CN1599612A - Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes - Google Patents
Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes Download PDFInfo
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Abstract
A combination therapy of at least one FBPase inhibitor and at least one other antidiabetic agent is disclosed.
Description
Related application
The application require the denomination of invention submitted on July 6th, 2000 for " FBP enzyme inhibitor and antidiabetic drug unite be used for the treatment of diabetes " provisional application series number 60/216,531 rights and interests are incorporated into the full content (comprising its accompanying drawing) of this provisional application among the application by reference at this.
Invention field
The present invention is used for the treatment of the open antidiabetic drug of at least a FBP enzyme inhibitor and at least a other types is united.
Background of invention
Diabetes are one of the most sick kinds of falling ill in the world today.Diabetics is divided into two classes, i.e. type i diabetes (insulin-dependent diabetes (IDDM)) and type ii diabetes (noninsulindependent diabetes (NIDDM)).
Generally be to adopt insulin and insulin analog to treat IDDM patient, yet a kind of hypotype that these Therapeutic Method can not fine these patients of treatment is called " the fragile type diabetes ".
NIDDM accounts for 90% of all types of diabetes sums, only just can influence 12-14 1,000,000 be grown up (total population 6.6%) in the U.S. according to this disease of estimation.The three kind main metabolic relevant with NIDDM are unusually: (a) the pancreatic secretion insulin is impaired, and (b) peripheral tissues's (as muscle and fat) produces resistance and (c) the excessive generation glucose of liver (being that hepatic glucose output is excessive) to insulin.These unusual common can cause on an empty stomach hyperglycemia and after the meal plasma glucose levels increase greatly.
Diabetes and multiple chronic complicating diseases, comprise microangiopathy (as retinopathy, nephropathy and neuropathy) and macroangiopathic (as coronary heart disease).There is cause effect relation in studies show that in a large number between chronic hyperglycemia and the known diabetic complication of animal model.In human body, proved this relation first by DCCT (DCCT) and the Stockholm Prospective Study gained result, shown that the dangerous significantly reduction of known diabetic syndrome takes place the IDDM diabetics of strict blood sugar control.Therefore, people expect that also strict blood sugar control also is of value to NIDDM patient.
The method that is used for the treatment of NIDDM patient at present not only needs to control the risk factor that life style causes, and needs control medicine interference factor.First-selected Therapeutic Method for NIDDM is generally strict control feed and workout scheme, this is because the NIDDM patient of overwhelming majority overweight promptly fat (67%), and the body weight reduction can make insulin secretion increase and/or insulin sensitivity increases, and therefore makes blood sugar recovery normal.But, since relatively poor and relatively poor to the compliance of Therapeutic Method to the reaction of Therapeutic Method, so only there is the blood sugar recovery of the people below 30% normal among these patients.Only the patient that hyperglycemia is controlled by diet generally can adopt oral antidiabetic drug and/or insulin to treat.
The oral drugs of four kinds of main types that the doctor generally uses are insulin secretagogue (as sulfaurea drugs: glibenclamide, glimepiride and glipizide), biguanide (as metformin and phenformin), insulin sensitizer (as rosiglitazone and pioglitazone) and Alpha-glucosidase inhibitor (as acarbose).Above-mentioned insulin secretagogue at defective be the pancreatic secretion insulin, this defective is found in the diabetics usually.Conventional medicament that this paradiabetes adopted and new medicine such as meglitinide class medicine (such as nateglanide and repaglinide) can be by combining and the stimulating pancreas uelralante with adenosine triphosphate (the ATP)-dependency potassium channel of pancreatic beta cell.Other insulin secretagogue comprises glucagon-like peptide (GLP-1), and its significant feature site also is the β cell.People estimate the medicine such as dipeptidyl peptidase-IV (DPP-IV) inhibitor that prolong the GLP-1 half-life also can be used as insulin secretagogue.
Biguanides has come into operation and has reached many decades.Although the mechanism of action of this class medicine is still unclear, in recent years, people have determined that the effect of metformin reduction glucose mainly is because this medicine suppresses liver glucose output.
Insulin sensitizer is another kind of oral drugs.The antidiabetic drug that peroxisome hypertrophy factor activator receptor (PPAR-γ) seemingly proposes in the recent period is the effect target of insulin sensitizer.It is reported, this class medicine can strengthen insulin-mediated to the disposing capacity of glucose and suppress the output of liver glucose, and insulin secretion is not had direct stimulation.
Adopt sulphur urea, biguanide and insulin sensitizer that the clinical data that NIDDM patient treats is shown: even when maximum therapeutic dose, the gentle hematochrome Alc of fasting blood G/W level can not reduced to the below horizontal of chronic diabetes syndrome patient yet.
The oral drugs of a last quasi-tradition are the alpha-Glucosidase classes.Alpha-Glucosidase be responsible for that complicated Hydrocarbon digest in gastrointestinal tract and simply Hydrocarbon at the systemic enzyme of gastrointestinal tract.Alpha-glucosidase inhibitor prevents the quick digestion of Hydrocarbon, delays their absorption thus.Moving of these inhibitor passivation GLPPs, this phenomenon is usually observed in diabetics.
A large amount of test approach is the excessive generation at liver glucose.The medicine that belongs to this type of liver glucose output inhibitor comprises: (a) glycogen phosphorylase inhibitors, these inhibitor can prevent preserving of liver glycogen, (b) G-6-Pase inhibitor, the release of the glucose that the blocking-up of these inhibitor causes owing to gluconeogenesis and glycogenolysis, (c) glucagon antagonist, these antagonisies work to the stimulation that liver glucose produces by reducing glucagon, (d) dextrin agonist, these agonist partly are that the secretion by glucagon suppression improves Blood glucose control, and (e) fatty acid oxidation inhibitors, these inhibitor reduce the stimulation that fatty acid oxidations produce gluconeogenesis.
Result from U.K.Diabetes Prospective Study shows, the treatment of the maximal dose that the patient is carried out with insulin, sulphur urea or metformin all can not maintain fasting glucose normal level (U.K.Prospective Diabetes Study16.Diabetes, 44:1249-158 (1995)) during reaching the research in 6 years.Can not fully estimate the long-term control that can this class medicine keep blood glucose according to clinical experience for the insulin sensitizer of nearest proposition.But the effectiveness of insulin sensitizer needs the cooperation of pancreatic function, and therefore, this class medicine is worth limited when treatment diabetes in late period.So in the NIDDM field, people still need alternative medicine.
It is believed that the feature of NIDDM is that to produce that speed improves mainly be J.Clin.Invest 90:1323-1327 (1992) such as () Magnusson because the up regulation of gluconeogenesis to liver glucose.Gluconeogenesis is the biosynthesis pathway of an altitude mixture control, wherein needs the participation of 11 kinds of enzymes, and by the effect of these enzymes, some precursor such as lactate, pyruvate, alanine and glycerol are converted into glucose.7 kinds of enzymes can the catalysis back reaction, is public for gluconeogenesis and glycolysis.4 kinds of enzyme catalysiss are unique reactions for gluconeogenesis, and these enzymes are pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1 and G-6-Pase.Be subjected to the control of these enzymes (corresponding steps of catalysis glycolysis direction) specific activity and substrate effectiveness by total influx of this approach.Dietary factor (as carbohydrate, protein and fat) and hormone (as insulin, glucagon, glucocorticoid and epinephrine) are by gene expression and transcribe the enzymatic activity that back mechanism is coordinated gluconeogenesis and glycolytic pathway.
Gruber reported once that the part nucleoside can reduce the blood glucose levels of whole animal by suppressing the FBP enzyme.These chemical compounds form corresponding Monophosphate by phosphorylation at first and show activity.Gruber etc. (U.S.Patent No.5,658,889, EP 0 427 799 B1) disclose and have adopted the inhibitor in the AMP site of FBP enzyme to treat diabetes.WO 98/39342 (U.S.Patent No.6,054,587), WO 98/39343 (U.S.Patent No.6,110,903), WO 98/39344 and WO 00/14095 have also described employing FBP enzyme inhibitor and have treated diabetes.
Summary of the invention
In view of to generally the needing of diabetes remedy, people still need the further Therapeutic Method to diabetes.The applicant thinks, can not be at this list of references of discussing as prior art, and all these lists of references all are incorporated into its full content among the application by reference.
The present invention relates to diabetes or in response to blood sugar increasing and/or periphery insulin sensitivity raise and/or insulin secretion increases other diseases and disorderly combinational therapeutic methods and compositions.Described Therapeutic Method comprises the while or gives at least a FBP enzyme inhibitor and at least a antidiabetic drug in the different time, in the hope of obtaining required reaction.Although any suitable antidiabetic drug all can be united use with the FBP enzyme inhibitor, but the antidiabetic drug that is used for the present invention be selected from usually following one or more: (a) insulin secretagogue is (as the sulphur urea, non-sulphur urea, the GLP-1 receptor stimulating agent, the medicine of DPP-IV inhibitor or other known promotion insulin secretions), (b) insulin or insulin analog, (c) insulin sensitizer (as rosiglitazone and pioglitazone), (d) biguanide (as metformin and phenformin), (e) Alpha-glucosidase inhibitor (as acarbose), (f) glycogen phosphorylase inhibitors, (g) G-6-Pase inhibitor, (h) glucagon antagonist, (i) dextrin agonist, or (j) fatty acid oxidation inhibitors.
In certain embodiments of the invention, at least a FBP enzyme inhibitor and at least a aforesaid antidiabetic drug united make liver glucose output reduce greatly, promptly well below when not using the FBP enzyme inhibitor, adopting glucose to reduce the effect that antidiabetic drug produced of dosage separately.And, described therapeutic alliance makes the increase of insulin sensitivity and/or insulin secretion also be higher than the viewed result of any medicine of independent use far away, and described treatment also to carbohydrate and/or lipid (as fat) with and/or protein metabolism mechanism bring about a wholesome effect.
In certain embodiments of the invention, described combinational therapeutic methods has obtained and any other the Therapeutic Method similar effects of independent use, but its therapeutic dose significantly reduces.This phenomenon may be useful especially, as, when described Therapeutic Method causes potential side effect.For example, in certain embodiments of the invention, combinational therapeutic methods of the present invention is used to weaken some potential side effect that the FBP ihibitors for treatment causes.Equally, combinational therapeutic methods of the present invention can weaken the potential side effect that other antidiabetic drug causes, as hyperinsulinemia, hypoglycemia, weight increase, gastrointestinal disorder, abnormal liver function and cardiovascular side effects.
Only adopt the reaction rate of the Therapeutic Method of antidiabetic drug to compare with not adopting the FBP enzyme inhibitor, combinational therapeutic methods of the present invention can improve primary reaction speed (primaryresponse rate).In addition, combinational therapeutic methods of the present invention also can reduce, delays or prevent the incidence rate of Secondary cases failure (secondary failure).
The invention still further relates to treatment and suffer from the method and composition of animal of diabetes, described method comprises the compositions of at least a other antidiabetic drugs that give at least a FBP enzyme inhibitor that described animal contains medicinal effective dose and medicinal effective dose.In certain embodiments, compositions of the present invention can be used for the treatment of, improves or prevent one or more diabetic symptoms.Except that treatment suffered from the method and composition of animal of diabetes, the present invention comprised that also treatment is the disease of feature or the method and composition of disorder (comprising obesity, hypertension, the glucose tolerance that slackens, gastrointestinal tract type diabetes and polycystic ovary syndrome) with the insulin resistance.And, adopt some embodiment of combinational therapeutic methods also can treat effectively to suffer from syndrome X, nephropathy or pancreatitic individuality.Particularly preferred combinational therapeutic methods has these useful purposes and high efficiency and hypotoxicity.
Definition
Also as used in this, except that clearly indicating, following term is defined as has following meaning according to the present invention:
Term " diabetes " comprises NIDDM and IDDM.
Term " fragile type diabetes " refers to the unsettled insulin-dependent diabetes mellitus of blood glucose, it is characterized in that the regular extreme fluctuation between hypoglycemia and hyperglycemia.
The group that the name of the X among formula II, II-A, III, III-A, IV, IV-A, V-1, V-1-A, V-2, V-2-A, X, XA, VII-1, VII-1-A, VII-2 and the VII-2-A, X2, X3 and X4 group is connected by phosphorus begins and is finished by the group that hetero-aromatic ring or aromatic ring connect.For example, when the X among the formula V-1 is alkylamino, mean (YR1) 2-alk-NR-hetero-aromatic ring of structure P (O).
Equally, A, B, D, E, L, J, the A in hetero-aromatic ring or the aromatic ring ", B ", D ", E ", A
2, L
2, E
2, J
2, J
3, J
4, J
5, J
6, J
7And Y
3Group and other substituent groups are described in the following manner, and promptly the group that connects with hetero-aromatic ring or aromatic ring finishes.Generally speaking, finish to name substituent group with the group on the junction point.
Term " aryl " refers to have the aromatic group that 5-14 annular atoms and at least one ring have the conjugated pi electron system.Term " aryl " comprises isocyclic aryl, heterocyclic aryl and two aromatic yl group, and all these groups are optional to be substituted.The aryl that is fit to comprises, as, phenyl and furan-2,5-two bases.
" isocyclic aryl " is such group, and the annular atoms on the wherein said aromatic ring is a carbon atom.Isocyclic aryl comprises monocycle isocyclic aryl and multi-ring or condensed compounds, as the optional naphthyl that replaces.
" heterocyclic aryl " or " heteroaryl " is the group of carbon atom for have 1-4 hetero atom in aromatic ring as annular atoms, remaining annular atoms.The hetero atom that is fit to comprises as oxygen, sulfur, nitrogen and selenium.The heteroaryl that is fit to comprises that as furyl, thienyl, pyridine radicals, pyrrole radicals, N-low alkyl group pyrrole radicals, pyridine radicals-N-oxide, pyrimidine radicals, pyrazinyl, imidazole radicals etc. all these groups are optional to be substituted.
Term " ring formation " or " ring formation " refer to form cyclic group again on existing aryl or heteroaryl.Should can be carbocyclic ring or heterocycle by the new ring that forms, saturated or unsaturated, and contain 2-9 new atom, wherein 0-3 can be the hetero atom that is selected from N, O and S.Should " ring formation " can comprise that the atom of X group is as a new part that forms ring.For example, when addressing formula XA, phrase " L
2And E
2Form the cyclic group of ring formation together " comprise following formula:
Term " two aryl " representative contains the aryl of an above aromatic ring, comprises condensed ring system and the aryl that is replaced by other aryl.This type of group is optional to be substituted.The two aryl that are fit to comprise as naphthyl and xenyl.
Term " alicyclic ring " refers to be combined with the group of aliphatic series and cyclic group character.This type of cyclic group includes, but is not limited to aromatic group, cycloalkyl and bridge joint cycloalkyl.Described cyclic group comprises heterocycle.Cyclohexenyl group ethyl and cyclohexyl ethyl are the example of suitable alicyclic group.This type of group can be chosen wantonly and be substituted.
Term " optional replacement " comprises by 0-4 group that independently is selected from following substituent group replacement: low alkyl group; lower aryl; rudimentary aralkyl; rudimentary alcyl; Heterocyclylalkyl; hydroxyl; lower alkoxy; rudimentary aryloxy group; the perhalogeno alkoxyl; aralkoxy; heteroaryl; heteroaryl oxygen base; heteroaryl alkyl; assorted aralkoxy; azido; amino; guanidine radicals; amidino groups; halo; lower alkylthio; oxo; the acyl group alkyl; carboxyl ester; carboxyl;-carboxamido (carboxamido); nitro; acyloxy; aminoalkyl; the alkylamino aryl; alkylaryl; alkyl amino alkyl; alkoxy aryl; arylamino; arylalkylamino; phosphono; sulfonyl;-carboxamido alkylaryl;-carboxamido aryl; hydroxy alkyl; haloalkyl; the alkyl amino alkyl carboxyl-; the aminocarboxylic amidoalkyl-; cyano group; low-grade alkoxy alkyl; rudimentary whole haloalkyl and alkoxy aryl alkyl.
Term " replacement " comprises by 1-4 group that independently is selected from following substituent group replacement: low alkyl group; lower aryl; rudimentary aralkyl; rudimentary alcyl; Heterocyclylalkyl; hydroxyl; lower alkoxy; rudimentary aryloxy group; the perhalogeno alkoxyl; aralkoxy; heteroaryl; heteroaryloxy; heteroaryl alkyl; assorted aralkoxy; azido; amino; guanidine radicals; amidino groups; halo; lower alkylthio; oxo; the acyl group alkyl; carboxyl ester; carboxyl;-carboxamido; nitro; acyloxy; aminoalkyl; the alkylamino aryl; alkylaryl; alkyl amino alkyl; alkoxy aryl; arylamino; arylalkylamino; phosphono; sulfonyl;-carboxamido alkylaryl;-carboxamido aryl; hydroxy alkyl; haloalkyl; the alkyl amino alkyl carboxyl-; the aminocarboxylic amidoalkyl-; cyano group; low-grade alkoxy alkyl; rudimentary whole haloalkyl and alkoxy aryl alkyl." aryl of replacement " and " heteroaryl that replaces " preferably refer to by the aryl and the heteroaryl of 1-3 substituent group replacement.Preferred described substituent group is selected from low alkyl group, lower alkoxy, rudimentary whole haloalkyl, halo, hydroxyl and amino.When describing R
5Or R
55During group, " replacement " do not comprise ring formation.
Term " aralkyl " refers to the alkyl that replaced by aryl.The aralkyl that is fit to comprises benzyl, picolyl etc., and can choose wantonly and be substituted.Term " aralkyl-" refer to divalent group-aryl-alkylidene-.
Term " alkylaryl-" refer to group-alk-aryl-, be alkylidene at this " alk "." rudimentary-alkylaryl-" refers to that wherein alkylidene is this type of group of low-grade alkylidene.
When describing organic group or chemical compound, adopting term " rudimentary " is respectively they to be limited, and for example it contains maximum 10 (comprising 10), preferred maximum 6 (comprising 6), is preferably 1-4 carbon atom.This type of group can be for straight chain, side chain or cyclic.
Term " arylamino " (a) and " arylalkylamino " (b) refer to group-NRR ' respectively, wherein in (a), R is an aryl, R ' is hydrogen, alkyl, aralkyl or aryl, and in (b), R is an aralkyl, R ' is hydrogen, aralkyl, aryl or alkyl.
Term " acyl group " refers to-C (O) R that wherein R is an alkyl or aryl.
Term " carboxyl " refers to-C (O) OH.
Term " carboxyl ester " refers to-C (O) OR that wherein R is alkyl, aryl, aralkyl or alcyl, and all these groups are optional to be substituted.
Term " oxo " refers in the alkyl=O.
Term " amino " refers to-NRR ' that wherein R and R ' independently are selected from hydrogen, alkyl, aryl, aralkyl and alcyl, and outside the dehydrogenation, every other group is optional to be substituted; And R and R ' can form the ring-type ring system.
Term " carbonylamino " and " carbonylamino-" refer to respectively RCONR-and-CONR-, wherein each R independently is a hydrogen or alkyl.
Term " halogen " or " halo " refer to-F ,-Cl ,-Br and-I.
Term " alkyl amino alkyl carboxyl-" refers to group alkyl-NR-alk-C (O)-O-, and wherein " alk " is alkylidene, and R is hydrogen or low alkyl group.
Term " alkyl amino-carbonyl-" refer to group-alk-NR-C (O)-, wherein " alk " is alkylidene, R is hydrogen or low alkyl group.
Term " oxygen base alkyl-" refers to group-O-alk-, and wherein " alk " is alkylidene.
Term " oxygen base alkylamino-" refers to group-O-alk-NR-, and wherein " alk " is alkylidene, and R is hydrogen or low alkyl group.Therefore, "-oxygen base alkylamino-" with "-oxygen base alkylene amino-" synonym.
Term " alkyl carboxyl alkyl-" refers to group-alk-C (O)-O-alk-, wherein each " alk " and independent be alkylidene.
