyl acetate solution of hydrogenchloride or the dichloromethane solution of trifluoroacetic acid the tertiary butyl is removed, obtained acid 10.Adopt peptide coupler such as the castro ' s reagent (BOP) or the PyBOP of standard again, adopt alkali as at suitable solvent such as N, the diisopropyl ethyl amine in the dinethylformamide is coupled to intermediate 6 with acid, produces compound 14.Adopt catalyzer such as palladium/charcoal, in solvent such as tetrahydrofuran (THF) and ethanol, the Cbz group is removed through hydrogenation.Amine 15 usefulness SULPHURYL CHLORIDE are handled in The suitable solvent such as methylene dichloride in the presence of alkali such as 4-methylmorpholine, obtain compound 16.
Perhaps, the process that adopts standard makes the Cbz group deprotection of compound 9 as in the presence of catalyzer such as palladium/charcoal in The suitable solvent such as tetrahydrofuran (THF) and ethanol.Amine 11 and SULPHURYL CHLORIDE are reacted in The suitable solvent such as methylene dichloride and are obtained 12 in the presence of alkali such as 4-methylmorpholine.Adopt standard procedure (Greene commonly known in the art, T.W., Wuts, P.G.W., Protecting Groups in Organic synthesis, the 2nd edition, John Wiley and Sons, In c.New, York, (1991)), the tertiary butyl is removed, obtained acid 13 as the ethyl acetate solution of hydrogenchloride or the dichloromethane solution of trifluoroacetic acid.Adopt peptide coupler such as the castro ' s reagent (BOP) or the PyBOP of standard again, adopt alkali as at suitable solvent such as N, the diisopropyl ethyl amine in the dinethylformamide is coupled to intermediate 6 with acid 13, generation compound 16.Adopt standard procedure optionally to remove R
a, R
bAnd R
cWork as R
aAnd R
bBe tertbutyloxycarbonyl (Boc) and R
cDuring for hydrogen, the Boc group can be removed by handling in The suitable solvent such as methylene dichloride Huo diox as trifluoroacetic acid or hydrochloric acid with acid, obtains compound 17.Then, in the presence of alkali such as sodium bicarbonate,, in N '-dimethyl formamide, with compound 17 alkylations, obtain compound 18 with alkylogen at The suitable solvent such as N.Reaction scheme 3
Wherein, R
3, R
5, R
12-R
15, R
a, R
b, R
c, n and m such as preceding definition, Ar is an aryl.
In reaction scheme 3, in the presence of alkali such as sodium ethylate, in The suitable solvent such as ethanol, handle ethoxy methylene diethyl malonate 19, the pyrimidine 21 that obtains replacing with amidine 20.With the glycine Equivalent such as the monobromo-acetic acid tert-butyl ester it is carried out alkylation, adopt alkali such as tetrabutyl ammonium fluoride, hexamethyl two silicon lithium nitride or sodium hydrides, in The suitable solvent, as tetrahydrofuran (THF) or N, dinethylformamide obtains ester 22.Ester is hydrolyzed in The suitable solvent such as methyl alcohol or ethanol with lithium hydroxide or sodium hydroxide, obtains acid 23.Then, in the presence of alkali such as triethylamine, handle acid, obtain acyl azide, make it carry out the curtius' rearrangement reaction with benzyl alcohol again, form the 5-aminopyrimidinone 24 of carbobenzoxy-(Cbz) (Cbz) protection with diphenyl phosphoryl azide (DPPA).Adopt catalyzer such as palladium/charcoal, in The suitable solvent such as tetrahydrofuran (THF) and ethanol, the Cbz group of compound 24 is removed through hydrogenation.Amine 25 usefulness SULPHURYL CHLORIDE are handled in The suitable solvent such as methylene dichloride in the presence of alkali such as 4-methylmorpholine, obtain compound 26.Adopt standard procedure (Greene commonly known in the art, T.W., Wuts, P.G.W., Protecting Groups in Organic synthesis, the 2nd edition, John Wiley and Sons, Inc.New, York, (1991)), the tertiary butyl is removed, obtained acid 27 as the dichloromethane solution of trifluoroacetic acid.Adopt peptide coupler such as the castro ' s reagent (BOP) or the PyBOP of standard again, adopt alkali as at suitable solvent such as N, the diisopropyl ethyl amine in the dinethylformamide is coupled to intermediate 6 with acid 27, generation compound 28.Adopt standard procedure optionally to remove R
a, R
bAnd R
cWork as R
aAnd R
bBe tertbutyloxycarbonyl (Boc) and R
cDuring for hydrogen, the Boc group can be removed by handling in The suitable solvent such as methylene dichloride Huo diox as trifluoroacetic acid or hydrochloric acid with acid, obtains compound 29.Then, in the presence of alkali such as sodium bicarbonate,, in the dinethylformamide, with compound 29 alkylations, obtain compound 30 with alkylogen at The suitable solvent such as N.
Reaction scheme 4
Reaction scheme 4 explanation Z=-OCO-of the present invention ,-CO-or-NR
2The preparation method of the compound of CO-.Amine 11 and carbalkoxy chlorine or aryloxy carbonyl chlorine or chloride of acid are in the presence of alkali such as 4-methylmorpholine or triethylamine; in The suitable solvent such as methylene dichloride, react; perhaps, in The suitable solvent such as methylene dichloride or toluene, handle, obtain compound 31 with isocyanic ester.Adopt standard procedure (Greene commonly known in the art, T.W., Wuts, P.G.W., Protecting Groups in Organic synthesis, the 2nd edition, John Wiley and Sons, Inc.New, York, (1991)), the tertiary butyl is removed, obtained acid 32 as the ethyl acetate solution of hydrogen chloride gas or the dichloromethane solution of trifluoroacetic acid.Adopt peptide coupler such as the castro ' s reagent (BOP) or the PyBOP of standard again, adopt alkali as at suitable solvent such as N, the diisopropyl ethyl amine in the dinethylformamide is coupled to intermediate 6 with acid 32, generation compound 33.Perhaps, amine 15 usefulness carbalkoxy chlorine or aryloxy carbonyl chlorine or chloride of acid are handled in The suitable solvent such as methylene dichloride in the presence of alkali such as 4-methylmorpholine or triethylamine, obtain compound 33.Adopt standard procedure optionally to remove R
a, R
bAnd R
cWork as R
aAnd R
bBe tertbutyloxycarbonyl (Boc) and R
cDuring for hydrogen, the Boc group can be removed by handling in The suitable solvent such as methylene dichloride Huo diox as trifluoroacetic acid or hydrochloric acid with acid, obtains compound 34.Then, in the presence of alkali such as sodium bicarbonate,, in the dinethylformamide, with compound 34 alkylations, obtain compound 35 with alkylogen at The suitable solvent such as N.
Reaction scheme 5 and 6 provides at the intermediate described in reaction scheme 1 and 2 and the example of synthesis step, with the compound of production VII, wherein, R
1-Z-is R
1-SO
2-.Variable in reaction scheme " m " is 0-8, preferred 0 or 1.Synthesis step in these reaction schemes is in embodiments of the invention 1 and 2 illustrated.Reaction scheme 5
Reaction scheme 6
The pharmacologically acceptable salt of formula VII compound (water or oil soluble or water or oil-dispersing property product) comprises conventional non-toxic salt or the quaternary ammonium salt that is for example formed by inorganic or organic acid or alkali.The example of this acid salt comprises: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, glucoheptonic acid, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecane hydrochlorate.Alkali salt comprises ammonium salt, an alkali metal salt such as sodium salt and sylvite, alkaline earth salt such as calcium salt and magnesium salts, with the salt of organic bases such as dicyclohexyl amine salt, N-methyl-D-glucamine salt and the salt that forms with amino acid such as arginine, Methionin etc.Equally, nitrogenous basic group can be quaternized by following reagent, as elementary alkyl halide such as methyl, ethyl, propyl group and Butyryl Chloride, bromine and iodine; Dialkylsulfates is as dimethyl, diethyl, dibutyl; With diamyl sulfuric ester, long-chain halogenide, as decyl, lauryl, myristyl and stearyl chloride, bromine and iodine, aralkyl halide such as benzyl and phenethyl bromide etc.The acid that preferably is used to form acid salt is hydrochloric acid and acetate.
Compound exhibits of the present invention new potential metal, acid, mercaptan and the serpin of one class.The example of the serine protease that is suppressed by The compounds of this invention comprises: neutrophil elastoser, the proteolytic ferment that relates in the pulmonary emphysema pathogeny; Quimotrase, trypsinase, digestive ferment; Pancreatin elastoser, and cathepsin G, a kind of also relevant chymotrypsin-like proteolytic enzyme with white corpuscle; Zymoplasm and factor Xa, the proteolytic ferment in the blood coagulation approach.The purposes of compound of the present invention also comprises the inhibition of thermolysin, metalloprotein, stomach en-, acid albumin.Compound of the present invention preferably is used for suppressing trypsin-like proteolytic enzyme.
The compounds of this invention suppresses Quimotrase and tryptic final application is the treatment pancreatitis.Concerning its final application, the biochemical parameters of the effectiveness of The compounds of this invention and other enzyme rejection characteristic is easy to confirm through standard biological chemical technology commonly known in the art.Certainly, the final actual dose scope of using of their specificity will depend on the character and the severity of the disease of the patient that treated or animal, and determine by the diagnostician.Estimate that reaching the adoptable dosage range of effective therapeutic action is about 0.01-10mg/kg/ days.
Because have the effect of unique Trombin inhibiting, compound of the present invention can be applicable to many therepic use.As a kind of thrombin inhibitors, but the production of compound Trombin inhibiting of the present invention.Therefore, these compounds can be used for treating or prevent because abnormality vein or the artery thrombosis relevant with its zymoplasm production or effect are the disease of feature.These diseases include but not limited to: degree of depth venous thrombosis; The blood coagulation septic shock of propagating in the blood vessel, viral infectious and cancer; Myocardial infarction; Apoplexy; Coronary artery bypass; The eye scleroproein forms; Hip resets; With because thrombolytic therapy or the thrombosis that causes through skin coronary angioplasty (PCTA).Other purposes comprises that described thrombin inhibitors is as antithrombotics, itself or embedding or physical connection are to the material of the device that is used for producing blood collecting, blood circulation and blood storage, described device for example is conduit, haemodialysis control unit, blood collecting syringe and pipe, and blood line.Compound of the present invention also can be used as antithrombotics in external circulation of blood.
Through metal has demonstrated and can reduce restenosis, but can form thrombus.Form for reducing stent thrombosis, a kind of method is that coating, embedding or covalent bonding thrombin inhibitors are to rack surface.Compound of the present invention can be used in this purposes.Compound of the present invention can connect or embedding to solubility and/or Biodegradable polymeric, thereby coat to timbering material.This polymkeric substance can comprise Polyvinylpyrolidone (PVP), poly-hydroxy-propyl methyl acid amides-phenol, poly-hydroxy ethyl-asparagine acid amides-phenol or the polyoxyethylene-polylysine that is replaced by the palmityl residue, poly(lactic acid), polyglycolic acid, the multipolymer of poly(lactic acid) and polyglycolic acid, poly epsilon caprolactone lactone, multi-hydroxybutyrate, poe, polyacetal, poly-dihydropyrane, the crosslinked or amphiphilic block copolymer of the polybutylcyanoacrylate and the water-sol.Referring to EP761251, EP604022, CA2,164,684, WO96/11668, WO96/32143 and WO96/38136.
Because the effect of zymoplasm pair cell type host such as smooth muscle cell, endotheliocyte and neutrophil, compound of the present invention also can be used for treatment or prevention adult respiratory distress syndrome; Inflammatory response; Wound healing; Perfusion infringement again; Atherosclerosis is placed with the damage of following restenosis such as capsule angioplasty, atherosclerotic plaque surgical blanking and arterial bracket.
Compound of the present invention can be used for treating tumorigenesis and transfer and neurodegenerative disease, as presenile dementia and Parkinson's disease.When as thrombin inhibitors, the effective dosage ranges of compound administration of the present invention is about 0.1-500mg/kg body weight, preferred 0.1-10mg/kg body weight, 1 administration of dosage every day or 2-4 administration of branch.
When as thrombin inhibitors of the present invention, compound of the present invention can be used in combination with thrombolytic agent such as tissue plasmin activator, streptokinase and urokinase.In addition, compound of the present invention can be used in combination such as but not limited to Fibrinogen antagonistic and thromboxane receptor antagonist with other antithrombotic formation or anti-freezing medicine.
Thrombin inhibitors also can be used in combination with the soluble polymer as target medicine carrier.This polymkeric substance can comprise: polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl Methacrylamide-phenol, poly-hydroxyethyl amino-succinamic acid-phenol or the polyoxyethylene-polylysine that replaces with the palmityl residue.And then, thrombin inhibitors can be used to realize that the biodegradable polymkeric substance of medicine sustained release combines use with a class, and described polymkeric substance for example is the multipolymer, poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid, the crosslinked or amphipathic segmented copolymer of poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.
Human leukocyte elastase is discharged by the polymorphonuclear leukocyte at the inflammation site place, therefore, is the cause of disease of many kinds of diseases.Compound of the present invention estimates to have anti-inflammatory action, can be used for treating gout, rheumatoid arthritis and other inflammatory diseases, and is used for the treatment of pulmonary emphysema.The leukocyte elastase inhibition activity of The compounds of this invention is measured by following method.Cathepsin G is also with sacroiliitis, gout pulmonary emphysema and glomerulonephritis with because the lung that causes of pulmonary infection infects relevant.The final Application Areas of the enzyme inhibition matter of formula I compound is easy to determine by standard biological chemical technology as known in the art.
Cathepsin G's inhibition activity of compound can be measured by following method in the scope of the invention.Adopt Baugh etc., the method for biological chemistry 15:836 (1979) obtains partially purified human cathepsin g preparation.Leukocyte granules is the main source that is used to prepare leukocyte elastase and cathepsin G's (chymotrypsin-like activity).With leukocytolysis and isolate particle.Leukocyte granules is the sodium acetate extraction of 0.20M with the pH value, and extraction liquid is 4 ℃ of 0.05M Tris damping fluid dialysed overnight of using the pH8.0 that contains 0.05M NaCl down.Between dialysis period, be settled out the albumen cut, by centrifugal with its separation.This cut comprises the chymotrypsin-like activity of most leukocyte granules.Concrete substrate is prepared according to each enzyme, promptly N-Suc-Ala-Ala-Pro-Val-to p-nitroanilide and Suc-Ala-Ala-Pro-Phe-to p-nitroanilide.The back is a kind of not by the leukocyte elastase hydrolysis.Zymin experimentizes in the Hepes of the 0.10M of 2.00mL damping fluid, and the pH of described damping fluid is 7.5, comprises 0.50M NaCl, 10% methyl-sulphoxide and 0.0020M Suc-Ala-Ala-Pro-Phe-to p-nitroanilide as substrate.The hydrolysis of p-nitroanilide substrate is detected under 405nrn and 25 ℃.
The compounds of this invention is as the neutrophil elastase inhibitor and depend on the character and the severity of disease as the useful dosage of cathepsin G's inhibitor, and definite by the diagnostician, the general range that is used for above-mentioned disease is the 0.01-10mg/kg body weight/day.
The present invention suppresses urokinase or the active compound of Profibrinolysin can be used for the treatment of excessive cell growth property disease effectively.Like this, compound of the present invention also can be used for treating benign prostatauxe and prostate cancer, treats psoriasis and is used as aborticide.Should be used for finally saying that the effect of the enzyme rejection characteristic of The compounds of this invention and other biochemical parameters are easy to by well known to a person skilled in the art Measurement for Biochemistry definite for it.The actual dose scope of concrete Application Areas will be determined by the diagnostician.Can estimate that the general dosage range that reaches effective therapeutic action is about 0.01-10mg/kg/ days.
Other purposes of compound of the present invention comprises the analysis to the commercially available reagent enzyme of avtive spot concentration.For example, Quimotrase is with the standard reagent supply, and it is active clinical quantitative at pancreas liquid and ight soil to be used for Quimotrase.This experiment is used for diagnosing stomach and intestine and pancreatic disease.The pancreas elastoser also is purchased with doing α in the blood plasma
1-antitrypsin carries out quantitative reagent.α in the blood plasma in serious inflammatory diseases
1-antitrypsin increases, and α
1-antitryptic deficiency increases relevant with the pneumonopathy incidence.Compound of the present invention can be used to strengthen tolerance range and the reproducibility by to testing as the titrimetry stdn that is purchased elastoser of agent delivery.Referring to U.S. patent 4,499,082.
In the process of purifying particular proteins, there is the reproduction problem in the protease activity in some protein extract, and it may make the albumen sepn process complicate and bring harm.Some proteolytic enzyme that is present in the extract may be forbidden in the purification step of The compounds of this invention, and this retrains various proteoclastic enzymes more tightly.
Pharmaceutical composition of the present invention can deliver medicine to any animal that can realize the The compounds of this invention beneficial effect.Wherein, modal in the described animal is human, but the present invention is not limited to this.
Pharmaceutical composition of the present invention can carry out administration by any mode that reaches its purpose.For example, can pass through the following manner administration: parenterai administration, subcutaneous administration, intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, cheek administration or ocular administration.Perhaps, or simultaneously adopt the oral administration mode.Dosage will depend on patient's age, healthy state and body weight, Zhi Liao kind, and frequency and required effect for the treatment of alive if desired simultaneously.
Except pharmaceutical active compounds, new pharmaceutical preparation can comprise suitable pharmaceutically acceptable carrier, but comprises vehicle and the auxiliary agent that makes active compound be processed into the preparation of drug use.
Pharmaceutical preparation of the present invention can ordinary method production, for example, and by processes such as routine mixing, granulation, system drageeing, dissolving or freeze-drying.Therefore, the pharmaceutical preparation that orally uses can optionally be pulverized the mixture that forms, and after adding suitable auxiliary agent granular mixture be processed as required by active compound is mixed with solid excipient, obtains tablet or dragee core.
Suitable vehicle specifically can be weighting agent, as carbohydrate, for example, lactose or sucrose, mannitol or Sorbitol Powder, cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or secondary calcium phosphate, and tackiness agent are as starch paste, for example can adopt W-Gum, wheat starch, rice fecula, yam starch, gelatin, tragacanth, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, sodium carboxy methyl cellulose and/or Polyvinylpyrolidone (PVP).If necessary, can add disintegrating agent, as above-mentioned solution and carboxymethyl solution, cross-linking polyethylene pyrrolidone, agar or alginic acid or its salt are as sodiun alginate.Above-mentioned auxiliary agent can be for flowing regulator and lubricant such as silica gel, talcum, stearic acid or its salt, as Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol.The dragee core has suitable sugar-coat, and it should resist gastric juice if necessary.For this reason, can adopt concentrated sugar solution, optionally comprise gum arabic, talcum, Polyvinylpyrolidone (PVP), polyoxyethylene glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to produce the dressing of resistant to gastric juice, can adopt suitable cellulose preparation, as ethanoyl cellulose phthalate or HYDROXY PROPYL METHYLCELLULOSE phthalic ester.Dyestuff or pigment can add in tablet or the dragee dressing, for example are used to discern or for the property combination of active compound doses.
Other medicine that can orally use comprises the push-in type capsule that gelatin makes, and the soft seal capsule that is made by gelatin and softening agent such as glycerine or sorbyl alcohol.The push-in type capsule can comprise granular active compound, its can with weighting agent such as lactose, tackiness agent such as starch and/or lubricant such as talcum or accelerator acid magnesium and optionally stablizer be mixed together.In soft capsule, active compound preferred dissolution or be suspended in the appropriate liquid is in fatty oil or whiteruss.In addition, can add stablizer.
The suitable preparation of parenterai administration comprises: the aqueous solution of the active compound of water-soluble form, for example, and water-soluble salt, alkaline solution and cyclodextrin comprise mixture.Particularly preferred alkali salt is for using Tris, choline hydroxide, Bis-Tris propane, N-methylglucosamine or arginic ammonium salt.One or more modifications or unmodified cyclodextrin can be used to stable and increase the water-soluble of The compounds of this invention.The useful cyclodextrin that is used for this purpose is disclosed in following document: U.S. patent 4,727,064,4,764,604 and 5,024,998.
In addition, as suitable oily injectable suspensions, suspension administration that also can active compound.Suitable lipophilicity solvent or carrier comprise fatty oil, as sesame oil or Acrawax, in ethyl oleate or triglyceride level or polyoxyethylene glycol-400 (compound is dissolvable in water PEG-400).Moisture injectable suspensions can comprise the material that increases suspension viscosity, for example, and carboxymethyl cellulose, sorbyl alcohol and/or dextran.Optionally, this suspension also can comprise stablizer.
The compound of formula VII can with as following embodiment 3 described radioiodines carry out mark, or adopt permutoid reaction to carry out mark.Perhaps, the compound of radioiodine mark can be by corresponding bromine compounds through tributyl stannyl intermediate preparation.Referring to: U.S. patent 5,122,361, the document is incorporated herein by reference.
The present invention also comprises and is used in the composition that carries out the thrombus in vivo imaging in the Mammals, and wherein, described composition comprises the compound of the formula VII that has cooperated radioactive atom.
For formula VII compound, suitable radioactive atom comprises: Co-57, Cu-67, Ga-67, Ga-68, Ru-97, Tc-99m, In-111, In-113m, Hg-197, Au-198 and Pb-203.Particularly, technetium-99m (Tc-99m) is the radioactive atom that a kind of ideal is used for imaging because of its nulcear properties.It is gamma ray radiator and the single photon energy with 140keV, and the transformation period is about 6 hours, and it is easy to buy from the Mo-99/Tc-99 manufacturer.Rhenium-186 and-188 also has the γ emissivity, makes it can be by imaging.Preferred compositions comprises radioactive atom Tc-99m.
Composition of the present invention can be expediently finished and is prepared by being suitable for carrying out the radioisotopic formula VII compound of having of external detection.
The compound of formula VII can come mark so that composition of the present invention to be provided by any techniques well known in the art.For example, these compounds can carry out mark by sequestrant such as diethylene triaminepentaacetic acid(DTPA) (DTPA) or metallothionein(MT), but these two kinds of materials all covalent bonding to formula VII compound.
Usually, to comprise the composition of technetium-99m be like this preparation in the present invention: form the aqueous mixture of a kind of technetium-99m and reductive agent and water soluble ligand, then, this mixture is contacted with formula VII compound of the present invention.For example, imaging compounds of the present invention prepares like this: the compound that makes technetium-99m (oxidation state) and the present invention have the chelating position reacts in the presence of reductive agent, and forming a kind of is the stable complex of going back the technetium-99m (IV or V valence state) of ortho states.
A kind of embodiment of the present composition is that the formula VII compound with the technetium-99 m labeled DTPA of having chelating position carries out mark and makes.This can combine with the aqueous solution that comprises citrate buffer solution and Ya Xi reductive agent by the compound of the present invention with predetermined amount (about 5 μ g-0.5mg), adds the acid of the technetium excessively sodium of the new wash-out that comprises predetermined amount radioactivity (about 15mCi) then.After mixture is at room temperature cultivated, reaction mixture is carried on by sterilizing filter in the syringe of protection (0.2-0.22 μ m), then, be scattered in as required in the 0.9% injection salt solution.
The another embodiment of the present composition is by making with technetium-99 m labeled formula VII compound with metallothionein(MT) chelating position.This can combine the solubility title complex that forms a kind of technetium-99m (going back ortho states) and two glucoheptonic acid molecules with the inferior tin aqueous solution of glucoheptonic acid by crossing technetium-99m acid sodium aqueous solution, then, the VII compound that this solution and formula is had a metallothionein(MT) adherent with it merges.After technetium-99m being become from the glucoheptonic acid title complex under the condition of metallothionein(MT) of formula VII compound mixture cultivated for some time, form the composition of mtc labeled of the present invention.