Term " alkyl " refers to saturated aliphatic group, comprises straight chain, side chain and cyclic group.Alkyl group can be chosen wantonly and be substituted.The alkyl that is fit to comprises the group (as methyl, isopropyl and cyclopropyl) that contains about 20 carbon atoms of 1-as those.
Term " cyclic alkyl " or " cycloalkyl " refer to be 3-10 atom, the more preferably alkyl of the cyclic group of 3-6 atom.The cyclic group that is fit to comprises norborny and cyclopropyl.This type of group can be substituted.
Term " heterocyclic radical " and " Heterocyclylalkyl " refer to 3-10 atom, more preferably 3-6 atom and contain at least one hetero atom, a preferred 1-3 heteroatomic cyclic group.The hetero atom that is fit to comprises oxygen, sulfur and nitrogen.Heterocyclic radical can connect by nitrogen-atoms on the described ring or carbon atom.The heterocyclic radical that is fit to comprises pyrrolidinyl, morpholino, morpholino ethyl and pyridine radicals.
Term " phosphono " refers to-PO
3R
2, wherein R is selected from-H, alkyl, aryl, aralkyl and alcyl.
Term " sulfonyl " refers to-S (O)
2OR, wherein R is selected from H, alkyl, aryl, aralkyl and alcyl.
Term " alkenyl " refers to contain the unsaturated group of at least one carbon-to-carbon double bond, comprises straight chain, side chain and cyclic group.Alkenyl can be chosen wantonly and be substituted.The alkenyl that is fit to comprises pi-allyl." 1-alkenyl " refers to the alkenyl of double bond position in first carbon atom and second carbon atom.If this 1-alkenyl links to each other with the another one group, for being connected in the W substituent group on annular phosphonate or the phosphoramidate (phosph (oramid) ate), so then on first carbon atom, link to each other as this group.
Term " alkynyl " refers to contain the unsaturated group of at least one carbon-to-carbon triple bond, comprises straight chain, side chain and cyclic group.Alkynyl can be chosen wantonly and be substituted.The alkynyl that is fit to comprises acetenyl." 1-alkynyl " refers to that triple bond is positioned at the alkynyl of first carbon atom and second carbon atom.If this 1-alkynyl links to each other with the another one group, be the W substituent group that is connected on annular phosphonate or the phosphoramidate as this group, so then on first carbon atom, link to each other.
Term " alkylidene " refers to bivalence straight chain, side chain or ring-type radical of saturated aliphatic group.
Term " cycloalkylidene-COOR
3" refer in ring, contain the divalent cyclic alkyl group or the heterocyclic radical of 4-6 atom, have 0-1 hetero atom that is selected from O, N and S.Described cycloalkyl or heterocyclic radical quilt-COOR
3Replace.
Term " acyloxy " refers to ester group-O-C (O) R, and wherein R is-H, alkyl, alkenyl, alkynyl, aryl, aralkyl or alcyl.
Term " aminoalkyl-" refers to group NR
2-alk-, wherein " alk " is alkylidene, R is selected from-H, alkyl, aryl, aralkyl and alcyl.
Term " alkyl hydroxy-" refers to have the alkyl chain of a side-OH.When this term was used to describe the X group, described-OH was positioned at the α position of phosphorus atoms.
Term " alkyl amino alkyl-" refers to alkyl-NR-alk-, and wherein " alk " is alkylidene, and R is-H or low alkyl group." lower alkyl amino alkyl-" refers to that wherein said alkyl and alkylidene are the group of low alkyl group and low-grade alkylidene.
Term " arylamino alkyl-" refers to aryl-NR-alk-, and wherein " alk " is alkylidene, R is-and H, alkyl, aryl, aralkyl or alcyl.In " lower aryl aminoalkyl-", described alkylidene is a low-grade alkylidene.
Term " alkylamino aryl-" refer to alkyl-NR-aryl-, wherein " aryl " is divalent group, R is-H, alkyl, aralkyl or alcyl.In " lower alkyl amino aryl-", described alkyl is a low alkyl group.
Term " alkoxy aryl-" refers to the aryl that alkoxy replaces.In " lower alkoxy aryl-", described alkyl is a low alkyl group.
Term " aryloxy alkyl-" refers to the alkylidene that replaced by aryloxy group.
Term " sweet-smelling alkoxy alkyl-" refers to group aryl-alk-O-alk-, and wherein " alk " is alkylidene." rudimentary sweet-smelling alkoxy alkyl-" refers to that wherein said alkylidene is this type of group of low-grade alkylidene.
Term " alkoxyl-" or " alkyl oxy-" refer to group-alk-O-, and wherein " alk " is alkylidene.Term " alkoxyl-" refers to group alkyl-O-.
Term " alkoxyalkyl-" or " alkyl oxy alkyl-" refer to group-alk-O-alk-, and wherein each " alk " independently is selected from alkylidene.In " low-grade alkoxy alkyl-", each alkylidene is a low-grade alkylidene.
Term " alkylthio group-" or " alkylthio group-" refer to respectively group alkyl-S-and-alk-S-, wherein " alk " is alkylidene.
Term " alkylthio alkyl-" refers to group-alk-S-alk-, wherein each " alk " independently be selected from alkylidene.In " rudimentary-alkylthio alkyl-", each alkylidene is a low-grade alkylidene.
Term " alkoxy-carbonyl oxy-" refers to alkyl-O-C (O)-O-.
Term " aryloxycarbonyl oxygen base-" refers to aryl-O-C (O)-O-.
Term " alkylthio group ketonic oxygen base-" refers to alkyl-S-C (O)-O-.
Term " alkoxycarbonyl amino-" refers to-alk-O-C (O)-NR
1, wherein " alk " is alkylidene, R
1Be selected from-H, alkyl, aryl, alcyl and aralkyl.
Term " alkyl amino-carbonyl amino-" refers to-alk-NR
1-C (O)-NR
1, wherein " alk " is alkylidene, each R
1Independently be selected from H, alkyl, aryl, aralkyl and alcyl.
Term " acylamino-" or " carboxamido " refer to NR
2-C (O)-and RC (O)-NR
1, wherein each R and R
1Independently be selected from H, alkyl, aryl, aralkyl and alcyl.This term does not comprise urea-NR-C (O)-NR-.
Term " carboxamido alkylaryl " and "-the carboxamido aryl " refer to aryl-alk-NR respectively
1-C (O)-and ar-NR
1-C (O)-, wherein " ar " is aryl, " alk " be alkylidene, each R
1Independently be selected from H, alkyl, aryl, aralkyl and alcyl.
Term " alkyl carboxamido " or " alkyl-carbonyl-amino-" refer to group-alk-C (O) N (R)-, wherein " alk " is alkylidene, R is-H or low alkyl group.
Term " alkyl amino-carbonyl-" refer to group-alk-NR-C (O)-, wherein " alk " is alkylidene, R is H or low alkyl group.
Term " aminocarboxylic amidoalkyl-" refers to group NR
2-C (O)-N (R)-alk-, wherein R is alkyl or H, " alk " is alkylidene." rudimentary aminocarboxylic amidoalkyl-" refers to that wherein " alk " is this type of group of low-grade alkylidene.
Term " thio-carbonate " refers to-O-C (S)-O-, no matter be in the chain group or in cyclic group.
Term " hydroxy alkyl " refers to by the alkyl of one-OH replacement.
Term " haloalkyl " refers to by an alkyl that is selected from the halo group replacement of I, Cl, Br and F.
Term " cyano group " refers to-C ≡ N.
Term " nitro " refers to-NO
2
Term " acyl group alkyl " refers to alkyl-C (O)-alk-, and wherein " alk " is alkylidene.
Term " heteroaryl alkyl " refers to the alkyl that replaced by heteroaryl.
When addressing X, X
2, X
3Or X
4The time, term " 1,1-dihalo alkyl-" refers to that the halogen of 1-position wherein is positioned at X, the X of the α position of phosphorus atoms
2, X
3Or X
4Group.
Term " perhalogeno " refers to the group that each c h bond on alicyclic ring wherein or the aryl is all replaced by C-halo key.The whole haloalkyl that is fit to comprises as-CF
3With-CFCl
2
Term " guanidine radicals " refers to-NR-C (NR)-NR
2With-N=C (NR
2)
2, wherein each R group independently is selected from-H, alkyl, alkenyl, alkynyl, aryl and alcyl, and outside the dehydrogenation, every other group all can be substituted.
Term " amidino groups " refers to-C (NR)-NR
2, wherein each R group independently is selected from-H, alkyl, alkenyl, alkynyl, aryl and alcyl, and outside the dehydrogenation, every other group all can be substituted.
Term " 2-thiazolyl-" or " 2-oxazolyl-" or " 2-selenazoles base " refer to corresponding alkali, are connected in X, the X of 2 of described heterocycles
2, X
3Or X
4On the group.
Term " pharmaceutically acceptable salt " comprises the salt of the chemical compound of formula I, IA, II, II-A, III, III-A, IV, IV-A, V-1, V-1-A, V-2, V-2-A, VI, VI-A, VII-1, VII-1-A, VII-2, VII-2-A, X or XA, and by chemical compound of the present invention and organic or inorganic acid or the common deutero-prodrug of alkali.The acid that is fit to comprises example hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, right-toluenesulfonic acid and maleic acid.
Term " prodrug " at this refers to such chemical compound, and promptly when giving organism, these chemical compounds produce " medicine " (bioactive compound) through spontaneous chemical reaction, enzymatic chemical reaction or the one or more steps among both.The standard prodrug relevant with the FBP enzyme inhibitor is that group is connected in functional group such as HO-, HS-, HOOC-, R
2The last formation of N-, described group can remove in vivo.The prodrug of these functional groups is well known in the art, and usually is used to improve oral administration biaavailability or other are of value to the character of preparation, the release or the activity of medicine.The prodrug of standard includes, but is not limited to carboxylate; wherein said group is alkyl, aryl, aralkyl, acyloxy alkyl, alkoxy-carbonyl oxy alkyl; and the ester of hydroxyl, sulfur alkohol and amine, wherein the group of Lian Jieing is acyl group, alkoxy carbonyl, amino carbonyl, phosphate radical or sulfate radical.Also comprise phosphonic standard prodrug, and in formula I, IA, II, II-A, III, III-A, IV, IV-A, V-1, V-1-A, V-2, V-2-A, VI, VI-A, VII-1, VII-1-A, VII-2, VII-2-A, X and XA, represent by R1.The above-mentioned group that provides only is exemplary, but not enumerates one by one, and those skilled in the art can prepare the variant of other known precursors medicines.This type of prodrug of formula I, IA, II, II-A, III, III-A, IV, IV-A, V-1, V-1-A, V-2, V-2-A, VI, VI-A, VII-1, VII-1-A, VII-2, VII-2-A, X and XA chemical compound is also included within the scope of the present invention.The chemical conversion that prodrug must experience certain form could produce bioactive chemical compound.In some cases, the biological activity of described prodrug is usually less than medicine itself, and they are to be used for waiting and improving usefulness or safety by raising oral administration biaavailability, drug effect half-life.
Term " prodrug ester " includes, but is not limited to the combination of following groups and these groups as used herein:
[1] by the acyloxy Arrcostab of formula A representative, in document (Farquhar etc., J.Pharm.Sci.72,324-325 (1983)) these esters have been carried out sufficient introduction, formula A is as follows:
Formula A
Wherein: R, R ' and R " independent is H, alkyl, aryl, alkylaryl or alcyl (referring to WO 90/08155 and WO 90/10636).
[2] other acyloxy Arrcostabs (shown in B) that wherein form alicyclic ring also are possible.Show, these esters can be in cell through beginning, be the consecutive reaction of the supposition of a series of eliminations reactions subsequently by taking off esterification, thereby produce phosphorated nucleoside (as Freed etc., Biochem.Pharm.38:3193-3198 (1989)).
Formula B
Wherein: R is-H, alkyl, aryl, alkylaryl, alkoxyl, aryloxy group, alkylthio group, arylthio, alkylamino, arylamino, cycloalkyl or alcyl.
[3] in the beta-Lactam antibiotic field, people have carried out studying (J.Antibiotics such as Tatsuo Nishimura, 1987,40 (1), 81-90 to the another kind of dibasic acid esters that is known as the alkoxy-carbonyl oxy methyl ester; For a review see Ferres, H., Drugs ofToday, 1983,19,499), this class dibasic acid esters is suc as formula shown in the A, and wherein R is alkoxyl, aryloxy group, alkylthio group, arylthio, alkylamino and arylamino; R ' and R " be H, alkyl, aryl, alkylaryl and alcyl independently.Recently; Cathy; (Abstract from AAPS WesternRegional Meeting such as M.S.; April; studies show that 1997), (9-[(R)-the 2-phosphonium mesitoyl methoxy] propyl group) bioavailability of alkoxy-carbonyl oxy methyl esters prodrug in Canis familiaris L. of adenine can be up to 30%.
[4] aryl ester also be used as the phosphonic acid ester prodrug (as Erion, DeLambert etc., J.Med.Chem.37:498,1994; Serafinowska etc., J.Med.Chem.38:1372,1995).In the research that animal and human's body carries out, ester (proester) produces parent phosphonic acids (formula C) before phenyl and single and the polysubstituted phenyl.Khamnei and Torrence are at J.Med.Chem.; Described among the 39:4109-4115 (1996) Y wherein for another approach of the adjacent carboxylate of phosphate radical.
Formula C
Wherein: Y is H, alkyl, aryl, alkylaryl, alkoxyl, acyloxy, halogen, amino, alkoxy carbonyl, hydroxyl, cyano group or alcyl.
[5] report is also arranged, benzyl ester produces the parent phosphonic acids.In some cases, adopt the substituent group of right-position can quicken hydrolysis.Under the effect of enzyme such as oxidase, esterase etc., can more easily make benzyl analog [formula D, X=H, OR or O (CO) R or O (CO) OR] produce the 4-hydroxy compounds with 4-acyloxy or 4-alkoxyl.Mitchell etc. in J.Chem.Soc.Perkin Trans.I2345 (1992) and Brook etc. in WO 91/19721, addressed the example of this class prodrug:
Formula D
Wherein X and Y independently are H, alkyl, aryl, alkylaryl, alkoxyl, acyloxy, hydroxyl, cyano group, nitro, whole haloalkyl, halo or alkoxy carbonyl; R ' and R " be H, alkyl, aryl, alkylaryl, halogen and alcyl independently.
[6] people have also described and have been used for ester before hepatocyte is transmitted the sulfur-bearing phosphonic acids of FBP enzyme inhibitor.These preceding esters contain the thio-ethyl part suc as formula the protection shown in the E.Described phosphonic one or more oxygen are esterified.Need produce free thiol acid group owing to produce the mechanism of action that takes off esterification, so various thiol protective group is possible.For example, reduce disulphide (Puech etc., Antiviral Res., 22:155-174 (1993)) by the method for reductase mediation.After the hydrolysis of esterase mediation, monothioester also can produce free thiol acid group (Benzaria, etc., J.Med.Chem., 39:4958 (1996)).May be cyclic analogs also, be used for discharging phosphonate ester at isolating rat hepatocytes.The cyclic disulfide that illustrates below never has report, is new therefore.
Formula E
In formula E, Z is alkyl-carbonyl, alkoxy carbonyl, aryl carbonyl, aryloxycarbonyl or alkylthio group.
The example of the prodrug that other are fit to comprises the preceding esters of following example: Biller and Magnin (U.S.Patent No.5,157,027); Serafinowska etc., J.Med.Chem.38,1372 (1995); Starrett etc., J.Med.Chem.37,1857 (1994); Martin etc., J.Pharm.Sci.76,180 (1987); Alexander etc., Collect.Czech.Chem.Commun, 59,1853 (1994); And EPO patent application 0 632 048 A1.Some structure type of describing is optional to be substituted, and is included in the 2-oxo-1 of condensed lactone (formula E-1 and E-2) that the ω position connects and the optional replacement that links to each other with oxygen on the phosphorus by methylene, 3-dioxole (dioxolene) (formula E-3), as:
3-benzo [c] furanonyl 2-oxo-tetrahydrofuran-5-base 2-oxo-4,5-two dehydrogenations-1,3-
E-1 E-2 dioxolanes methyl
E-3
Wherein R is-H, alkyl, cycloalkyl or alcyl; And
Y is-H, alkyl, aryl, alkaryl, cyano group, alkoxyl, acyloxy, halogen, amino, alcyl or alkoxy carbonyl.
The prodrug of formula E-3 is the example of " the optional alcyl that replaces ", and wherein said annulus contains carbonate (carbonate) or thio-carbonate (thiocarbonate).
(7) ester also can be used for transmitting the FBP enzyme inhibitor to hepatocyte before the propyl phosphonous acid ester.These preceding esters can contain hydroxyl and hydroxy derivatives in the 3-position of propyl group, shown in F.Shown in F, R wherein and X group can form ring system.One or more oxygen of phosphonic acids part (phosphonate) can be esterified.
Formula F
Wherein R is alkyl, aryl or heteroaryl;
X is hydrogen, alkyl-carbonyl oxygen base or alkoxy-carbonyl oxy; And
Y is alkyl, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, halogen, hydrogen, hydroxyl, acyloxy or amino.
[8] the phosphoramidic acid ester derivant also has been developed to the prodrug of phosphate ester (as McGuigan etc., J.Med.Chem., 1999,42:393 and the document wherein quoted) and the prodrug (Bischofberger etc. of phosphonate ester, U.S.5,798,340 reach the document of wherein quoting), shown in G and H.
Formula G formula H
Owing to infer that compare the cyclic amino phosphate ester with non--cyclic amino phosphate ester has high stability, thus to the cyclic amino phosphate ester as the phosphonate ester prodrug also carried out studying (as Starrett etc., J.Med.Chem., 1994,37:1857).
It is reported that the nucleoside prodrug of another kind of type is combination (Egron etc., the Nucleosides ﹠amp of S-acyl group-2-thio-ethyl ester and phosphoramidate; Nucleotides, 1999,18,981), shown in J.
Formula J
Report according to document, other prodrug also are possible, as the ethyl that replaces, for example McGuigan etc. is at Bioorg Med.Chem.Lett., disclosed two (three chloroethyls) ester and Meier among the 3:1207-1210 (1993), C. wait at Bioorg.Med.Chem.Lett. the nucleoside ester of the phenyl of report and benzyl combination among the 7:99-104 (1997).
Work as R
6=R
6, when V=W, W '=H and V and W all point to (point up) or point to down (point down), following structure
Have along the symmetrical plane of the two keys of phosphorus-oxygen.Work as R
6=R
6, V=W, W '=H and V and W all be substituted at described planar opposite face, one of them points to down and another points to when going up, this structure has symmetrical centre or the alternative axle along the two keys of phosphorus-oxygen of symmetry.For wherein each-NR
6The structure that quilt-O-replaces, situation also is like this.
When the spatial chemistry of the phosphorus that is used to describe the cyclic amino phosphate ester, " cis-spatial chemistry " to represent V or W be trans configuration with respect to the two keys of phosphorus-oxygen.
Term " ring-type 1 ', 3 '-propane ester ", " ring-type 1,3-propane ester ", ring-type 1 ', 3 '-propyl diester " and " ring-type 1, the 3-propyl diester " refer to following structure:
Statement " V
2And Z
2Link to each other to form together by an other 3-5 atom and contain 5-7 atom, optionally contain 1 hetero atom and replaced by hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, these substituent groups are connected in distance and are connected on the carbon atom of three atoms of two Y groups on the phosphorus " comprise under array structure:
The structure of last left side of face has 3 carbon atoms in addition, and these 3 carbon atoms have formed 5 yuan of cyclic groups.This type of cyclic group must have listed replacement position and treat oxidation.