Technetium-99m is preferably water miscible.Be preferably basic metal or alkaline-earth metal Pertechnetate (TcO
4 -).Technetium-99m preferably obtains with the fresh technetium acid na form of crossing from aseptic technetium-99m producer (as the Mo-99/Tc-99m producer from routine).But, also can adopt acceptable technetium-99m on the physiology in any other source.
The reductive agent that is used for this method be on the physiology acceptable being used for technetium-99m is reduced into IV or V valence state or is used for squama by its oxidation state reductive reductive agent from its oxidation state.Adoptable reductive agent is tin protochloride, tin protofluoride, the inferior tin of glucoheptonic acid, stannous tartrate and V-Brite B.Preferred reductive agent is the inferior tin of inferior tin reductive agent, particularly tin protochloride or glucoheptonic acid.For example, tin protochloride is a reductive agent, and its consumption is μ g/mL.Particularly preferred concentration is about 300-500 μ g/mL.
Citric acid cooperates with technetium-99m and forms stable technetium-99m-citric acid compound soon.When the compound with formula VII contacts, can promptly under mild conditions, realize quantitatively technetium-99m being transformed by its citric acid compound basically the inner complex position of accepted way of doing sth VII compound.The consumption of citric acid (in Trisodium Citrate) can be from about 0.5mg/mL to maximum meltage medium.The consumption of optimization citric acid is 15-30 μ g/mL.
Consumption with formula VII compound of chelating character can be 0.001 to about 3mg/mL, and preferred about 0.017 to about 0.15mg/mL.At last, can be about 1-50mCi with the consumption of the technetium-99m of Pertechnetate form, the mCi amount of preferred every mg The compounds of this invention is about 30-150.
Another kind of composition of the present invention comprises the compound of the present invention with the In-111 mark.
The present invention also comprises compound compositions of the present invention, and it can be used for thrombus imaging in the mammalian body, and said composition comprises the compound that the formula VII that cooperated the paramagnetic atom represents.
Preferred paramagnetic atom is that atomicity is 21-29,42,44 and divalence or the trivalent element of 58-70.Suitable ion comprises: chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III) and ytterbium (III).Owing to have very strong magnetic moment, preferably adopt gadolinium (III), terbium (III), dysprosium (III), holmium (III) and erbium (III).The preferred especially paramagnetic atom that adopts is gadolinium (III).
Composition of the present invention can make by compound and the paramagnetic atom chemical combination with formula VII.For example, the metal oxide of suitable paramagnetic atom or metal-salt (for example nitrate, muriate or vitriol) are dissolved or be suspended in a kind of comprising in water and the medium of alcohol as methyl alcohol, ethanol or Virahol.The formula VII compound that mixture is added to equimolar amount is in the solution of similar water-bearing media and stir.Reaction mixture is carried out moderate heating to be finished until reaction.The insoluble composition that forms is passed through filtering separation, and soluble composition can desolventize separation by steaming.If the acidic group on the chelating position still is present in the composition of the present invention, then can add inorganic or organic bases even amino acid so that sour title complex is changed into neutral compound so that the isolated or purified of homogeneous compositions.Organic bases or basic aminoacids can be used as neutralizing agent, can also adopt oxyhydroxide, carbonate or the supercarbonate of mineral alkali such as sodium, potassium or lithium.
The present invention also comprises diagnosis composition, and it can be used for thrombus in vivo imaging in the Mammals, and said composition comprises the radiolabeled compound of the formula VII of pharmaceutically acceptable carrier and diagnosis significant quantity.Aforesaid composition can be used as these diagnosis compositions easily.
Need will depend on administering mode, the mammiferous type and the described concrete mammiferous physical property of being treated as " the diagnosis significant quantity " of the composition of dosage.The relation of these factors and definite dosage is that the pharmacodiagnosis those skilled in the art are known.Equally, diagnosis significant quantity and medication are that to reach best effect be specific, but will depend on such as body weight, meals, dosage regimen and the known other factors of pharmacodiagnosis those skilled in the art simultaneously.Thus, imaging dosage should be enough to detect the existence of preparation on the position that might have thrombus.Usually, it is about 5-20 μ Ci that the radiology imaging will require the dosage of pharmaceutical composition of the present invention, preferred about 10 μ Ci.It is about 0.001-5mmol/kg that nuclear magnetic resonance will require dosage, preferably about 0.005-0.5mmol/kg compound of the formula VII of paramagnetic atom cooperation.Under any situation, all can learn the actual dose of determining according to the position of thrombus in the prior art.
" pharmaceutically acceptable carrier " of being used for using in the body is that pharmaceutical field is known, for example states in following document: Remington ' s Pharmaceutical Sciences, MackPublishing Co. (A.R.Gennaro edit.1985).
The present invention also comprises and is used to preserve or administration and the diagnosis composition that makes.These compositions will comprise sanitas, stablizer and dyestuff.For example, can add Sodium Benzoate, Sorbic Acid and P-hydroxybenzoic acid sodium as sanitas, Id.At 1449.In addition, also can add antioxidant and suspension agent.
In-vivo imaging method of the present invention also provides ratio the present superior several advantages of imaging technique that are used for surveying or detecting thrombus existence, size, degeneration or growth that adopt.Particularly, the invention provides compound and composition, diagnosis composition can design poling and closely combine with zymoplasm, and zymoplasm is relevant with thrombus, thereby reduces because the radiation that can not the bonded preparation causes or " background " of paramagnetic circulation cause.And then, carry out in-vivo imaging by injection compound of the present invention, composition or diagnosis composition in being preced with, expect the almost generation of moment, this is because these preparations will be immediately with saturated with thrombus bonded zymoplasm.
Thereby the present invention also comprises mammiferous thrombus in-vivo imaging method, comprise the steps: (1) but to compound of the present invention, composition or the diagnosis composition of Mammals administration diagnosis receiving amount; (2) thrombus in the detection blood vessel.
When adopting the compound, composition of this method or diagnosis composition in vivo, " administration " finished by non-enteron aisle mode, with system mode or the administration of local target mode.The system administration is to enter suitable and enterable vein or artery by injecting compound of the present invention, composition, diagnosis composition.This includes but not limited to the intravenously administrable by ankecubutal.The administration of local target mode is to enter in the injection site vein or artery that comprise thrombus far away by injecting the nearly health central flows of compound of the present invention, composition or diagnosis composition.This includes but not limited to that direct injection advances the coronary artery vascular system with the crown thrombus of imaging, be injected into carotid artery so that thrombus in the imaging of brain vascular system, or the injection enter sufficient vein with deep venous thrombosis imaging to leg.
Equally, transmitting composition of the present invention to the method in thrombosis site all can regard as in term " administration " scope.For example, having the compound that the formula VII at bonded chelating position with it represents can be injected in the Mammals, subsequently the time afterwards, by form radioactive atom in the body of thrombosed site, composition has comprised the compound of the general formula that cooperates with radioactive atom.Perhaps, the compound compositions that comprises the general formula that cooperates with radioactive atom can be injected in the Mammals.
By passing through the imaging detection thrombosis at localized radioactive atom in thrombus place or paramagnetic atom.
The radioactive atom relevant with diagnosis composition with composition of the present invention preferably adopts can be surveyed gamma-emitting radiation detection means and come imaging, as gamma camera etc.Usually, the radiophotography camera can adopt conversion medium (wherein, high-octane gamma-rays is absorbed, and the electronics of ballistic phonon is replaced electronics when returning its track condition), be arranged on the photodetector (determining the position of ballistic phonon) in the space exploration chamber and analyze the photon in the chamber, detect and the Circuits System that produces image.
The paramagnetic atom relevant with the present composition and diagnosis composition can be surveyed in nuclear magnetic resonance (MRI) system.In this system, adopt high-intensity magnetic field to make the atom in patient body carry out the arrangement of nuclear spin vector.Because the existence meeting magneticinterfering field of localized paramagnetic atom in thrombus, patient's image can be read by the nucleus that returns its balanced arrangement.
Following embodiment is used to illustrate method and composition of the present invention, but they are not determinate.Within the spirit and scope of the present invention, those skilled in the art will can run into the change of various conditions and parameter usually, and this is conspicuous.Embodiment 13-benzyl sulfuryl amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate
1.3-benzyloxycarbonyl amino-6-methyl-2-pyridone
With diphenyl phosphoryl azide (11.9mL, 55mmol) add to 2-hydroxyl-6-picoline-3-formic acid (7.65g, 50mmol) and triethylamine (7.7mL is in no Shui diox (100mL) solution 55mmol), with the vlil that forms.After 16 hours, add again triethylamine (7.7mL, 55mmol) and benzylalcohol (5.7mL 50mmol), refluxed solution 24 hours again.With the reaction mixture vacuum concentration, resistates distributes between methylene dichloride (200mL) and salt solution (100mL), with 10% hcl acidifying to pH1.(2 * 100mL), dried over sodium sulfate is used in usefulness salt water washing (100mL) to organic layer, filters with the saturated sodium bicarbonate washing.After vacuum steams solvent, in resistates, add methyl alcohol (100mL) and hexane (20mL), collect solid, with methyl alcohol (50mL) washing, drying obtains title compound, is white solid (7.2g, 56%).
1H-NMR(300MHz，CDCl
3)δ12.82(s，1H)，8.06(d，J＝7.0Hz，1H)，7.69(s，1H)，7.42(m，5H)，6.09(d，J＝7.5Hz，1H)，5.22(s，2H)，2.32(s，3H)。2.3-benzyloxycarbonyl amino-6-methyl isophthalic acid-(tertiary butyloxycarbonyl ylmethyl)-2-pyridone
With the monobromo-acetic acid tert-butyl ester (3.9g, 20mmol) add to 3-benzyloxycarbonyl amino-6-methyl-2-pyridone that the previous step in the stirring makes (5.15g, 20mmol) and cesium carbonate (6.5g is 20mmol) in N, in the suspension of dinethylformamide (50mL), under 40 ℃, stir and spend the night.Solids removed by filtration concentrates the filtrate high vacuum.Resistates is dissolved in the ethyl acetate (150mL), and water (2 * 50mL) and salt solution (50mL) washing, use dried over sodium sulfate, vacuum concentration.After vacuum steams solvent, obtain title compound, be white crystalline solid (4.2g, 56%).
1H-NMR(300MHz，CDCl
3)δ7.95(d，J＝7.3Hz，1H)，7.76(8，1H)，1.37(m，5H)，6.09(d，J＝7.6Hz，1H)，5.19(8，2H)，4.75(s，2H)，2.32(8，3H)，1.47(s，9H)。3. 3-amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone
3-benzyloxycarbonyl amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2 pyridones that previous step is made (4.1g, 11mmol) and (air bag) hydrogenation 1.5 hours under nitrogen atmosphere of the mixture of 10%Pd/C (400mg) in ethanol (100mL).Remove catalyzer by diatomite filtration, filtrate is concentrated, obtain title compound, be white solid.(2.55g，97％)。
1H-NMR(300MHz，CDCl
3)δ6.49(d，J＝7.3Hz，1H)，5.92(d，J＝7.3Hz，1H)，4.75(s，2H)，2.19(s，3H)，1.47(s，9H)。4. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone
Under 0 ℃; 3-amino-6-methyl isophthalic acid-(tert-butoxycarbonyl the methyl)-2-pyridone (960mg that makes to previous step; 4.0mmol) and N-methylmorpholine (840 μ L, add in methylene dichloride 8.0mmol) (40mL) solution α-tosyl group chlorine (765mg, 4.0mmol).Reaction mixture was stirred 1 hour down at 0 ℃.Add methylene dichloride (50mL) again.With the dichloromethane solution that forms with full sodium bicarbonate (2 * 50mL), 10% citric acid (3 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate.Solvent is concentrated, obtain a kind of solid, (1: 2,60mL) washing obtained title compound, is a kind of white solid (1.4g, 89%) with ethyl acetate/hexane with it.
1H-NMR(300MHz，CDCl
3)δ?7.35(d，J＝7.5Hz，1H)，7.31(m，5H)，7.20(s，1H)，6.02(d，J＝7.4Hz，1H)，4.75(s，2H)，4.31(s，2H)，2.27(s，3H)，1.51(s，9H)。5. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone
Under 0 ℃, 3-benzyl sulfuryl amino-6-methyl 1-(tert-butoxycarbonyl methyl)-2-pyridone that HCl gas bubbling is made by previous step (1.4g, 3.57mmol) in the suspension in the stirring in ethyl acetate (15mL) until forming solution.After at room temperature 2 hours, form a kind of heavy-gravity suspension.Mixture is outgased with nitrogen, filter, obtain title compound, be a kind of white solid.(1.1g，92％)。
1H-NMR(300MHz，CDCl
3)δ8.67(s，1H)，7.34(m，5H)，7.12(d，J＝7.5Hz，1H)，6.10(d，J＝7.6Hz，1H)，4.78(s，2H)，4.51(s，2H)，2.26(8，3H)。6. 3-(benzyloxycarbonyl amino)-1-propyl alcohol
Under 0 ℃, (3.75g, (3.4g 20mmol) stirs mixture 3 hours down at 0 ℃ the benzyl chloroformate in methylene dichloride 50mmol) (40mL) solution in the slow adding methylene dichloride (10mL) to 3-amino-1-propyl alcohol.Add methylene dichloride (50mL) again, with solution with 10% citric acid (3 * 50mL) and salt solution (50mL) washing, use dried over sodium sulfate.After solvent removed in vacuo, resistates used by filtered through silica gel carry out purifying (1: 1 ethyl acetate: hexane), obtain title compound, be a kind of white solid (4.05g, 97%).
1H-NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8Hz, 2H), 3.33 (t, J=6.1Hz, 2H), 2.63 (br s, 1H), 1.69 (quintet, J=6.1Hz, 2H).(7.N-[3-carbobenzoxy-(Cbz) base amino)-1-propoxy-] phthalic imidine
3-(the benzyloxycarbonyl amino)-1-propyl alcohol (4.0g that makes to previous step, 19mmol), N-hydroxyphthalimide (3.26g, 20mmol) and triphenyl phosphine (5.25g, add in tetrahydrofuran (THF) 20mmol) (80mL) solution diethyl azodiformate (3.5g, 20mmol).Reaction mixture at room temperature stirred spend the night.Add ethyl acetate (200mL), solution with saturated sodium bicarbonate (2 * 100mL) and salt solution (100mL) wash, use dried over sodium sulfate.After steaming solvent, resistates obtains title compound with flash column chromatography purifying (dichloromethane solution of methylene dichloride to 4% ethyl acetate), is a kind of white solid (6.85g, 100%).
1H-NMR (300MHz, CDCl
3) δ 7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8Hz, 2H), 3.51 (q, J=6.1Hz, 2H), 1.99 (quintet, J=6.0Hz, 2H).8. 3-(benzyloxycarbonyl amino)-1-propoxy-amine
Go up N-[3-(benzyloxycarbonyl amino)-1-propoxy-that step makes forward] phthalic imidine (1.42g, and adding 40% methylamine in ethanol 4.0mmol) (20mL) and tetrahydrofuran (THF) (20mL) solution (2mL, 25mmol).Solution was at room temperature stirred 1 hour.Steam solvent, resistates by silica gel (3: 1 ethyl acetate: hexane is to ethyl acetate), is obtained title compound, be a kind of white solid (870mg, 97%).
1H-NMR (300MHz, CDCl
3) δ 7.36 (m, 5H), 5.38 (brs, 2H), 5.09 (8,2H), 5.08 (br s, 1H), 3.73 (t, J=5.9Hz, 2H), 3.29 (q, J=6.2Hz, 2H), 1.79 (quintet, J=6.2Hz, 2H).9.[N, N '-two (tertbutyloxycarbonyl)] and 3-(benzyloxycarbonyl amino)-1-propoxy-guanidine
3-(the benzyloxycarbonyl amino)-1-propoxy-amine that makes to previous step (860mg, N 3.84mmol), add in dinethylformamide (20mL) solution [N, N '-two (tert-butoxycarbonyl)] amidino groups pyrazoles (1.25g, 4.0mmol).Mixture at room temperature stirred spend the night, high vacuum steams solvent, and resistates with flash column chromatography purifying (dichloromethane solution of 0-5% ethyl acetate), is obtained title compound, is a kind of water white oil (1.60g, 89%).
1H-NMR (300MHz, CDCl
3) δ 9.10 (br s, 1H), 7.74 (br s, 1H), 7.35 (m, 5H), 5.55 (brs, 1H), 5.10 (s, 2H), 4.12 (t, J=6.1Hz, 2H), 3.32 (t, J=6.4Hz, 2H), 1.87 (quintet, J=6.2Hz, 2H), 1.50 (s, 9H), 1.47 (8,9H).10.[N, N '-two (tert-butoxycarbonyl)] and 3-amino-1-propoxy-guanidine
[the N that previous step is made, N '-two (tert-butoxycarbonyl)] 3-(benzyloxycarbonyl amino)-1-propoxy-guanidine (760mg, 1.7mmol) and the mixture of 10%Pd/C (80mg) in ethanol (20mL) and tetrahydrofuran (THF) (20mL) in down hydrogenation 30 minutes of atmosphere atmosphere (air bag).By the diatomite filtration catalizer, with the filtrate vacuum concentration, with resistates by Waters Sep-Pak purifying (10g, 95: 5 methylene dichloride: methyl alcohol, with ammoniacal liquor saturated), obtain title compound, be a kind of water white oil (160mg, 28%).
1H-NMR (300MHz, CDCl
3) δ 4.12 (t, J=6.1Hz, 2H), 2.85 (t, J=6.7Hz, 2H), 1.84 (quintet, J=6.2Hz, 2H), 1.50 (s, 9H), 1.48 (5,9H).11. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [3-(guanidine radicals oxygen base propyl group) amino carbonyl methyl] }-2-pyridone
The 3-benzyl sulfuryl amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone (152mg that makes to step 5; 0.45mmol) and [N that makes of previous step; N '-two (tert-butoxycarbonyl)] 3-amino-1 propoxy-guanidine (150mg; 0.45mmol) and diisopropyl ethyl amine (90 μ L; 0.5mmol) N; add in the mixture in the dinethylformamide (10mL) Castro ' s reagent (BOP) (221mg, 0.5mmol).Mixture at room temperature stirred spend the night.Add ethyl acetate (100mL), solution with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (2 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate.After vacuum steams solvent, with resistates Waters Sep-Pak purifying (10g, 4: 1 ethyl acetate: hexane), obtain title compound, be a kind of colourless foam thing (270mg, 92%).
1H-NMR(300MHz，CDCl
3)δ9.02(s，1H)，8.70(s，1H)，8.58(8，1H)，8.27(t，J＝5.6Hz，1H)，7.34(m，5H)，7.12(d，J＝7.6Hz，1H)，6.08(d，J＝7.7Hz，1H)，4.70(s，2H)，4.50(s，2H)，3.88(t，J＝6.3Hz，2H)，3.18(t，J＝6.4Hz，2H)，2.24(s，3H)，1.75(t，J＝6.5Hz，2H)，1.39(s，18H)。
12. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate
At room temperature; 3-benzyl sulfuryl amino-6-methyl isophthalic acid-{ [N that previous step is made; N '-two (tert-butoxycarbonyl)] [3-(guanidine radicals oxygen base propyl group) amino carbonyl methyl]-the 2-pyridone (130mg, 0.2mmol) and the mixture of trifluoroacetic acid (2mL) in methylene dichloride (5mL) stirred 1 hour.After vacuum steams solvent, resistates with Waters Sep-Pak purifying (10g, the dichloromethane solution of 10% methyl alcohol), is obtained title compound, be a kind of colourless foam thing (55mg, 61%).
1H-NMR (300MHz, DMSO-d
6) δ 8.57 (8,1H), 8.35 (t, J=5.7Hz, 1H), 7.62 (br s, 4H), 7.34 (m, 5H), 7.12 (d, J=7.5Hz, 1H), 6.09 (d, J=7.7Hz, 1H), 4.70 (s, 2H), 4.52 (s, 2H), 3.81 (t, J=6.4Hz, 2H), 3.20 (q, J=6.4Hz, 2H), 2.25 (s, 3H), 1.77 (quintet, J=6.5Hz, 2H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
26N
6O
5S:451.2 (M+H), 473.2 (M+Na); Measured value: 451.5,473.5.Embodiment 23-benzyl sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
(1.N-[2-benzyloxycarbonyl amino) oxyethyl group] phthalic imidine
To N-(2-hydroxyethyl) benzyl carbamate (5.9g, 30mmol), N-hydroxyphthalimide (4.9g, 30mmol) and triphenyl phosphine (7.9g, add in tetrahydrofuran (THF) 30mmol) (100mL) solution diethyl azodiformate (5.2g, 30mmol).Reaction mixture at room temperature stirred spend the night.Add ethyl acetate (200mL), with solution with saturated sodium bicarbonate (2 * 100mL) and salt solution (100mL) wash, use dried over sodium sulfate.After steaming solvent, resistates obtains title compound with flash column chromatography purifying (dichloromethane solution of methylene dichloride to 4% ethyl acetate), is a kind of white solid (9.3g, 91%).
1H-NMR(300MHz，CDCl
3)δ7.84(m，2H)，7.78(m，2H)，7.37(m，5H)，5.97(br?s，1H)，5.14(s，2H)，4.27(t，J＝4.9Hz，2H)，3.51(q，J＝5.2Hz，2H)。2. 2-(benzyloxycarbonyl amino) amine ethoxylate
N-[2-(benzyloxycarbonyl amino) oxyethyl group that makes to previous step] phthalic imidine (1.36g, add in ethanol 4.0mmol) (20mL) and tetrahydrofuran (THF) (20mL) solution 40% methylamine (2mL, 25mmol).Reaction mixture was at room temperature stirred 1 hour.After steaming solvent, resistates obtains title compound by silica gel purification (3: 1 ethyl acetate: hexane is to ethyl acetate), is a kind of white solid (800mg, 95%).
1H-NMR(300MHz，CDCl
3)δ7.36(m，5H)，5.47(br?s，2H)，5.21(br?s，1H)，5.10(s，2H)，3.72(t，J＝5.0Hz，2H)，3.44(q，J＝5.0Hz，2H)。3.[N, N '-two (tertbutyloxycarbonyl)] and 2-(benzyloxycarbonyl amino) oxyethyl group guanidine
2-(benzyloxycarbonyl amino) amine ethoxylate that makes to previous step (780mg, N 3.7mmol), add in dinethylformamide (20mL) solution [N, N '-two (tert-butoxycarbonyl)] amidino groups pyrazoles (1.25g, 4.0mmol).Mixture at room temperature stirred spend the night, steam solvent under the high vacuum.Resistates with flash column chromatography purifying (dichloromethane solution of 0-5% ethyl acetate), is obtained title compound, be a kind of water white oil (1.55g, 93%).
1H-NMR(300MHz，CDCl
3)δ9.08(s，1H)，7.67(s，1H)，7.33(m，5H)，6.21(br?s，1H)，5.21(brs，1H)，5.11(s，2H)，4.12(t，J＝4.8Hz，2H)，3.54(q，J＝4.9Hz，2H)，1.49(s，9H)，1.46(s，9H)。4.[N, N '-two (tertbutyloxycarbonyl)] and 2-amino ethoxy guanidine
[the N that previous step is made, N '-two (tert-butoxycarbonyl)] 2-(benzyloxycarbonyl amino) oxyethyl group guanidine (730mg, 1.5mmol) and the mixture of 10%Pd/C (70mg) in ethanol (20mL) and tetrahydrofuran (THF) (20mL) in down hydrogenation 30 minutes of nitrogen atmosphere (air bag).By the diatomite filtration catalizer, with the filtrate vacuum concentration.With resistates carry out Waters Sep-Pak purifying (10g, 95: 5 methylene dichloride: methyl alcohol, with ammoniacal liquor saturated), obtain title compound, be a kind of water white oil (290mg, 61%).
1H-NMR(300MHz，CDCl
3)δ9.08(brs，1H)，4.08(t，J＝5.2Hz，2H)，2.99(q，J＝5.1Hz，2H)，1.50(s，9H)，1.48(s，9H)。5. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-2-pyridone
The 3-benzyl sulfuryl amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone (152mg that makes to embodiment 1 step 5; 0.45mmol), [N that makes of previous step; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy guanidine (143mg; 0.45mmol) and diisopropyl ethyl amine (90 μ L; 0.5mmol) N; adding Castro ' s reagent (BOP) in the dinethylformamide (10mL) (221mg, 0.5mmol).Mixture at room temperature stirred spend the night.Add ethyl acetate (100mL), with solution with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (2 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate.After vacuum steams solvent, resistates Waters Sep-Pak purifying (10g, 4: 1 ethyl acetate: hexane), obtain title compound, be a kind of colourless foam thing (270mg, 94%).
1H-NMR(300MHz，CDCl
3)δ9.22(s，1H)，8.41(t，J＝5.0Hz，1H)，8.02(s，1H)，7.62(s，1H)，7.34(s，1H)，7.29(m，5H)，5.99(d，J＝7.7Hz，1H)，4.89(s，2H)，4.31(s，2H)，4.13(t，J＝5.0Hz，2H)，3.62(q，J＝5.1Hz，2H)，2.30(s，3H)，1.52(s，9H)，1.48(s，9H)。6. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
At room temperature; 3-benzyl sulfuryl amino-6-methyl isophthalic acid-{ [N that previous step is made; N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone (255mg, 0.4mmol) and the mixture of trifluoroacetic acid (4mL) in methylene dichloride (8mL) stirred 1 hour.After vacuum steamed solvent, resistates obtained title compound with Waters Sep-Pak purifying (10g, the dichloromethane solution of 10% methyl alcohol), is colourless foam thing (160mg, 92%).
1H-NMR(300MHz，DMSO-d
6)δ8.58(s，1H)，8.49(t，J＝5.5Hz，1H)，7.73(br?s，4H)，7.35(m，5H)，7.13(d，J＝7.6Hz，1H)，6.11(d，J＝7.7Hz，1H)，4.74(s，2H)，4.52(s，2H)，3.84(t，J＝5.3Hz，2H)，3.40(m，2H)，2.26(s，3H)。
Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
24N
6O
5S:437.2 (M+H), 459.1 (M+Na); Measured value: 437.3,459.2.Embodiment 3
A. (0.025g, (0.098mmol) (0.03g 0.1mmol) handles methylene dichloride 0.052mmol) (2mL) solution with 4 iodobenzene SULPHURYL CHLORIDE for Fluka, 0.033g with diethylamino ethyl polystyrene resin with amine 1.With mixture jolting at room temperature 5 hours, add again aminomethylpolystyre.e resin as the scavenging agent of excessive SULPHURYL CHLORIDE (Adv.Chem.Tech., 0.1g, 0.2mmol).Add methylene dichloride (2mL) again, the mixture jolting is spent the night.The reaction mixture that will comprise resin is poured in the silicagel column (5g SepPak), carries out gradient elution with the dichloromethane solution of 10-50% ethyl acetate.Collect suitable cut, on Savant, be evaporated to dried.Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
27H
37N
6O
9SI-2 t-Boc:549.1, measured value: 549.3.
B. at room temperature, methylene dichloride (2mL) solution of sulphonamide 2 is handled also jolting 4 hours with trifluoroacetic acid (1mL).Remove methylene dichloride by Savant, resistates is carried out purifying (5g SepPak) with silicagel column, with the dichloromethane solution wash-out of 5% methyl alcohol.Merge suitable cut, be evaporated to driedly, obtain 3 of 19.6mg (69% yield, 2 steps), be a kind of jelly.
1H-NMR(300Mhz，CDCl
3)δ10.95(s，1H)，9.48(s，1H)，8.42(t，2H，J＝5.6Hz)，7.90(d，2H，J＝8.6Hz)，7.72(8，4H)，7.56(d，2H，J＝8.6Hz)，7.26(d，1H，J＝7.5Hz)，6.10(d，1H，J＝7.7Hz)，4.60(8，2H)，3.96(s，2H)，3.80(t，2H，J＝5.3Hz)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SI:549.1, measured value: 549.0.
C.[I-125] can replace the cold iodine compound in the step to iodobenzene SULPHURYL CHLORIDE (A.S.Keston etc., J.Amer.Chem.Soc.68:1390 (1946)), form [I-125] 3.Embodiment 43-benzyl sulfuryl amino-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1. 3-benzyl sulfuryl amino-1-(tertiary butyloxycarbonyl ylmethyl)-2-pyridone
Under 0 ℃, to 3-amino-1-(tert-butoxycarbonyl methyl)-2-pyridone (1.12g, 5.0mmol) and N-methylmorpholine (1.5mL, add in methylene dichloride 10.0mmol) (40mL) solution α-toluene sulfonyl chloride (950mg, 5.0mmol).Reaction mixture was stirred 1 hour down at 0 ℃.Add methylene dichloride (50mL) again.With the solution that forms with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (3 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate, filter, filtrate is concentrated, obtain a kind of solid, it is used ethyl acetate/hexane (1: 2,60mL) washing, obtain title compound, be a kind of white solid (1.8g, 96%).
1H-NMR(300MHz，CDCl
3)δ7.42(brs，1H)，7.36(d，J＝7.3Hz，1H)，7.31(m，5H)，6.92(d，J＝7.0Hz，1H)，6.14(t，J＝7.2Hz，1H)，4.58(s，2H)，4.34(s，2H)，1.51(s，9H)。2. 3-benzyl sulfuryl amino-1-carboxyl methyl-2-pyridone
Under 0 ℃, (1.7g, ethyl acetate 4.5mmol) (15mL) suspension is until forming solution with 3-benzyl sulfuryl amino-1-(tert-butoxycarbonyl methyl)-2-pyridone that the hydrogen chloride gas bubbling makes by the previous step in stirring.After at room temperature 2 hours, form heavy-gravity suspension.Mixture is outgased with nitrogen, filter, obtain title compound, be a kind of white solid (1.4g, 97%).
1H-NMR(300MHz，CDCl
3)δ8.76(s，1H)，7.45(dd，J＝7.0，1.8Hz，1H)，7.32(m，5H)，7.19(dd，J＝7.2，1.8Hz，1H)，6.16(t，J＝7.1Hz，1H)，4.69(s，2H)，4.56(s，2H)。3. 3-benzyl sulfuryl amino-1-{[N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-the 2-pyridone
The 3-benzyl sulfuryl amino-1-carboxyl methyl-2-pyridone (129mg that makes to previous step; 0.4mmol), [N that makes of embodiment 2 steps 4; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy guanidine (143mg; 0.45mmol) and two diisopropyl ethyl amines (90 μ L; 0.5mmol) N; add in dinethylformamide (10mL) solution Castro ' s reagent (BOP) (221mg, 0.5mmol).Mixture at room temperature stirred spend the night.Add ethyl acetate (100mL), solution with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (2 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate, after vacuum steams solvent, resistates Waters Sep-Pak purifying (10g, 4: 1 ethyl acetate: hexane), obtain title compound, be a kind of colourless foam thing (170mg, 68%).
1H-NMR(300MHz，CDCl
3)δ9.22(s，1H)，8.49(brs，1H)，7.44(s，1H)，7.34(dd，J＝7.3，1.7Hz，1H)，7.29(m，5H)，7.02(dd，J＝7.0，1.7Hz，1H)，6.12(t，J＝7.1Hz，1H)，4.73(8，2H)，4.34(s，2H)，4.15(m，2H)，3.65(m，2H)，1.52(s，9H)，1.49(s，9H)。4. amino carbonyl methyl 3-benzyl sulfuryl amino-1-[(2-guanidine radicals oxygen base ethyl)]-2-pyridone trifluoroacetate
3-benzyl sulfuryl amino-1-{[N that previous step is made; N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone (155mg, 0.25mmol) and the mixture of trifluoroacetic acid (2mL) in methylene dichloride (3mL) under room temperature, stirred 2 hours.After vacuum steams solvent, resistates with Waters Sep-Pak purifying (10g, the dichloromethane solution of 10% methyl alcohol), is obtained title compound, be a kind of colourless foam thing (160mg, 92%).
1H-NMR(300MHz，DMSO-d
6)δ11.00(s，1H)，8.66(s，1H)，8.45(t，J＝5.3Hz，1H)，7.72(brs，4H)，7.40(d，J＝6.9Hz，1H)，7.33(m，5H)，7.19(d，J＝7.0Hz，1H)，6.19(d，J＝7.0Hz，1H)，4.62(s，2H)，4.55(s，2H)，3.83(t，J＝5.1Hz，2H)，3.39(m，2H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
17H
22N
6O
5S:423.1 (M+H), 445.1 (M+Na); Measured value: 423.3,445.0.Embodiment 53-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-(tertbutyloxycarbonyl carbonyl methyl)-2-pyridone
Under 0 ℃, 3-amino-6-methyl isophthalic acid-(tert-butoxycarbonyl the methyl)-2-pyridone (1.42g that makes to embodiment 1 step 3,5.88mmol) and N-methylmorpholine (1.29mL, 11.76mmol) methylene dichloride (40mL) solution in add 3-Methyl benzenesulfonyl chlorine (1.12g, 5.88mmol).Reaction mixture at room temperature stirred spend the night, add methylene dichloride (60mL) again.With the dichloromethane solution that forms with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (3 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate.After steaming solvent, resistates obtains title compound with flash column chromatography purifying (dichloromethane solution of 5-10% ethyl acetate), is a kind of white solid (2.1g, 91%).
1H-NMR(300MHz，CDCl
3)δ7.63(m，2H)，7.55(brs，1H)，7.42(d，1H，J＝8Hz)，7.32(m，2H)，6.01(d，1H，J＝8Hz)，4.64(8，2H)，2.37(s，3H)，2.20(s，3H)，1.43(s，9H)。2. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-carboxyl methyl-2 pyridone
Under 0 ℃; 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone (2.0g that the hydrogen chloride gas bubbling is made by the previous step in stirring; 5.09mmol) ethyl acetate (50mL) suspension, until forming solution.After at room temperature 2 hours, form heavy-gravity suspension.Mixture is outgased with nitrogen, filter, obtain title compound, be a kind of white solid (1.36g, 80%).
1H-NMR(300MHz，DMSO-d
6)δ9.38(s，1H)，7.62(m，2H)，7.41(m，2H)，7.25(d，1H，J＝8Hz)，6.09(d，1H，J＝8Hz)，4.67(s，2H)，2.35(s，3H)，2.20(s，3H)。3. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-2-pyridone
3-(the 3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-carboxyl methyl-2 pyridone (1.26g that makes to previous step; 3.75mmol), [N that makes of embodiment 2 steps 4; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy guanidine (1; 33g; 3.75mmol) and diisopropyl ethyl amine (1.29g; 10.0mmol) N, add in dinethylformamide (30mL) solution Castro ' s reagent (BOP) (2.0g, 4.47mmol).Mixture at room temperature stirred spend the night.Add ethyl acetate (150mL), solution with saturated sodium bicarbonate (2 * 50mL), 10% citric acid (2 * 50mL) and salt solution (50mL) wash, use dried over sodium sulfate, after vacuum steams solvent, resistates twice (1: 1 ethyl acetate: hexane of column chromatography purifying; The dichloromethane solution of 2% methyl alcohol then), obtains title compound, be a kind of white solid (2.25g, 92%).
1H-NMR(300MHz，CDCl
3)δ9.17(s，1H)，8.34(t，J＝5.1Hz，1H)，7.66(m，4H)，7.48(d，J＝7.6Hz，1H)，7.32(m，2H)，6.00(d，J＝7.7Hz，1H)，4.80(s，2H)，4.10(t，J＝5.3Hz，2H)，3.59(q，J＝5.4Hz，2H)，2.38(s，3H)，2.25(s，3H)，1.55(s，9H)，1.45(s，9H)。4. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
At room temperature; previous step make with 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N; N '-two (tert-butoxycarbonyl)] [3-(guanidine radicals oxygen base propyl group) amino carbonyl methyl]-the 2-pyridone (2.24g, 3.44mmol) and the mixture of trifluoroacetic acid (10mL) in methylene dichloride (20mL) stirred 4 hours.After vacuum steamed solvent, resistates obtained title compound with column chromatography purifying (dichloromethane solution of 10% methyl alcohol), is a kind of white solid (1.59g, 82%).
1H-NMR(300MHz，CD
3OD)δ7.61(m，2H)，7.47(d，1H，J＝7.6Hz)，7.38(m，2H)，6.20(dd，1H，J＝7.7Hz，0.7Hz)，4.70(s，2H)，3.93(t，2H，J＝5.2Hz)，3.48(t，2H，J＝5.2Hz)，2.37(s，3H)，2.29(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24SN
6O
5: 437.5 (M+H); Measured value: 437.2.5. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
(2.75g is 5.0mmol) with (10mL) and salt solution (80mL) processing for 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate that previous step is made.Hydrochloric acid with 20% is adjusted to 1 with the pH value of mixture, the mixture that forms is stirred go out product until crystallization.Filter collecting precipitation, with the icy water washing, in the vacuum oven 45 ℃ dry 2 days down, obtain title compound, be pale solid (2.25g, 95%).mp：177-179℃。
1H-NMR(300MHz，DMSO-d
6)δ11.1(s，1H)，9.3(s，1H)，8.6(t，J＝7.5Hz，1H)，7.75(brs，4H)，7.42(m，4H)，7.25(d，J＝7.6Hz，1H)，6.10(d，J＝7.7Hz，1H)，4.65(s，2H)，3.80(t，J＝5.2Hz，2H)，3.40(q，J＝5.2Hz，2H)，2.35(8，3H)，2.24(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24SN
6O
5: 437.5 (M+H); Measured value: 437.2.Embodiment 63-(carbobenzoxy-(Cbz)) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
3-benzyloxycarbonyl amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone by the preparation of embodiment 1 step 2 prepares title compound, adopts the step 5 of embodiment 1 and the step 5 and 6 of embodiment 2.
1H-NMR(300MHz，DMSO-d
6)δ11.03(s，1H)，8.47(t，J＝5.4Hz，1H)，8.30(s，1H)，7.76(brs，4H)，7.73(d，J＝7.5Hz，1H)，7.40(m，5H)，6.18(d，J＝7.7Hz，1H)，5.15(s，2H)，4.73(8，2H)，3.82(t，J＝5.3Hz，2H)，3.38(m，2H)，2.24(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
24N
6O
5: 417.2 (M+H), 439.2 (M+Na), 455.1 (M+K); Measured value: 417.3,439.4,455.4.Embodiment 73-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(1-(1-guanidine radicals oxygen ylmethyl) cyclopropyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
(1.1-benzyloxycarbonyl amino) cyclopropane methyl alcohol
Under 0 ℃, (500mg adds B in tetrahydrofuran (THF) 2.1mmol) (5mL) solution to 1-(benzyloxycarbonyl amino) cyclopropane-carboxylic acid
2H
6-THF (1M, 2.1mL, 2.1mmol).Mixture at room temperature stirred spend the night, handle, and (3 * 10mL) extract with methylene dichloride with salt of wormwood (1.0g is in 5mL water).Organic layer is used dried over sodium sulfate with salt solution (10mL) washing.After steaming solvent, resistates carries out chromatography (1: 1 ethyl acetate: hexane), obtain title compound, be a kind of white solid (200mg, 43%).
1H-NMR(300MHz，CDCl
3)δ7.35(m，5H)，5.30(brs，1H)，5.10(s，2H)，3.61(s，2H)，3.02(brs，1H)，0.86(s，4H)。(2.N-[1-benzyloxycarbonyl amino) cyclopropane methoxyl group] phthalic imidine
Adopt the process of embodiment 2 steps 1, (200mg 0.9mmol) makes title compound to 1-(benzyloxycarbonyl amino) the cyclopropane methyl alcohol that the employing previous step makes, and is a kind of white solid (295mg, 90%).
1H-NMR(300MHz，CDCl
3)δ7.83(m，2H)，7.79(m，2H)，7.37(m，5H)，6.23(brs，1H)，5.13(s，2H)，4.18(s，2H)，0.93(m，2H)，0.72(m，2H)。(3.[1-benzyloxycarbonyl amino) cyclopropane methoxyl group] amine
Adopting the process of embodiment 2 steps 2, N-[1-(benzyloxycarbonyl amino) the cyclopropane methoxyl group that adopts previous step to make] (290mg 0.8mmol) makes title compound to phthalic imidine, is a kind of water white oil (180mg, 95%).
1H-NMR(300MHz，CDCl
3)δ7.35(m，5H)，5.60(brs，2H)，5.23(brs，1H)，5.09(s，2H)，3.64(s，2H)，0.89(m，4H)。4.[N, N '-two (tert-butoxycarbonyl)] and [1-(benzyloxycarbonyl amino) cyclopropane methoxyl group] guanidine
Adopt the process of embodiment 2 steps 3, [1-(benzyloxycarbonyl amino) cyclopropane methoxyl group] amine (180mg that makes by previous step system, 0.76mmol) and (N, N '-two tert-butoxycarbonyl) amidino groups pyrazoles (280mg, 0.9mmol) make title compound, be a kind of water white oil (330mg, 91%).
1H-NMR(300MHz，CDCl
3)δ9.10(brs，1H)，8.02(brs，1H)，7.35(m，5H)，5.74(brs，1H)，5.09(8，2H)，4.03(8，2H)，1.49(s，9H)，1.47(s，9H)，0.91(m，4H)。5.[N, N '-two (tert-butoxycarbonyl)] and (1-amino-cyclopropane methoxyl group) guanidine
Adopt the process of embodiment 2 steps 4, (330mg 0.69mmol) makes title compound to [N, N '-two (tert-butoxycarbonyl)] [1-(benzyloxycarbonyl amino) cyclopropane methoxyl group] guanidine that is made by previous step, is a kind of water white oil (200mg, 84%).
1H-NMR(300MHz，CDCl
3)δ9.09(brs，1H)，3.96(8，2H)，1.52(s，9H)，1.48(s，9H)，0.67(m，2H)，0.60(m，2H)。6. 3-benzyl sulfuryl amino-6-methyl isophthalic acid-{ [N, N '-two (tert-butoxycarbonyl [1-(1-(guanidine radicals oxygen ylmethyl) cyclopropyl amino) carbonyl methyl) }-2-pyridone
Adopt the process of embodiment 2 steps 5; [the N that makes by previous step; N '-two (tert-butoxycarbonyl)] (1-amino-cyclopropane methoxyl group) guanidine (100mg; 0.3mmol) and 3-benzyl sulfuryl amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone (100mg of making of embodiment 1 step 5; 0.3mmol) make title compound; be a kind of colourless foam thing (120mg, 60%).
1H-NMR(300MHz，CDCl
3)δ9.08(brs，1H)，7.74(s，1H)，7.72(s，1H)，7.31(d，J＝7.5Hz，1H)，7.26(m，5H)，6.00(d，J＝7.7Hz，1H)，4.79(s，2H)，4.30(s，2H)，3.97(s，2H)，2.31(s，3H)，1.51(s，9H)，1.48(s，9H)，1.04(m，2H)，0.87(m，2H)。7. 3-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(1-(1-guanidine radicals oxygen ylmethyl) cyclopropyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
Adopt the process of embodiment 2 steps 6; 3-benzyl sulfuryl amino-the 6-methyl isophthalic acid-{ [N that makes by previous step; N ' two (tert-butoxycarbonyl)] [1-(1-(guanidine radicals oxygen ylmethyl) encircles amino) carbonyl methyl] }-2 pyridone (110mg; 0.166mmol) make title compound; be a kind of white solid (85mg, 89%).
1H-NMR(300MHz，DMSO-d
6)δ1.88(brs，1H)，8.78(s，1H)，8.60(s，1H)，7.73(brs，4H)，7.33(m，5H)，7.13(d，J＝7.5Hz，1H)，6.11(d，J＝7.7Hz，1H)，4.71(s，2H)，4.50(5，2H)，3.80(s，2H)，2.23(s，3H)，0.86(m，2H)，0.78(m，2H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
20H
26N
6O
5S:463.2 (M+H), 485.2 (M+Na); Measured value: 463.1,485.2.Embodiment 83-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(4-guanidine radicals oxygen base) piperidino carbonyl methyl]-2-pyridone trifluoroacetate
Adopt the process of embodiment 1 step 6-10 and embodiment 2 steps 5 and 6, make title compound, be a kind of colourless foam thing by the 4-hydroxy piperidine.
1H-NMR(300MHz，DMSO-d
6)δ11.14(s，1H)，8.57(s，1H)，7.74(brs，4H)，7.34(m，5H)，7.12(d，J＝7.6Hz，1H)，6.09(d，J＝7.9Hz，1H)，5.02(s，2H)，4.52(s，2H)，3.89(m，3H)，3.36(m，1H)，3.13(m，1H)，2.20(s，3H)，2.00(m，1H)，1.81(m，1H)，1.72(m，1H)，1.56(m，1H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
21H
28N
6O
5S:477.2 (M+H), 499.2 (M+Na), 515.1 (M+K); Measured value: 477.0,498.9,514.9.Embodiment 93-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1.3-benzyl chloride base SULPHURYL CHLORIDE
With the 3-chlorobenzyl chloride (1.61g, 10mmol) and Sulfothiorine (1.6g, 10mmol) mixture heating up in methyl alcohol (10mL) and water (10mL) refluxed 3 hours.Mixture is cooled to 0 ℃, adds Glacial acetic acid (10mL) and ice.The chlorine bubbling by the suspension that forms 40 minutes, is regularly added ice to keep ice/liquid mixture.After adding 1 hour, with mixture with extracted with diethyl ether (3 * 20mL), the extraction liquid after the merging with 5% sodium bisulfite (2 * 20mL) and salt solution (20mL) wash, use dried over sodium sulfate.After steaming solvent, resistates obtains title compound with flash column chromatography purifying (methylene dichloride), is a kind of white solid (1.5g, 67%).
1H-NMR(300MHz，CDCl
3)δ7.30-7.50(m，4H)，4.83(8，2H)。(2.3-3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-(tertiary butyloxycarbonyl ylmethyl)-2-pyridone
Adopt the process of embodiment 1 step 4, the 3-benzyl chloride base SULPHURYL CHLORIDE (113mg that makes by previous step, 0.5mmol) and 3-amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone (120mg of making of embodiment 1 step 3,0.5mmol) make title compound, be a kind of white solid (180mg, 84%).
1H-NMR(300MHz，CDCl
3)δ7.37(d，J＝7.6Hz，1H)，7.30(m，4H)，7.20(8，1H)，6.02(d，J＝7.7Hz，1H)，4.78(s，2H)，4.27(s，2H)，2.27(s，3H)，1.50(s，9H)。3. 3-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone
Adopt the process of embodiment 1 step 5, (170mg 0.4mmol) makes title compound to 3-(the 3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone that is made by previous step, is pale solid (150mg, 100%).