Statement " V and Z link to each other to form together to choose wantonly by an other 3-5 atom and contain 1 heteroatomic cyclic group, this cyclic group is aryl-condensed with β that is connected in the Y that links to each other with phosphorus and γ position " comprise descending array structure:
Array structure under statement " V and W link to each other by 3 other carbon atoms and form the optional cyclic group that contains 6 carbon atoms that replaces together; this group can be selected from following substituent group by 1 and replace: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio group ketonic oxygen base and aryloxycarbonyl oxygen base, these substituent groups are connected in distance and are connected on one of described other carbon atom of three atoms of Y group on the phosphorus " comprises:
Said structure has the acyloxy substituent group, and described substituent group distance Y has 3 carbon atoms, and has optional substituent group, methyl on new 6 yuan of rings that form.On following each position of said structure, has at least one hydrogen: the carbon that is connected in Z; Be labeled as " 3 " two carbon of α position of carbon; Be connected in above-mentioned " OC (O) CH
3" carbon of group.
Statement " W links to each other to form together to choose wantonly by an other 2-5 atom with W ' and contains 0-2 heteroatomic cyclic group, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement " comprises array structure down:
In the said structure, V=aryl, W and W ' are the cyclopropyl of spiro-condensed.
Term " annular phosphonate or phosphoramidate " refers to the following formula structure:
Wherein Y independently be-O-or-NR
6-.The carbon that is connected in V must have c h bond.The carbon that is connected in Z also must have c h bond.
Term " phosphonate ester or phosphoramidate " refers to phosphonate ester and phosphoramidate, is formula-PO (YR
1) (YR
1) chemical compound, comprise annular form, wherein Y independently be-O-or-NR
6-.
Term " raising " refers to increase or improve special nature.
Term " raising oral administration biaavailability " refers to that the parent drug of described dosage or prodrug (not belonging to the present invention) increase by 50% at least in the gastrointestinal absorption.More preferably increase by 100% at least.Normally compare, thereby obtain oral administration biaavailability by the measured value after measuring described prodrug, medicine or the drug metabolite value in blood, tissue or urine behind the oral administration and being administered systemically.
Term " parent drug " refers to any chemical compound that can the delivery of biologically active chemical compound.The parent drug form be P (O) (OH)
2-X-M, and be the prodrug of standard, as ester.
Term " drug metabolite " refers to that parent drug in vivo or any chemical compound of external generation, comprises biologically active drug.
Term " drug effect half-life " refers to after giving medicine or prodrug, observes pharmacological reaction and reduces half needed time.When described half-life increased preferably at least 50%, the drug effect half-life increased.
Term " pharmacokinetics half-life " refers to after giving medicine or prodrug, observes drug level and reduce half needed time in blood plasma or tissue.
Term " glycemic control " refers to reduce after the meal and/or the fasting blood glucose level, reduce hematochrome Alc concentration, improve glycosuria, reduce liver glucose output or overall glucose is handled or any other canonical parameters that are used to estimate the glucose homeostasis.
Term " therapeutic index " refers to produce the dosage of the medicine of the useful reaction of treatment or prodrug and the ratio of the dosage of have side effects (for example dead, as to indicate that toxicity and/or pharmacology side effect increase).
Term " biologically active drug " refers to produce all chemical substances of biological agent.Therefore, active medicine comprises picture P (O) (OH)
2The chemical compound of the same biologically active of-X-M.
Term " treatment effective dose " refers to have the amount of beneficial effect when treatment disease or disorder.
Detailed Description Of The Invention
The present invention relates to diabetes or in response to blood sugar increasing and/or periphery insulin sensitivity raise and/or insulin secretion increases other diseases and disorderly combinational therapeutic methods and compositions.Described Therapeutic Method comprises the while or gives at least a FBP enzyme inhibitor and at least a antidiabetic drug in the different time, in the hope of obtaining required reaction.Although any suitable antidiabetic drug all can be united use with the FBP enzyme inhibitor, but the antidiabetic drug that is used for the present invention be selected from usually following one or more: (a) insulin secretagogue is (as the sulphur urea, non-sulphur urea, the GLP-1 receptor stimulating agent, the medicine of DPP-IV inhibitor or other known promotion insulin secretions), (b) insulin or insulin analog, (c) insulin sensitizer (as rosiglitazone and pioglitazone), (d) biguanide (as metformin and phenformin), (e) Alpha-glucosidase inhibitor (as acarbose), (f) glycogen phosphorylase inhibitors, (g) G-6-Pase inhibitor, (h) glucagon antagonist, (i) dextrin agonist, or (j) fatty acid oxidation inhibitors.
In certain embodiments of the invention, at least a FBP enzyme inhibitor and at least a aforesaid antidiabetic drug united make liver glucose output reduce greatly, promptly well below when not using the FBP enzyme inhibitor, adopting glucose to reduce the effect that antidiabetic drug produced of dosage separately.And, described therapeutic alliance makes the increase of insulin sensitivity and/or insulin secretion also be higher than the viewed result of any medicine of independent use far away, and described treatment also to carbohydrate and/or lipid (as fat) with and/or protein metabolism mechanism bring about a wholesome effect.
In certain embodiments of the invention, described combinational therapeutic methods has obtained and any other the Therapeutic Method similar effects of independent use, but its therapeutic dose significantly reduces.This phenomenon may be useful especially, as, when described Therapeutic Method causes potential side effect.For example, in certain embodiments of the invention, combinational therapeutic methods of the present invention is used to weaken some potential side effect that the FBP ihibitors for treatment causes.Equally, combinational therapeutic methods of the present invention can weaken the potential side effect that other antidiabetic drug causes, as hyperinsulinemia, hypoglycemia, lactic acidosis, weight increase, gastrointestinal disorder, abnormal liver function and cardiovascular side effects.
Only adopt the reaction rate of the Therapeutic Method of antidiabetic drug to compare with not adopting the FBP enzyme inhibitor, combinational therapeutic methods of the present invention can improve primary reaction speed.In addition, combinational therapeutic methods of the present invention also can reduce, delays or prevent the incidence rate of Secondary cases failure.
The invention still further relates to treatment and suffer from the method and composition of animal of NIDDM or DDM, described method comprises the compositions of at least a other antidiabetic drugs that give at least a FBP enzyme inhibitor that described animal contains medicinal effective dose and medicinal effective dose.In certain embodiments, compositions of the present invention can be used for the treatment of, improves or prevent one or more NIDDM or IDDM symptom.Except that treatment suffered from the method and composition of animal of MIDDM or IDDM, the present invention comprised that also treatment is the disease of feature or the method and composition of disorder (comprising obesity, hypertension, the glucose tolerance that slackens, gastrointestinal tract type diabetes and polycystic ovary syndrome) with the insulin resistance.And, adopt some embodiment of combinational therapeutic methods also can treat effectively to suffer from syndrome X, nephropathy or pancreatitic individuality.Suffer from " the fragile type diabetes " individuality also can adopt some embodiments treatment of combinational therapeutic methods of the present invention.
Particularly preferred combinational therapeutic methods has above-mentioned useful purposes and high efficiency and hypotoxicity.For example in cell culture or experimental animal model, adopt the standard drug method, as passing through to measure LD
50And ED
50Can measure the toxicity of combinational therapeutic methods.
Can be by any suitable approach, comprise as oral, rectum, intranasal, part, vagina, parenteral (comprising subcutaneous, muscle, vein and Intradermal) and transdermal administration combination of the present invention.Preferred approach is oral.
Therapeutic alliance comprises and gives the host described medicine individually or simultaneously.In one embodiment, give two kinds of medicines simultaneously, these two kinds of medicines can be included in the same capsule, also can be included in the different capsules.In one embodiment, (in beginning on the feed to finish during this period of time to feed) gives two kinds of medicines in the time of on the feed.In another embodiment, give antidiabetic drug in the time of on the feed, and (as before sleeping) gives FBP enzyme inhibitor on an empty stomach.In one embodiment, gave two kinds of medicines respectively at interval in 1 hour, 30 minutes, 10 minutes, 5 minutes or 1 minute.In another embodiment, at first give a kind of medicine, then give first kind of medicine 1-12 hour, be generally 3-6 hour, 6-9 hour or give second kind of medicine after 9-12 hour.
The FBP enzyme inhibitor
Combination of the present invention comprises at least a FBP enzyme inhibitor.In most embodiment kind, described combination comprises a kind of FBP enzyme inhibitor.The FBP enzyme inhibitor that is used for the present invention (embodiment A-B), suppresses hepatocyte and produces glucose (Embodiment C-D), (embodiment E-G) or reduce the chemical compound of diabetes animal model blood glucose levels (EXAMPLE V and W) of animal glucose level on an empty stomach that reduces for suppressing people FBP enzymatic activity.Preferred FBP enzyme inhibitor be the chemical compound (embodiment A-B) that proves inhibitory enzyme activity through the vitro inhibition activity research.
In some cases, produce the FBP enzyme inhibitor and need chemical compound metabolism activation in vivo.It may be (embodiment A) of non-activity that this compounds suppresses in the screening at enzyme, having activity in hepatocyte also may non-activity (Embodiment C and D), but this phenomenon of reduction glucose proves that it is activated in vivo in animal models (embodiment K, V-Z, AA-JJ) normal, rat (embodiment E, F and G) and/or diabetes on an empty stomach.
Although the invention is not restricted to down array structure, described FBP enzyme inhibitor generally has the following formula structure:
Chemical compound or its pharmaceutically acceptable prodrug or the salt of special preferred formula I and IA:
Its Chinese style I and IA chemical compound are in vivo or the external M-PO that is converted into
3 2-, it suppresses the FBP enzyme.In these preferred chemical compounds:
Y independently is selected from-O-and-NR
6, prerequisite is as Y during for-O-, is connected in so-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, the optional aralkyl that replaces ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6-, so with-NR
6The R of-connection
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl and formation cyclic group, perhaps R together
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H; With
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkylidene ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 atom, optional contain a hetero atom that is selected from O, N and S and connect together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl and aralkyl, perhaps R
12And R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
Each R
12With each R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl, all these groups are optional to be substituted, perhaps R
12And R
13Link to each other by 2-6 carbon atom and to form optional 1 the heteroatomic cyclic group that is selected from O, N and S that comprises together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
Preferred such FBP enzyme inhibitor, i.e. M-PO wherein
3 2-IC to isolating people FBP enzyme
50Be less than or equal to 5 μ M.Same preferred FBP enzyme inhibitor is to the glucogenic inhibitory action IC of isolating rat hepatocytes
50The FBP enzyme inhibitor of≤50 μ M.The bonded chemical compound in AMP site of preferred especially and FBP enzyme.
Preferably, oral administration biaavailability is at least 5%.More preferably, oral administration biaavailability is at least 10%.
The prodrug of formula IA may have two kinds of isomeric form on phosphorus.Preferred phosphorus wherein is not chirality.Preferably with on the amino that phosphorus links to each other there is not chiral centre yet.Also preferably when n be 1 and R
12During for-H, with R
12And R
13The carbon that connects has S type three-dimensional chemical configuration.
On the one hand, preferred such formula I or formula IA chemical compound or its pharmaceutically acceptable prodrug or the salt of the present invention, promptly wherein M is-X-R
5, R
5Be selected from:
Wherein:
Each G independently is selected from C, N, O, O and Se, and wherein having only a G is O, S or Se, and a maximum G is N;
Each G ' independently is selected from C and N, and wherein being no more than two G ' is N;
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, every other group is all optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl, C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X passes through 2-4 atom with R for the optional linking group that replaces, this group
5Be connected with phosphorus atoms, comprise 0-1 hetero atom that is selected from N, O and S, except that following situation: if X is urea or carbamic acid root, have 2 hetero atoms so, the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein: X is selected from-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio group-alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2With
Prerequisite is:
1) when G ' is N, A, B, D or E are respectively zero;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not the linking group of two atoms, optional replacements-alkyl oxy-or choose wantonly replacement-alkylthio group-;
4) when G is N, A or B are not respectively halogen or the direct group that is connected with G by hetero atom;
5) when X is not aryl, R so
5Do not replaced: two or more aryl by following groups.
Preferred R
5Group comprises: pyrrole radicals; Imidazole radicals; Oxazolyl; Thiazolyl; Isothiazolyl; 1,2, the 4-thiadiazolyl group; Pyrazolyl; Isoxazolyl; 1,2,3-oxadiazole base; 1,2,4-oxadiazole base; 1,2,5-oxadiazole base; 1,3,4-oxadiazole base; 1,2, the 4-thiadiazolyl group; 1,3, the 4-thiadiazolyl group; Pyridine radicals; Pyrimidine radicals; Pyrazinyl; Pyridazinyl; The 1,3,5-triazines base; 1,2,4-triazine radical and 1,3-selenazoles base, all these substituent groups all contain at least one substituent group.
Preferably, R
5Not 2-thiazolyl or 2-oxazolyl.Work as R
5Be 2-thiazolyl, 2-oxazolyl or 2-selenazoles base and X for-alkoxyalkyl-,-alkylthio alkyl-,-alkoxyl-or-alkylthio group-time, so preferred A is not-CONH
2, and B be not-H.Equally, work as R
5Be 2-thiazolyl, 2-oxazolyl or 2-selenazoles base, so X be not-alkoxyalkyl-,-alkylthio alkyl-,-alkoxyl-or-alkylthio group-.
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Whole haloalkyl, C
1-C
6Haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
4,-SR
4,-N
3,-NHC (S) NR
4 2,-NHAc and zero.
B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
2 2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, all substituent groups are all optional to be substituted,
E is selected from-H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, aryl, C
4-C
6Alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-OR
3,-SR
3, C
1-C
6Whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted.
Each R
4Independently be selected from-H and C
1-C
2Alkyl.
More preferably formula I or IA chemical compound, wherein M is-X-R
5, R
5Be selected from:
With
Wherein:
A " be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Whole haloalkyl, C
1-C
6Haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2With-NHAc;
B " and D " independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl and halo, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
E " be selected from-H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
4-C
6Alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-OR
3,-SR
3, C
1-C
6Whole haloalkyl and halo, except that H ,-CN, whole haloalkyl and halo, all groups are all optional to be substituted; With
Each R
3Independently be selected from C
1-C
6Alkyl, C
6Aryl, C
3-C
6Heteroaryl, C
3-C
8Alcyl, C
2-C
7Heterolipid cyclic group, C
7-C
10Aralkyl and C
4-C
9Heteroarylalkyl;
Each R
4And R
9Independently be selected from-H and C
1-C
2Alkyl;
X is selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-and-alkoxy carbonyl-;
Each R
11Be selected from-NR
4 2,-OH ,-OR
3, C
1-C
6Alkyl, C
6Aryl and C
3-C
6Heteroaryl.
More preferably wherein X be-heteroaryl-or-alkoxy carbonyl-chemical compound.
Special preferred formula V-1-A and formula V-2-A chemical compound, wherein:
A " be selected from-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H;
B " be selected from-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3, OR
3With-NR
9 2
D " be selected from-H ,-C (O) R
11,-C (O) SR
3,-NR
9 2, alkyl, aryl, alcyl, halo and-SR
3
E " be selected from-H, C
1-C
6Alkyl, rudimentary alcyl, halo ,-CN ,-C (O) OR
3With-SR
3
Also preferred formula V-1, V-2, V-1-A and V-2-A chemical compound, wherein
Be selected from
With
Wherein:
C
*Has S type three-dimensional chemical configuration;
R
18And R
15Independently be selected from H and methyl;
Each R
12And R
13Independently be selected from-H, methyl, i-propyl group, i-butyl and benzyl, perhaps R
12And R
13By the continuous cycloalkyl that forms of 2-5 carbon atom;
N is 1;
R
14For-OR
17
R
16For-(CR
12R
13)
n-C (O)-R
14With
R
17Be selected from methyl, ethyl, propyl group, phenyl and benzyl.
Also especially preferred R wherein
5Be selected from the chemical compound of following structure:
Also especially preferred R wherein
5Be selected from the chemical compound of following structure:
Also especially preferred R wherein
5Be selected from the chemical compound of following structure:
One particularly preferred aspect, R
5For:
A " be selected from-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H;
B " be selected from-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3, OR
3With-NR
9 2With
X is selected from-heteroaryl-,-alkoxy carbonyl-and-alkyl amino-carbonyl-, all these groups are optional to be substituted.
More preferably wherein X is selected from methylene oxygen base (methylenoxy) carbonyl and furan-2, the chemical compound of 5-two bases and pharmaceutically acceptable salt and prodrug.More preferably such chemical compound, wherein A " be-NH
2, X is a furan-2,5-two bases and B " be-S (CH
2)
2CH
3A wherein " be-NH
2, X is a furan-2,5-two bases and B " be-CH
2-CH (CH
3)
2A wherein " be-NH
2, X is a furan-2,5-two bases and B " be-COOEt; A wherein " be-NH
2, X is a furan-2,5-two bases and B " be-SMe; Perhaps A wherein " be-NH
2, X is methylene oxygen base carbonyl and B " for-CH (CH
3)
2
Particularly preferred FBP enzyme inhibitor is the chemical compound of following formula:
Most preferred is such thiazoles, wherein A " be-NH
2, X is a furan-2,5-two bases and B " be-S (CH
2)
2CH
3, wherein
For
Or
C wherein
*Has S type spatial chemistry.
Also most preferred is such thiazoles, wherein A " be-NH
2, X is a furan-2,5-two bases and B " be-CH
2-CH (CH
3)
2Preferred especially such chemical compound, wherein
For
Or
C wherein
*Has S type spatial chemistry.
Another preferred aspect, the present invention relates to such chemical compound and pharmaceutically acceptable prodrug and salt, wherein R
5For
Wherein X is selected from furan-2,5-two base and methylene oxygen base carbonyls, A " be-NH
2More preferably wherein X is a furan-2,5-two bases and B " be-SCH
2CH
2CH
3Chemical compound.
Another preferred aspect, the present invention relates to such chemical compound and pharmaceutically acceptable prodrug and salt, wherein R
5For
A wherein " be-NH
2, E " and D " be-H B " being selected from cyclopropyl and n-pro-pyl, X is selected from furan-2,5-two base and methylene oxygen base carbonyls.
Another preferred aspect, the present invention relates to such chemical compound and pharmaceutically acceptable prodrug and salt, wherein R
5For
A wherein " be-NH
2, D " and be-H B " being selected from cyclopropyl and n-pro-pyl, X is selected from furan-2,5-two base and methylene oxygen base carbonyls.
Preferred X group comprises-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-and-alkoxy carbonyl.More preferably-heteroaryl-and-alkyl amino-carbonyl-.
Preferred formula IA chemical compound.
Also preferred formula XII, XIII and XIV chemical compound:
With
More preferably formula XII or XIV chemical compound:
Preferred A " group comprises-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H.Preferred A " group comprises-NH
2,-Cl ,-Br and-CH
3
Preferred B " group comprises-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3,-NR
9 2With-OR
3More preferably-H ,-C (O) OR
3,-C (O) SR
3, C
1-C
6Alkyl, alcyl, halo, heteroaryl and-SR
3
Preferred D " group comprises-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-NR
9 2With-SR
3More preferably-H ,-C (O) OR
3, low alkyl group, alcyl and halo.
Preferred E " group comprises-H C
1-C
6Alkyl, rudimentary alcyl, halogen ,-CN ,-C (O) OR
3,-SR
3With-CONR
4 2More preferably-H ,-Br and-Cl.
Preferred R
18Group comprises-H, methyl and ethyl.More preferably-H and methyl.Especially preferably-H.
Preferred chemical compound comprises such chemical compound, i.e. R wherein
12And R
13Independently be selected from respectively-H, methyl, ethyl, the n-propyl group, the i-propyl group, the n-butyl, the i-butyl ,-CH
2CH
2-SCH
3, phenyl and benzyl, perhaps R
12And R
13By the continuous cyclic alkyl that forms together of 2-5 carbon atom chain.More preferably R
12And R
13Independently be selected from-H methyl, i-propyl group, i-butyl and benzyl, perhaps R respectively
12And R
13By the continuous cyclic alkyl that forms together of 2-5 carbon atom chain.Also more preferably such chemical compound, wherein R
12And R
13Independently be selected from-H methyl, i-propyl group and benzyl, perhaps R respectively
12And R
13By the continuous cyclopenta that forms together of 4 carbon atoms.Preferred especially such chemical compound, wherein R
12And R
13Be-H, be methyl, perhaps R
12Be H, R
13Be selected from methyl, i-propyl group and benzyl.Most preferably such chemical compound, wherein working as n is 1, R
12During for-H, with R
12And R
13The carbon that connects has S type spatial chemistry.