1H-NMR(300MHz，CDCl
3)δ8.83(s，1H)，7.45(8，1H)，7.37(m，3H)，7.18(d，J＝7.5Hz，1H)，6.11(d，J＝7.6Hz，1H)，4.79(s，2H)，4.56(s，2H)，2.27(s，3H)。4. 3-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-2-pyridone
Adopt the process of embodiment 2 steps 5; 3-(the benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone (140mg that makes by previous step; 0.38mmol) and [N that makes of embodiment 2 steps 4; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy guanidine (120mg; 0.38mmol) make title compound; be a kind of colourless foam thing (140mg, 57%).
1H-NMR(300MHz，CDCl
3)δ9.20(S，1H)，8.46(bRS，1H)，8.02(s，1H)，7.59(s，1H)，7.32(m，3H)，7.18(m，1H)，6.00(d，J＝7.7Hz，1H)，4.91(s，2H)，4.26(s，2H)，4.14(t，J＝5.3Hz，2H)，3.63(q，J＝5.2Hz，2H)，2.31(8，3H)，1.52(s，9H)，1.49(s，9H)。5. 3-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
Adopt the process of embodiment 2 steps 6; 3-(the 3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N that makes by previous step; N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-2-pyridone (140mg; 0.22mmol) make title compound; be a kind of white solid (95mg, 74%).
1H-NMR(300MHz，DMSO-d
6)δ11.00(s，1H)，8.74(s，1H)，8.49(t，J＝5.5Hz，1H)，7.74(bRS，4H)，7.45(s，1H)，7.40(m，3H)，7.18(d，J＝7.5Hz，1H)，6.12(d，J＝7.7Hz，1H)，4.75(8，2H)，4.56(5，2H)，3.83(t，J＝5.4Hz，2H)，3.41(m，2H)，2.26(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
23ClN
6O
5S:471.1 (M+H), 493.1 (M+Na), 509.1 (M+K); Measured value: 471.2,493.2,509.2.
Following compound (embodiment 10-embodiment 27) prepares according to mode similar to Example 9.Embodiment 103-(3-trifluoromethyl benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.97 (s, 1H), 8.79 (s, 1H), 8.50 (t, J=4.6Hz, 1H), 7.74 (brs, 4H), 7.68 (m, 4H), 7.17 (d, J=7.5Hz, 1H), 6.11 (d, J=7.5Hz, 1H), 4.74 (8,2H), 4.68 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.41 (m, 2H), 2.25 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
23F
3N
6O
5S:505.1 (M+H), 527.1 (M+Na), 543.1 (M+K); Measured value: 505.1,527.1,543.1.Embodiment 113-(2-trifluoromethyl benzyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.00 (s, 1H), 9.12 (s, 1H), 8.50 (t, J=5.5Hz, 1H), 7.75 (brs, 4H), 7.68 (m, 3H), 7.57 (m, 1H), 7.24 (d, J=7.6Hz, 1H), 6.16 (d, J=7.7Hz, 1H), 4.76 (s, 2H), 4.66 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.39 (m, 2H), 2.28 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
23F
3N
6O
5S:505.1 (M+H), 527.1 (M+Na); Measured value: 505.1,527.1.Embodiment 123-(2-iodine benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.06 (s, 1H), 8.90 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.89 (d, J=7.9Hz, 1H), 7.78 (brs, 4H), 7.52 (d, J=7.7Hz, 1H), 7.39 (t, J=7.5Hz, 1H), 7.24 (d, J=7.5Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 6.15 (d, J=7.7Hz, 1H), 4.75 (s, 2H), 4.65 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.41 (m, 2H), 2.27 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23IN
6O
5S:563.1 (M+H), 585.1 (M+Na); Measured value: 562.7,584.7.Embodiment 133-(2-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR(300MHz，DMSO-d
6)δ10.95(s，1H)，8.90(s，1H)，8.50(t，J＝5.5Hz，1H)，7.70(brs，4H)，7.54(d，J＝7.1Hz，1H)，7.48(d，J＝7.5Hz，1H)，7.36(t，J＝7.3Hz，2H)，7.20(d，J＝7.5Hz，1H)，6.14(d，J＝7.7Hz，1H)，4.75(s，2H)，4.66(s，2H)，3.83(t，J＝5.3Hz，2H)，3.41(m，2H)，2.27(8，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23ClN
6O
5S:471.1 (M+H), 493.1 (M+Na); Measured value: 470.7,492.7.Embodiment 143-(2-bromobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.99 (s, 1H), 8.91 (s, 1H), 8.50 (t, J=5.6Hz, 1H), 7.74 (brs, 4H), 7.65 (d, J=7.8Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.29 (t, J=7.7Hz, 1H), 7.21 (d, J=7.5Hz, 1H), 6.14 (d, J=7.7Hz, 1H), 4.75 (s, 2H), 4.67 (8,2H), 3.83 (t, J=5.3Hz, 2H), 3.41 (m, 2H), 2.27 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23BrN
6O
5S:515.1 (M+H), 537.1 (M+Na); Measured value: 514.8,536.7.Embodiment 153-(3-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR(300MHz，DMSO-d
6)δ10.92(8，1H)，8.73(s，1H)，8.49(t，J＝5.4Hz，1H)，7.69(brs，4H)，7.38(m，1H)，7.22(m，3H)，7.17(d，J＝7.5Hz，1H)，6.12(d，J＝7.7Hz，1H)，4.74(s，2H)，4.56(8，2H)，3.83(t，J＝5.3Hz，2H)，3.39(m，2H)，2.26(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23FN
6O
5S:455.2 (M+H), 477.1 (M+Na), 493.1 (M+K); Measured value: 455.3,477.3,493.2.Embodiment 163-(4-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.02 (s, 1H), 8.66 (8,1H), 8.50 (t, J=5.5Hz, 1H), 7.75 (brs, 4H), 7.39 (s, 4H), 7.16 (d, J=7.5Hz, 1H), 6.11 (d, J=7.6Hz, 1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.41 (m, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF. alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23ClN
6O
5S:471.1 (M+H), 493.1 (M+Na); Measured value: 471.1,493.1.Embodiment 173-((2-chloro-6-fluorine) benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.96 (s, 1H), 9.11 (s, 1H), 8.49 (t.J=5.5Hz, 1H).7.71(brs，4H)，7.45(dd，J＝8.1，2.1Hz，1H)，7.37(d，J＝7.6Hz，1H)，7.28(d，J＝8.1Hz，1H)，7.23(d，J＝7.5Hz，1H)，6.16(d，J＝7.8Hz，1H)，4.74(s，2H)，4.68(s，2H)，3.83(t，J＝5.4Hz，2H)，3.40(t，J＝5.3Hz，2H)，2.27(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22ClFN
6O
5S:489.1 (M+H), 511.1 (M+Na); Measured value: 488.9,510.9.Embodiment 183-(2-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.03 (s, 1H), 8.86 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.76 (brs, 4H), 7.47 (m, 2H), 7.20 (m, 3H), 6.13 (d, J=7.7Hz, 1H), 4.74 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.5Hz, 2H), 3.39 (t, J=5.6Hz, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23FN
6O
5S:455.2 (M+H), 477.1 (M+Na); Measured value: 455.0,477.1.Embodiment 193-(4-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.04 (s, 1H), 8.63 (s, 1H), 8.51 (t, J=5.6Hz, 1H), 7.76 (brs, 4H), 7.39 (m, 2H), 7.16 (m, 3H), 6.11 (d, J=7.7Hz, 1H), 4.74 (s, 2H), 4.53 (s, 2H), 3.84 (t, J=5.3Hz, 2H), 3.41 (t, J=5.5Hz, 2H), 2.25 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
23FN
6O
5S:455.2 (M+H), 477.1 (M+Na); Measured value: 455.0,476.9.Embodiment 203-(2,3-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.92 (s, 1H), 9.02 (s, 1H), 8.49 (t, J=5.5Hz, 1H), 7.69 (brs, 4H), 7.64 (d, J=8.0Hz, 1H), 7.54 (d, J=7.7.Hz, 1H), 7.36 (t, J=7.9Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 6.15 (d, J=7.7Hz, 1H), 4.75 (s, 4H), 3.83 (t, J=5.3Hz, 2H), 3.41 (t, J=5.5Hz, 2H), 2.27 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22Cl
2N
6O
5S:505.1 (M+H), 527.1 (M+Na); Measured value: 504.8,527.1.Embodiment 213-(3,4-difluorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2 guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.99 (s, 1H), 8.77 (s, 1H), 8.49 (t, J=5.5Hz, 1H), 7.67 (brs, 4H), 7.49 (m, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.19 (d, J=7.5Hz, 1H), 6.13 (d, J=7.7Hz, 1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.3Hz, 2H), 3.39 (t, J=5.4Hz, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22F
2N
6O
5S:473.1 (M+H), 495.1 (M+Na); Measured value: 473.1,495.1.Embodiment 223-(2,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.99 (s, 1H), 8.99 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.74 (brs, 4H), 7.66 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.44 (d, J=8.3Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 6.15 (d, J=7.9Hz, 1H), 4.75 (s, 2H), 4.66 (s, 2H), 3.83 (t, J=5.3Hz, 2H), 3.41 (t, J=5.2Hz, 2H), 2.27 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22Cl
2N
6O
5S:505.1 (M+H), 527.1 (M+Na); Measured value: 505.1,527.1.Embodiment 233-(2,5-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.95 (s, 1H), 9.07 (s, 1H), 8.49 (t, J=5.5Hz, 1H), 7.71 (brs, 4H), 7.66 (s, 1H), 7.52 (d, J=8.5Hz, 1H), 7.45 (d, J=8.6Hz, 1H), 7.24 (d, J=7.5Hz, 1H), 6.15 (d, J=7.8Hz, 1H), 4.76 (s, 2H), 4.67 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.38 (t, J=5.5Hz, 2H), 2.27 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22Cl
2N
6O
5S:505.1 (M+H), 527.1 (M+Na); Measured value: 505.1,526.9.Embodiment 243-(3,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 10.96 (s, 1H), 8.82 (s, 1H), 8.50 (t, J=5.5Hz, 1H), 7.72 (brs, 4H), 7.66 (s, 1H), 7.61 (d, J=8.3Hz, 1H), 7.60. (d, J=8.3Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 6.12 (d, J=7.7Hz, 1H), 4.75 (s, 2H), 4.59 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.38 (m, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
22Cl
2N
6O
5S:505.1 (M+H), 527.1 (M+Na); Measured value: 504.8,526.8.Embodiment 253-(1-naphthyl methyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.02 (s, 1H), 8.72 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 8.20 (m, 1H), 7.93 (m, 1H), 7.75 (brs, 4H), 7.67 (m, 1H), 7.53 (m, 4H), 7.16 (d, J=7.5Hz, 1H), 6.10 (d, J=7.5Hz, 1H), 5.08 (s, 2H), 4.74 (s, 2H), 3.84 (t, J=5.2Hz, 2H), 3.42 (t, J=5.3Hz, 2H), 2.26 (s, 3H).Mass spectrum (LCMS, ESI), calculated value: C
22H
26N
6O
5S:487.5 (M+H); Measured value: 487.8.Embodiment 263-(2-naphthyl methyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.06 (s, 1H), 8.62. (s, 1H), 8.52 (t, J=5.3Hz, 1H), 7.86 (m, 4H), 7.78 (brs, 4H), 7.52 (m, 3H), 7.21 (d, J=7.5Hz, 1H), 6.07 (d, J=7.7Hz, 1H), 4.74 (s, 2H), 4.69 (s, 2H), 3.85 (t, J=5.2Hz, 2H), 3.43 (t, J=5.3Hz, 2H), 2.22 (s, 3H).Mass spectrum (LCMS, ESI), calculated value: C
22H
26N
6O
5S:487.5 (M+H); Measured value: 487.1.Embodiment 273-(2-methyl-benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1H-NMR (300MHz, DMSO-d
6) δ 11.07 (s, 1H), 8.72 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.78 (brs, 4H), 7.21 (m, 4H), 7.12 (d, J=7.5Hz, 1H), 6.11 (d, J=7.7Hz, 1H), 4.75 (s.2H), 4.54 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.41 (t, J=5.4Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H).Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
5S:451.3 (M+H); Measured value: 451.2.Embodiment 283-(3-benzyl chloride base alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
The 3-that (1.3-3-benzyl chloride base alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-(tertiary butyloxycarbonyl ylmethyl)-2-pyridone makes to embodiment 9 steps 2 (3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-(tert-butoxycarbonyl methyl)-2-pyridone (190mg; 0.44mmol) and salt of wormwood (276mg; 2.0mmol) add in the suspension in acetonitrile (10mL) methyl iodide (142mg, 1.0mmol).Mixture at room temperature stirred spend the night.In mixture, add entry (50mL), with ethyl acetate (3 * 30mL) extractions.(2 * 30mL) wash drying to organic layer with salt solution.Solvent is steamed, obtain title compound, be a kind of colourless foam thing (195mg, 100%).
1H-NMR(300MHz，CDCl
3)δ7.51(s，1H)，7.48(d，J＝7.5Hz，1H)，7.33(m，3H)，6.11(d，J＝7.6Hz，1H)，4.75(s，2H)，4.38(s，2H)，3.22(s，3H)，2.33(s，3H)，1.49(s，9H)。2. 3-(3-benzyl chloride base alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) aminocarboxyl ethyl]-2-pyridone trifluoroacetate adopts the step 5 of embodiment 1 and the step 5 and 6 of embodiment 2; 3-(3-benzyl chloride base alkylsulfonyl)-N-methylamino-6 methyl isophthalic acid-(tert-butoxycarbonyl the methyl)-2-pyridone that is made by previous step makes title compound, is a kind of white solid.
1H-NMR(300MHz，DMSO-d
6)δ10.97(s，1H)，8.50(t，J＝5.5Hz，1H)，7.73(brs，4H)，7.53(s，1H)，7.42(m，3H)，7.37(d，J＝7.5Hz，1H)，6.12(d，J＝7.5Hz，1H)，4.76(s，2H)，4.53(s，2H)，3.83(t，J＝5.4Hz，2H)，3.39(t，J＝5.5Hz，2H)，3.05(s，3H)，2.31(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
25ClN
6O
5S:485.1 (M+H), 507.1 (M+Na); Measured value: 485.1,507.1.Embodiment 293-(3,4-dichloro benzyl alkylsulfonyl)-N-methylamino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To prepare title compound with embodiment 28 similar modes.
1H-NMR(300MHz，DMSO-d
6)δ10.97(s，1H)，8.51(t，J＝5.5Hz，1H)，7.74(brs，5H)，7.66(d，J＝8.2Hz，1H)，7.45(m，1H)，7.42(d，J＝7.5Hz，1H)，6.22(d，J＝7.6Hz，1H)，4.77(s，2H)，4.55(s，2H)，3.83(t，J＝5.3Hz，2H)，3.39(t，J＝5.6Hz，2H)，3.05(s，3H)，2.32(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
24Cl
2N
6O
5S:519.1 (M+H), 541.1 (M+Na); Measured value: 519.3,541.4.Embodiment 303-(2-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1. 3-(carbobenzoxy-(Cbz)) amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone
(6.0g adds trifluoroacetic acid (12mL) in methylene dichloride 17mmol) (12mL) solution to 3-benzyloxycarbonyl amino-6-methyl isophthalic acid-(tert-butoxycarbonyl the methyl)-2-pyridone that makes to embodiment 1 step 2, and reaction mixture is at room temperature stirred.After 30 minutes, the vacuum concentration reaction mixture is dissolved in the methylene dichloride, dilutes with hexane.Filter the product that collecting precipitation goes out, vacuum-drying obtains the white solid of quantitative yield.
1H-NMR(300MHz，DMSO-d
6)δ13.17(brs，1H)，8.36(s，1H)，7.74(d，1H，J＝7.5Hz)，7.33(m，5H)，6.18(d，1H，J＝7.7Hz)，5.15(s，2H)，4.77(s，2H)，2.25(s，3H)。2. 3-benzyloxycarbonyl amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-the 2-pyridone: 3-(carbobenzoxy-(Cbz)) amino-6-methyl isophthalic acid-carboxyl methyl-2-pyridone (0.85g that makes to previous step, 2.5mmol) and [N that makes of embodiment 2 steps 4, N '-two (tert-butoxycarbonyl)] 3-amino-1-oxyethyl group guanidine (0.86g, 2.7mmol) N, add N in dinethylformamide (42mL) solution, the N-diisopropyl ethyl amine (0.59mL, 3.4mmol) and Castro ' s reagent (BOP; 1.31g, 3.0mmol).At room temperature stir to stir after 2 hours, reaction mixture is carried out vacuum concentration, crude product was with 3: 1 ethyl acetate: hexane carries out recrystallization, obtains colourless solid.
1H-NMR(300MHz，DMSO-d
6)δ9.11(s，1H)，8.71(s，1H)，8.36(m，1H)，8.30(s，1H)，7.74(d，1H，J＝7.6Hz)，7.37(m，5H)，6.16(d，1H，J＝8.1Hz)，5.15(s，2H)，4.72(s，2H)，3.87(t，2H，J＝5Hz)，3.39(m，2H)，2.81(d，2H，J＝IIHz)，2.24(s，3H)，1.42(s，9H)，1.39(s，9H)。3. 3-amino-6-methyl isophthalic acid-{ [N, N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-the 2-pyridone: 3-benzyloxycarbonyl amino-the 6-methyl isophthalic acid-{ [N that makes to previous step, N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-(0.80g is 1.3mmol) at 2: 1 ethanol: add 10% palladium (O)/gac (64mg) in the solution in the tetrahydrofuran (THF) (96mL) for the 2-pyridone.After with the nitrogen degassing and backfill, reaction mixture was under atmospheric pressure stirred 1 hour in hydrogen, use diatomite filtration, filtrate is carried out vacuum concentration, obtain colourless solid, it is not purified can be used for next step.4. 3-(2-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N; N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl }-the 2-pyridone: 3-amino-the 6-methyl isophthalic acid-{ [N that makes to previous step; N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-2-pyridone (0.11g; 0.23mmol) methylene dichloride (4mL) solution in add 2-chlorobenzene sulfonyl chloride (0.048g; 0.23mmol) and N-methylmorpholine (0.024mL, 0.22mmol).After at room temperature stirring 4 hours, reactant dilutes with methylene dichloride, with saturated sodium bicarbonate aqueous solution, 10% citric acid solution and salt water washing.Isolate organic layer and carry out vacuum-evaporation, crude product is not purified can be used.5. 3-(2-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate: 3-(2-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N, N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-2-pyridone that previous step is made is dissolved in the methylene dichloride (about 4mL) and at room temperature handled 4 hours with pure trifluoroacetic acid (about 2mL).After evaporation, crude product is dissolved in the methylene dichloride, with saturated sodium bicarbonate aqueous solution, 10% aqueous citric acid solution and salt water washing, use dried over sodium sulfate, filter evaporation.With crude product silica gel Waters Sep-Pak purifying (gradient elution: the dichloromethane solution of 10-50% ethyl acetate), obtain title compound (0.11g, 89%).
1H-NMR(300MHz，DMSO-d
6)δ10.97(s，1H)，9.21(s，1H)，8.45(t，1H，J＝5.6Hz)，8.01(m，1H)，7.73(brs，4H)，7.64(m，2H)，7.49(m，1H)，7.21(d，1H，J＝7.6Hz)，6.08(d，1H，J＝7.9Hz)，4.64(s，2H)，3.80(t，2H，J＝5.3Hz)，3.40(m，2H)，2.19(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
17H
21N
6O
5SCl:479.1 (M+Na), 457.1 (M+H), measured value: 479.4,457.3.Embodiment 313-(4-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 30, (0.048g 0.23mmol) makes title compound to adopt the 4-chlorobenzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.94(s，1H)，9.50(s，1H)，8.41(t，1H，J＝5.6Hz)，7.80(m，2H)，7.69(brs，4H)，7.60(m，2H)，7.28(d，1H，J＝7.6Hz)，6.11(d，1H，J＝7.7Hz)，4.60(s，2H)，3.79(t，2H，J＝5.3Hz)，3.39(m，2H)，2.20(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
17H
21N
6O
5SCl:479.1 (M+Na), 457.1 (M+H), measured value: 479.4,457.0.Embodiment 323-(phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 30, (0.030mL 0.23mmol) makes title compound to adopt benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ11.00(s，1H)，9.34(s，1H)，8.43(t，1H，J＝5.5Hz)，7.82(m，2H)，7.75(brs，4H)，7.60(m，3H)，7.26(d，1H，J＝7.6Hz)，6.09(d，1H，J＝7.6Hz)，4.61(s，2H)，3.79(t，2H，J＝5.3Hz)，3.38(m，2H)，2.19(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
17H
21N
6O
5SCl:445.1 (M+Na), 423.1 (M+H), measured value: 445.1,423.0.Embodiment 333-(3-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 30, (0.048g 0.23mmol) makes title compound to adopt the 3-chlorobenzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ11.14(brs，1H)，9.63(s，1H)，8.45(brs，1H)，7.77(m，6H)，7.55(t，1H，J＝7.9Hz)，7.29(d，1H，J＝7.6Hz)，6.11(d，1H，J＝7.7Hz)，4.61(s，2H)，3.79(t，2H，J＝5.3Hz)，3.39(m，2H)，2.20(s，3H)。Mass spectrum (MALDI-TOP, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
17H
21N
6O
5SCl:479.1 (M+Na), 457.1 (M+H), measured value: 479.0,457.0.Embodiment 343-(2-methyl sulphonyl phenyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 30 similar modes.
1H-NMR(300MHz，DMSO-d
6)δ8.32(t，J＝5.5Hz，1H)，8.21(d，J＝7.6Hz，1H)，8.13(d，J＝7.5Hz，H)，7.92(m，2H)，7.43(d，J＝7.4Hz，1H)，6.21(brs，4H)，6.12(d，J＝7.5Hz，1H)，4.58(s，2H)，3.68(t，J＝5.4Hz，2H)，3.47(s，3H)，3.29(t，2H，J＝5.6Hz)，2.17(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
18H
24N
6O
5S
2: 501.1 (M+H), 523.1 (M+Na), 539.1 (M+K); Measured value: 501.1,523.3,539.4.Embodiment 353-(2-naphthalene sulfonyl base) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1. 3-(2-naphthalene sulfonyl base) amino-6-methyl isophthalic acid-{ [N; N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-the 2-pyridone: 3-amino-the 6-methyl isophthalic acid-{ [N that makes to embodiment 30 steps 3; N '-two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-2-pyridone (0.050g; 0.10mmol) methylene dichloride (2mL) solution in add 2-naphthalic sulfonic chloride (0.023g; to.10mmol) and diethylamino methyl-polystyrene resin (0.033g, about 0.10mmol).After at room temperature stirring 5 hours, add amino methyl polystyrene resin (0.10g, about 0.20mmol) and methylene dichloride (2mL), with reaction mixture restir 16 hours.The suspension that forms is poured among the silica gel Waters Sep-Pak, and with the dichloromethane solution wash-out of 10-50% ethyl acetate, the product of wash-out is carried out vacuum concentration, be directly used in next step.2. 3-(2-naphthalene sulfonyl base) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate: the product of previous step is dissolved in methylene dichloride (about 2mL), and at room temperature handled 4 hours with pure trifluoroacetic acid (about 1mL).After evaporation, crude product with silica gel Waters Sep-Pak purifying, with the dichloromethane solution wash-out of 5% methyl alcohol, is obtained title compound (0.007g, 12%).
1H-NMR(300MHz，DMSO-dJ?O?8.42(m，1H)，7.98(m，3H)，7.78(dd，1H，J＝8.7Hz，1.9Hz)，7.63(m，2H)，7.55(d，1H，J＝7.6Hz)，6.19(dd，1H，J＝7.7Hz，0.8Hz)，4.64(s，2H)，3.83(t，2H，J＝5Hz)，3.42(t，2H，J＝5Hz)，2.26(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SCl:473.3 (M+H), measured value: 473.2.Embodiment 363-(4-bromophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, adopt 4-bromobenzene sulfonyl chloride (0.026g, 0.10mmol) preparation title compound.
1H-NMR(300MHz，DMSO-d
6)δ10.90(s，1H)，9.51(s，1H)，8.41(t，1H，J＝5.6Hz)，7.71(m，8H)，7.28(d，1H，J＝7.5Hz)，6.11(d，1H，J＝7.7Hz)，4.60(s，2H)，4.11(m，2H)，3.79(t，2H，J＝5.3Hz)，3.40(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SBr:503.0 (M+H), measured value: 503.0.Embodiment 373-(4-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.020g 0.10mmol) makes title compound to adopt 4-fluorobenzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.90(s，1H)，9.41(s，1H)，8.41(t，1H，J＝5.7Hz)，7.87(m，2H)，7.68(brs，4H)，7.36(m，2H)，7.28(d，1H，J＝7.5Hz)，6.10(d，1H，J＝7.7Hz)，4.60(s，2H)，4.10(brd?s，2H)，3.79(t，2H，5.3Hz)，3.41(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, E1I), calculated value: C
17H
21N
6O
5SF:441.2 (M+H), measured value: 441.2.Embodiment 383-(4-iodophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.030g 0.10mmol), makes title compound to adopt Pipsyl Chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.95(s，1H)，9.48(s，1H)，8.42(t，1H，J＝5.6Hz)，7.91(d，2H，J＝8.6Hz)，7.72(brs，4H)，7.56(d，2H，J＝8.6Hz)，7.27(d，1H，J＝7.6Hz)，6.10(d，1H，J＝7.7Hz)，4.60(s，2H)，3.80(t，2H，J＝5.3Hz)，3.39(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SI:549.1 (M+H), measured value: 549.0.Embodiment 393-(4-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.021g 0.10mmol) makes title compound by 4-anisole SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.93(s，1H)，9.11(s，1H)，8.42(m，1H)，7.77(d，2H，J＝9.0Hz)，7.67(m，4H)，7.24(d，1H，J＝7.5Hz)，7.04(d，2H，J＝8.9Hz)，6.08(d，1H，J＝8.0Hz)，4.61(s，2H)，3.79(m，5H)，3.40(m，2H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24N
6O
6S:453.3 (M+H), measured value: 453.2.Embodiment 403-(4-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.021g 0.10mmol) makes title compound to adopt 4-Methyl benzenesulfonyl chlorine.
1H-NMR(300MHz，DMSO-d
6)δ10.93(s，1H)，9.21(s，1H)，8.43(t，1H，J＝5.5Hz)，7.70(m，6H)，7.33(d，2H，J＝8.2Hz)，7.24(d，1H，J＝7.6Hz)，6.08(d，1H，J＝7.8Hz)，4.61(s，2H)，4.10(m，2H)，3.79(t，2H，J＝5.3Hz)，3.41(m，2H)，2.35(s，3H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24N
6O
5S:437.3 (M+H), measured value: 437.2.Embodiment 413-(3-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.10mmol) makes title compound to adopt 3-(trifluoromethyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.86(s，1H)，9.76(s，1H)，8.40(t，1H，J＝5.5Hz)，8.15(s，1H)，8.09(d，1H，J＝8.0Hz)，8.01(d，1H，J＝7.9Hz)，7.76(t，1H，J＝7.9Hz)，7.67(brs，4H)，7.32(d，1H，J＝7.5Hz)，6.12(d，1H，J＝7.7Hz)，4.59(s，2H)，3.78(t，2H，J＝5.3Hz)，3.39(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
21N
6O
5SF
3: 491.2 (M+H), measured value: 491.1.Embodiment 423-(3,4-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, adopt 3, (0.025g 0.10mmol) makes title compound to the 4-two chloro phenylsulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.90(s，1H)，9.73(s，1H)，8.41(t，1H，J＝5.5Hz)，8.05(d，1H，J＝2.1Hz)，7.80(d，1H，J＝8.4Hz)，7.70(m，5H)，7.32(d，1H，J＝7.5Hz)，6.13(d，1H，J＝7.7Hz)，4.60(s，2H)，3.79(t，2H，J＝5.3Hz)，3.40(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SCl
2: 491.2 (M+H), measured value: 491.2.Embodiment 433-(3-chloro-4-fluoro-phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.023g 0.10mmol) makes title compound to adopt 4-fluorobenzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.86(s，1H)。9.64(s，1H)，8.40(t，1H，J＝5.6Hz)，8.05(dd，1H，J＝6.9Hz，2.3Hz)，7.79(ddd，1H，J＝8.7Hz，4.5Hz，2.3Hz)，7.65(brd?s，4H)，7.57(t，1H，J＝8.9Hz)，7.31(d，1H，J＝7.5Hz)，6.12(d，1H，J＝7.6Hz)，4.60(s，2H)，3.79(t，2H，J＝5.3Hz)，3.40(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SFCl:475.2 (M+H), measured value: 475.2.Embodiment 443-(4-isopropyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.10mmol) makes title compound to adopt 4-isopropyl benzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.87(s，1H)，9.25(s，1H)，8.43(t，1H，J＝5.5Hz)，7.77(d，2H，J＝8.4Hz)，7.66(br?s，4H)，7.41(d，2H，J＝8.4Hz)，7.25(d，1H，J＝7.6Hz)，6.09(d，1H，J＝7.7Hz)，4.62(s，2H)，3.79(t，2H，J＝5.3Hz)，3.39(m，2H)，2.95(p，1H，J＝6.9Hz)，2.21(s，3H)，1.19(d，6H，J＝6.9Hz)。Mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.3 (M+H), measured value: 465.2.Embodiment 453-(3-fluorophenyl alkylsulfonyl)-amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.020g 0.10mmol) makes title compound to adopt 3-fluorobenzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.86(s，1H)，9.58(s，1H)，8.41(t，1H，J＝5.5Hz)，7.59(m，8H)，7.9(d，1H，J＝7.6Hz)，6.11(d.1H，J＝7.6Hz)，4.61(s，2H)，3.79(t，2H，J＝5.3Hz)，3.41(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SF:441.2 (M+H), measured value: 441.1.Embodiment 463-(3,5-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, adopt 3, (0.025g 0.10mmol) makes title compound to the 5-two chloro phenylsulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.86(s，1H)，9.85(s，1H)，8.41(t，1H，J＝5.5Hz)，7.93(t，1H，J＝1.8Hz)，7.83(d，2H，J＝1.8Hz)，7.66(brs，4H)，7.33(d，1H，J＝7.6Hz)，6.14(d，1H，J＝7.6Hz)，4.62(s，2H)，3.79(t，2H，J＝5.3Hz)，3.40(m，2H)，2.22(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SCl
2: 491.2 (M+H), measured value: 491.2.Embodiment 473-(3,4-Dimethoxyphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, adopt 3, (0.023g 0.10mmol) makes title compound to 4-dimethoxy benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.84(s，1H)，9.13(s，1H)，8.42(t，1H，J＝5.6Hz)，7.65(br?s，4H)，7.41(m，2H)，7.26(d，1H，J＝7.5Hz)，7.05(d，1H，J＝9.1Hz)，6.09(d，1H，J＝7.9Hz)，4.62(s，2H)，3.79(m，9H)，3.40(m，2H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
7S:483.3 (M+H), measured value: 483.1.Embodiment 483-(2-thienyl sulphonyl base) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 35, (0.020g 0.11mmol) makes title compound to adopt 2-thiophene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.90(s，1H)，9.48(s，1H)，8.44(t，1H，J＝5.4Hz)，7.90(dd，1H.J＝5.0Hz，1.3Hz)，7.69(brs，4H)，7.61(dd，1H，J＝3.8Hz，1.3Hz)，7.33(d，1H，J＝7.6Hz)，7.12(dd，1H，J＝4.9Hz，3.8Hz)，6.14(d，1H，J＝7.7Hz)，4.63(s，2H)，3.79(t，2H，J＝5.3Hz)，3.37(m，2H)，2.22(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
15H
20N
6O
5S
2: 429.6 (M+H), measured value: 429.1.Embodiment 493-(1-naphthalene sulfonyl base) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt the 1-naphthalic sulfonic chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.73(s，1H)，8.74(m，1H)，8.40(t，1H，J＝5.6Hz)，8.21(m，2H)，8.08(m，1H)，7.67(m，7H)，7.18(d.1H，J＝7.5Hz)，6.04(d，1H，J＝8.0Hz)，4.55(s，2H)，3.77(t，2H，J＝5.3Hz)，3.32(m，2H)，2.15(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
24N
6O
5S:473.6 (M+H), measured value: 473.2.Embodiment 503-(2,4,6-trimethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.021g 0.10mmol) makes title compound to adopt 2-mesitylene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.93(s，1H)，8.94(s，1H)，8.43(t，1H，J＝5.5Hz)，7.71(brd?s，4H)，7.12(d，1H，J＝7.5Hz)，6.99(s，2H)，6.07(d，1H，J＝7.7Hz)，4.60(s，2H)，3.79(t，2H，J＝5.3Hz)，3.35(q，2H，J＝5.2Hz)，2.55(s，6H)，2.23(s，3H)，2.18(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.6 (M+H), measured value: 465.2.Embodiment 513-(2-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.019g 0.10mmol) makes title compound to adopt o-toluenesulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.27(s，1H)，8.43(t，1H，J＝5.5Hz)，7.81(dd，1H，J＝7.9Hz，1.2Hz)，7.70(m，4H)，7.49(td，1H，J＝7.5Hz，1.3Hz)，7.34(dd，2H，J＝11Hz，8Hz)，7.19(d，1H，J＝7.5Hz)，6.06(d，1H，J＝7.7Hz)，4.61(s，2H)，3.79(t，2H，J＝5.2Hz)，3.36(m，2H)，2.61(s，3H)，2.18(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24N
6O
5S:437.6 (M+H), measured value: 437.1.Embodiment 523-(2,5-3,5-dimethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.11mmol) makes title compound to adopt p-Xylol-2-SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.92(s，1H)，9.19(s.IH)，8.45(t，1H，J＝5.4Hz)，7.68(m，5H)，7.24(m，3H)。6.07(d，1H，J＝7.6Hz)，4.63(s，2H)，3.80(t，2H，J＝5.2Hz)，3.37(m，2H)，2.54(s，3H)，2.28(s，3H)，2.18(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
5S:451.6 (M+H), measured value: 451.1.Embodiment 533-(2-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.020g 0.10mmol) makes title compound to adopt 2-fluorobenzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，CD
3OD)δ7.85(t，1H，J＝7.5Hz)，7.63(m，1H)，7.43(d，1H，J＝7.7Hz)，7.27(m，2H)，6.17(d，1H，J＝7.7Hz)，4.70(s，2H)，3.94(t，2H，J＝5.0Hz)，3.49(t，2H，J＝5.0Hz)，2.29(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
6O
5SF:441.5 (M+H), measured value: 441.1.Embodiment 543-(2-chloro-6-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.10mmol) makes title compound to adopt 2-chloro-6-Methyl benzenesulfonyl chlorine.
1H-NMR(300MHz，DMSO-d
6)δ10.98(s，1H)，9.05(s，1H)，8.44(t，1H，J＝5.4Hz)，7.74(brs，4H)，7.46(m，2H)，7.34(m，1H)，7.20(d，1H，J＝7.5Hz)，6.09(d，1H，J＝7.8Hz)，4.62(s，2H)，3.79(t，2H，J＝5.3Hz)，3.36(m，2H)，2.63(s，3H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
23N
6O
5SCl:471.0 (M+H), measured value: 471.1.Embodiment 553-(3-bromo-6-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.029g 0.10mmol) makes title compound to adopt 5-bromo-2-anisole SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.88(s，1H)，8.67(s，1H)，8.45(t，1H，J＝5.6Hz)，7.79(m，2H)，7.68(brs，4H)，7.24(d，1H，J＝7.5Hz)，7.16(d，1H，J＝8.9Hz)，6.10(d，1H，J＝7.8Hz)，4.65(s，2H)，3.80(m，5H)，3.37(m，2H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
23N
6O
6SBr:533.0 (M+H), measured value: 533.0.Embodiment 563-(3-chloro-2-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt 3-chloro-2 Methyl benzenesulfonyl chlorine.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.65(s，1H)，8.43(t，1H，J＝5.5Hz)，7.81(dd，IH，J＝7.9Hz，0.8Hz)，7.69(m，5H)，7.33(t，1H，J＝8.0Hz)，7.23(d，1H，J＝7.6Hz)，6.08(d，1H，J＝7.7Hz)，4.61(s，2H)，3.80(t，2H，J＝5.3Hz)，3.36(m，2H)，2.65(s，3H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
23N
6O
5SCl:471.0 (M+H), measured value: 471.1.Embodiment 573-(2-chloro-5-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.027g 0.10mmol) makes title compound to adopt 2-chloro-5 (trifluoromethyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.90(s，1H)，8.43(t，1H，J＝5.5Hz)，8.31(d，1H，J＝1.8Hz)，8.01(dd，1H，J＝8.5Hz，2.0Hz)，7.90(d，1H，J＝8.3Hz)，7.69(brs，4H)，7.32(d，1H，J＝7.6Hz)，6.13(d，1H，J＝7.8Hz)，4.64(s，2H)，3.79(t，4H，J＝5.4Hz)，3.35(m，2H)，2.22(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
20N
6O
5SClF
3: 525.0 (M+H), measured value: 525.1.Embodiment 583-(2,4 dichloro benzene base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.10mmol) makes title compound to adopt the 2,4 dichloro benzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.46(s，1H)，8.43(t，1H，J＝5.5Hz)，7.96(d，1H，J＝8.6Hz)，7.86(d，1H，J＝2.1Hz)，7.69(brs，4H)，7.57(dd，1H，J＝8.6Hz，2.1Hz)，7.23(d，1H，J＝7.6Hz)，6.10(d，1H，J＝7.7Hz)，4.62(s，2H)，3.80(t，2H，J＝5.2Hz)，3.37(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SCl
2: 491.4 (M), measured value: 491.1.Embodiment 593-(4-ethenylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.021g 0.11mmol) makes title compound to the vinylbenzene SULPHURYL CHLORIDE in employing.
1H-NMR(300MHz，DMSO-d
6)δ10.92(s.1H)，9.34(s，1H)，8.42(t.1H，J＝5.4Hz)，7.79(d，2H，J＝8.4Hz)，7.71(brs.4H)，7.62(d，2H，J＝8.4Hz)，7.26(d，1H，J＝7.6Hz)，6.78(dd，1H，J＝17.7Hz，11.0Hz)，6.09(d，1H，J＝7.7Hz)，5.99(d，1H，J＝17.6Hz)，5.44(d，1H，J＝11.1Hz)，4.60(s，2H)，3.78(t，2H，J＝5.2Hz)，3.35(m，2H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
24N
6O
5S:449.6 (M+H), measured value: 449.2.Embodiment 603-(2-butoxy-5-(1, the 1-dimethyl propyl) phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, 2-(n-butoxy)-(0.033g 0.10mmol) makes title compound to 5-(2 '-isopentyl) benzene sulfonyl chloride in employing.
1H-NMR (300MHz, DMSO-d
6) δ 10.88 (brd s, 1H), 8.44 (br s, 1H), 8.11 (s, 1H), 7.68 (m, 5H), 7.53 (dd, 1H, J=8.7Hz, 2.4Hz), 7.16 (d, 1H, J=7.6Hz), 7.10 (d, 1H, J=8.8Hz), 6.03 (d, 1H, J=7.8Hz), 4.66 (s, 2H), 4.01 (t, 2H, J=6.4Hz), 3.80 (t, 2H, J=5.2Hz), 3.39 (m, 2H), 2.14 (s, 3H), 1.76 (m, 2H), 1.57 (m, 2H), 1.47 (m, 2H), 1.22 (s, 6H), 0.94 (t, 3H, J=7.4Hz), 0.55 (t, 3H, J=7.3Hz). mass spectrum (LCMS, ESI), calculated value: C
26H
40N
6O
6S:565.8 (M+H), measured value: 565.2.Embodiment 613-(3-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.10mmol) makes title compound to adopt the 3-nitrobenzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.81(brs，1H)，9.85(brs，1H)，8.56(t，1H，J＝1.9Hz)，8.43(dd，1H，J＝8.3Hz，1.4Hz)，8.34(m，1H)，8.18(d，1H，J＝8.2Hz)，7.81(t，1H，J＝8.0Hz)，7.60(brs，4H)，7.34(d，1H，J＝7.6Hz)，6.13(d，1H，J＝7.7Hz)，4.55(s，2H)，3.77(m，2H)，3.38(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
7O
7S:468.2 (M+H), measured value: 469.2.Embodiment 623-(4-chloro-3-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.026g 0.10mmol) makes title compound to adopt 4-chloro-3 nitrobenzene sulfonyl chlorides.
1H-NMR(300MHz，DMSO-d
6)δ10.90(brs，1H)，9.92(brs，1H)，8.44(d，1H，J＝2.1Hz)，8.38(t，1H，J＝5.6Hz)，8.02(dd，1H，J＝8.5Hz，2.1Hz)，7.92(d，1H.J＝8.5Hz)，7.68(brs，4H)，7.36(d，1H，J＝7.5Hz)，6.15(d，1H，J＝7.9Hz)，4.58(brs，2H)，3.79(t，2H，J＝5.4Hz)，3.38(m，2H)，2.22(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
7O
7SCl:502.0 (M+H), measured value: 502.1.Embodiment 633-(4-methyl carbonylamino phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt 4-(acetylamino) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.86(brs，1H)，10.32(s，1H)，9.13(s，1H)，8.41(t，1H，J＝5.5Hz)，7.76(d，2H，J＝8.9Hz)，7.69(d，2H，J＝9.0Hz)，7.63(brs，4H)，7.23(d，1H，J＝7.6Hz)，6.08(d，1H，J＝8.1Hz)，4.61(s，2H)，3.79(t，2H，J＝5.4Hz)，3.39(m，2H)，2.19(s，3H)。2.07(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
25N
7O
6S:480.2 (M+H), measured value: 480.2.Embodiment 643-(4-tert-butyl-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt 4-(tertiary butyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.85(s，1H)，9.27(s，1H)，8.43(t，1H，J＝5.4Hz)，7.79(d，2H，8.5Hz)，7.65(brs，4H)，7.56(d，2H，J＝8.6Hz)，7.25(d，1H，J＝7.6Hz)，6.09(d，1H，J＝7.9Hz)，4.62(s，2H)，3.79(t，2H，J＝5.3Hz)，3.40(m，2H)，2.19(s，3H)。1.28(s，9H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
30N
6O
5S:479.3 (M+H), measured value: 479.2.Embodiment 653-(4-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.10mmol) makes title compound to adopt 4-(trifluoromethyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.92(s，1H)，9.73(s，1H)，8.40(t，1H，J＝5.5Hz)，8.01(d，2H，J＝8.2Hz)，7.91(d，2H，J＝8.5Hz)，7.69(brs，4H)，7.31(d，1H，J＝7.5Hz)，6.12(d，1H，J＝8.0Hz)，4.59(s，2H)，3.78(t，2H，J＝5.3Hz)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
21N
6O
5SF
3: 491.2 (M+H), measured value: 491.2.Embodiment 663-(3-cyano-phenyl alkylsulfonyl) amino-6-methyl-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.020g 0.10mmol) makes title compound to adopt 3-cyano group benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.91(brs，1H)，9.73(brs，1H)，8.40(t，1H，J＝5.6Hz)，8.27(t，1H.J＝1.6Hz)，8.09(dd，1H，J＝7.9Hz，1.6Hz)，7.72(m，5H)，7.33(d，1H，J＝7.5Hz)，6.12(d，1H，J＝7.6Hz)，4.59(s，2H)，4.10(brs，2H)，3.79(t，2H，J＝5.3Hz)，3.38(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
21N
7O
5S:448.2 (M+H), measured value: 449.2.Embodiment 673-(4-methyl sulphonyl phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.024g 0.10mmol) makes title compound to adopt 4-(methyl sulphonyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.87(s，1H)，9.78(s，1H)，8.40(t，1H，J＝5.4Hz)，8.06(s，4H)，7.66(brs，4H)，7.32(d，1H，J＝7.5Hz)，6.12(d，1H，J＝7.8Hz)，4.59(s，2H)，3.78(t，2H，J＝5.2Hz)，3.40(m，2H)，3.28(s，3H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
24N
6O
7S
2: 501.2 (M+H), measured value: 501.1.The red sulfonamido of embodiment 683--6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, adopt dansyl chloride (0.027g.0.10mmol) to make title compound.
1H-NMR(300MHz，DMSO-d
6)δ10.98(s，1H)，9.66(s，1H)，8.39(m，3H)，8.20(d，1H，J＝7.3Hz)，7.75(brs，4H)，7.58(m，2H)，7.25(d，1H，J＝7.6Hz)，7.16(d，1H，J＝7.6Hz)，6.04(d，1H，J＝7.7Hz)，4.59(s.2H)，3.79(t，2H.J＝5.1Hz)，3.35(m，2H)，2.82(s，6H)，2.15(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
23H
29N
7O
5S:516.7 (M+H), measured value: 516.2.Embodiment 693-(pentafluorophenyl group alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.028g 0.11mmol) makes title compound to adopt the penta fluoro benzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，CD
3OD)δ7.55(d，1H，J＝7.6Hz)，6.27(d，1H，J＝7.6Hz)，4.68(s，2H)，3.94(t，2H，J＝5.0Hz)，3.48(t，2H.J＝5.0Hz)，2.33(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
16H
17N
6O
5SF
5: 513.5 (M+H), measured value: 513.1.Embodiment 703-(2,5-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, adopt 2, (0.025g 0.10mmol) makes title compound to the 5-two chloro phenylsulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，9.68(s，1H)，8.44(t，1H，J＝5.5Hz).8.03(d，1H，J＝2.1Hz)，7.70(m，6H)，7.29(d，1H，J＝7.6Hz)，6.13(d，1H，J＝7.9Hz)，4.65(s，2H)，3.80(t，2H，J＝5.2Hz)，3.39(m，2H)，2.22(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SCl
2: 491.0 (M+H), measured value: 491.1.Embodiment 713-(2-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt the 2-nitrobenzene sulfonyl chloride.
1H-NMR(300MHz，CD
3OD)δ8.00(dd，1H，J＝7.6Hz，1.7Hz)，7.91(dd，1H，J＝7.8Hz，1.4Hz)，7.77(m，2H)，7.59(d，1H，J＝7.6Hz)，6.26(dd，1H，J＝7.7Hz，0.8Hz)，4.70(s，2H)，3.92(t，2H，J＝5.2Hz)，3.48(t，2H，J＝5.2Hz)，2.31(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
21N
7O
7S:468.5 (M+H), measured value: 468.1.Embodiment 723-two (4-nitrophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.10mmol) makes title compound to adopt the 4-nitrobenzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ11.17(s，1H)，8.43(d，4H，J＝8.9Hz)，8.12(d，4H，J＝8.9Hz)，7.84(m，4H)，7.60(d.1H，)＝7.6Hz)，6.34(d，1H，J＝7.8Hz)，4.63(s，2H)，3.82(m，2H)，3.38(m，2H)，2.29(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
23H
24N
8O
11S
2: 653.6 (M+H), measured value: 653.1.Embodiment 733-(2,5-Dimethoxyphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, adopt 2, (0.023g 0.10mmol) makes title compound to 5-dimethoxy benzene sulfonyl chloride.