Preferably, n is the integer of 1-2.More preferably n is 1.
Preferred chemical compound comprises such chemical compound, i.e. each R wherein
14Independently be selected from-OR
17With-SR
17And R
17Be selected from the optional methyl that replaces, ethyl, propyl group, t-butyl and benzyl.More preferably such chemical compound, i.e. each R wherein
14Independently be selected from-OR
17And R
17Be selected from methyl, ethyl, propyl group and benzyl.Most preferably such chemical compound, i.e. R wherein
17Be selected from ethyl and benzyl.
Preferred such chemical compound, i.e. R wherein
15Be not H.More preferably such chemical compound, i.e. R wherein
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By 2-6 atom, optional comprise that a heteroatomic chain that is selected from O, N and S links to each other.Also more preferably such chemical compound, i.e. R wherein
15And R
16Independently be selected from C
1-C
6Alkyl, perhaps R
15And R
16By 2-6 atom, optional comprise that a hetero atom that is selected from O, N and S links to each other.On the one hand, preferred especially such chemical compound, promptly wherein-NR
15R
16Be cyclic amine.Preferred especially such chemical compound, promptly wherein-NR
15R
16Be selected from morpholinyl and pyrrolidinyl.
Preferred such chemical compound, i.e. R wherein
16For-(CR
12R
13)
n-C (O)-R
14The chemical compound of preferred especially following formula:
Wherein X is selected from furan-2,5-two bases;-alkoxy carbonyl-and-alkyl amino-carbonyl-.
More preferably such chemical compound, promptly wherein n is 1.Preferred especially such chemical compound is promptly worked as R
12And R
13When inequality, H so
2N-CR
12R
13-C (O)-R
14Be naturally occurring amino acid whose ester or its monothioester; And R
14Be selected from-OR
17With-SR
17
More preferably such chemical compound, promptly wherein n is l and R
18Be selected from-H methyl and ethyl;
R
12And R
13Independently be selected from-H, methyl, the i-propyl group, i-butyl and benzyl are perhaps by the continuous cyclic alkyl that forms together of the chain of 2-5 carbon atom;
R
14Be OR
17R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; And R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By 2-6 atom, optional comprise that a heteroatomic chain that is selected from O and N links to each other.
On the one hand, preferred formula IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is
Wherein:
G " be selected from-O-and-S-;
A
2, L
2, E
2And J
2Be selected from-NR
4 2,-NO
2,-H ,-OR
2,-SR
2,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO
2R
9,-SO
2NR
4 2,-CN ,-S (O) R
3, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps L
2And E
2Or E
2And J
2Be formed with the cyclic group of ring together;
X
2Be selected from-CR
2 2-,-CF
2-,-OCR
2 2-,-SCR
2 2-,-C (O)-O-,-C (O)-S-,-C (S)-O-and-CR
2 2-NR
19-, and the atom that wherein links to each other with phosphorus is a carbon atom; Prerequisite is X
2Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
19Be selected from low alkyl group ,-H and-COR
2
More preferably such chemical compound, i.e. G wherein " be-S-.Most preferably such chemical compound, i.e. A wherein
2, L
2, E
2And J
2Independently be selected from-H ,-NR
4 2, S-C ≡ N, halogen ,-OR
3, hydroxyl ,-alkyl (OH), aryl, alkoxy carbonyl ,-SR
3, rudimentary whole haloalkyl and C
1-C
5Alkyl, perhaps L
2And E
2Form the cyclic group of ring formation together.More preferably A
2, L
2, E
2And J
2Independently be selected from-H ,-NR
4 2,-S-C ≡ N, halogen, lower alkoxy, hydroxyl, low alkyl group (hydroxyl), lower aryl and C
1-C
5Alkyl, L
2And E
2Form the cyclic group of ring formation together.
Most preferred A
2Group comprises-NH
2,-H, halo and C
1-C
5Alkyl.
Most preferred L
2And E
2Independently be selected from-H ,-S-C=N, lower alkoxy, C
1-C
5Alkyl, low alkyl group (hydroxyl), lower aryl and halogen, perhaps L
2And E
2Form the cyclic group of the ring formation that contains 4 other carbon atoms together.
Most preferred J
2Group comprises-H and C
1-C
5Alkyl.
Preferred X
2Group comprises-CF
2-,-CH
2-,-C (O)-O-,-CH
2-O-,-CH
2-S-,-CH
2-NH-and-CH
2-N (C (O) CH
3)-.More preferably-CH
2-O-,-CH
2-S-and-CH
2-N (C (O) CH
3)-.Most preferably-CH
2-O-.
One preferred aspect, comprise such chemical compound and pharmaceutically acceptable salt thereof and prodrug, wherein A
2Be selected from-H ,-NH
2,-CH
3,-Cl and-Br;
L
2For-H, low alkyl group, halogen, lower alkoxy, hydroxyl ,-alkylene group-OH, perhaps L
2With E
2Form cyclic group together, described cyclic group is selected from aryl, cycloalkyl, heteroaryl and Heterocyclylalkyl; E
2Be selected from H, low alkyl group, halogen, SCN, elementary alkoxy carbonyl and lower alkoxy, perhaps L
2With L
2Form cyclic group together, described cyclic group is selected from aryl, cyclic alkyl, heteroaryl and Heterocyclylalkyl; J
2Be selected from H, halogen and low alkyl group;
G " be-S-;
X
2For-CH
2-O-.
More preferably such chemical compound, i.e. R wherein
18Be selected from-H methyl and ethyl;
R
12And R
13Independently be selected from-H, methyl, the i-propyl group, i-butyl and benzyl, perhaps linking to each other by 2-5 carbon atom forms cyclic alkyl together;
R
14For-OR
17
R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; With
R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By the 2-6 atom, optional comprise that 1 hetero atom that is selected from O and N links to each other.
Also more preferably such chemical compound, wherein A
2Be NH
2, L
2Be selected from-Et and-Cl, E
2Be selected from-SCN ,-Et and-Br, J
2For-H.Preferred especially such chemical compound, promptly wherein
Be selected from
With
C wherein
*Has S type spatial chemistry.
Preferred R
18Group comprises-H, methyl and ethyl.More preferably-H and methyl.Especially preferably-H.
Preferred chemical compound comprises such chemical compound, i.e. R wherein
12And R
13Independently be selected from respectively-H, methyl, ethyl, the n-propyl group, the i-propyl group, the n-butyl, the i-butyl ,-CH
2CH
2-SCH
3, phenyl and benzyl, perhaps R
12And R
13Form cyclic alkyl together by 2-5 carbon atom.More preferably R
12And R
13Independently be selected from-H methyl, i-propyl group, i-butyl and benzyl, perhaps R respectively
12And R
13Form cyclic alkyl together by 2-5 carbon atom.Also more preferably such chemical compound, i.e. R wherein
12And R
13Independently be selected from-H methyl, i-propyl group and benzyl, perhaps R respectively
12And R
13By the continuous cyclopenta that forms together of 4 carbon atoms.Preferred especially such chemical compound, i.e. R wherein
12And R
13Be-H, be methyl, perhaps R
12Be H R
13Be selected from methyl, i-propyl group and benzyl.Most preferably such chemical compound, promptly working as n is 1, R
12During for-H, so with R
12And R
13The carbon that connects has S type spatial chemistry.
Preferably, n is the integer of 1-2.More preferably n is 1.
Preferred chemical compound comprises such chemical compound, i.e. each R wherein
14Independently be selected from-OR
17With-SR
17And R
17Be selected from the optional methyl that replaces, ethyl, propyl group, t-butyl and benzyl.More preferably such chemical compound, i.e. each R wherein
14Independently be selected from-OR
17R
17Be selected from methyl, ethyl, propyl group and benzyl.Most preferably such chemical compound, i.e. R wherein
17Be selected from ethyl and benzyl.
Preferred such chemical compound, i.e. R wherein
15Be not H.More preferably such chemical compound, i.e. R wherein
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By the 2-6 atom, optional comprise that a hetero atom that is selected from O, N and S links to each other.Also more preferably such chemical compound, i.e. R wherein
15And R
16Independently be selected from C
1-C
6Alkyl, perhaps R
15And R
16By the 2-6 atom, optional comprise that a hetero atom that is selected from O, N and S links to each other.On the one hand, preferred especially such chemical compound, promptly wherein-NR
15R
16Be cyclic amine.Preferred especially such chemical compound, promptly wherein-NR
15R
16Be selected from morpholinyl and pyrrolidinyl.
Preferred such compound R
16For-(CR
12R
13)
n-C (O)-R
14
More preferably such chemical compound, wherein n is 1, R
18Be selected from-H methyl and ethyl;
R
12And R
13Independently be selected from-H, methyl, the i-propyl group, i-butyl and benzyl, perhaps linking to each other by 2-5 carbon atom forms cyclic alkyl together;
R
14For-OR
17
R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; With
R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By the 2-6 atom, appoint and to comprise that 1 heteroatomic chain that is selected from O and N links to each other.Particularly preferred
Chemical compound with following formula:
More preferably such chemical compound, promptly wherein n is 1.Preferred especially such chemical compound is promptly wherein worked as R
12And R
13When inequality, H so
2N-CR
12R
13-C (O)-R
14Be naturally occurring amino-acid ester or monothioester; And R
14Be selected from-OR
17With-SR
17
On the one hand, the chemical compound of preferred formula IA or formula I and pharmaceutically acceptable prodrug and salt, wherein M is
Wherein:
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group comprises aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form cyclic group with Y, and described cyclic group comprises aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aryloxy alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, every other group is optional to be substituted;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
Each R
9Independently be selected from-H alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
On the other hand, the invention provides aforesaid formula I or formula IA chemical compound, prerequisite also comprises:
A) work as X
3(alkene, in the time of alkene), A is-N (R so for alkyl or alkylidene
8 2);
B) X
3Not alkylamine and the alkyl amino alkyl that phosphonate ester and acid replace; With
C) A, L, E, J and Y
3Only can form 0-2 cyclic group together.
More preferably such chemical compound, i.e. X wherein
3Be not-alkoxyalkyl-,-alkoxyl-,-alkylthio alkyl-and-alkylthio group-.Preferred especially such chemical compound promptly wherein also comprises prerequisite: work as X
3During for aryl or alkylaryl, described aryl or alkylaryl are not by 1, and 4-is connected (linked 1,4 through a six-membered aromatic ring) with 6 yuan of aromatic rings.
Particularly preferred benzimidazole compound comprises such chemical compound, A wherein, L and E independently be selected from-H ,-NR
8 2,-NO
2, hydroxyl, halogen ,-OR
7, alkyl amino-carbonyl ,-SR
7, rudimentary whole haloalkyl and C
1-C
5Alkyl, perhaps E and J form cyclic group together; And wherein J is selected from-H, halogen, and low alkyl group, rudimentary hydroxy alkyl ,-NR
8 2, rudimentary R
8 2The N-alkyl, low-grade halogenated alkyl, rudimentary whole haloalkyl, low-grade alkenyl, low-grade alkynyl, lower aryl, heterocyclic radical and alcyl; Wherein Y is selected from alcyl and low alkyl group; X
3Be selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-and-alkoxy carbonyl-.More preferably such chemical compound, promptly wherein:
R
18Be selected from-H methyl and ethyl;
R
12And R
13Independently be selected from-H, methyl, the i-propyl group, i-butyl and benzyl, perhaps linking to each other by 2-5 carbon atom forms cyclic alkyl together;
R
14For-OR
17
R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; With
R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16By the 2-6 atom, optional comprise that 1 hetero atom that is selected from O and N links to each other.Most preferably such chemical compound, promptly wherein A be selected from-H ,-NH
2,-F and-CH
3
L is selected from-H ,-F ,-OCH
3, Cl and CH
3
E is selected from-H and-Cl;
J is selected from-H, halo, C
1-C
5Hydroxy alkyl, C
1-C
5Haloalkyl, C
1-C
5R
8 2The N-alkyl, C
1-C
5Alcyl and C
1-C
5Alkyl;
X
3Be selected from-CH
2OCH
2-,-methylene oxygen base carbonyl-and-furan-2,5-two bases-; With
Y is a low alkyl group.
Also more preferably such benzimidazole, wherein A is-NH
2, L is-F, and E is-H, and J is an ethyl, and Y is isobutyl group and X
3For-furan-2,5-two bases-; Perhaps
Wherein A is-NH
2, L is-F, and E is-H, and J is N, the N-dimethylaminopropyl, Y is isobutyl group and X
3For-furan-2,5-two bases-.
Preferred especially such chemical compound, promptly wherein
Be selected from
With
C wherein
*Has S type spatial chemistry.
On the one hand, preferred such formula III chemical compound and pharmaceutically acceptable prodrug and the salt of the present invention:
Wherein:
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, the perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl are perhaps with Y
3Form cyclic group together, described cyclic group is selected from aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aryloxy alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, every other group is optional to be substituted;
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, the optional aralkyl that replaces ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, form cyclic group, perhaps R
1And R
1Form the group of following formula together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps form two coordination alkyl together;
R
9Be selected from alkyl, aralkyl and alcyl;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps with R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that a hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14, low alkyl group, lower aryl, rudimentary aralkyl, perhaps with R
15By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
In formula III, preferred A, L and E group comprise-H ,-NR
8 2,-NO
2, hydroxyl, alkyl amino-carbonyl, halogen ,-OR
7,-SR
7, rudimentary whole haloalkyl and C
1-C
5Alkyl, perhaps E and J form cyclic group together.This type of cyclic group can be aromatic ring shape alkyl, perhaps is Heterocyclylalkyl, and can choose wantonly and be substituted.The aromatic group that is fit to comprises thiazole.Particularly preferred A, L and E group are-NR
8 2,-H, hydroxyl, halogen, lower alkoxy, rudimentary whole haloalkyl and low alkyl group.
In formula III, preferred A group comprises :-NR
8 2,-H, halogen, rudimentary whole haloalkyl and low alkyl group.
In formula III, preferred L and E group comprise-H lower alkoxy, low alkyl group and halogen.
In formula III, preferred J group comprises-H, halogen, and low alkyl group, rudimentary hydroxy alkyl ,-NR
8 2, rudimentary R
8 2The N-alkyl, low-grade halogenated alkyl, rudimentary whole haloalkyl, low-grade alkenyl, low-grade alkynyl, lower aryl, heterocyclic radical and alcyl are perhaps with Y
3Form cyclic group together.This type of cyclic group can be aromatics cyclic alkyl or heterocyclic radical, and can choose wantonly and be substituted.Particularly preferred J group comprises-H, halogen and low alkyl group, rudimentary hydroxy alkyl ,-NR
8 2, rudimentary R
8 2N-alkyl, low-grade halogenated alkyl, low-grade alkenyl, alcyl and aryl.Preferred especially alcyl and low alkyl group.
In formula III, preferred X
3Group comprises-alkyl-,-alkynyl-,-aryl-,-alkoxyalkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-1,1-dihalo alkyl-,-carbonylic alkyl-and-alkyl (OH)-.Preferred especially-heteroaryl-,-alkyl amino-carbonyl-,-1,1-dihalo alkyl-and-alkoxyalkyl-.Also especially preferably-heteroaryl-,-alkyl amino-carbonyl-and-alkoxyalkyl-.Especially preferably-the methylamino carbonyl-,-methoxy-and-furan-2,5-two bases-.
Another preferred aspect, work as X
3During for aryl or alkylaryl, by 1,4-'s these groups does not link to each other with 6 yuan of aromatic rings.
In the formula III, preferred Y
3Group comprises-H, alkyl, and aralkyl, aryl and alcyl, except that H, every other group is optional to be substituted.Preferred especially low alkyl group and alcyl.
Preferred R
4And R
7Group comprises-H and low alkyl group.
Of formula III chemical compound preferred aspect, A, L and E independently be-H, low alkyl group, hydroxyl, halogen, lower alkoxy, rudimentary whole haloalkyl and-NR
8 2X
3For-aryl-,-alkoxyalkyl-,-alkyl-,-alkylthio group-,-1,1-dihalo alkyl-,-carbonylic alkyl-,-alkyl (hydroxyl)-,-alkyl amino-carbonyl-and-alkyl-carbonyl-amino-; And R
4And R
7Independently be-H and low alkyl group respectively.Preferred especially such chemical compound, A wherein, L and E independently be-H, low alkyl group, halogen and-NR
8 2J is-H halogen, haloalkyl, hydroxy alkyl, R
8 2The N-alkyl, low alkyl group, lower aryl, heterocyclic radical and alcyl are perhaps with Y
3Form cyclic group together; And X
3For-heteroaryl-,-alkyl amino-carbonyl-,-1,1-dihalo alkyl-and-alkoxyalkyl-.Preferred especially such chemical compound, wherein A be-H ,-NH
2,-F and-CH
3, L is-H ,-F ,-OCH
3,-Cl and-CH
3, E is-H and-CH
3, J is-H halo, C
1-C
5Hydroxy alkyl, C
1-C
5Haloalkyl, C
1-C
5R
8 2The N-alkyl, C
1-C
5Alcyl and C
1-C
5Alkyl, X
3For-CH
2OCH
2-and-furan-2,5-two bases-, and Y
3Be low alkyl group.Most preferably following compounds and salt thereof and prodrug and salt thereof, wherein:
1) A is-NH
2, L is-F that E is-H that J is-H Y
3Be isobutyl group, X
3For-furan-2,5-two bases-;
2) A, L and J are-H that E is-Cl Y
3Be isobutyl group, X
3For-furan-2,5-two bases-;
3) A is-NH
2, L is-F that E and J are-H Y
3Be cyclopropyl methyl and X
3For-furan-2,5-two bases-;
4) A is-NH
2, L is-F that E is-H that J is an ethyl, Y
3Be isobutyl group and X
3For-furan-2,5-two bases-;
5) A is-CH
3, L is-Cl that E and J are-H Y
3Be isobutyl group and X
3For-furan-2,5-two bases-;
6) A is-NH
2, L is-F that E is-H that J is-Cl Y
3Be isobutyl group and X
3For-furan-2,5-two bases-;
7) A is-NH
2, L is-F that E is-H that J is-Br Y
3Be isobutyl group and X
3For-CH
2OCH
2-; With
8) A, L, E and J are-CH
3, Y
3Be cyclopropyl methyl and X
3For-furan-2,5-two bases-.
Also preferred especially such chemical compound, wherein A is-NH
2, L is-F, and E is-H, and J is the bromo propyl group, bromo butyl, chloro butyl, cyclopropyl, hydroxypropyl, perhaps N, N-dimethylaminopropyl and X
3For-furan-2,5-two bases-.In preferred prodrug or its hydrochlorate, R
1Be oxy acid methyl neopentyl.
On the other hand, preferred such formula I or I-A chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is
Wherein
Z
6Be selected from alkyl and halogen,
U
6And V
6Independently be selected from hydrogen, hydroxyl, acyloxy perhaps forms the rudimentary cyclic group that contains at least one oxygen together;
W
6Be selected from amino and low-grade alkyl amino.