1H-NMR(300MHz，CD
3OD)δ7.38(d，1H，J＝7.7Hz)，7.35(d，1H，J＝2.8Hz)，7.12(dd，1H，J＝9.0Hz，2.8Hz)，7.04(d，1H，J＝9.0Hz)，6.13(d，1H，J＝7.7Hz)，4.73(s，2H)，3.95(t，2H，J＝5.0Hz)，3.83(s，3H)，3.76(s，3H)，3.50(t.2H，J＝5.1Hz).2.26(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
7S:483.6 (M+H), measured value: 483.1.Embodiment 743-(4-propyl group phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.022g 0.10mmol) makes title compound to adopt 4-n-propylbenzene SULPHURYL CHLORIDE.
1H-NMR (300MHz, CD
3OD) δ 7.70 (m, 2H), 7.47 (d, 1H, J=7.6Hz), 7.30 (d, 2H, J=7.9Hz), 6.19 (d, 1H, J=7.7Hz), 4.70 (s, 2H), 3.93 (t, 2H, J=5.0Hz), 3.48 (t, 2H, J=5.0Hz), 2.63 (t, 2H, J=7.6Hz), 2.29 (s, 3H), 1.63 (sextet, 2H, J=7.5Hz), 0.92 (t, 3H, J=7.3Hz). mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.6 (M+H), measured value: 465.2.Embodiment 753-(2-methyl-5-nitro phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.024g 0.10mmol) makes title compound to adopt 2-methyl-5 nitrobenzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ11.04(s，1H)，9.87(s，1H)，8.45(d，1H，J＝2.5Hz)，8.38(t，1H，J＝5.5Hz)，8.30(dd，1H.J＝8.4Hz，2.5Hz)，7.77(brs，4H)，7.65(d，1H，J＝8.5Hz)，7.32(d，1H，J＝7.5Hz)，6.12(d，1H，J＝7.6Hz)，4.55(s，2H)，3.78(t，2H，J＝5.3Hz)，3.32(m，2H)，2.75(s，3H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
23N
7O
7S:482.5 (M+H), measured value: 482.1.Embodiment 763-(2-trifluoromethyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.10mmol) makes title compound to adopt 2-(trifluoromethyl) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.95(s，1H)，9.50(s，1H)，8.45(t，1H，J＝5.4Hz)，8.15(m，1H)，7.98(m，1H)，7.80(m，2H)，7.73(brs，4H)，7.28(d，1H，J＝7.6Hz)，6.12(d，1H，J＝7.7Hz)，4.63(s，2H)，3.80(t，2H，J＝5.2Hz)，’3.36(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
21N
6O
5SF
3: 491.5 (M+H), measured value: 491.1.Embodiment 773-(2,3-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, adopt 2, (0.023g 0.09mmol) makes title compound to the 3-two chloro phenylsulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ11.02(s，1H)，9.58(s，1H)。8.45(t，1H，J＝5.5Hz)，7.97(dd，1H，J＝8.0Hz，1.3Hz)，7.91(dd，1H，J＝8.1Hz，1.3Hz)，7.77(brs，4H)，7.50(t，1H，J＝8.0Hz)，7.24(d，1H，J＝7.5Hz)，6.10(d，1H，J＝7.7Hz)，4.63(s，2H)，3.80(t，2H，J＝5.2Hz)，3.36(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SCl
2: 491.0 (M+H), measured value: 491.1.Embodiment 783-(2-Trifluoromethoxyphen-l alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.10mmol) makes title compound to adopt 2-(trifluoromethoxy) benzene sulfonyl chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.93(s，1H)，9.31(s，1H)，8.44(t，1H，J＝5.5Hz)，7.98(dd，1H，J＝7.9Hz，1.6Hz).7.75(m，5H)，7.51(m，2H)，7.26(d，1H.J＝7.5Hz)，6.11(d.1H，J＝7.7Hz)，4.63(s，2H)，3.80(t，2H，J＝5.3Hz)，3.36(m，2H)，2.21(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
21N
6O
6SF
3: 507.5 (M+H), measured value: 507.1.Embodiment 793-(4-(3-chloro-2-cyano-benzene oxygen) phenyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.032g 0.10mmol) makes title compound to benzene sulfonyl chloride to adopt 4-(3-chloro-2-cyano-benzene oxygen).
1H-NMR(300MHz，DMSO-d
6)δ10.95(s，1H)，9.43(s，1H)，8.43(t，1H.J＝5.3Hz)，7.89(d，2H，J＝8.7Hz)，7.72(m，5H)，7.57(d，1H，J＝8.1Hz)，7.30(m，3H)，7.11(d，1H，J＝8.4Hz)，6.11(d，1H，J＝7.7Hz)，4.61(s，2H)，3.79(t，2H，J＝5.0Hz)，3.34(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
24H
24N
7O
6SCl:574.0 (M+H), measured value: 574.1.Embodiment 803-(2-chloro-4-fluorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.023g 0.10mmol) makes title compound to adopt 2-chloro-4-fluorobenzene SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.92(m，1H)，9.34(s，1H)，8.44(t，1H，J＝5.5Hz)，8.04(dd，1H，J＝8.9Hz，5.9Hz)，7.69(m.5H)，7.36(m，1H)，7.23(d，1H，J＝7.6Hz)，6.10(d，1H，J＝7.7Hz)，4.63(s，2H)，3.80(t，2H，J＝5.0Hz)，3.37(m，2H)，2.20(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SClF:475.0 (M+H), measured value: 475.1.Embodiment 813-(5-chloro-2-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.025g 0.11mmol) makes title compound to adopt 5-chloro-2-anisole SULPHURYL CHLORIDE.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，8.67(s，1H)，8.44(t，1H，J＝5.4Hz)，7.68(m，6H)，7.23(m，2H)，6.10(d，1H，J＝7.8Hz)，4.65(s，2H)，3.79(m，5H)，3.38(m，2H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
18H
23N
6O
6SCl:487.0 (M+H), measured value: 487.1.Embodiment 823-(2-methoxyl group-5-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, methoxyl group-(0.023g 0.11mmol) makes title compound to 5-Methyl benzenesulfonyl chlorine to adopt 2-.
1H-NMR(300MHz，DMSO-d
6)δ10.88(s，1H)，8.45(t，1H，J＝5.5Hz)，8.29(s.1H)，7.68(brs，4H)，7.58(d.1H，J＝1.9Hz)，7.40(dd，1H，J＝8.5Hz，1.9Hz)，7.20(d，1H.J＝7.6Hz)，7.07(d，1H，J＝8.5Hz)，7.16(d，1H，J＝8.9Hz)，6.07(d，1H，J＝7.7Hz)，4.65(s，2H)，3.80(m，5H)，3.39(m，2H)，2.27(s，3H)，2.17(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
6S:467.6 (M+H), measured value: 467.1.Embodiment 833-(4-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.026g 0.10mmol) makes title compound to adopt 4-phenyl benzene sulfonyl chloride.
1H-NMR (300MHz, DMSO-d
6) δ 10.90 (s.1H), 9.41 (s, 1H), 8.42 (t, 1H, J=5.4Hz), 7.91 (d, 2H, J=8.5Hz), 7.83 (d, 2H, J=8.5Hz), 7.71 (m, 6H), 7.46 (m, 3H), 7.31 (d, 1H, J=7.6Hz), 6.11 (d, 1H, J=7.7Hz), 4.61 (s, 2H), 3.76 (t, 2H, J=5.0Hz), 3.37 (m, 2H), 2.19 (s, 3H), mass spectrum (LCMS, ESI), calculated value: C
23H
26N
6O
5S:499.6 (M+H), measured value: 499.2.Embodiment 843-(5-chlorothiophene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, chlorothiophene-(0.023g 0.11mmol) makes title compound to the 2-SULPHURYL CHLORIDE to adopt 5-.
1H-NMR(300MHz，DMSO-d
6)δ10.93(s，1H)，9.76(s，1H)，8.44(t，1H，J＝5.5Hz)，7.67(brs，4H)。7.46(d，1H，J＝4.1Hz)，7.34(d，1H.J＝7.5Hz)，7.18(d，1H.J＝4.1Hz)，6.16(d，1H，J＝7.7Hz)，4.64(s，2H)，3.80(t，2H，J＝5.2Hz)，3.38(m，2H)，2.24(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
15H
19N
6O
5S
2Cl:463.0 (M+H), measured value: 463.1.Embodiment 853-(6-chloronaphthalene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.026g 0.10mmol) makes title compound to adopt 2-(6-chlorine) naphthalic sulfonic chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.87(s，1H)，9.53(s，1H)，8.53(s，1H)，8.38(t，1H，J＝5.5Hz)，8.17(m，2H)，8.05(d，1H，J＝8.8Hz)，7.91(dd，1H，J＝8.7Hz，1.8Hz)，7.68(m，5H)，7.32(d，1H，J＝7.6Hz)，6.09(d，1H，J＝7.9Hz)，4.56(s，2H)，3.76(t，2H，J＝5.2Hz)，3.36(m，2H)，2.17(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
23N
6O
5SCl:507.0 (M+H), measured value: 507.1.Embodiment 863-(6-bromonaphthalene-2-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 35 described processes, (0.033g 0.11mmol) makes title compound to adopt 2-(6-bromine) naphthalic sulfonic chloride.
1H-NMR(300MHz，DMSO-d
6)δ10.85(s，1H)，9.53(s，1H)，8.52(s，1H)，8.38(t，1H，J＝5.4Hz)，8.33(s，1H)，8.11(d，1H.J＝8.8Hz)，8.04(d，1H，J＝8.8Hz)，7.90(dd，1H，J＝8.7Hz，1.6Hz)，7.79(dd.IH.J＝8.8Hz，1.8Hz)，7.66(brs，4H)，7.32(d，1H，J＝7.6Hz)，6.08(d，1H，J＝7.7Hz)，4.56(s，2H)，3.76(t，2H，J＝5.2Hz)，3.39(m，2H)，2.17(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
23N
6O
5SBr:553.0 (M+H), measured value: 553.0.Embodiment 873-(3-bromophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As embodiment 2 described processes, (0.128g 0.501mmol) makes title compound to adopt the 3-bromobenzene sulfonyl chloride.
1H-NMR(300MHz，CD
3OD)δ7.98(t，1H.J＝1.8Hz)，7.75(m，2H)，7.50(d，1H，J＝7.6Hz)，7.40(t，1H，J＝8.0Hz)，6.22(d，1H，J＝7.6Hz)，4.69(s，2H)，3.93(t，2H，J＝5.2Hz)，3.49(t，2H，J＝5.2Hz)，2.31(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
6O
5SBr:501.5 (M+H), measured value: 501.3.Embodiment 883-(quinoline-8-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 30 similar modes.
1H-NMR(300Hz，CD
3OD)δ9.06-9.05(m，1H)，8.40-8.37(m，2H)，8.16(d，J＝7.0Hz，1H)，7.68-7.59(m，3H)，6.06(d，J＝7.6Hz，1H)，4.57(s，2H)，3.71(t，J＝10.5Hz，2H)，3.34-3.33(m，2H)，2.17(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
20H
23SO
5N
7: 474.4 (M+H); Measured value: 474.3.Embodiment 893-(quinoline-5-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 30 similar modes.
1H-NMR(300Hz，CD
3OD)δ9.32(brs，1H)，8.62-8.30(rn，4H)，7.73-7.70(m.1H)，7.28(brs，1H)，6.12(d，J＝6.6Hz，1H)，4.62(s，2H)，3.64(brs，2H)，3.37(brs，2H)，2.23(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
20H
23SO
5N
7: 474.4 (M+H); Measured value: 474.3.Embodiment 903-(1-Methylimidazole-4-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 30 similar modes.
1H-NMR(300Hz，CD
3OD)δ7.73(brs，2H)，7.36(d，1H)，6.37-6.35(m，2H)，4.89(s，2H)，3.86(bs，2H)，3.43(brs，2H)，3.34(s，3H)，2.34(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
15H
22SO
5N
8: 427.4 (M+H); Measured value 427.4.Embodiment 913-(3-toluquinoline-8-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 30 similar modes.
1H-NMR(300Hz，CD
3OD)δ8.89(d，J＝2.2Hz，1H)，8.30(dd，J＝1.3，7.3Hz，1H)，8.17-8.16(m，1H)，8.10(dd，J＝1.3，7.0Hz，1H)，7.62(t，J＝7.4Hz，1H)，7.50(d，J＝7.6Hz，1H)，6.09(d，J＝7.1Hz，1H)，4.59(s，2H)，3.90(t，J＝5.1Hz，2H)，2.55(s，3H)，2.19(S，3H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
26SO
5N
7: 488.5 (M+H); Measured value 488.5.Embodiment 923-(2-pyridyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1. 3-(2-pyridyl sulfonyl) amino-6-methyl isophthalic acid-{ [N, N '-two (tertbutyloxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-2-pyridone
Under 0 ℃, (500mg, bubbling fed chlorine 1 hour to the 2-mercaptopyridine in stirring 4.5mmol) and in the mixture of 1N HCl (5mL).(dried over sodium sulfate is used in 3 * 50mL) extractions, concentrates, and obtains a kind of clarifying oil, and it is used immediately with methylene dichloride with reaction mixture.With N, N-dimethyl aminopyridine (200mg) adds to the 2-pyridine SULPHURYL CHLORIDE (50mg in the stirring, 0.178mmol) and 3-amino-6-methyl isophthalic acid-{ [N of making of embodiment 30 steps 3, N ' two (tert-butoxycarbonyl)] [3-(guanidine radicals oxygen base ethyl) aminocarboxyl] }-(78mg is 0.162mmol) in the mixture in methylene dichloride (2mL) for the 2-pyridone.Reaction mixture was stirred 16 hours, and vacuum concentration carries out purifying (4% methyl alcohol/96% methylene dichloride) with silica gel column chromatography, obtains title compound, is a kind of white solid (34mg, 30%).Mass spectrum (LCMS, ESI), calculated value: C
26H
37SO
9N
7: 624.6 (M+H); Measured value 624.1.2. 3-(2-pyridyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
3-(2-pyridyl sulfonyl) amino-6-methyl isophthalic acid-{ [N in stirring; N ' two (tert-butoxycarbonyl)] [2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl] }-(34mg 0.055mmol) adds trifluoroacetic acid (0.5mL) in the mixture in methylene dichloride (1mL) to the 2-pyridone.Reaction mixture was at room temperature stirred 2 hours, and go up purifying (10% methyl alcohol/89% methylene dichloride, 1% trifluoroacetic acid), obtain title compound, be a kind of yellow solid (9mg, 39%) at Waters Sep-Pak (2g).
1H-NMR(300Hz，CD
3OD)δ8.92(s，1H)，8.70(brs，1H)，8.15(d，J＝8.0Hz，1H)，7.57-7.49(m，2H)，6.23(d.J＝7.6Hz，1H)，4.67(s，1H)，3.91(t，J＝5.0Hz，2H)，3.47(t，J＝5.0Hz，2H)，2.30(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
16H
21SO
5N
7: 424.4 (M+H); Measured value 424.1.Embodiment 933-(3-pyridyl sulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 92 similar modes.1H-NMR(300Hz，CD3OD)δ8.92(brs，1H)，8.70(brs，1H)，8.16(d，J＝8.0Hz，1H)，7.57-7.49(m，2H)，6.23(d，J＝7.6Hz，1H)，4.67(s，2H)，3.9(t，J＝5.0Hz，2H)，3.47(t，J＝5.0Hz，2H)，2.30(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
16H
21SO
5N
7: 424.4 (M+H); Measured value 424.1.Embodiment 943-(4-ethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the embodiment 2, (0.102g 0.498mmol) makes title compound to adopt 4-ethylbenzene SULPHURYL CHLORIDE.
1H-NMR (300MHz, CD
3OD) δ 7.71 (d, 2H, J=8.4Hz), 7.47 (d, 1H, J=7.6Hz), 7.31 (d, 2H, J=8.4Hz), 6.19 (dd, 1H, J=7.7Hz, 0.5Hz), 4.71 (s, 2H), 3.93 (t, 2H, J=5.1Hz), 3.48 (t, 2H, J=5.1Hz), 2.68 (q, 2H, J=7.6Hz), 2.29 (s, 3H), 1.22 (t, 3H, J=7.6Hz). mass spectrum (LCMS, ESI), calculated value: C
19H
25N
6O
5S:450.5 (M+H), measured value: 451.2.Embodiment 953-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl)-N-methylamino carbonyl methyl]-2-pyridone trifluoroacetate
As process as described in the step 5 and 6 of the step 6-10 of embodiment 1 and embodiment 2, adopt 2-(methylamino) ethanol to make title compound.
1H-NMR(300Hz，CD
3OD)δ7.65(m，2H)，7.35(m，2H)，6.16(m，1H)，5.04-5.01(m，2H)，3.97-3.92(m，2H)，3.69-3.63(m，2H)，3.29(s，3H)，2.36(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26SO
5N
6: 451.4 (M+H); Measured value: 451.4.Embodiment 963-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
1. 3-cyano group-6-sec.-propyl-2 (1H)-pyridone:
Under nitrogen atmosphere, anhydrous tetrahydro furan (100mL) solution of 3-cyano group-6-methyl 2 (1H)-pyridone (10.0g.74.6mmol) is cooled to-78 ℃, lentamente with the lithium diisopropylamine solution (40mL that injects through syringe, 1.4M, add 85mL again, 2.0M, 226mmol altogether) reaction.After being warming up to 0 ℃, restir 2 hours, (10mL 160mmol) at room temperature stirred 18 hours again to add methyl-iodide.Reactant is poured in the sodium hydroxide (300mL) of 0.67N, be separated, water layer washs with ether, the organic layer water extraction after the merging.Water layer after the merging with the 6N hcl acidifying to pH be 4, use dichloromethane extraction again, dichloromethane layer salt water washing without dried over sodium sulfate, is filtered.Filtrate is carried out vacuum concentration, with resistates with flash column chromatography (1: 1 methylene dichloride: ethyl acetate) purifying, obtain title compound, be a kind of lurid solid (2.15g, 18%).
1H-NMR (300MHz, CDCl
3) δ 13.25 (brs, 1H), 7.84 (d, 1H, J=7.5Hz), 6.23 (d, 1H, J=7.5Hz), 3.00 (septet, 1H, J=7.0Hz), 1.36 (s, 3H), 1.34 (s, 3H).Also reclaimed monomethylation by product 3-cyano group-6-ethyl-2 (1H) pyridone (5.50g, 50%) from post.It can be used for preparing the title compound of embodiment 97.
1H-NMR(300MHz，CDCl
3)δ7.84(d.J＝7.5Hz，1H)，6.23(d，J＝7.4Hz，1H)，2.76(q，J＝7.6Hz，2H)，1.35(t，J＝7.5Hz，3H)。2. 3-carboxyl-6-sec.-propyl-2 (1H)-pyridone:
(2.92g 18.0mmol) is dissolved in the 50%v/v sulfuric acid (45mL) of heat 3-cyano group-6-sec.-propyl-2 (1H) pyridone that previous step is made, and refluxes 3 hours.After being cooled to room temperature, reaction mixture is poured in the frozen water of 200mL, filter and collect the precipitation that forms, wash with water, again by air and vacuum-drying, obtain title compound (2.83g, 87%), be a kind of white solid.
1H-NMR (300MHz, CDCl
3) δ 13.67 (s, 1H), 12.75 (brs, 1H), 8.56 (d, 1H, J=7.5Hz), 6.56 (dd, 1H, J=7.6Hz, 1.6Hz), 3.02 (septet, 1H, J=6.9Hz), 1.41 (s, 3H), 1.39 (s, 3H).3. 3-(carbobenzoxy-(Cbz)) amino-6-sec.-propyl-2 (1H)-pyridone:
3-carboxyl-6-sec.-propyl-2 (1H)-pyridone (2.82g that previous step is made; 15.6mmol), diphenyl phosphoryl azide (3.50mL; 16.2mmol) and triethylamine (2.30mL, 16.5mmol) 1, the middle backflow of 4-diox (100mL) 16 hours.Add benzyl alcohol (1.65mL, 16.5mmol) and triethylamine (2.40mL 17.2mmol), refluxed reaction mixture 24 hours again.After with the reaction mixture vacuum concentration, resistates is dissolved in the methylene dichloride, use the salt water washing of salt solution, saturated sodium bicarbonate and the pH7 of pH1, use dried over mgso, filter.Filtrate after the evaporation with flash column chromatography purifying (gradient elution, the dichloromethane solution of 10%-25% ethyl acetate), is obtained title compound, be a kind of lurid solid (1.10g, 25%).
1H-NMR (300MHz, CDCl
3) δ 11.61 (brs, 1H), 8.05 (bRd, 1H, J=7.2Hz), 7.67 (s, 1H), 7.39 (m, 5H), 6.08 (d, 1H, J=7.7Hz), 5.21 (s, 2H), 2.80 (septet, 1H, J=6.9Hz), 1.28 (s, 3H), 1.26 (5,3H).4. 3-(carbobenzoxy-(Cbz)) amino-6-sec.-propyl-1-(tert-butoxycarbonyl methyl)-2-pyridone:
(1.10g 3.84mmol) is dissolved in the tetrahydrofuran (THF) (30mL) 3-(carbobenzoxy-(Cbz)) amino-6-sec.-propyl-1-2 (1H)-pyridone that previous step is made, and is cooled to 0 ℃ under nitrogen atmosphere.(4.2mL, 4.2mmol) solution stir reaction mixture 1 hour to add the hexane of two (trimethyl silyl) Lithamide of 1.0M through syringe.(0.70mL 4.3mmol), at room temperature stirred reaction mixture 16 hours again to add bromo-acetic acid tert-butyl through syringe again.Behind vacuum concentration, crude product flash column chromatography purifying (1: 1 hexane: ethyl acetate), obtain title compound, be a kind of light yellow oil (1.38g, 90%).
1H-NMR(300MHz，CDCl
3)δ8.00(bRd，1H，J＝7.8Hz)，7.78(s，1H)，7.36(m，5H)，6.15(d，1H，J＝7.9Hz)，5.19(s，2H)，4.79(s，2H)，2.72(m，1H)。1.46(5，9H)，1.26(5，3H)，1.23(s，3H)。Mass spectrum (MALDI-TOF, gentisinic acid matrix), calculated value: C
22H
28N
2O
5: 423.2 (M+Na), measured value: 423.6.5. 3-amino-6-sec.-propyl-1-(tert-butoxycarbonyl methyl)-2-pyridone:
3-(carbobenzoxy-(Cbz)) amino-6-sec.-propyl-1-(tert-butoxycarbonyl methyl)-2-pyridone (1.35 that previous step is made, 3.37mmol) and 10% palladium (O)/gac (0.12g) be dissolved in the methyl alcohol (50mL), the degassing, use the nitrogen backfill, stirring 2 hours under envrionment temperature and the pressure and under the nitrogen atmosphere.By diatomite reaction mixture being filtered then, with filtrate evaporation, obtain title compound, is a kind of golden oil, and it is not purified can be used for next step.6. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-(tertiary butyloxycarbonyl ylmethyl)-2-pyridone: (1.0mL 9.1mmol) is dissolved in the methylene dichloride (20mL) and is cooled to 0 ℃ for 3-amino-6-sec.-propyl-1-(tert-butoxycarbonyl methyl)-2-pyridone (being assumed to be 3.37mmol) that previous step is made and N-methylmorpholine.(0.67g, methylene dichloride 3.5mmol) (5mL) solution at room temperature stirred reaction mixture 16 hours toluene sulfonyl chloride between adding.After vacuum-evaporation, crude product is dissolved in the methylene dichloride, with 10% aqueous citric acid solution, saturated sodium bicarbonate and salt water washing, use dried over mgso, filter.With the filtrate evaporation, obtaining title compound (1.24g.88%) is a kind of tawny solid.
1H-NMR(300MHz，CDCl
3)δ7.65(m，2H)，7.58(brs，1H)，7.46(d，1H，J＝7.8Hz)，7.33(m，2H)，6.08(d，1H，J＝7.9Hz)，4.69(s，2H)~2.67(m，1H)，2.38(s，3H)，1.41(5，9H)，1.22(s，3H)，1.19(s，3H)。7. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-(carboxyl methyl)-2-pyridone:
(1.24g 2.95mmol) is dissolved in the methylene dichloride (20mL) 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-(tert-butoxycarbonyl methyl)-2 pyridones that previous step is made, and at room temperature reacts 2 hours with trifluoroacetic acid (8mL).After vacuum-evaporation, crude product is dissolved in the methylene dichloride, with damping fluid and the salt water washing of pH7, use dried over mgso, filter.With the filtrate evaporation, obtain title compound (0.72g, 67%), be a kind of light yellow solid.Mass spectrum (LCMS, ESI), calculated value: C
17H
20N
2O
5S:365.4 (M+H), measured value: 365.1.8. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-{[N, N '-two (tertbutyloxycarbonyl)]-2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl }-the 2-pyridone:
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-(carboxyl methyl)-2-pyridone (0.71g that previous step is made; 1.95mmol), Castro ' s reagent (BOP; 0.905g; 2.05mmol) and [N that makes of embodiment 2 steps 4; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy guanidine (0.710g; 2.00mmol) be dissolved in the methylene dichloride (40mL), and (0.75mL 5.4mmol) at room temperature reacts 3 hours with triethylamine.Behind vacuum concentration, crude product is dissolved in the methylene dichloride, with 10% aqueous citric acid solution, saturated sodium bicarbonate and salt water washing, use dried over sodium sulfate, filter.Filtrate after the evaporation obtains title compound with flash column chromatography purifying (dichloromethane solution of 5% methyl alcohol), is a kind of light yellow solid (0.70g, 54%).
1H-NMR(300MHz，CDCl
3)δ9.15(8，1H)，8.34(bRt，1H，J＝5.0Hz)，7.67(m，3H)，7.59(s，IH)，7.40(d，1H，J＝7.9Hz)，7.34(m，2H)，6.06(d，1H，J＝7.9Hz)，4.86(s，2H)，4.09(m，2H)，3.58(dd，2H，J＝8.8Hz，5.0Hz)，2.86(m，1H)，2.38(s，3H)，1.52(s，9H)，1.47(s，9H)，1.20(s，3H)，1.17(s，3H)。9. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-{2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl }-2-pyridonium salt hydrochlorate:
3-(the 3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-{[N that previous step is made; N '-two (tert-butoxycarbonyl)]-2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl }-2-pyridone (0.70g; 1.05mmol) be dissolved in the methylene dichloride (10mL), and at room temperature reacted 2.5 hours with trifluoroacetic acid (5mL).Crude product after the evaporation is carried out freeze-drying with acetonitrile/water, with flash column chromatography purifying (gradient elution, the dichloromethane solution of 10%-20% methyl alcohol, saturated with ammoniacal liquor), ethanol (20mL) solution evaporation by 4N HCl obtains title compound, be a kind of white solid (0.36g, 68%).
1H-NMR(300MHz，DMSO-d
6)δ10.91(brs，1H)，9.34(brds，1H)，8.49(t，1H，J＝5.5Hz)，7.65(m，6H)，7.43(m，2H)，7.28(d，1H，J＝7.8Hz)，6.14(d，1H，J＝7.9Hz)，4.69(s，2H)，3.79(t，2H，J＝5.3Hz)，3.38(m，2H)，2.79(m，1H)，2.35(s，3H)，1.13(s，3H)，1.08(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.5 (M+H), measured value: 465.1.Embodiment 973-(3-aminomethyl phenyl alkylsulfonyl) amino-6-ethyl-1-[(guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 96 similar modes.
1H-NMR(300MHz，DMSO-d
6)δ10.92(s，1H)，9.32(s，1H)，8.42(t，J＝5.6Hz，1H)，7.71(brs.4H)，7.67(s，1H)，7.64(t，J＝3.0Hz，1H)，7.42(d，J＝6.1Hz，1H)，7.29(d，J＝7.7Hz，1H)，6.07(d，J＝7.8Hz，1H)，4.62(s，2H)，3.79(t，J＝5.4Hz，2H)，3.34(t，J＝5.6Hz，2H)，2.24(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
26N
6O
5S:451.2 (M+H), 473.2 (M+Na); Measured value: 451.1,473.0.Embodiment 983-(3-aminomethyl phenyl alkylsulfonyl) amino-6-propyl group-1-{2-(guanidine radicals oxygen base ethyl) amino carbonyl methyl }-2-pyridone trifluoroacetate
To make title compound with embodiment 96 similar modes.
1H-NMR (300MHz, DMSO-d
6) δ 11.25 (5,1H), 9.32 (s, 1H), 8.48 (t, 1H, J=5.5Hz), 7.91 (brs, 4H), 7.63 (m, 2H), 7.42 (m, 2H), 7.29 (d, 1H, J=7.7Hz) .6.07 (d, 1H, J=7.7Hz), 4.61 (s, 2H), 3.81 (t, 2H, J=5.3Hz), 3.35 (m, 2H), 2.45 (t, 2H, J=7.7Hz), 2.35 (s, 3H), 1.50 (sextet, 2H, J=7.5Hz), 0.89 (t, 3H, J=7.3Hz).Mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.5 (M+H), measured value: 465.1.Embodiment 993-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N "-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate (0.2g with the preparation of embodiment 5 steps 5; 0.42mmol) N; dinethylformamide (6mL) solution sodium bicarbonate (0.78g; 9.2mmol) handle; handle (0.32mL with methyl-iodide again; 5mmol), at room temperature stirred subsequently 2.5 hours.Reaction mixture is evaporated under high vacuum, with the resistates brine treatment, and with 1M salt acid for adjusting pH value to 1.Filter and collect insoluble substance.Water layer dichloromethane extraction (5x).Dichloromethane extraction liquid after the merging extracts (2x) with saturated sodium bicarbonate.With the 1M salt acid for adjusting pH value to 1 of the sodium bicarbonate water extract after merging.Filter and collect insoluble substance, merge with the solid of handling from acid brine.With solid dried overnight under high vacuum, handle with methyl alcohol then, remove by filter insoluble substance.With the filtrate evaporation, obtain title compound, be a kind of white solid (154mg, 75%).
1H-NMR(300MHz，DMSO-d
6)δ9.30(5，1H)，8.85(t，J＝5.3Hz，1H)，8.14(s，4H)，7.61-7.66(m，2H)，7.39-7.44(m，2H)，7.23(d，J＝7.6Hz，1H)，6.08(d，J＝8.2Hz，1H)，4.67(m，2H)，3.91(t，J＝5.1Hz，2H)，3.39(m，2H)，3.28(s，3H)，2.35(5，3H)，2.19(5，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26N
6O
5S:451 (M+H); Measured value: 451.2.451.2 peak value MS-MS provide 408.9 (M-C (=NH) NH).Embodiment 1003-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(N " ethyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
To make title compound with embodiment 99 similar modes.
1H-NMR (300MHz, DMSO-d
6) δ 9.26 (brs, 1H), 8.55 (t, 1H, J=5.2Hz), 7.95 (brs, 4H), 7.64 (m, 2H), 7.42 (rn, 2H), 7.24 (d, 1H, J=7.5Hz), 6.08 (d, 1H, J=7.7Hz), 4.63 (s, 2H), 3.87 (brt, 2H, J=5.0Hz), 3.66 (q, 2H, J=6.9Hz), 2.35 (s, 3H), 2.19 (s, 3H), 1.09 (t, 3H, J=6.9Hz). mass spectrum (LCMS, ESI), calculated value: C
20H
28N
6O
5S:465.5 (M+H), measured value: 465.1.423.0 peak value MS-MS provide 423.0 (M-C (=NH) NH).Embodiment 1013-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N " benzyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
To make title compound with embodiment 99 similar modes.Mass spectrum (LCMS, ESI), calculated value: C
25H
30N
6O
5S:527.6 (M+H), the peak value MS-MS of measured value: 527.0. 527.0 provide 485.0 (M-C (=NH) NH).Embodiment 1023-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N " butyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate
To make title compound with embodiment 99 similar modes.
1H-NMR(300MHz，CDCl
3/CD
3OD)δ7.64(m，2H)，7.42(d，1H，J＝7.7Hz)，7.36(In，2H)，6.11(d，1H，J＝7.7Hz)，4.70(s，2H)，3.58(t，2H，J＝7.3Hz)，3.49(t，2H，J＝4.9Hz)，2.39(5，3H)，2.30(5，3H)，1.64(m，2H)，1.36(m，4H)，0.95(t，3H，J＝7.2Hz)。Mass spectrum (LCMS, ESI), calculated value: C
22H
32N
6O
5S:493.6 (M+H), measured value: 493.3.493.3 the MS-MS of peak value provides 452.0 (M-C (=NH) NH).Embodiment 1033-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
1.[N, N '-two (tert-butoxycarbonyl)] and 2-(benzyloxycarbonyl amino) oxyethyl group-N-methylguanidine
[the N that makes to embodiment 2 steps 3, N '-two (tert-butoxycarbonyl)] 2-(benzyloxycarbonyl amino) oxyethyl group guanidine (905mg, 2.0mmol), methyl alcohol (121 μ L, 3.0mmol) and triphenyl phosphine (790mg, 3.0mmol) tetrahydrofuran (THF) (30mL) solution in add diethyl azodiformate (520mg, 3.0mmol).Mixture at room temperature stirred spend the night.Add ethyl acetate (50mL), (dried over sodium sulfate is used in 2 * 40mL) washings with saturated sodium bicarbonate (40mL), salt solution.After steaming solvent, resistates with purification by flash chromatography (dichloromethane solution of 0-4% ethyl acetate), is obtained title compound, be a kind of white solid (385mg, 41%).
1H-NMR(300MHz，CDCl
3)δ7.36(m，5H)，5.30(brs，1H)，5.11(s，2H)，4.12(4J＝5.0Hz，2H)，3.50(t，J＝5.0Hz，2H)，3.07(5，3H)，1.48(s，9H)，1.43(s，9H)。2.[N, N '-two (tert-butoxycarbonyl)] and 2-amino ethoxy-N-methylguanidine
[the N that previous step is made, N '-two (tert-butoxycarbonyl)] and 2-(benzyloxycarbonyl amino) oxyethyl group-N-methylguanidine (700mg, 1.5mmol), the mixture of 10%Pd/C (70mg) in methyl alcohol (20mL) and chloroform (5mL) be in down hydrogenation 1 hour of nitrogen atmosphere (air bag).Remove catalyzer by diatomite filtration, filtrate is carried out vacuum concentration.With resistates with purification by flash chromatography (95: 5 methylene dichloride: methyl alcohol, with ammoniacal liquor saturated), obtain title compound, be a kind of colourless foam thing (250mg, 50%).
1H-NMR(300MHz，CDCl
3)δ4.14(t，J＝5.0HZ，2H)，3.09(5，3H)，3.06(q，J＝5.0Hz，2H)，1.50(5，9H)，1.46(s，9H)。3. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N, N '-two (butoxy carbonyl)] [2-(N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone
3-(the 3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-carboxyl methyl-2 pyridone (253mg that makes to embodiment 5 steps 2; 0.75mmol), [N that makes of previous step; N '-two (tert-butoxycarbonyl)] 2-amino ethoxy-N-methylguanidine (250mg; 0.75mmol), diisopropyl ethyl amine (180 μ L; 1.0mmol) N; add in dinethylformamide (10mL) solution Castro ' s reagent (BOP) (355mg, 0.8mmol).Mixture at room temperature stirred spends the night, add ethyl acetate (50mL), with saturated sodium bicarbonate (2 * 20mL), 10% citric acid (2 * 20mL) and salt solution (20mL) wash, use dried over sodium sulfate.After vacuum boils off solvent, resistates twice (2: 1 ethyl acetate: hexane of column chromatography purifying; The dichloromethane solution of 2% methyl alcohol then), obtains title compound, be a kind of white solid (380mg.78%).
1H-NMR(300MHz，CDCl
3)δ8.12(s，1H)，7.67(m，3H)，7.48(d，J＝7.6Hz，1H)，7.34(s，1H)，7.31(s.1H)，7.09(m，1H)，6.08(d，J＝7.8Hz，1H)，4.61(s，2H)，4.02(t，J＝5.1Hz，2H)，3.46(q，J＝5.3Hz，2H)，3.09(5，3H)，2.39(s，3H)，2.37(s，3H)，1.53(s，9H)，1.47(s，9H)。4. 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
3-(the 3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-{ [N that previous step is made; N '-two (butoxy carbonyl)] [2-(N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone (370mg, 0.57mmol) and the mixture of trifluoroacetic acid (2mL) in methylene dichloride (3mL) at room temperature stirred 2 hours.After vacuum steamed solvent, resistates obtained title compound with WatersSep-Pak purifying (10g, the dichloromethane solution of 10% methyl alcohol), is a kind of colourless foam thing (310mg, 96%).
1H-NMR(300MHz，DMSO-d
6)δ10.91(s，1H)，9.28(s，1H)，8.43(t，J＝5.5Hz，1H)，8.09(d，J＝5.0Hz，1H)，7.93(brs，2H)，7.66(5，1H)，7.62(In，1H)，7.43(m，2H)，7.24(d，1H，J＝7.6Hz)，6.09(d，1H，J＝7.7Hz)，4.62(s.2H)，3.79(t，2H，J＝5.2Hz)，3.35(q，2H，J＝5.4Hz)，2.77(d，J＝4.8Hz，3H)，2.35(s，3H)，2.19(s，3H)。Mass spectrum (LCMS, ESI), calculated value: C
19H
26SN
6O
5: 451.0 (M+H); Measured value: 451.1.451.1 the MS-MS of peak value provides 394.9 (M-C (=NH) NCH
3).Embodiment 1043-(benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-(2-N-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone trifluoroacetate
To make title compound with embodiment 103 similar modes.
1H-NMR(300MHz，DMSO-d
6)δ10.89(s，1H)，8.57(s，1H)，8.47(t，J＝5.5Hz，1H)，8.09(brs，1H)，7.93(s，2H)，7.34(m，5H)，7.13(d，J＝7.5Hz，1H)，6.10(d，J＝7.7Hz，1H)，4.73(s，2H)，4.51(s，2H)，3.83(t，J＝5.4Hz，2H)，3.41(m，2H)，2.77(d，J＝4.9Hz，3H)，2.25(s，3H)。Mass spectrum (MALDI-TOF, alpha-cyano-4-hydroxycinnamic acid matrix), calculated value: C
19H
26N
6O
5S:451.2 (M+H), 473.2 (M+Na); Measured value: 451.4,473.5.451.4 the MS-MS of peak value provides 394.9 (M-C (=NH) NCH
3).Embodiment 1053-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N-methoxycarbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridonium salt hydrochlorate (0.2g that embodiment 5 steps 5 are made; 0.42mmol) suspension N in acetonitrile (10mL); N-diisopropyl ethyl amine (0.08mL; 0.46mmol) and Ue-5908 (0.05mL, 0.46mmol) processing.Reaction mixture at room temperature stirred spend the night.Add solvent N again, dinethylformamide (5mL) acts on solution.(0.30mL 2.76mmol) and with reaction mixture stirred 2 days to add Ue-5908.Reaction mixture is evaporated to driedly under high vacuum, resistates is carried out purifying (5g SepPak) with silicagel column, the dichloromethane solution that adopts 4% methyl alcohol obtains the required product of 0.071g (29%) as eluting solvent, is a kind of white solid.
1H-NMR (300MHz, DMSO-d
6) δ 9.65 (s, 1H), 9.30 (s, 1H), 8.28 (t, J=5.5Hz, 1H), and 7.60-7.67 (m, 2H), 7.38-7.44 (m, 2H), 7.23 (d, J=7.5Hz, 1H), 6.20 (5,2H), 6.06 (d, J=7.6Hz, 1H), 4.61 (m, 2H), 3.73 (t, J=5.5Hz, 2H), 3.61 (5,3H), 3.27-3.31 (m, 2H), 2.35 (s, 3H), 2.18 (s, 3H).Mass spectrum (LCMS, ESI), calculated value: C
20H
26N
6O
7S:495 (M+H); Measured value: 495.0.Embodiment 1063-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N, N ', N " three ethoxycarbonyls) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone
3-(3-aminomethyl phenyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) the amino carbonyl methyl]-2-pyridonium salt hydrochlorate (237mg that makes to embodiment 5 steps 5; 0.5mmol) and N; N-diisopropyl ethyl amine (180 μ mL; 1.0mmol) N; add in dinethylformamide (10mL) solution Ue-5908 (150 μ L, 1.0mmol).Mixture at room temperature stirred spend the night.Steam to remove N under high vacuum, dinethylformamide is dissolved in resistates in the methylene dichloride (50mL), with 10% citric acid (2 * 20mL) and salt solution (20mL) wash, use dried over sodium sulfate.After steaming solvent, resistates with Waters Sep-Pak purifying (10g, the dichloromethane solution of 30-40% ethyl acetate), is obtained title compound, be a kind of white solid (210mg, 65%).
1H-NMR(300MHz，CDCl
3)δ9.33(brs，1H)，8.64(s，1H)，8.58(brs，1H)，7.97(m，2H)，7.52(d，J＝7.5Hz，1H)，7.26(m，2H)，6.15(d，J＝7.7Hz，1H)，4.70-5.00(m，2H)，4.40(q，J＝7.1Hz，2H)，4.21(q，J＝7.2Hz，2H)，4.07(q，J＝7.1Hz，2H)，3.85(m，2H)，3.54(m，2H)，2.41(s，3H)，2.39(s，3H)，1.41(t，J＝7.1Hz，3H)，1.30(t，J＝7.2Hz，3H)，1.09(t，J＝7.1Hz，3H)。Mass spectrum (LCMS, ESI), calculated value: C
27H
36N
6O
11S:653.0 (M+H); Measured value: 653.0.Embodiment 1073-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N, N '-di ethoxy carbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N-ethoxy carbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone
3-(3-aminomethyl phenyl) sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) the amino carbonyl methyl]-2-pyridonium salt hydrochlorate hydrochloride (475mg that makes to embodiment 5 steps 5; 1.0mmol) and N-methylmorpholine (220 μ L; 2.0mmol) N; add in N '-dimethyl formamide (10mL) solution Ue-5908 (150mL, 1.0mmol).Mixture at room temperature stirred spend the night.Steam N under high vacuum, dinethylformamide is dissolved in resistates in the methylene dichloride (50mL), and (2 * 20mL), salt solution (20mL) washs and is dry with 10% citric acid.After steaming solvent; resistates Waters Sep-Pak purifying (10g; 30-40% ethyl acetate dichloromethane solution; use the dichloromethane solution of 25% methyl alcohol again); obtain 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N; N '-di ethoxy carbonyl) amino carbonyl methyl guanidine radicals oxygen base ethyl)]-the 2-pyridone, be a kind of white solid (320mg, 55%).
1H-NMR(300MHz，CDCl
3)δ9.34(brs，1H)，8.74(s，1H)，8.59(brs，1H)，7.67(5，1H)，7.64(m，1H)，7.60(8，1H)，7.38(d，J＝7.5Hz，1H)，7.32(d，J＝5.2Hz，2H)，6.01(d，J＝7.6Hz，1H)，4.97+4.67(m，2H)，4.40(q，J＝7.1Hz，2H)，4.14(q，J＝7.1Hz，2H)，4.36+3.91(m，2H)，3.52(m.2H)，2.38(5，3H)，2.26(s，3H)，1.42(t，J＝7.1Hz.3H)，1.21(t，J＝7.1Hz，3H)。Mass spectrum (LCMS, ESI), calculated value: C
24H
32N
6O
9S:581.2 (M+H); Measured value: 581.0.3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-(N-ethoxy carbonyl) guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone is a kind of white solid (80mg, 16%).
1H-NMR(300MHz，CDCl
3)δ8.30(brs，1H)，8.17(brs，1H)，7.56(m，4H)，7.33(m，2H)，6.14(d，J＝7.7Hz，1H)，5.77(brs，2H)，4.67(brs，2H)，4.35(q，J＝7.1Hz，2H)，3.85(m，2H)，3.42(m，2H)，2.44(s，3H)，2.36(5，3H)，1.39(t，J＝7.1Hz，3H)。Mass spectrum (LCMS, ESI), calculated value: C
21H
28N
6O
7S:509.1 (M+H); Measured value: C21509.1.Embodiment 1083-(3-aminomethyl phenyl carbonyl) amino-6-methyl isophthalic acid-[2-N "-(3-phenyl propyl) guanidine radicals oxygen base ethyl] amino carbonyl methyl }-2-pyridonium salt hydrochlorate
To prepare title compound with embodiment 99 similar modes.
1H-NMR(300MHz，DMSO-d
6)δ9.25(s，1HO，8.65(t，1H，J＝5Hz)，8.03(brs，3H)，7.78(brs，1H)，7.64(m，2H)，7.26(m，10H)，6.01(m，1H)，4.63(brs，2H)，3.89(t，2H，J＝4.9Hz)，3.71(t，2H，J＝7Hz)，2.58(m，2H)，2.34(s，3H)，2.16(s，3H)，1.87(m，2H)。Mass spectrum (LCMS, ESI), calculated value: C
27H
34N
6O
5S:555.0 (M+H), measured value: 555.1.555.1 the MS-MS of peak value provides 513.0 (M-C (=NH) NH).Embodiment 109 tablet preparation
Preparation as described below comprises 25.0,50.0 and the tablet of the following active compound of 100.0mg respectively:
A.3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(3-guanidine radicals oxygen base propyl group) amino carbonyl methyl]-2-pyridone; With
B.3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone comprises the tablet of 25-100mg active compound
Quantity-mgActive compound 25.0 50.0 100.0 Microcrystalline Celluloses 37.25 100.0 200.0 modified food W-Gums 37.25 4.25 8.5 Magnesium Stearates 0.50 0.75 1.5
All active compounds, Mierocrystalline cellulose and part W-Gum are mixed, be a granulated into 10% corn starch paste.With the granule sieving that forms, drying is mixed with other W-Gum and Magnesium Stearate again.The particle that forms is pressed into every comprises 25.0,50.0 and the sheet of 100.0mg activeconstituents respectively.The preparation of embodiment 110 intravenous solution
The intravenous dosage forms of above-mentioned active compound is according to following preparation: active compound 0.5-10.0mg Trisodium Citrate 5-50mg citric acid 1-15mg sodium-chlor 1-8mg water for injection (USP) is in right amount to 1ml
Adopt above-mentioned consumption, active compound at room temperature is dissolved in the water for injection (USP of the sodium-chlor, citric acid and the Trisodium Citrate that have made, formulary referring to American Pharmacopeia/country, 1995, by United States Pharmacopeial Convention, Inc., Rockville, Maryland publishes, (1994)) solution in.The vitro inhibition of the enzyme behind embodiment 111 purifying
Reagent: all buffering salts are that (St.Louis MO) obtains with highest purity by Sigma Chemical Company.Enzyme substrates is to derive from N-benzoyl-Phe-Val-Arg-of Sigma to p-nitroanilide (Sigma; B7632); N-benzoyl-Ile-Glu-Gly-Arg-is to p-nitroanilide hydrochloride (Sigma; B2291); N-p-toluenesulfonyl-Gly-Pro-Lys-is to p-nitroanilide (Sigma T6140); N-succinyl-Ala-Ala-Pro-Phe-to p-nitroanilide (Sigma S7388) and N-CBZ-Val-Gly-Arg-to p-nitroanilide (Sigma 7271) and derive from BACHEM (King of Prussia, N-succinyl-Ala-Ala-Pro-Arg-PA) to p-nitroanilide (BACHEM L-1720) and N-succinyl-Ala-Ala-Pro-Val-to p-nitroanilide (BACHEM L-1770).