Of the present invention is formula VI chemical compound more on the one hand:
Wherein
Z
6Be selected from alkyl and halogen,
U
6And V
6Independently be selected from hydrogen, hydroxyl, acyloxy perhaps forms the rudimentary cyclic group that contains at least one oxygen together;
W
6Be selected from amino and lower alkyl amino;
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, the optional aralkyl that replaces ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With independently be selected from as Y-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkylidene ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
18With R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
On the other hand, the invention provides such formula I and formula IA, wherein M is:
Wherein:
A
2Be selected from-NR
8 2,-NHSO
2R
3,-OR
25,-SR
25, halogen, low alkyl group ,-CON (R
4)
2, guanidine, amidine ,-H and whole haloalkyl;
E
2Be selected from-H, halogen, lower alkylthio, rudimentary whole haloalkyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy ,-CN and-NR
7 2
X
3Be selected from-alkyl (hydroxyl)-;-alkyl-;-alkynyl-;-aryl-;-carbonyl-alkyl-;-1,1-dihalo alkyl-;-alkoxyalkyl-;-alkyl oxy-;-alkylthio alkyl-;-alkylthio group-;-alkyl amino-carbonyl-;-alkyl-carbonyl-amino-; Alcyl-;-aralkyl-;-alkylaryl-;-alkoxy carbonyl-;-ketonic oxygen base alkyl-;-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted, and prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, outside the dehydrogenation, all groups all can be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps two R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
Each R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
Each R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps two R
8Form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl; And
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
On the other hand, preferred such formula II chemical compound and pharmaceutically acceptable prodrug and the salt of the present invention:
Wherein
A
2Be selected from-NR
8 2,-NHSO
2R
3,-OR
25,-SR
25, halogen, low alkyl group ,-CON (R
4)
2, guanidine, amidine ,-H and whole haloalkyl;
E
2Be selected from-H, halogen, lower alkylthio, rudimentary whole haloalkyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy ,-CN and-NR
7 2
X
3Be selected from-alkyl (hydroxyl)-;-alkyl-;-alkynyl-;-aryl-;-carbonyl-alkyl-;-1,1-dihalo alkyl-;-alkoxyalkyl-;-alkyl oxy-;-alkylthio alkyl-;-alkylthio group-;-alkyl amino-carbonyl-;-alkyl-carbonyl-amino-; Alcyl-;-aralkyl-;-alkylaryl-;-alkoxy carbonyl-;-ketonic oxygen base alkyl-;-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted, and prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, outside the dehydrogenation, all groups all can be substituted;
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-(CO) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps two R
8Form two coordination alkyl;
R
9Be selected from alkyl, aralkyl and alcyl;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl; With
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
18With R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHr
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms together of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
In formula II, preferred A
2Group comprises-NR
8 2, low alkyl group, rudimentary whole haloalkyl, lower alkoxy and halogen.Especially preferably-NR
8 2And halogen.Especially preferably-NR
8 2Most preferably-NH
2
In formula II, preferred E
2Group comprises-H, halogen, rudimentary whole haloalkyl ,-CN, low alkyl group, lower alkoxy and lower alkylthio.Particularly preferred E
2Group comprises-H ,-SMe ,-Et and-Cl.Preferred especially-H and-SCH
3
In formula II, preferred X
3Group comprises-alkyl-,-alkynyl-,-alkoxyalkyl-,-alkylthio group-,-aryl-,-1,1-dihalo alkyl-,-carbonylic alkyl-,-heteroaryl-,-alkyl-carbonyl-amino-and-alkyl amino-carbonyl.Especially preferably by 1-3 be selected from halogen and-substituent group of OH replaces-alkyl-.Especially preferably-alkyl amino-carbonyl-,-alkoxyalkyl-and-heteroaryl-.Preferably-and alkoxyalkyl-group comprises-methoxy-.Preferably-heteroaryl-group comprise optional substituted-furan-2,5-two bases-.
In formula II, preferred Y
3Group comprises aralkyl, alcyl, and alkyl and aryl, all groups are optional to be substituted.Be preferably low alkyl group especially.Particularly preferred Y
3Group comprises (2-naphthyl) methyl, cyclohexyl ethyl, phenylethyl, nonyl, the cyclohexyl propyl group, ethyl, cyclopropyl methyl, cyclobutylmethyl phenyl, (2-methyl) propyl group, neopentyl, cyclopropyl, cyclopenta, (1-imidazole radicals) propyl group, 2-ethoxy benzyl, 1-hydroxyl-2,2 dimethyl propyl, 1-chloro-2,2-dimethyl propyl, 2, the 2-dimethylbutyl, 2-(spiral shell-3 ', 3 '-dimethyl hexamethylene-4-thiazolinyl) propyl group and 1-methyl neopentyl.Preferred especially neopentyl and isobutyl group.
Preferred R
4And R
7Group is-H and low alkyl group.Especially preferably-H and methyl.
Another preferred aspect, A
2For-NR
8 2Perhaps halogen, E
2Be-H, halogen ,-CN, low alkyl group, rudimentary whole haloalkyl, lower alkoxy, perhaps lower alkylthio, X
3For-alkyl-,-alkoxyalkyl-,-alkynyl-,-1,1-dihalo alkyl-,-carbonylic alkyl-,-alkyl (OH)-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkylthio group-,-aryl-or-heteroaryl-and R
4And R
7For-H or low alkyl group.Preferred especially such chemical compound, wherein Y
3Be aralkyl, aryl, alcyl, perhaps alkyl.
Another preferred aspect, A
2For-NR
8 2, E
2For-H, Cl-or methyl mercapto, X
3For optional replace-furan-2,5-two bases-or-alkoxyalkyl-.Preferred especially such chemical compound, wherein A
2For-NH
2, X
3For-furan-2,5-two bases-or-methoxy-, Y
3Be low alkyl group.Most preferably such chemical compound, wherein E
2Be H, X
3For-furan-2,5-two bases-, Y
3Be neopentyl; Perhaps E
2For-SCH
3, X
3For-furan-2,5-two bases-, Y
3Be isobutyl group; Perhaps E
2For-H, X
3For-furan-2,5-two bases-, Y
3Be 1-(3-chloro-2,2-dimethyl)-propyl group.
Preferred especially such chemical compound, wherein R
1For-CH
2O-C (O)-C (CH
3)
3
In one aspect of the invention, preferred formula I or formula IA chemical compound or its pharmaceutically acceptable prodrug or salt, M is:
Wherein
B
5Be selected from-NH-,-N=and-CH=;
D
5Be selected from
With
Q
5Be selected from-C=and-N-;
Prerequisite is:
Work as B
5During for-NH-, Q
5For-C=and D
5For
Work as B
5During for-CH=, Q
5For-N-and D
5For
Work as B
5During for-N=, D
5For
A, E and L independently are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl are perhaps with Y
3Form the cyclic group that is selected from following group together: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-, alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
3
Preferred such formula IV chemical compound and pharmaceutically acceptable prodrug and salt:
Wherein:
B
5Be selected from-NH-,-N=and-CH=;
D
5Be selected from
Q
5Be selected from-C=and-N-;
Prerequisite is:
Work as B
5During for-NH-, Q
5For
-C=And D
5For
Work as B
5During for-CH=, Q
5For-N-and D
5For
Work as B
5During for-N=, D
5For
And Q
5For-C=;
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O)
nR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, the perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl are perhaps with Y
3Form cyclic group together, described cyclic group is selected from aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aryloxy alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, every other group is optional to be substituted;
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps form two coordination alkyl together;
R
9Be selected from alkyl, aralkyl and alcyl;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
12With R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
In formula IV, preferred A, L and E group comprise-H ,-NR
8 2,-NO
2, hydroxyl, halogen ,-OR
7, alkyl amino-carbonyl ,-SR
7, rudimentary whole haloalkyl and C
1-C
5Alkyl, perhaps E and J form cyclic group together.This type of cyclic group can be aromatics or cyclic alkyl, can choose wantonly to be substituted.The aromatic group that is fit to comprises thiazole.Particularly preferred A, L and E group are-NR
8 2,-H, hydroxyl, halogen, lower alkoxy, rudimentary whole haloalkyl and low alkyl group.
In formula IV, preferred A group comprises-NR
8 2, low alkyl group ,-H, halogen and rudimentary whole haloalkyl.
In formula IV, preferred L and E group comprise-H lower alkoxy, low alkyl group and halogen.
In formula IV, preferred J group comprises-H, halogen, and low alkyl group, rudimentary hydroxy alkyl ,-NR
8 2, rudimentary R
8 2The N-alkyl, low-grade halogenated alkyl, rudimentary whole haloalkyl, low-grade alkenyl, low-grade alkynyl, lower aryl, heterocyclic radical and alcyl are perhaps with Y
3Form cyclic group together.This type of cyclic group can be aromatics or cyclic alkyl, can choose wantonly and be substituted.Particularly preferred J group is-H, halogen, and low alkyl group, rudimentary hydroxy alkyl ,-NR
8 2, rudimentary R
8 2N-alkyl, low-grade halogenated alkyl, low-grade alkenyl, alcyl and aryl.
In formula IV, preferred X
3Group comprises-alkyl-,-alkynyl-,-alkoxyalkyl-,-alkylthio group-,-aryl-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-1,1-dihalo alkyl-,-carbonylic alkyl-and-alkyl (OH)-.Preferred especially-1,1-dihalo alkyl-,-alkyl amino-carbonyl-,-alkoxyalkyl-and-heteroaryl-.In particularly preferred this compounds, X
3For-heteroaryl-,-alkyl amino-carbonyl-and-alkoxyalkyl-.Most preferably-the methylamino carbonyl-,-methoxy-and-furan-2,5-two bases.
One preferred aspect, X
3Be not-(C
2-C
3Alkyl) amino carbonyl-.
In formula IV, preferred Y
3Group comprises-H, alkyl, and aryl, aralkyl and alcyl, except that H, every other group is optional to be substituted.Particularly preferred Y
3Group comprises low alkyl group and alcyl.
Preferred R
4And R
7Group comprises-H and low alkyl group.
Of formula IV preferred aspect, B
5Be NH, D
5For
And Q
5For-C=.Another preferred aspect, B
5For-N=, D
5For
And Q
5For-C=.
Another of formula IV preferred aspect, A, L and E independently are-NR
8 2, low alkyl group, rudimentary whole haloalkyl, lower alkoxy, halogen ,-OH or-H, X
3For-aryl-,-alkoxyalkyl-,-alkyl-,-alkylthio group-,-1,1-dihalo alkyl-,-carbonylic alkyl-,-alkyl (hydroxyl)-,-alkyl amino-carbonyl-and-alkyl-carbonyl-amino-, R
4And R
7Independently be-H or low alkyl group respectively.Preferred especially such chemical compound, A wherein, L and E independently be-H, low alkyl group, halogen and-NR
8 2J is-H, halogen, and haloalkyl, hydroxy alkyl ,-R
8 2The N-alkyl, low alkyl group, lower aryl, heterocyclic radical and alcyl are perhaps with Y
3Form cyclic group together; X
3For-heteroaryl-,-alkyl amino-carbonyl-,-1,1-dihalo alkyl-and-alkoxyalkyl-.Preferred especially such chemical compound, wherein A be-H ,-NH
2,-F or-CH
3, L is-H ,-F ,-OCH
3Or-CH
3, E is-H or-CH
3, J is-H halo, C
1-C
5Hydroxy alkyl, C
1-C
5Haloalkyl, C
1-C
5R
8 2The N-alkyl, C
1-C
5Alcyl or C
1-C
5Base, X
3For-CH
2OCH
2-or-furan-2,5-two bases-; And Y
3Be low alkyl group.Preferred such chemical compound, wherein B
5Be NH, D
5For
Q
5Be-C=, perhaps B wherein
5For-N=, D
5For
And Q
5Be C=.
Most preferably such chemical compound, wherein:
1) A is-NH
2, L is-F that E is-H that J is-H Y
3Be isobutyl group, X
3For-furan-2,5-two bases-;
2) A is-NH
2, L is-F that E is-H that J is-Cl Y
3Be isobutyl group, X
3For-furan-2,5-two bases-.
3) A is-H, and L is-H that E is-Cl that J is-H B
5For-NH, D
5For
Q
5For-C=and
Y
3Be isobutyl group; With
4) A is-CH
3, L is-H that E is-H that J is-H B
5For-N=, D
5For
Q
5For-C=, Y
3Be isobutyl group.
Preferred especially such chemical compound, wherein R
1For-CH
2OC (O)-C (CH
3)
3
On the other hand, the preferred especially such chemical compound of the present invention, A wherein, L and E be-H, low alkyl group, halogen or-NR
8 2, J is-H, halogen, and low alkyl group, lower aryl, heterocyclic radical, perhaps alcyl is perhaps with Y
3Form cyclic group together, X
3For-heteroaryl-,-alkyl amino-carbonyl-or-alkoxyalkyl-.
On the other hand, preferred such formula V-1 or V-2 chemical compound:
Wherein:
Each G independently is selected from C, N, O, S and Se, and wherein to have only a G be that O, S or Se and a maximum G are N;
Each G ' independently is selected from C and N, and wherein being no more than two G ' is N;
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-s (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, every other group is all optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X is the optional linking group that replaces, this group by 2-4 atom, comprise that 0-1 is individual and be selected from the hetero atom of N, O and S R
5Be connected with phosphorus atoms, except that following situation: if X is urea or carbamic acid root, have 2 hetero atoms so, the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein: X is selected from-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups are all optional to be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9-work forming cyclic alkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
12With R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, this cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
Prerequisite is:
1) when G ' is N, A, B, D or E are respectively zero;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not any two atoms linking group, the optional replacement-alkyl oxy-or optional replacement the-alkylthio group-;
4) when G is N, A or B are not respectively halogen or the direct group that is connected with G by hetero atom;
5) when X is not aryl, R so
5Do not replaced: two or more aryl by following groups.
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H.
One preferred aspect, formula V-1 and formula V-2 chemical compound are such chemical compound,
Wherein:
A " be selected from-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H;
B " be selected from-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3, OR
3With-NR
9 2
D " be selected from-H ,-C (O) R
11,-C (O) SR
3,-NR
9 2, alkyl, aryl, alcyl, halo and-SR
3
E " be selected from-H C
1-C
6Alkyl, rudimentary alcyl, halo ,-CN ,-C (O) OR
3With-SR
3
X is selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkoxyl-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all groups are optional to be substituted;
When two Y groups be-during O-, R so
1Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R
2)
2OC (O) R
3,-C (R
2)
2OC (O) OR
3With-H; Perhaps
When a Y be-during O-, so with-R that O-is connected
1Be the optional aryl that replaces; With another Y be-NR
6In-time, is so with-NR
6The R of-connection
1Be selected from-C (R
4)
2COOR
3With-C (R
2)
2COOR
3Perhaps
When Y be-O-or-NR
6, R so
1And R
1Form together:
Or
Or
Wherein
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3, CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H; With
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
One particularly preferred aspect, the M in formula I chemical compound and pharmaceutically acceptable salt thereof and the prodrug is-X-R
5, at this R
5For
X is selected from methylene oxygen base carbonyl and furan-2,5-two bases; At least one Y group is-O-.More preferably such chemical compound, promptly wherein when Y be-during O-, so with-R that O-is connected
1Independently be selected from-H, the optional phenyl that replaces ,-CH
2OC (O)-tBu ,-CH
2OC (O) Et and CH
2OC (O)-iPr; When Y is-NR
6In-time, is so with-NR
6The R of-connection
1Independently be selected from-C (R
2)
2COOR
3,-C (R
4)
2COOR
3, perhaps when Y be-O-or-NR
6-and at least one Y be-during O-, R so
1And R
1For
Wherein
V is selected from optional aryl that replaces and the optional heteroaryl that replaces; With Z, W ' and W be H; And
R
6Be selected from-H and low alkyl group.
Most preferably following compounds and salt thereof, wherein:
1) A " be-NH
2, X is a furan-2,5-two bases, B " be-CH
2-CH (CH
3)
2
2) A " be-NH
2, X is a furan-2,5-two bases, B " be-COOEt;
3) A " be-NH
2, X is a furan-2,5-two bases, B " be-SCH
3
4) A " be-NH
2, X is a furan-2,5-two bases, B " be-SCH
2CH
2CH
3
5) A " be-NH
2, X is a methylene oxygen base carbonyl, B " be-CH (CH
3)
2
6) A " be-NH
2X is a furan-2,5-two bases, B " be the 4-morpholinyl.
Another particularly preferred aspect, M is-X-R in formula I and pharmaceutically acceptable salt thereof and the prodrug
5, at this R
5For
X is a furan-2,5-two base and methylene oxygen base carbonyls, A " be-NH
2At least one Y group is-O-.Preferred especially such chemical compound, promptly wherein when Y be-during O-, each R so
1Independently be selected from-H, the optional phenyl that replaces ,-CH
2OC (O)-tBu ,-CH
2OC (O) Et and-CH
2OC (O)-iPr; Perhaps working as Y is-NR
6-time, each R so
1Independently be selected from-C (R
2)
2C (O) OR
3With-C (R
4)
2COOR
3Perhaps independently be selected from-O-and-NR as Y
6-, R so
1And R
1For
Wherein
V is selected from optional aryl that replaces and the optional heteroaryl that replaces; And Z, W ' and W are H.Also preferred especially such chemical compound, i.e. B wherein " be-SCH
2CH
2CH
3
Another particularly preferred aspect, M is-X-R in formula I chemical compound and pharmaceutically acceptable salt thereof and the prodrug
5, at this R
5For
A " be-NH
2, E " and D " be-H B " be n-propyl group and cyclopropyl, X is a furan-2,5-two base and methylene oxygen base carbonyls; At least one Y group is-O-.Preferred especially such chemical compound, i.e. R wherein
1Be selected from-H the optional phenyl-CH that replaces
2OC (O)-tBu ,-CH
2OC (O) Et and-CH
2OC (O)-iPr,
Perhaps working as Y is-NR
6, each R so
1Independently be selected from-C (R
2)
2C (O) OR
3With-C (R
4)
2COOR
3
Perhaps independently be selected from-O-and-NR as any one Y
6-and at least one Y be-during O-, R so
1And R
1For
Wherein
V is selected from optional aryl that replaces and the optional heteroaryl that replaces; And Z, W ' and W are H.
Another particularly preferred aspect, the M in formula I chemical compound and pharmaceutically acceptable salt thereof and the prodrug is-X-R
5, at this R
5For
A " be-NH
2, D " and be-H B " be n-propyl group or cyclopropyl, X is a furan-2,5-two bases or methylene oxygen base carbonyl; At least one Y group is-O-.Preferred especially such chemical compound, promptly wherein when Y be-during O-, R so
1Be selected from-H, the optional phenyl that replaces ,-CH
2OC (O)-tBu ,-CH
2OC (O) Et and-CH
2OC (O)-iPr;
Perhaps working as a Y is-O-and its corresponding R
1For-phenyl, another Y is-NH-and its corresponding R simultaneously
1Be-CH (Me) C (O) OEt, perhaps when at least one Y group be-during O-, R so
1And R
1For
Wherein
V is selected from optional aryl that replaces and the optional heteroaryl that replaces; And Z, W ' and W are H.
Preferred such formula X chemical compound and pharmaceutically acceptable prodrug and salt:
Wherein:
G " be selected from-O-and-S-;
A
2, L
2, E
2And J
2Be selected from-NR
4 2,-NO
2,-H ,-OR
2,-SR
2,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO
2R
9,-SO
2NR
4 2,-CN ,-S (O) R
3, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps L
2And E
2Or E
2And J
2Form the cyclic group of ring formation together;
X
2Be selected from-CR
2 2-,-CF
2-,-CR
2 2-O-,-CR
2 2-S-,-C (O)-O-,-C (O)-S-,-C (S)-O-and-CR
2 2-NR
19-, and the atom that wherein links to each other with phosphorus is a carbon atom; Prerequisite is X
2Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
R
19Be selected from low alkyl group ,-H and-COR
2With
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
12With R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16By the continuous cyclic group that forms together of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms of 2-6 atom, described cyclic group is chosen wantonly and is comprised 1 hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
On the one hand, preferred such formula X chemical compound and pharmaceutically acceptable salt and prodrug, wherein A
2Be selected from-H ,-NH
2,-CH
3,-Cl and-Br;
L
2For-H, low alkyl group, halogen, lower alkoxy, hydroxyl ,-alkylene group-OH, perhaps L
2With E
2Form cyclic group together, this cyclic group comprises aryl, cyclic alkyl, heteroaryl and Heterocyclylalkyl;
E
2Be selected from H, low alkyl group, halogen, SCN, elementary alkoxy carbonyl and lower alkoxy, perhaps E
2With L
2Form cyclic group together, this cyclic group comprises aryl, cyclic alkyl, heteroaryl, perhaps Heterocyclylalkyl;
J
2Be selected from H, halogen and low alkyl group;
G " be-S-;
X
2For-CH
2-O-; And
At least one Y group is-O-.Also preferred especially such chemical compound, wherein A
2Be NH
2, G " and be-S-L
2Be Et, E
2Be SCN and J
2Be H.More preferably such chemical compound, promptly one of them Y is-O-and its corresponding R
1Be the optional phenyl that replaces, another Y is-NH-and its corresponding R simultaneously
1For-C (R
2)
2-COOR
3Work as R
1For-CHR
3COOR
3The time, so accordingly-NR
6-
*CHR
3COOR
3Preferably has L type spatial chemistry.