People's α-zymoplasm, people's factor Xa and fibrolan derive from Enzyme R
eSearchLaboratories (South Bend, Indiana).Ox alpha-chymotrypsin (SigmaC4129), bovine trypsin (Sigma T8642) and human kidney cells urokinase (Sigma U5004) all derive from Sigma.Human leukocyte elastase derive from Elastin Products (Pacific, MO).
K
iMeasure: all experiments all based on test compounds can inhibiting peptide to the catalytic hydrolysis of p-nitroanilide substrates enzymes.At typical K
iIn the mensuration, substrate prepares in DMSO and is diluted to the experiment damping fluid, and described damping fluid is made up of 50mM HEPES and 200mM NaCl, and its pH is 7.5.The ultimate density of each substrate is listed below.Usually, concentration of substrate is lower than K
mThe experiment measuring value.Test compounds is made the DMSO solution of 1.0mg/mL.Dilution comprises 200 times of concentration ranges to obtain 8 kinds of ultimate density values in DSMO.Enzyme solution makes in the experiment damping fluid with the concentration of listing below.
At typical K
iIn the mensuration, 280mL substrate solution, 10mL test compounds solution are added in each hole of 96 orifice plates with suction pipe, with plate under 37 ℃ in Molecular Devices plate thermal equilibrium above 15 minutes.Make the reaction beginning by the aliquots containig that adds 10mL, be recorded in the increase of the 15 minutes absorption values in 405nm place.Be used for calculating corresponding to data than total substrate hydrolysis low 10%.Speed (absorption value is rate over time) by the sample that does not comprise test compounds is drawn as the function of test compounds concentration with the ratio of the speed of the sample that comprises test compounds.Data are carried out linear regression, calculate the slope value of line.The inverse of slope value is the K of experiment measuring
iValue.
Zymoplasm: thrombin activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-succinyl-Ala-Ala-Pro-Arg-.Substrate solution be 32mM (32mM＜＜K
m=180mM) experiment buffer preparation.Final DMSO concentration is 4.3%.People's α-zymoplasm of purifying is diluted to the solution of 15nM.Final reagent concentration is: [zymoplasm]=0.5nM, [substrate N-succinyl-Ala-Ala-Pro-Arg-is to p-nitroanilide]=32mM.
Factor X[FXa]: the FXa activity is estimated the ability of p-nitroanilide hydrochloride with its hydrolysis substrate N-benzoyl-Ile-Glu-Gly-Arg-.Substrate solution be 51mM (51mM＜＜K
m=1.3mM) experiment buffer preparation.Final DMSO concentration is 4.3%.People's factor X of purifying is diluted to the solution of 300nM.Final reagent concentration is: [FXa]=10nM, [N-benzoyl-Ile-Glu-Gly-Arg-is to the p-nitroanilide hydrochloride]=51mM.
Tryptase: the plasmin enzymic activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-p-toluenesulfonyl-Gly-Pro-Lys-.Substrate solution be 37mM (37mM＜＜K
m=243mM) experiment buffer preparation.Final DMSO concentration is 4.3%.The fibrolan of purifying is diluted to the solution of 240nM.Final reagent concentration is: [Tryptase]=2.7nM, [N-p-toluenesulfonyl-Gly-Pro-Lys-is to p-nitroanilide]=37mM.
Quimotrase: chymotrypsin activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-succinyl-Ala-Ala-Pro-Phe-.Substrate solution be 14mM (14mM＜＜K
m=62mM) experiment buffer preparation.Final DMSO concentration is 4.3%.The BCTR of purifying is diluted to the solution of 81nM.Final reagent concentration is: [Quimotrase]=2.7nM, [N-succinyl-Ala-Ala-Pro-Phe-is to p-nitroanilide]=14mM.
Trypsinase: tryptic activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-benzoyl-Phe-Val-Arg-.Substrate solution be 13mM (13mM＜＜K
m=291mM) experiment buffer preparation.Final DMSO concentration is 4.3%.The bovine trypsin of purifying is diluted to the solution of 120nM.Final reagent concentration is: [trypsinase]=4nM, [N-benzoyl-Phe-Val-Arg-is to p-nitroanilide]=13mM.
Elastoser: elastase activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-succinyl-Ala-Ala-Pro-Val-.Substrate solution be 19mM (19mM＜＜K
m=89mM) experiment buffer preparation.Final DMSO concentration is 4.3%.The human leukocyte elastase of purifying is diluted to the solution of 750nM.Final reagent concentration is: [elastoser]=25nM, [N-succinyl-Ala-Ala-Pro-Val-is to p-nitroanilide]=19mM.
Urokinase: urokinase activity is estimated the ability of p-nitroanilide with its hydrolysis substrate N-CBZ-Val-Gly-Arg-.Substrate solution be 100mM (100mM＜＜K
m=1.2mM) experiment buffer preparation.Final DMSO concentration is 4.3%.People's kidney urokinase of purifying is diluted to the solution of 1.2mM.Final reagent concentration is: [urokinase]=40nM, [N-CBZ-Val-Gly-Arg-is to p-nitroanilide]=100mM.The results are shown in the following table of The compounds of this invention.
Table 1Experiment, K
i(nM) or (inhibiting rate %, (nM))
| Embodiment number | Zymoplasm | FXa | Quimotrase | Elastoser | Tryptase | Trypsinase |
| 1 | 53 | 0@24,000 | 0@24,000 | ?0@24,000 | ?0@24,000 | 0@24,000 |
| 2 | 7.9 | 24,000 | 14,000 | ?0@24,500 | ?0@24,500 | 0@24,500 |
| 4 | 29 | 7,900 | ?0@79,000 | |||
| 5 | 6.0 | 0@24,600 | ?0@24,600 | ?0@24,600 | 0@24,600 | |
| 8 | 43 | ?0@56,000 | 0@56,000 | |||
| 16 | 2.0 | 2,200 | ?0@19,000 | 4,000 | ||
| 24 | 2.0 | 2,200 | ?0@18,000 | 7,600 | ||
| 30 | 61 | 7.600 | 0@23,500 | ?0@23,500 | ?0@23,500 | 0@23,500 |
| 38 | 51 | 420 | 0@20,000 | ?0@20,000 | ?0@20,000 | 0@20,000 |
| 55 | 220 | 2,100 | 2,300 | |||
| 71 | 580 | 8,700 | 0@12,000 | ?0@12,000 | ?0@12,000 | 0@12,000 |
| 85 | 290 | 1,300 | 0@18,000 | ?0@18,000 | ?0@18,000 | 1,600 |
The result shows that compound of the present invention is the thrombin inhibitors of effective and highly selective.
More than describe the present invention in detail, be appreciated that those of ordinary skill in the art under the prerequisite that does not deviate from scope of the present invention or embodiment, in various conditions, prescription and other parameter area, can implement the present invention.The patent and the public publication of all references all are incorporated herein by reference.
Claims (44)
1, the compound of a kind of formula VII or its solvate, hydrate or pharmacologically acceptable salt:
Wherein:
R
1Be C
3-9Cycloalkyl, C
4-7Cycloalkyl C
1-4Alkyl, C
6-10Aryl, C
6-10Virtue C
1-4Alkyl, heterocyclic radical or heterocycle C
1-4Alkyl, each group all optionally is substituted;
Z is-SO
2-or-OCO-;
Het is:
Wherein
R
3, R
4And R
5Be hydrogen, C independently of one another
1-12Alkyl, C
3-7Cycloalkyl, trifluoromethyl,
Halogen or cyano group;
R
7Be hydrogen;
R
8Be hydrogen, C
1-6Alkyl, C
6-10Virtue C
1-4Alkyl or carbalkoxy;
R
12, R
13, R
14And R
15Be hydrogen or C independently of one another
1-6Alkyl;
Perhaps R
12And R
13Lump together formation-(CH
2)
y-, wherein, y is 2-7, and R
14And R
15As give a definition;
R
14And R
15Be hydrogen independently of one another;
X is an oxygen;
R
a, R
bAnd R
cBe hydrogen, C independently of one another
1-6Alkyl or C
1-6Carbalkoxy;
N is 0-4; With
M is 0-4.
2, according to the compound of claim 1, wherein, R
1Be C
6-10Aryl (C
1-4) alkyl, C
6-10Aryl, C
4-7Cycloalkyl (C
1-4) alkyl, heterocyclic radical or heterocycle (C
1-4) alkyl, above-mentioned any group can replace or not be substituted; Wherein, described heterocyclic radical or heterocycle (C
1-4) heterocycle of alkyl is a 5-7 unit monocycle, or 9-10 unit bicyclic heterocycles, it is saturated or undersaturated, and comprises the heteroatoms that 1-3 is selected from N, O and S.
3, according to the compound of claim 2, wherein, R
1Be C
6-10Aryl (C
1-4) alkyl, C
6-10Aryl, or C
4-7Cycloalkyl (C
1-4) alkyl, above-mentioned any group can replace by following 1-5 group or not be substituted: hydroxyl, nitro, trifluoromethyl, halogen, C
1-6Alkyl, C
2-6Alkenyl, C
6-10Aryl, C
1-6Alkoxyl group, C
6-10Aryl (C
1-6) alkoxyl group, C
1-6Aminoalkyl group, C
1-6Aminoalkoxy, amino, list (C
1-4) alkylamino, two (C
1-4) alkylamino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Hydroxyalkyl, C
2-6Hydroxy alkoxy base, (C
1-6) alkoxyl group (C
2-6) alkoxyl group, list and two C
1-4Alkylamino (C
2-6) alkoxyl group, C
2-10Single (carboxyalkyl) is amino, two (C
2-10Carboxyalkyl) amino, C
6-14Aryl (C
1-6) alkoxy carbonyl, C
2-6Alkynyl group carbonyl, C
1-6Alkyl sulphonyl, C
2-6Alkenyl alkylsulfonyl, C
2-6Alkynyl group alkylsulfonyl, C
6-10Aryl sulfonyl, C
6-10Aryl (C
1-6) alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulfonyl amino, C
6-10Arenesulfonyl amino, C
6-10Virtue (C
1-6) alkyl sulfonyl amino, amidino groups, guanidine radicals, C
1-6Alkyl imino amino, formyl radical imino-amino, C
2-6Carboxyl alkoxyl group, C
2-6Carboxyalkyl, C
2-6Carboxyalkyl amino, cyano group, trifluoromethoxy or perfluor oxyethyl group.
4, according to the compound of claim 1, wherein, R
3, R
4And R
5Be hydrogen, methyl, ethyl, propyl group, chlorine, bromine, trifluoromethyl, cyclopropyl or sec.-propyl independently of one another.
5, according to the compound of claim 1, wherein, R
3And R
4Be hydrogen.
6, according to the compound of claim 1, wherein, R
5Be hydrogen, halogen, C
1-5Alkyl, C
3-5Cycloalkyl or trifluoromethyl.
7, according to the compound of claim 1, wherein,
R
3And R
4Be independently from each other hydrogen or methyl and
R
5Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl-, 1-amyl group, R-2-amyl group, S-2-amyl group, 3-amyl group, S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl or R-1-(2-methyl)-butyl.
8, according to the compound of claim 7, wherein, R
5Be hydrogen, methyl, ethyl, propyl group or sec.-propyl.
9, according to the compound of claim 1, wherein, Z is-SO
2-.
10, according to the compound of claim 1, wherein, X is an oxygen.
11, according to the compound of claim 1, wherein, R
8Be hydrogen, C
1-6Alkyl or C
6-10Aryl (C
1-4) alkyl.
12, according to the compound of claim 1, wherein, R
12, R
13, R
14And R
15Be hydrogen or C independently of one another
1-6Alkyl.
13, according to the compound of claim 12, wherein, R
12, R
13, R
14And R
15Be hydrogen, methyl, ethyl, propyl group, normal-butyl independently of one another.
14, according to the compound of claim 1, wherein, R
a, R
bAnd R
cBe hydrogen or C independently of one another
1-6Alkyl.
15, according to the compound of claim 14, wherein, R
a, R
bAnd R
cBe independently of one another hydrogen, methyl, ethyl, propyl group, normal-butyl ,-CO
2CH
3,-CO
2CH
2CH
3With-CO
2CH
2CH
2CH
3
16, according to the compound of claim 15, wherein, R
a, R
bAnd R
cBe hydrogen.
17, according to the compound of claim 1, wherein, n is 0 or 1, and m is 0 or 1.
18, according to the compound of claim 1, wherein:
R
1Be C
6-10Aryl (C
1-4) alkyl, C
6-10Aryl or C
4-7Cycloalkyl (C
1-4) alkyl, any group can be replaced by following substituting group or not be substituted: hydroxyl, nitro, trifluoromethyl, halogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkoxyl group, C
6-10Aryl (C
1-6) alkoxyl group, C
1-6Aminoalkyl group, C
1-6Aminoalkoxy, amino, list (C
1-4) alkylamino, two (C
1-4) alkylamino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Hydroxyalkyl, C
2-6Hydroxy alkoxy base, (C
1-6) alkoxyl group (C
2-6) alkoxyl group, list and two C
1-4Alkylamino (C
2-6) alkoxyl group, C
2-10Single (carboxyalkyl) is amino, two (C
2-10Carboxyalkyl) amino, C
6-14Aryl (C
1-6) alkoxy carbonyl, C
2-6Alkynyl group carbonyl, C
1-6Alkyl sulphonyl, C
2-6Alkenyl alkylsulfonyl, C
2-6Alkynyl group alkylsulfonyl, C
6-10Aryl sulfonyl, C
6-10Aryl (C
1-6) alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulfonyl amino, C
6-10Arenesulfonyl amino, C
6-10Aryl (C
1-6) alkyl sulfonyl amino, amidino groups, guanidine radicals, C
1-6Alkyl imino amino, formyl radical imino-amino, C
2-6Carboxyl alkoxyl group, C
2-6Carboxyalkyl, carboxyalkyl amino, cyano group, trifluoromethoxy or perfluor oxyethyl group;
Het is:
Wherein
R
3And R
4Be independently from each other hydrogen or methyl and
R
5Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl-, 1-amyl group, R-2-amyl group, S-2-amyl group, 3-amyl group, S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl or R-1-(2-methyl)-butyl;
Z is-SO
2-;
R
12, R
13, R
14And R
15Be one of following radicals independently of one another: hydrogen or C
1-6Alkyl;
X is an oxygen;
R
8Be hydrogen, C
1-4Alkyl or C
6-10Aryl (C
1-6) alkyl;
R
a, R
bAnd R
cFor hydrogen, methyl, ethyl, propyl group or normal-butyl ,-CO
2CH
3,-CO
2CH
2CH
3With-CO
2CH
2CH
2CH
3
N is 0 or 1, and m is 0 or 1.
19, according to the compound of claim 1, wherein
Z is-SO
2-,
R
1For replacing or unsubstituted C
6-01Aryl or C
6-10Virtue C
1-4Alkyl,
X is an oxygen, R
8Be hydrogen, C
1-4Alkyl or C
6-10Aryl (C
1-6) alkyl and
R
a, R
bAnd R
cBe hydrogen.
20, according to the compound of claim 19, wherein,
R
1For replacing or unsubstituted benzyl or phenyl.
21, the claim 1 of a kind of formula VIII compound or its solvate, hydrate or pharmacologically acceptable salt,
Wherein, Z ' be-OCO-or-SO
2-;
R
21For:
R
22(CH
2)
k, wherein, k is 0-4, (R
22)
2CH (CH
2)
k, wherein, k is 0-4 and R
22Can be identical or different, wherein, (R
22)
2Also can be a ring substituents on CH, by C
3-7Cycloalkyl, C
7-12Dialkyl group represents, perhaps 5-7 unit's monocycle or 9-10 unit bicyclic heterocycle, it can be saturated or undersaturated, its comprise 1-3 heteroatoms that is selected from N, O and S and
R
22Be hydrogen; Phenyl can be replaced by following one or more substituting groups or not be substituted: C
1-4Alkyl, C
1-4Alkoxyl group, halogen, trifluoromethyl, hydroxyl, COOH or CONH
2Naphthyl; Xenyl; 5-7 unit's monocycle or 9-10 unit bicyclic heterocycle, it can be saturated or undersaturated, and it comprises 1-3 heteroatoms that is selected from N, O and S;
R
25Be hydrogen; C
1-4Alkyl; C
3-7Cycloalkyl or trifluoromethyl;
R
a, R
bAnd R
cBe hydrogen independently of one another;
R
32, R
33, R
34And R
35Be hydrogen or C independently of one another
1-6Alkyl, perhaps R
32And R
33Lump together formation-(CH
2)
y-, wherein, y is 2-5, and R
34And R
35As give a definition;
R
34And R
35Independent separately is hydrogen;
R
28Be hydrogen, C
1-4Alkyl or C
6-10Aryl (C
1-4) alkyl,
X ' is an oxygen;
N is 0-4; With
M is 0-2.
22, according to the compound of claim 21, wherein, Z ' is-SO
2-.
23, according to the compound of claim 21, wherein, R
21Be R
22(CH
2)
k, (R
22)
2CH (CH
2)
k, phenyl or (phenyl)
2-CH.
24, according to the compound of claim 21, wherein, R
25Be C
1-4Alkyl.
25, according to the compound of claim 24, wherein, R
25Be methyl.
26, according to the compound of claim 21, wherein, R
28Be hydrogen, C
1-4Alkyl or benzyl.
27, according to claim 1 compound, wherein
R
1Be phenyl, benzyl, 1-naphthyl methyl, 2-naphthyl methyl, pyridyl, pyridylmethyl, quinolyl or quinolyl methyl, it can be replaced by 1-5 following radicals or not be substituted: chlorine, methoxyl group, methyl, trifluoromethyl, cyano group, nitro, methyl sulphonyl, amino or dimethylamino.
28, according to the compound of claim 1, wherein, R
1Be 8-quinolyl, 5-methyl-8-quinolyl, 8-quinolyl methyl, 5-methyl-8-quinolyl methyl, 4-benzo-2,1,3-thiadiazolyl group, 5-chloro-2-thienyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl, isoquinolyl, pyridylmethyl, isoquinolyl methyl, tetrahydric quinoline group and tetrahydroquinoline ylmethyl.
29, according to the compound of claim 1, wherein, m and n are 0, R
12, R
13, R
14And R
15Be hydrogen.
30, according to the compound of claim 1, it is one of following compound:
3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-benzyl sulfuryl amino-6-methyl isophthalic acid-[(1-(1-guanidine radicals oxygen ylmethyl) cyclopropyl) amino carbonyl methyl]-2-pyridone;
3-(3-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-iodine benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-bromobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(4-benzyl chloride base alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-chloro-6-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(4-luorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2,3-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3,4-difluorobenzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(2,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2,5-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3,4-dichloro benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(1-naphthyl methyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(2-methyl-benzyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-benzenesulfonyl amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3-chloro-phenyl-alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(4-p-methoxy-phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3,4-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3-bromophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3,4-dichlorophenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(4-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(4-ethylphenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-sec.-propyl-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-ethyl-1-[2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-propyl group-1-[(2-guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-N "-methyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-N " butyl guanidine radicals oxygen base ethyl) amino carbonyl methyl]-the 2-pyridone;
3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[2-N " (3-phenyl propyl) guanidine radicals oxygen base ethyl] amino carbonyl methyl }-the 2-pyridone;
With its pharmacologically acceptable salt.
31, a kind of pharmaceutical composition that is used to suppress the mammalian proteins hydrolysis, it comprises compound and the pharmaceutically acceptable carrier or the thinner of the claim 1 of arrestin hydrolysis significant quantity.
32, according to the pharmaceutical composition of claim 31, it comprises the described compound that suppresses trypsin-like proteolytic enzyme significant quantity.
33, the pharmaceutical composition of claim 31 is used to prepare the purposes that suppresses mammalian proteins hydrolysis medicine.
34, according to the purposes of claim 33, mammalian proteins wherein is a trypsin-like proteolytic enzyme.
35, the pharmaceutical composition of claim 31 is used to prepare the purposes of treatment mammalian pancreas inflammation, thrombosis, local asphyxia, apoplexy, restenosis, pulmonary emphysema or inflammation medicine.
36, the pharmaceutical composition of claim 31 is used for preparing the purposes that blood plasma platelet aggregation that inhibition causes by zymoplasm and Fibrinogen solidify medicine.
37, the compound of claim 1 is used to prepare the purposes that suppresses blood coagulation enzyme medicine.
38, the compound of claim 1 is used for preparing the purposes that suppresses blood formation platelet aggregation drugs.
39, the compound of claim 1 is used for preparing the purposes that suppresses blood thrombosis medicine.
40, a kind of device that is used for blood collecting, blood circulation and blood storage, wherein, described device comprises the melagatran of significant quantity or macromole as antithrombotics, or be embedded in or physical connection constitutes in the material of described apparatus structure to one or more, its improvements are that one or more compounds that adopt claim 1 are as thrombin inhibitors.
41, according to the device of claim 40, wherein, described device is conduit, haemodialysis control unit, blood collection unit, syringe, blood collection tube, blood line or outside blood circulation device.
42, according to the device of claim 40, wherein,, described device inserts the support in the Mammals but being surgery.
43, a kind of preparation method of alkoxyl group guanidine of claim 1 comprises:
Make the compound reaction of compound or its salt and the formula X of formula IX:
Wherein, R
3, R
4, R
5, R
12, R
13, R
14, R
15, R
a, R
b, R
c, n and m all as claim 1 definition and
R
51Be hydrogen or R
1-Z-, wherein, R
1With the definition of Z such as claim 1 and
Condition is R
a, R
bAnd R
cBe hydrogen.
44, the compound of claim 1, it is 3-(3-aminomethyl phenyl alkylsulfonyl) amino-6-methyl isophthalic acid-[(2-guanidine radicals oxygen ethyl) amino carbonyl methyl]-2-pyridone or its solvate, hydrate or pharmacy acceptable salt.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6647597P | 1997-11-26 | 1997-11-26 | |
| US6732497P | 1997-12-05 | 1997-12-05 | |
| US6910798P | 1998-03-23 | 1998-03-23 | |
| US60/066,475 | 1998-03-23 | ||
| US60/067,324 | 1998-03-23 | ||
| US60/069,107 | 1998-03-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1283189A CN1283189A (en) | 2001-02-07 |
| CN1125051C true CN1125051C (en) | 2003-10-22 |
Family
ID=27370978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98812495A Expired - Fee Related CN1125051C (en) | 1997-11-26 | 1998-11-25 | Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1125051C (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997001338A1 (en) * | 1995-06-27 | 1997-01-16 | Merck & Co., Inc. | Pyridinone-thrombin inhibitors |
| US5658930A (en) * | 1994-12-13 | 1997-08-19 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
| WO1997030708A1 (en) * | 1996-02-22 | 1997-08-28 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
-
1998
- 1998-11-25 CN CN98812495A patent/CN1125051C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5658930A (en) * | 1994-12-13 | 1997-08-19 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
| WO1997001338A1 (en) * | 1995-06-27 | 1997-01-16 | Merck & Co., Inc. | Pyridinone-thrombin inhibitors |
| WO1997030708A1 (en) * | 1996-02-22 | 1997-08-28 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
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| Publication number | Publication date |
|---|---|
| CN1283189A (en) | 2001-02-07 |
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