Also more preferably such chemical compound, promptly one of them Y is-O-and its corresponding R
1For-phenyl, another Y is-NH-and its corresponding R simultaneously
1For-CH (Me) CO
2Et.
At formula I, II, III, IV, V-1, V-2, VI, VII-1, in VII-2 or the X chemical compound, preferred two Y groups are-O-; Perhaps a Y is-O-, and another Y is-NR
6-.When only there being a Y to be-NR
6In-time, so preferred and W and the immediate Y of W ' are-O-.Most preferably two Y groups are-prodrug of O-.
Another particularly preferred aspect, two Y groups are-O-, and R
1And R
1For
The phenyl of V for being replaced by the 1-3 halogen.Preferred especially 3-bromo-4-fluoro phenyl, 3-chlorophenyl, 3-bromo phenyl and 3,5-dichloro-phenyl.
Another particularly preferred aspect, a Y is-O-and its corresponding R
1Be phenyl, perhaps be selected from the phenyl that following substituent group replaces :-NHC (O) CH by 1-2
3,-F ,-Cl ,-Br ,-C (O) OCH
2CH
3With-CH
3Another Y is-NR simultaneously
6-and its corresponding R
1For-C (R
2) COOR
3Each R
2Independently be selected from-H ,-CH
3With-CH
2CH
3Preferred R
6Be-H, and with-R that NH-is connected
1For-CH (Me) CO
2Et.
Another aspect the invention provides down facial VII chemical compound and pharmaceutically acceptable prodrug and salt:
At this R
55Be selected from:
With
Wherein:
G
2Be selected from C, O and S;
G
3And G
4Independently be selected from C, N, O and S;
Wherein: a) G
2, G
3And G
4In be no more than one for O or S; B) work as G
2During for O or S, G
3And G
4In be no more than one for N; C) G
2, G
3And G
4In at least one is C; And d) G
2, G
3And G
4Not C entirely;
G
5, G
6And G
7Independently be selected from C and N, wherein G
5, G
6And G
7In be no more than two for N;
J
3, J
4, J
5, J
6And J
7Independently be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O)
2NR
4 2,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, alkylidene aryl, whole haloalkyl, haloalkyl, aryl, heteroaryl, alkylidene-OH ,-C (O) R
11,-OR
11,-alkylidene-NR
4 2,-alkylidene-CN ,-CN ,-C (S) NR
4 2,-OR
2,-SR
2,-N
3,-NO
2,-NHC (S) NR
4 2With-NR
21COR
2
X
4Be selected from:
I) has the linking group of 2-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-furyl-,-thienyl-,-pyridine radicals-,-oxazolyls-,-imidazole radicals-,-phenyl-,-pyrimidine radicals-,-pyrazinyl-and-alkynyl-, all these groups are optional to be substituted; With
The linking group that ii) has 3-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-,-alkoxyl-,-alkylthio group-,-the alkyl-carbonyl oxygen base-,-alkyl-S (O)-,-alkyl-S (O)
2-and-alkoxyalkyl-, all these groups are optional to be substituted;
Y independently is selected from-O-and-NR
6-;
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, the optional arylmethylene alkyl that replaces ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR
3With-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When any one Y independently be selected from-O-and-NR
6-time, R so
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkyl ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
R
7Be rudimentary R
3
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2OR
20
R
15Be selected from-H, rudimentary aralkyl, lower aryl, rudimentary aralkyl, perhaps R
15With R
16Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps two R on the N
17Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
18With R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
19Independently be selected from-H and lower acyl;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
R
21Be selected from-H and rudimentary R
3
N is the integer of 1-3;
Prerequisite is:
1) works as G
5, G
6Or G
7During for N, J
4, J
5Or J
6Be respectively zero;
2) work as G
2, G
3Or G
4During for O or S, J
3, J
4Or J
5Be respectively zero;
3) work as G
3Or G
4During for N, J so
4Or J
5It respectively is not halogen or by hetero atom and G
3Or G
4The direct group of Xiang Lianing;
4) if two Y are-NR
6, and R
1And R
1Do not link to each other and form cyclic amino phosphate ester, at least one R so
1For-(CR
12R
13)
n-C (O)-R
14
5) have only as another YR
1For-NR
18-C (R
12R
13)
n-C (O)-R
14The time, R
1Just can be selected from low alkyl group.
The X that is fit to
4Group comprises
I) has the linking group of 2-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-furyl-,-thienyl-,-pyridine radicals-,-oxazolyls-,-imidazole radicals-,-pyrimidine radicals-,-pyrazinyl-and-alkynyl-, all these groups are optional to be substituted; With
The linking group that ii) has 3-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-,-alkoxyl-,-alkylthio group-,-the alkyl-carbonyl oxygen base-,-alkyl-S (O)-,-alkyl-S (O)
2-and-alkoxyalkyl-, all these groups are optional to be substituted.
Another aspect the invention provides down facial VII chemical compound and pharmaceutically acceptable prodrug and salt:
At this R
55Be selected from:
Wherein:
G
2Be selected from C, O and S;
G
3And G
4Independently be selected from C, N, O and S;
Wherein: a) G
2, G
3And G
4In be no more than one for O or S; B) work as G
2During for O or S, G
3And G
4In be no more than one for N; C) G
2, G
3And G
4In at least one is C; And d) G
2, G
3And G
4Not C entirely;
G
5, G
6And G
7Independently be selected from C and N, wherein G
5, G
6And G
7In be no more than two for N;
J
3, J
4, J
5, J
6And J
7Independently be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O)
2NR
4 2,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, alkylidene aryl, whole haloalkyl, haloalkyl, aryl, heteroaryl, alkylidene-OH ,-C (O) R
11,-OR
11,-alkylidene-NR
4 2,-alkylidene-CN ,-CN ,-C (S) NR
4 2,-OR
2,-SR
2,-N
3,-NO
2,-NHC (S) NR
4 2With-NR
21COR
2
X
4Be selected from:
I) has the linking group of 2-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-furyl-,-thienyl-,-pyridine radicals-,-oxazolyls-,-imidazole radicals-,-phenyl-,-pyrimidine radicals-,-pyrazinyl-and-alkynyl-, all these groups are optional to be substituted; With
The linking group that ii) has 3-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-,-alkoxyl-and-alkoxyalkyl-, all these groups are optional to be substituted;
Y independently is selected from-O-and-NR
6-;
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, the optional arylmethylene alkyl that replaces ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6-and connected R
1For-(CR
12R
13)
n-C (O)-R
14The time, another YR so
1Independently be selected from-NR
15R
16,-OR
7And NR
18-(CR
12R
13)
n-C (O)-R
14
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When any one Y independently be selected from-O-and-NR
6-time, R so
1And R
1Be together-alkyl-the S-S-alkyl-and form cyclic group, perhaps R
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkyl ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, aryl, aralkyl, alkoxy-carbonyl oxy alkyl and lower acyl, perhaps with R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
7Be rudimentary R
3
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
13And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl respectively, all these groups are optional to be substituted, perhaps R
12And R
13By 2-6 carbon atom, optional comprise that 1 heteroatomic chain that is selected from O, N and S links to each other and form cyclic group together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2OR
20
R
15Be selected from-H, rudimentary aralkyl, lower aryl, rudimentary aralkyl, perhaps R
15With R
16Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps R
15With R
16Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps two R on the N
17Link to each other by 2-6 atom, optionally comprise 1 hetero atom that is selected from O, N and S;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps R
18With R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
R
19Independently be selected from-H and lower acyl;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
R
21Be selected from-H and rudimentary R
3
N is the integer of 1-3;
Prerequisite is:
1) works as G
5, G
6Or G
7During for N, J
4, J
5Or J
6Be respectively zero;
2) work as X
4During for the furyl that replaces, J so
3, J
4, J
5And J
6In at least one is not-H or zero;
3) work as X
4When not being the furyl that replaces, the J among the formula VII-5 so
3, J
4, J
5And J
6Or the J among the formula VII-6
3, J
4, J
5, J
6And J
7In at least two be not-H or zero;
4) work as G
2, G
3Or G
4During for O or S, J
3, J
4Or J
5Be respectively zero;
5) work as G
3Or G
4During for N, J so
4Or J
5It respectively is not halogen or by hetero atom and G
3Or G
4The direct group of Xiang Lianing;
6) if two Y are-NR
6, and R
1And R
1Do not link to each other and form cyclic amino phosphate ester, at least one R so
1For-(CR
12R
13)
n-C (O)-R
14
7) work as X
4For-alkyl-carbonyl-amino-or-alkyl amino-carbonyl-time, G so
5, G
6And G
7Not C entirely;
8) work as X
4For-alkoxyalkyl-, and G
5, G
6And G
7When being C, J
4And J
6All do not replaced by the amine of acidylate;
9) work as R
55During for the phenyl that replaces, J
4, J
5And J
6Be not purine radicals, purine radicals alkylidene, assorted (the deaza)-purine radicals of denitrification or the assorted purine radicals alkylidene of denitrification;
10) have only when another-YR
1Be NR
18-C (R
12R
13)
n-C (O)-R
14The time, R
1Just be selected from low alkyl group;
11) work as R
55Be the phenyl that replaces, and X
4During for ethynylene, J
4Or J
6It is not heterocyclic radical;
12) work as X
4During for ethynylene, G so
5Or G
7Can not be N.
On the one hand, the invention provides following formula VII-1 chemical compound:
On the other hand, the invention provides following formula VII-2 chemical compound:
On the one hand, the invention provides following formula VII-1-A chemical compound again:
On the one hand, the invention provides following formula VII-2-A chemical compound in addition:
On the one hand, the invention provides formula VII-1 or VII-2 chemical compound, other prerequisite is to work as X
4For-alkoxyalkyl-and R
55The thienyl that be to replace, when the furyl of replacement or the phenyl of replacement, J so
4, J
5, perhaps J
6Be not halo or alkenyl.
On the other hand, the invention provides formula VII-1 or VII-2 chemical compound, other prerequisite is to work as X
4For-alkoxyalkyl-time, R so
55Be not thienyl, the furyl of replacement or the phenyl of replacement that replaces.
On the one hand, the invention provides formula VII-1 or VII-2 chemical compound again, other prerequisite is to work as X
4For-alkoxy carbonyl-and G
5, G
6And G
7When being C, J so
3And J
7It not the group that connects by nitrogen-atoms.
On the one hand, the invention provides formula VII-1 or VII-2 chemical compound again, other prerequisite is to work as X
4For-alkoxyalkyl-or-alkoxy carbonyl-time, R so
55It is not the phenyl that replaces.
Again on the one hand, the invention provides formula VII-1 or VII-2 chemical compound, wherein when Y be-during O-, so with-R that O-is connected
1Independently be selected from-H, the optional aryl that replaces, the optional alcyl that replaces, optional carbonate or the thio-carbonate of containing of described annulus, the optional aryl alkylene that replaces-,-C (R
2)
2OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3With-alkyl-S-S-alkyl hydroxy;
When Y is-NR
6In-time, is so with-NR
6-continuous R
1Independently be selected from-H and-(CR
12R
13)
n-C (O) R
14
Perhaps independently be selected from-O-and-NR as any one Y
6-time, R so
1And R
1For
Wherein
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
In yet another aspect, the invention provides such chemical compound, promptly wherein when two Y groups be-during O-, R so
1Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R
2)
2OC (O) R
3,-C (R
2)
2OC (O) OR
3With-H; Perhaps working as Y is-NR
6In-time, is so with-NR
6The R of-connection
1Be selected from-C (R
4)
2-C (O) OR
3With-C (R
2)
2C (O) OR
3Perhaps when another Y group be-during O-, so with-R that O-is connected
1Be selected from the optional aryl that replaces ,-C (R
2)
2OC (O) R
3With-C (R
2)
2OC (O) OR
3This compounds is-O-and R for two Y groups wherein
1Chemical compound for H.
In yet another aspect, the invention provides such chemical compound, promptly wherein at least one Y is-O-and R
1And R
1Be following formula together:
Wherein
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
In yet another aspect, the invention provides such chemical compound, promptly one of them Y is-O-, R
1Be the optional aryl that replaces; Another Y is-NR
6-, wherein with-NR
6The R of-connection
1Be selected from-C (R
4)
2C (O) OR
3With-C (R
2)
2C (O) OR
3On the other hand, the present invention is such chemical compound, wherein with-R that O-is connected
1Be selected from phenyl and be selected from the phenyl that following substituent group replaces :-NHC (O) CH by 1-2
3,-F ,-Cl ,-Br ,-C (O) OCH
2CH
3With-CH
3Wherein with-NR
6The R of-connection
1For-C (R
2)
2C (O) OR
3Each R
2Independently be selected from-CH
3,-CH
2CH
3With-H.In this compounds, the substituent group of described phenyl is selected from 4-NHC (O) CH
3,-Cl ,-Br, 2-C (O) OCH
2CH
3With-CH
3
In yet another aspect, the invention provides formula VII chemical compound, wherein
J
3, J
4, J
5, J
6And J
7Independently be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-SO
2NR
4 2, low alkyl group, low-grade alkenyl, low-grade alkylaryl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, lower aryl, low-grade alkylidene-OH ,-OR
11,-CR
2 2NR
4 2,-CN ,-C (S) NR
4 2,-OR
2,-SR
2,-N
3,-NO
2,-NHC (S) NR
4 2,-NR
21COR
2,-CR
2 2CN;
X
4Be selected from:
I) 2,5-furyl, 2,5-thienyl, 1,3-phenyl, 2,6-pyridine radicals, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2,4-imidazole radicals, 2,6-pyrimidine radicals, 2,6-pyrazinyl;
Ii) ethynylene; With
The linking group that iii) has 3 atoms, the number of described atom are to be determined by the minimum atomic number between aromatic ring carbon and the phosphorus atoms, and be selected from alkyl-carbonyl-amino-,-alkyl amino-carbonyl-,-alkoxy carbonyl-and-alkoxyalkyl-;
When two Y groups be all-during O-, R so
1Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R
2)
2OC (O) R
3,-C (R
2)
2OC (O) OR
3With-H; Perhaps
When a Y be-during O-, so with-R that O-is connected
1Be the optional aryl that replaces; When another Y is-NR
6, so with-NR
6The R of-connection
1Be selected from-C (R
4)
2C (O) OR
3With-C (R
2)
2C (O) OR
3Perhaps
When Y be-O-or-NR
6-time, R so
1And R
1Be following formula together:
Or
Or
Wherein
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
In yet another aspect, the invention provides such chemical compound and pharmaceutically acceptable salt thereof and prodrug, i.e. R wherein
55Be the phenyl that replaces; X
4Be furan-2,5-two bases; J
3, J
4, J
5, J
6And J
7Independently be selected from-OR
3,-SO
2NHR
7,-CN ,-H, halo ,-NR
4 2,-(CH
2) aryl ,-(CH
2) the NH aryl and-NO
2At least one Y group is-O-.
In yet another aspect, the invention provides such chemical compound, promptly wherein as Y be-O-, so with-R that O-is connected
1Independently be selected from-H, the optional phenyl that replaces ,-CH
2OC (O)-tBu ,-CH
2OC (O) OEt and-CH
2OC (O) OiPr;
When Y is-NR
6In-time, is so with-NR
6The R of-connection
1Independently be selected from-C (R
2)
2C (O) OR
3,-C (R
4)
2C (O) OR
3, perhaps
When Y be-O-or-NR
6-and at least one Y be-during O-, R so
1And R
1Be following formula together:
Wherein
V is selected from optional aryl that replaces and the optional heteroaryl that replaces; And Z, W ' and W are H; With
R
6Be selected from-H and low alkyl group.
Another face the invention provides such chemical compound, and promptly wherein two Y groups are-O-and R
1For-H.In yet another aspect, the invention provides such chemical compound, promptly wherein two Y groups are-O-and R
1For-CH
2OC (O) OEt.Aspect another one, the invention provides such chemical compound, promptly wherein two Y groups are-O-and R
1And R
1Be following formula together:
V is by the phenyl of 1-3 halogen replacement.In this compounds, V is selected from 3,5-dichloro-phenyl, 3-bromo-4-fluoro phenyl, 3-chlorophenyl, 2-bromo phenyl and 3-bromo phenyl.
On the one hand, the invention provides such chemical compound, promptly wherein n is 1 and and R
12And R
13The carbon that connects has S type spatial chemistry.
In yet another aspect, the invention provides such chemical compound, i.e. R wherein
15Be not H.
Aspect another, the invention provides formula VII-1 or VII-2 chemical compound, wherein-NR
15R
16Be cyclic amine.In this compounds ,-NR
15R
16Be selected from morpholine and pyrrolidinyl.In yet another aspect, the invention provides such chemical compound, wherein R
16Group comprises-(CR
12R
13)
n-C (O)-R
14Aspect another, the invention provides the chemical compound of following formula
In this compounds, n is 1.On the one hand, the invention provides such chemical compound, wherein work as R
12And R
13When inequality, R so
14-C (O)-CR
12R
13-NH
2Be naturally occurring amino acid whose ester or monothioester; And R
14Be selected from-OR
17With-SR
17
On the one hand, the invention provides such chemical compound, promptly one of them Y is-O-and its corresponding R
1Be the optional phenyl that replaces, another Y is-NH-and its corresponding R simultaneously
1For-C (R
2)
2-COOR
3Work as R
1For-CHR
3COOR
3The time, so accordingly-NR
6-
*CHR
3COOR
3Generally has L type spatial chemistry.
With regard to aforementioned, the present inventor is intended to comprise any combination of the inferior Markush group (sub-Markush group) of variable group among above-mentioned Markush group and the following Table A-Q.
Table A. variable radicals R
1Inferior Markush group table
| Inferior Markush group | R 1 |
| ?1 | The optional aryl that replaces, the optional benzyl that replaces ,-C (R 2) 2OC(O)R 3、 -C(R 2) 2O-C(O)OR 3With-H |
| ?2 | The optional aryl that replaces ,-C (R 2) 2OC(O)R 3With-C (R 2) 2O- C(O)OR 3 |
| ?3 | Aryl and-C (R 2) 2-aryl |
| ?4 | -alkylidene-S-S-alkylidene-hydroxyl ,-alkylidene-S-C (O) R 3And alkylidene-S-S-S-alkylidene hydroxyl or R 1And R 1Alkylidene-S-S-alkylidene forms cyclic group together |
| ?5 | -H |
| ?6 | -C(R 2) 2C(O)OR 3 |
| ?7 | -C(R 4) 2-C(O)OR 3、-C(R 2) 2C(O)OR 3 |
| ?8 | -C(R 2) 2OC(O)R 3、-C(R 2) 2OC(O)OR 3 |
| ?9 | The optional aryl that replaces |
| ?10 | R 1And R 1Be alkyl-S-S-alkyl-form thus cyclic group together |
| ?11 | The optional phenyl that replaces ,-CH 2OC(O)-t-Bu、-CH 2OC(O)OEt、 -CH 2OC (O) O-iPr and H |
| ?12 | H, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replacement-alkylidene aryl ,-C (R 2) 2OC(O)R 3、-C(R 2) 2-O-C(O)OR 3、- C(R 2) 2OC(O)SR 3,-alkylidene-S-C (O) R 3With-alkylidene-S-S-alkylidene hydroxyl |
| ?13 | H and-(CR 12R 13) n-C(O)R 14 |
The variable radicals R of table B.
4Inferior Markush group table
| Inferior Markush group | R 4 |
| ?1 | -H, low alkyl group and lower aryl |
| ?2 | -H，C 1-C 4Alkyl |
| ?3 | H |
| ?4 | The phenyl that replaces |
| ?5 | The 4-hydroxy phenyl |
| ?6 | R 4And R 4By 2-5 atom, optional comprise that is selected from an O, the hetero atom of N and S |
| ?7 | R 4And R 4By 2-5 atom, optional comprise an O |
The variable radicals R of table C.
12Inferior Markush group table
| Inferior Markush group | ?R 12 |
| ?1 | -H, methyl, ethyl, the n-propyl group, the i-propyl group, the n-butyl, the i-butyl ,-CH 2CH 2-SCH 3, phenyl and benzyl |
| ?2 | -H, methyl, i-propyl group, i-butyl and benzyl |
| ?3 | -H, methyl, i-propyl group and benzyl |
| ?4 | -methyl |
| ?5 | ?-H |
| ?6 | ?R 12And R 13Connect the formation cyclic alkyl by 2-5 carbon atom |
| ?7 | ?R 12And R 13Connect the formation cyclopenta by 4 carbon atoms |
| ?8 | With R 13Inequality, and R 14-C(O)-CR 12R 13-NH 2Be naturally occurring amino acid whose ester or monothioester, R 14Be selected from OR 17And SR 17 |
The variable radicals R of table D.
13Inferior Markush group table
| Inferior Markush group | ?R 13 |
| ?1 | -H, methyl, ethyl, the n-propyl group, the i-propyl group, the n-butyl, the i-butyl ,-CH 2CH 2-SCH 3, phenyl and benzyl |
| ?2 | -H, methyl, i-propyl group, i-butyl and benzyl |
| ?3 | -H, methyl, i-propyl group and benzyl |
| ?4 | Methyl, i-propyl group and benzyl |
| ?5 | -methyl |
| ?6 | ?-H |
| ?7 | ?R 12And R 13By the continuous cyclic alkyl that forms together of 2-5 carbon atom |
| ?8 | ?R 12And R 13Connect the formation cyclopenta by 4 carbon atoms |
| ?9 | With R 12Inequality, and R 14-C(O)-CR 12R 13-NH 2Be naturally occurring amino acid whose ester or monothioester, R 14Be selected from OR 17And SR 17 |
The variable radicals R of table E.
15Inferior Markush group table
| Inferior Markush group | ?R 15 |
| ?1 | Low alkyl group and rudimentary aralkyl |
| ?2 | ?C 1-C 6Alkyl |
| ?3 | Methyl, ethyl and propyl group |
| ?4 | ?R 15And R 16By 2-6 atom, optional comprise that is selected from an O, the hetero atom of N and S |
| ?5 | ?R 15And R 16By 2-6 atom, optional comprise a hetero atom that is selected from O and N |
The variable radicals R of table F.
16Inferior Markush group table
| Inferior Markush group | ??R 16 |
| ??1 | Low alkyl group and rudimentary aralkyl |
| ??2 | ??C 1-C 6Alkyl |
| ??3 | ??C 1-C 3Alkyl |
| ??4 | ??R 15And R 16By 2-6 atom, optional comprise that is selected from an O, the hetero atom of N and S |
| ??5 | ??R 15And R 16By 2-6 atom, optional comprise a hetero atom that is selected from O and N |
| ??6 | Low alkyl group |
The variable radicals X of table G.
4Inferior Markush group table
| Inferior Markush group | ??X 4 |
| ?1 | 2,5-furyl, 2,5-thienyl, 2,6-pyridine radicals, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2, the 4-imidazole radicals, 2, the 6-pyrimidine radicals, 2,6-pyrazinyl and 1,3-phenyl |
| ?2 | 2,5-furyl, 2,6-pyridine radicals, 2,5-oxazolyl, 2,4-imidazole radicals and 1,3-phenyl |
| ?3 | 2,5-furyl, methylene oxygen base carbonyl, methylene oxygen methylene and methylene-amino carbonyl |
| ?4 | 2, the 5-furyl |
| ?5 | Ethynylene |
| ?6 | -alkylidene carbonylamino-,-the alkylidene amino carbonyl-,-alkylidene oxygen base carbonyl-and-alkylidene oxygen base alkylidene |
| ?7 | -methylene carbonylamino-,-the methene amido carbonyl-,-methylene oxygen base carbonyl-and-methylene oxygen methylene |
| ?8 | Alkylidene oxygen base alkylidene |
| ?9 | Alkylidene oxygen base carbonyl |
| ?1O | Alkylidene oxygen base alkylidene and alkylidene oxygen base carbonyl |
The inferior Markush group table of the variable group V of table H.
| Inferior Markush group | ??V |
| ?1 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl |
| ?2 | The heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkynyl and 1-alkenyl |
| ?3 | Aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement, |
| ?4 | The aryl of aryl and replacement |
| ?5 | The heteroaryl of heteroaryl and replacement |
| ?6 | The optional bicyclic heteroaryl that replaces contains at least one nitrogen-atoms |
| ?7 | The phenyl of phenyl and replacement |
| ?8 | 3,5-dichloro-phenyl, 3-bromo-4-fluoro phenyl, the 3-chlorophenyl, 2-bromo phenyl, 3,5-difluoro-benzene base and 3-bromo phenyl, and the two keys of this group and phosphorus-oxygen are trans |
| ?9 | 3,5-dichloro-phenyl, 3-bromo-4-fluoro phenyl, 3-chlorophenyl, 2-bromo phenyl, 3,5-difluoro-benzene base, phenyl and 3-bromo phenyl |
| ?10 | 3,5-dichloro-phenyl, 3-bromo-4-fluoro phenyl, 3-chlorophenyl, 3,5-difluoro-benzene base and 3-bromo phenyl |
| ?11 | The 4-pyridine radicals |
| ?12 | ??-H |
| Inferior Markush group | V |
| ?13 | V and W connect the cyclic group that forms the optional replacement that contains 6 carbon atoms by 3 other carbon atoms, and be selected from hydroxyl by one, acyloxy, alkoxy-carbonyl oxy, the substituent group of alkylthio group ketonic oxygen base and aryloxycarbonyl oxygen base replaces, and these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?14 | V and W connect the cyclic group that forms the optional replacement that contains 6 carbon atoms by 3 other carbon atoms, and be selected from hydroxyl, acyloxy, alkoxy-carbonyl oxy, the substituent group of alkylthio group ketonic oxygen base and aryloxycarbonyl oxygen base is single to be replaced, and these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?15 | V and W form together and are selected from following cyclic group :-CH 2CH(OH)-CH 2-、-CH 2CH-(OCOR 3)-CH 2-and-CH 2CH-(OCO 2R 3)-CH 2- |
| ?16 | V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contain 1 hetero atom, described cyclic group with the β of Y and γ position on aryl-condensed |
| ?17 | V links to each other by an other 3-5 atom with Z and forms cyclic group together, choose wantonly and contain 1 hetero atom, described cyclic group on the β of Y and γ position with aryl-condensed, described aryl is the optional monocyclic aryl that replaces, the linking group between Z and the aryl be selected from O ,-CH 2CH 2、 -OCH 2With-CH 2O |
| ?18 | And have identical aryl among the W, the aryl of replacement, the heteroaryl of heteroaryl or replacement, V and W are cis |
| ?19 | Optional aryl that replaces and the optional heteroaryl that replaces |
The variable group V of table 1.
2Inferior Markush group table
| Inferior Markush group | ??V 2 |
| ?1 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl |
| ?2 | H, alkyl, alcyl, aralkyl, aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?3 | Aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?4 | The aryl of aryl and replacement |
| ?5 | Heteroaryl, the heteroaryl of replacement |
| ?6 | The optional bicyclic heteroaryl that replaces contains at least one nitrogen-atoms |
| ?7 | The phenyl of phenyl and replacement |
| ?8 | 3,5-dichloro--phenyl, 3-bromo-4-fluoro phenyl, 3-chloro-phenyl, 3-bromo-phenyl, 2-bromo phenyl and 3,5-two fluoro-phenyl |
| ?9 | The 4-pyridine radicals |
| ?10 | ??V 2And W 2By the continuous cyclic group that forms optional replacement together of 3 other carbon atoms, this group contains 6 carbon atoms and is selected from following substituent group by 1 and replaces: hydroxyl, acyloxy, alkoxy carbonyl-oxygen base, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?11 | ??V 2And W 2By the continuous cyclic group that forms optional replacement together of 3 other carbon atoms, this group contains 6 carbon atoms and is selected from the single replacement of following substituent group: hydroxyl, acyloxy, alkoxy carbonyl-oxygen base, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| Inferior Markush group | ??V 2 |
| 12 | ??V 2And W 2Form together and be selected from following cyclic group: CH 2- ??CH(OH)-CH 2-、-CH 2CH-(OCOR 3)-CH 2-and-CH 2CH- ??(OCO 2R 3)-CH 2- |
| 13 | ??V 2And Z 2Linking to each other together by an other 3-5 atom, formation contains 5-7 annular atomses, choose wantonly and contain 1 heteroatomic cyclic group, and can be replaced: hydroxyl by following groups, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, these substituent groups are connected in distance and are connected on the carbon atom of three atoms of Y group on the phosphorus |
| 14 | ??-H |
The inferior Markush group table of the variable group W of table J.
| Inferior Markush group | ??W |
| ?1 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl |
| ?2 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement |
| ?3 | ??-H、-R 3, aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?4 | Aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?5 | Identical with W ' |
| ?6 | ??-H |
| ?7 | V links to each other by 3 other carbon atoms with W and forms the optional cyclic group that replaces together, this group contains 6 carbon atoms and is selected from following substituent group by 1 and replaces: hydroxyl, acyloxy, alkoxy carbonyl-oxygen base, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?8 | V links to each other by 3 other carbon atoms with W and forms the optional cyclic group that replaces together, this group contains 6 carbon atoms and is selected from the single replacement of following substituent group: hydroxyl, acyloxy, alkoxy carbonyl-oxygen base, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?9 | V and W form together and are selected from following cyclic group-CH 2CH(OH)- ??CH 2-、-CH 2CH-(OCOR 3)CH 2-and-CH 2CH-(OCO 2R 3)-CH 2 |
| ?10 | V and W form together and are selected from following cyclic group-CH 2CH(OH)- ??CH 2-、-CH 2CH-(OCOR 3)-CH 2-and-CH 2CH-(OCO 2R 3)-CH 2 |
| ?11 | W links to each other by an other 2-5 atom with W ' and forms cyclic group together, this cyclic group is chosen wantonly and is contained 0-2 hetero atom, with V be aryl, the heteroaryl of the aryl of replacement, heteroaryl or replacement |
| ?12 | The aryl identical with V, the aryl of replacement, the heteroaryl of heteroaryl or replacement, and W and V are cis |
Table K. variable group W ' inferior Markush group table
| Inferior Markush group | ??W′ |
| ?1 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl |
| ?2 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement |
| ?3 | ??-H、-R 3, aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?4 | Identical with W |
| ?5 | ??-H |
| ?6 | W links to each other by an other 2-5 atom with W ' and forms cyclic group together, this cyclic group is chosen wantonly and is contained 0-2 hetero atom, with V be aryl, the heteroaryl of the aryl of replacement, heteroaryl or replacement |
The variable group W of table L.
2Inferior Markush group table
| Inferior Markush group | ??W 2 |
| ?1 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl |
| ?2 | -H, alkyl, aralkyl, alcyl, the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement |
| ?3 | ??-H、-R 3, aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?4 | Aryl, the aryl of replacement, the heteroaryl of heteroaryl and replacement |
| ?5 | With W " identical |
| ?6 | ??-H |
| ?7 | ??V 2And W 2By the continuous cyclic group that forms optional replacement together of 3 other carbon atoms, this group contains 6 carbon atoms and is selected from following substituent group by 1 and replaces: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?8 | ??V 2And W 2By the continuous cyclic group that forms optional replacement together of 3 other carbon atoms, this group contains 6 carbon atoms and is selected from the single replacement of following substituent group: hydroxyl, acyloxy, alkoxy carbonyl-oxygen base, alkylthio group-ketonic oxygen base and aryloxy group-ketonic oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms that are connected in three atoms of Y group on the phosphorus |
| ?9 | ??V 2And W 2Form together and be selected from following cyclic group-CH 2CH(OH)- ??CH 2-、-CH 2CH-(OCOR 3)CH 2-and-CH 2CH-(OCO 2R 3)- ??CH 2 |
| ?10 | ??V 2And W 2Form together and be selected from following cyclic group-CH 2CH(OH)- ??CH 2-、-CH 2CH-(OCOR 3)-CH 2-and-CH 2CH-(OCO 2R 3)- ??CH 2 |
The inferior Markush group table of the variable group Y of table M.
| Inferior Markush group | ??Y |
| ?1 | Two Y groups are-O- |
| ?2 | Two Y groups are-NR 6- |
| ?3 | Y is and W ' W, W " and W 2Group is adjacent-O- |
| ?4 | Y is and V or V 2Group is adjacent-O- |
| ?5 | A Y is-NR 6-, a Y is-O- |
| ?6 | A Y is-NR 6-, another YR 1For-NR 15R 16、-OR 7Or NR 18-(CR 12R 13) n-C(O)-R 14 |
| ?7 | A Y is-NR 6-, another yR 1For-NR 15R 16, and R 15Be not H |
| ?8 | A Y is-NR 6-, another YR 1For-NR 15R 16, and R 16For-(CR 12R 13) n-C(O)-R 14 |
| ?9 | Two Y groups are all-NR 6-, so make described phosphonate ester precursor portions have plane by the two keys of phosphorus-oxygen |
| ?10 | A Y is-NR 6-, another YR 1For-NR 15R 16, this-NR 15R 16Be cyclic amine |
| ?11 | A Y is-NR 6-, another YR 1For-NR 15R 16, this-NR 15R 16Be selected from morpholinyl and pyrrolidinyl |
| ?12 | A Y is-NR 6-, another YR 1For-NR 15R 16, this-NR 15R 16For-(CR 12R 13) n-C(O)R 14 |
The inferior Markush group table of the variable group Z of table N.
| Inferior Markush group | ??Z |
| ?1 | ??-OR 2、-SR 2、-R 2-、-NR 2 2、-OC(O)R 3、-OCO 2R 3、-SC(O)R 3、 ??-SCO 2R 3、-NHC(O)R 2、-NHCO 2R 3、-(CH 2)p-OR 2With-(CH 2)p-SR 2 |
| ?2 | ??-OR 2、-R 2、-OC(O)R 3、-OCO 2R 3、-NHC(O)R 2、- ??NHCO 2R 3、-(CH 2) p-OR 2With-(CH 2) p-SR 2 |
| ?3 | ??-OR 2、-H、-OC(O)R 3、-OCO 2R 3With-NHC (O) R 2 |
| ?4 | ??-CHR 2OH、-CHR 2O-C(O)R 3With-CHR 2O-CO 2R 3， |
| ?5 | ??-CHR 2OH、-CHR 2OC(O)R 3、-CHR 2OC(S)R 3、- ??CHR 2OC(S)OR 3、-CHR 2OC(O)SR 3、-CHR 2OCO 2R 3、- ??OR 2、-SR 2、-CHR 2、-CHR 2N 3、-CH 2Aryl ,-CH (aryl) OH, CH (CH=CR 2 2)OH?CH(C≡CR 2)OH、-R 2、-NR 2 2、-OCOR 3、 ??-OCO 2R 3、-SCOR 3、-SCO 2R 3、-NHCOR 2、-NHCO 2R 3、 ??-CH 2The NH aryl ,-(CH 2) p-OR 2With-(CH 2) p-SR 2 |
| ?6 | ??-OR 2、-SR 2、-CHR 2N 3、-R 2、-OC(O)R 2、-OCO 2R 3、- ??SC(O)R 3、-SCO 2R 3、-NHC(O)R 2、-NHCO 2R 3、-CH 2The NH aryl ,-(CH 2) p-OR 2With-(CH 2) p-SR 2 |
| ?7 | ??-OR 2、-R 2、-OC(O)R 3、-OCO 2R 3、-CH 3、-NHC(O)R 2、 ??-NHCO 2R 3、-(CH 2) p-OR 2With-(CH 2) p-SR 2 |
| ?8 | ??-H，OR 2With-NHC (O) R 2 |
| ?9 | ??-H |
| ?10 | V and Z by an other 3-5 atom, optionally comprise that 1 hetero atom links to each other and form cyclic group together, this cyclic group on the β of Y and γ position with aryl-condensed |
| ?11 | W links to each other by an other 3-5 atom with Z and forms cyclic group together, choose wantonly and contain 1 hetero atom, V is an aryl, the aryl that replaces, the heteroaryl of heteroaryl or replacement |
The inferior Markush group table of the variable group Z ' of table O.
| Inferior Markush group | ??Z’ |
| ?1 | ??-OR 2、-SR 2、-R 2、-NR 2 2、-OC(O)R 3、-OCO 2R 3、-SC(O)R 3、 ??-SCO 2R 3、-NHC(O)R 2、-NHCO 2R 3、-(CH 2)p-OR 19With-(CH 2) p-SR 19 |
| ?2 | ??-OR 2、-R 2、-OC(O)R 3、-OCO 2R 3、-NHC(O)R 2、- ??NHCO 2R 3、-(CH 2) p-OR 19With-(CH 2)p-SR 19 |
| ?3 | ??-OR 2、-H、-OC(O)R 3、-OCO 2R 3With-NHC (O) R 2 |
| ?4 | ??-CHR 2OH、-CHR 2O-C(O)R 3With-CHR 2O-CO 2R 3 |
| ?5 | ??-OH、-OC(O)R 3、-OCO 2R 3With-OC (O) SR 3 |
| ?6 | ??-OH、-OC(O)R 3With-OCO 2R 3 |
| ?7 | ??-OR 2、-SR 2、-CHR 2N 3、-R 2、-OC(O)R 2、-OCO 2R 3、- ??SC(O)R 3、-SCO 2R 3、-NHC(O)R 2、-NHCO 2R 3、-CH 2The NH aryl ,-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?8 | ??-OR 2、-R 2、-OC(O)R 2、-OCO 2R 3、-CH 3、-NHC(O)R 2、 ??-NHCO 2R 3、-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?9 | ??-H，OR 2With-NHC (O) R 2 |
| ?10 | ??-H |
The variable group Z of table P.
2Inferior Markush group table
| Inferior Markush group | ??Z 2 |
| ?1 | ??-OR 2、-SR 2、-NR 2、-NR 2 2、-OC(O)R 3、-OCO 2R 3、-SC(O)R 3、 ??-SCO 2R 3，NHC(O)R 2、-NHCO 2R 3、-CH 2The NH aryl ,-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?2 | ??-OR 2、-R 2、-OC(O)R 3、-OCO 2R 3、-NHC(O)R 2、- ??NHCO 2R 3、-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?3 | ??-OR 2、-H、-OC(O)R 3、-OCO 2R 3With-NHC (O) R 2 |
| ?4 | ??-CHR 2OH、-CHR 2O-C(O)R 3With-CHR 2O-CO 2R 3 |
| ?5 | ??-CHR 2OH、-CHR 2OC(O)R 3、-CHR 2OC(S)R 3， ??CHR 2OCO 2R 3、-CHR 2OC(O)SR 3、-CHR 2OC(S)OR 3,-CH (aryl) OH, CH (CH=CR 2 2)OH，CH(C≡CR 2)OH、-SR 2、 ??-CH 2The NH aryl ,-CH 2Aryl |
| ?6 | ??-CHR 2OH、-CHR 2OC(O)R 3、-CHR 2OC(S)R 3， ??CHR 2OCO 2R 3，-CHR 2OC(O)SR 3、-CHR 2OC(S)OR 3、- ??CH 2Aryl |
| ?7 | ??-OR 2、-SR 2、-CHR 2N 3、-R 2、-OC(O)R 2、-OCO 2R 3、- ??SC(O)R 3、-SCO 2R 3、-NHC(O)R 2、-NHCO 2R 3、-CHH 2The NH aryl ,-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?8 | ??-OR 2、-R 2、-OC(O)R 2、-OCO 2R 3、-CH 3、-NHC(O)R 2、 ??-NHCO 2R 3、-(CH 2) p-OR 19With-(CH 2) p-SR 19 |
| ?9 | ??-H，OR 2With-NHC (O) R 2 |
| ?10 | ??-H |
| ?11 | ??V 2And Z 2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, this group is optional to be contained 1 hetero atom and is replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, these substituent groups are connected in distance and are connected on the carbon atom of three atoms of Y group on the phosphorus |
The variable group table of table Q.Markush
| Markush organizes A | Markush organizes B | Markush organizes C | Markush organizes D | Markush organizes E | |
| ?n | 1 and 2 | ?1 | ?2 | 1, and be connected in R 12And R 13Carbon have S type spatial chemistry | |
| ?p | ??2 | ?3 | |||
| ?R 2 | -H, low alkyl group, lower aryl, rudimentary alcyl and rudimentary aralkyl | Ethyl, methyl and H | H and aryl | ?-H | |
| ?R 3 | Low alkyl group, lower aryl, rudimentary alcyl and rudimentary aralkyl | Low alkyl group, lower aryl | Ethyl and methyl |
| Markush organizes A | Markush organizes B | Markush organizes C | Markush organizes D | Markush organizes E | |
| ?R 55 | The phenyl that replaces, the pyrrole radicals that replaces, replace the De oxazolyl, the thiazolyl that replaces, the isothiazolyl that replaces, the pyrazolyl that replaces, replace the De isoxazolyl, the pyridine radicals that replaces, the thienyl that replaces, the furyl, the pyrimidine radicals of replacement and the pyridazinyl of replacement that replace | The pyrrole radicals that replaces, replace the De oxazolyl, the thiazolyl that replaces, the isothiazolyl that replaces, the pyrazolyl that replaces, replace the De isoxazolyl, the pyridine radicals that replaces, the thienyl that replaces, the furyl, the pyrimidine radicals of replacement and the pyridazinyl of replacement that replace | The pyrrole radicals that replaces, replace the De oxazolyl, the thiazolyl that replaces, the isothiazolyl that replaces, the pyrazolyl that replaces, replace the De isoxazolyl, the pyridine radicals, the pyrimidine radicals of replacement and the pyridazinyl of replacement that replace | The thienyl, the furyl of replacement and the phenyl of replacement that replace | The phenyl that replaces |
| ?R 6 | -H; low alkyl group; the acyloxy alkyl, alkoxy carbonyl-oxygen base alkyl and lower acyl | -H and low alkyl group, the acyloxy alkyl | -H and C 1-C 6Alkyl | -H, methyl and ethyl | -H and methyl |
| R 7 | Low alkyl group, lower aryl and rudimentary alcyl | Low alkyl group and lower aryl | Lower aryl | The phenyl that replaces | Phenyl, the phenyl that is replaced by following groups: 4-NHC (O)-CH 3、-Cl、 -Br，2- C(O)O- CH 2CH 3Or-CH 3 |
| R 11 | Alkyl and aryl | Low alkyl group | C 1-C 4Alkyl | Methyl |
| Markush organizes A | Markush organizes B | Markush organizes C | Markush organizes D | Markush organizes E | |
| ?R 14 | OR 17，SR 17And NR 2R 20 | OR 17And SR 17 | OR 17 | ||
| ?R 17 | Low alkyl group, lower aryl, rudimentary aralkyl, alcyl, perhaps R 17And R 17By 2-6 atom, optional comprise that 1 hetero atom that is selected from N, O and S links to each other | Methyl, ethyl, isopropyl, propyl group, t-butyl and benzyl | Methyl, ethyl, isopropyl, propyl group and benzyl | Ethyl and isopropyl | |
| ?R 18 | -H, low alkyl group, aryl and aralkyl, R 12And R 18By the continuous cyclic group that forms together of 1-4 atom | -H and low alkyl group | -H, methyl and ethyl | ||
| ?R 19 | -H and acetyl group | -H | |||
| ?R 20 | -H，C 1-C 4Alkyl, C 4-C 6-aryl, C 2-C 7Alcyl and C 5-C 7Aralkyl | -H and C 1-C 4Alkyl | |||
| ?D” | -H, alkyl, OH and-OC (O) R 3 | -H | |||
| ?G 2 | C and O | C | O | ||
| ?G 3 | C and S | C | S | ||
| ?G 4 | C and N | C | N |
| Markush organizes A | Markush organizes B | Markush organizes C | Markus h organizes D | Markush organizes E | |
| ?J 3 | -H、-NR 4 2、- C(O)NR 4 2、-CO 2R 3, halo ,-S (O) 2NR 4 2, low alkyl group, rudimentary alcyl, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, lower aryl, low-grade alkylaryl, low-grade alkylidene-OH,-OR 11、-CR 2 2NR 4 2、- CN、-C(S)NR 4 2、- OR 2、-SR 2、-N 3、- NO 2、- NHC(S)NR 4 2、- NR 21C(O)R 2With-CR 2 2CN | -H、-NO 2Low alkyl group, lower alkyl aryl, lower alkoxy, rudimentary whole haloalkyl, halo ,-CH 2NHR 4、- C(O)NR 4 2、- S(O) 2NHR 4、- OH、-NH 2With-NHC (O) R 2 | -OCH 3,-CN ,-H, halo ,-NH 2With-NO 2 | ?-OCH 3 | -H、-OR 3、 NO 2, halo ,-(CH 2) 2-aryl ,-(CH 2) 2-NH aryl, S (O) 2NHR 7、-CN、-NR 4 2 |
| Markush organizes A | Markush organizes B | Markush organizes C | Markus h organizes D | Markush organizes E | |
| ?J 4 | -H、-NR 4 2、- C(O)NR 4 2、-CO 2R 3, halo ,-S (O) 2NR 4 2Low alkyl group, rudimentary alcyl, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, lower aryl, low-grade alkylaryl, low-grade alkylidene-OH,-OR 11、-CR 2 2NR 4 2、- CN、-C(S)NR 4 2、- OR 2、-SR 2、-N 3、- NO 2、- NHC(S)NR 4 2、- NR 21C(O)R 2With-CR 2 2CN | -H、-NO 2Low alkyl group, the lower alkyl aryl, lower alkoxy, rudimentary whole haloalkyl, halo,-CH 2NHR 4、- C(O)NR 4 2、- S(O) 2NHR 4、- OH、-NH 2With-NHC (O) R 2 | -OCH 3,-CN ,-H, halo ,-NH 2With-NO 2 | Not halo or alkenyl | -H、-OR 3、- NO 2, halo ,-(CH 2) 2-aryl ,-(CH 2) 2-NH aryl, S (O) 2NHR 7、-CN、-NR 4 2 |
| Markush organizes A | Markush organizes B | Markush organizes C | Markus h organizes D | Markush organizes E | |
| ?J 5 | -H、-NR 4 2、- C(O)NR 4 2、-CO 2R 3, halo ,-S (O) 2NR 4 2Low alkyl group, rudimentary alcyl (lower alkenyl), low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, low-grade alkylaryl, lower aryl, low-grade alkylidene-OH,-OR 11、- CR 2 2NR 4 2-CN、- C(S)NR 4 2、-OR 2、- SR 2、-N 3、-NO 2、- NHC(S)NR 4 2、- NR 21C(O)R 2With-CR 2 2CN | -H、-NO 2Low alkyl group, the lower alkyl aryl, lower alkoxy, rudimentary whole haloalkyl, halo,-CH 2NHR 4、- C(O)NR 4 2、- S(O) 2NHR 4、- OH、-NH 2With-NHC (O) R 2 | -OCH 3,-CN ,-H, halo ,-NH 2With-NO 2 | Not halo or alkenyl | -H、-OR 3、 NO 2, halo ,-(CH 2) 2-aryl ,-(CH 2) 2-NH aryl, S (O) 2NHR 7、-CN、-NR 4 2 |
| Markush organizes A | Markush organizes B | Markush organizes C | Markush organizes D | Markush organizes E | |
| ?J 6 | -H、-NR 4 2、- C(O)NR 4 2、-CO 2R 3, halo ,-S (O) 2NR 4 2Low alkyl group, rudimentary alenyl, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, lower aryl, low-grade alkylaryl, low-grade alkylidene-OH,-OR 11、- CR 2 2NR 4 2、-CN、- C(S)NR 4 2、-OR 2、- SR 2、-N 3、-NO 2、- NHC(S)NR 4 2、- NR 21C(O)R 2With-CR 2 2CN | -H、-NO 2Low alkyl group, the lower alkyl aryl, lower alkoxy, rudimentary whole haloalkyl, halo,-CH 2NHR 4、- C(O)NR 4 2、- S(O) 2NHR 4、- OH、-NH 2With-NHC (O) R 2 | -OCH 3,-CN ,-H, halo ,-NO 2With-CH 2NHR 4 | Not halo or alkenyl | -H、-OR 3、- NO 2, halo ,-(CH 2) 2-aryl ,-(CH 2) 2-NH aryl, S (O) 2NHR 7、-CN、NR 4 2 |
| Markush organizes A | Markush organizes B | Markush organizes C | Markush organizes D | Markush organizes E | |
| ?J 7 | -H、-NR 4 2、- C(O)NR 4 2、-CO 2R 3, halo ,-S (O) 2NR 4 2Low alkyl group, rudimentary alcyl, low-grade alkenyl, low-grade alkynyl, rudimentary whole haloalkyl, low-grade halogenated alkyl, lower aryl, low-grade alkylaryl, low-grade alkylidene-OH,-OR 11、-CR 2 2NR 4 2、- CN、-C(S)NR 4 2、- OR 2、-SR 2、-N 3、- NO 2、- NHC(S)NR 4 2、- NR 21C(O)R 2With-CR 2 2CN | -H、-NO 2Low alkyl group, lower aryl, the lower alkyl aryl, lower alkoxy, rudimentary whole haloalkyl, halo,-CH 2NHR 4、- C(O)NR 4 2、- S(O) 2NHR 4、- OH、-NH 2With-NHC (O) R 2 | -OCH 3,-CN ,-H, halo and low alkyl group | ||
| ?W 3 | H, alkyl | -H | |||
| ?W” | The heteroaryl of the aryl of-H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement, 1-alkenyl and 1-alkynyl | -H、R 3, aryl, replacement the heteroaryl of aryl, heteroaryl and replacement | -H, alkyl, aralkyl, alcyl, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces | With W 2Identical | -H |
| ?G 5 | C | N | |||
| ?G 6 | C | N | |||
| ?G 7 | C | N |
Generally speaking, to the preferred substituted V among formula I, II, III, IV, V-1, V-2, VI, VII-1, VII-2 or the X, Z, W, W ', V, Z, W, W ', V
2, Z
2, W
2, W ', Z ', D ', D " and W3 selects so that they have one or more following character:
(1) improves oxidizing reaction rate, because this reacts for rate-determing step and therefore competes with the medicine reset procedure;
(2) improve in aqueous solution and the stability in the presence of other non--p450 enzymes;
(3) improve the penetrance of cell, as the substituent group neutral or have high molecular weight, because these two kinds of character all limit oral administration biaavailability and cell-penetrating;
(4) after initial oxidation reaction, the open-loop products that has following one or more character by generation promotes β-elimination reaction;
A) cyclisation again;
B) the limited covalency hydration of experience;
C) by helping to attract proton to promote β-elimination reaction;
D) hinder to form the additive reaction of stablize addition product, as the hydroxylation product of mercaptan and initial generation or with open loop after the nucleophilic addition of the carbonyl that produces; With
E) metabolism of limited reactions intermediate (as open loop ketone);
(5) produce non-toxicity and non-mutagenic by-product with following one or more characteristics.Can reduce by two kinds of character by the substituent group that adopts restriction Michael addition, reaction, as
A) give electronics Z group, this group can reduce two bond polarities;
B) the Z group of steric restriction and β-carbon nucleophilic addition;
C) eliminating the Z group that tautomerization (enol＞ketone) or the two keys of hydrolysis (as enamine) elimination are passed through in the reaction back again;
D) contain and add to α, on the alpha, beta-unsaturated ketone with the V group of the group that forms ring;
E) form the Z group of stable ring by Michael additive reaction with two keys; With
F) increase the group that By-product Toxicology is eliminated by one or more following characteristics:
(i) be confined to liver; With
(ii) make them that toxicity is eliminated reaction (as the ketone reduction reaction) sensitivity; With
(6) can produce the pharmacologically active product.
In another aspect of this invention, when Y independently be selected from-O-and-NR
6The time, prerequisite is:
When Y be-during O-, so with-R that O-is connected
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, optional carbonate or the thio-carbonate of containing of described annulus, optional replace-aryl alkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, is so with-NR
6-continuous R
1Independently be selected from-H ,-[C (R
2)
2] q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2] q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2; With
Perhaps when having only a Y for-O-, so-O-is not the part that contains the cyclic group of another Y, another Y is-N (R
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6-time, R so
1And R
1For
Wherein
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
More preferably such chemical compound, promptly wherein when two Y groups be-during O-, R so
1Independently be selected from the optional aryl that replaces, the optional benzyl that replaces ,-C (R
2)
2OC (O) R
3,-C (R
2)
2OC (O) OR
3With-H; With
When Y is-NR
6In-time, is so with-NR
6The R of-connection
1Be selected from-C (R
4)
2-COOR
3With-C (R
2)
2COOR
3With another Y group be-during O-, so with-R that O-is connected
1Be selected from the optional aryl that replaces ,-C (R
2)
2OC (O) R
3With-C (R
2)
2OC (O) OR
3
In yet another aspect, when a Y be-during O-, its corresponding R so
1Be phenyl, another Y is-NH-, and its corresponding R
1For-CH
2CO
2Et.
Another preferred aspect, when a Y be-during O-, its corresponding R so
1Be phenyl, another Y is-NH-, and its corresponding R
1For-C (Me)
2CO
2Et.
Another preferred aspect, when a Y be-during O-, its corresponding R so
1Be 4-NHC (O) CH
3-phenyl, another Y are-NH-, and its corresponding R
1For-CH
2COOEt.
Another preferred aspect, when a Y be-during O-, its corresponding R so
1Be 2-CO
2Et-phenyl, another Y are-NH-, and its corresponding R
1For-CH
2CO
2Et.
Another preferred aspect, when a Y be-during O-, its corresponding R so
1Be 2-CH
3-phenyl, another Y are-NH-, and its corresponding R
1For-CH
2CO
2Et.
In yet another aspect, preferred such chemical compound, promptly wherein two Y groups are-O-R
1For aryl or-C (R
2)
2-aryl.
Also preferred such chemical compound, promptly wherein two Y groups are O-, and at least one R
1Be selected from-C (R
2)
2-OC (O) R
3With-C (R
2)
2-OC (O) OR
3
In yet another aspect, preferred such chemical compound, promptly wherein two Y groups are-O-, and at least one R
1For-alkyl-S-S-alkyl hydroxy ,-alkyl-S-C (O) R
3With-alkyl-S-S-S-alkyl hydroxy, perhaps R
1And R
1Be-alkyl-S-S-alkyl-form thus cyclic group together.
On the one hand, preferred especially such chemical compound, promptly wherein two Y groups are-O-, and R
1Be H.
In yet another aspect, preferred especially such chemical compound, wherein two Y groups are-O-, and R
1For-CH
2OC (O) OEt.
More preferably such chemical compound, promptly wherein at least one Y is-O-, and R
1And R
1Form together:
Or
Or
Wherein a) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
B) two Y groups all are not-NR
6-;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
R
6Be selected from-H and low alkyl group.
On the other hand, more preferably such chemical compound, promptly one of them Y is-O-, and R
1Be the optional aryl that replaces; With another Y be-NR
6-,-NR
6-on R
1Be selected from-C (R
4)
2COOR
3With-C (R
2)
2C (O) OR
3Preferred especially such chemical compound is wherein with-R that O-is connected
1Be-phenyl, with-R that NH-is connected
1For-CH (Me) CO
2Et ,-NH
*CH (Me) CO
2Et is the L configuration.
Preferred especially such chemical compound is wherein with-R that O-is connected
1Be selected from phenyl and by 1-2 be selected from the phenyl that following substituent group replaces :-NHAc ,-F ,-Cl ,-Br ,-COOEt and-CH
3With-NR
6The R that connects
1For-C (R
2)
2COOR
3, R wherein
2And R
3Independently be-H ,-CH
3With-Et.In this compounds, when with-R that O-is connected
1For quilt-NHAc or-during phenyl that COOEt replaces, so preferred-NHAc is in the 4-position, and-COOEt is in the 2-position.More preferably such chemical compound, wherein the substituent group on the phenyl of Qu Daiing is 4-NHC (O) CH
3,-Cl ,-Br, 2-C (O) OCH
3CH
3Or-CH
3
In one aspect of the invention, the prodrug of preferred formula 6-i:
Wherein
V is selected from heteroaryl, 1-alkenyl and the 1-alkynyl of aryl, heteroaryl and the replacement of aryl, replacement.The V group of preferred formula 6-i is the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.Preferred Y is-O-.The aromatic yl group of particularly preferred aryl and replacement comprises the phenyl of phenyl and replacement.Particularly preferred heteroaryl groups comprise monocycle that replace with unsubstituted heteroaryl groups.Preferred especially 4-pyridine radicals and 3-pyridine bromide base.
The V group of preferred formula 6-i is the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.Preferred Y is-O-.The aromatic yl group of particularly preferred aryl and replacement comprises phenyl and the phenyl that is replaced by 1-3 halogen.Preferred especially 3,5-dichloro-phenyl, 3-bromo-4-fluoro phenyl, 3-chlorophenyl and 3-bromo phenyl.
Also preferred especially V is selected from the heteroaryl that the bicyclic heteroaryl that contains at least one nitrogen-atoms and monocycle replace.Most preferably the heteroaryl of this type of heteroaryl and replacement is respectively 4-pyridine radicals and 3-pyridine bromide base.
Also preferred V and Z by an other 3-5 atom, choose wantonly and contain 1 hetero atom and link to each other and form cyclic group together, this cyclic group is in β and the γ position and aryl-condensed of the Y that links to each other with phosphorus.In this compounds, preferred described aryl is the optional monocyclic aryl that replaces, and the linking group of the γ position of Z and aryl is selected from O, CH
2, CH
2CH
2, OCH
2Or CH
2O.
In yet another aspect, preferred V links to each other by 3 other carbon atoms with W and forms the optional cyclic group that replaces together, this cyclic group contains 6 carbon atoms and is selected from the single replacement of following substituent group by one: hydroxyl, acyloxy, alkoxy-carbonyl oxy, alkylthio group ketonic oxygen base and aryloxycarbonyl oxygen base, these substituent groups are connected in apart from one of described other 3 carbon atoms of Y3 the atom that links to each other with phosphorus.In this compounds, more preferably V and W form together and are selected from following cyclic group :-CH
2-CH (OH)-CH
2-, CH
2CH (OCOR
3)-CH
2-and-CH
2CH (OCO
2) R
3)-CH
2-.
Another kind of preferred V group is the 1-alkene.Knownly occur on benzyl and the allylic carbon by the enzymatic oxidation reaction of p450.
On the one hand, preferred V group is-H that this moment, Z was selected from-CHR
2OH ,-CHR
2OCOR
3With-CHR
2OCO
2R
3
In yet another aspect, when V is an aryl, when the aryl of replacement, the heteroaryl of heteroaryl or replacement, preferred Z group comprises-OR
2,-SR
2,-CHR
2N
3,-R
2,-NR
2 2,-OCOR
2,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
pOR
2With-(CH
2)
p-SR
2Preferred Z group comprises-OR
2,-R
2,-OCOR
2,-OCO
2R
3,-CH
3,-NHCOR
2,-NHCO
2R
3,-(CH
2)
p-OR
2With ,-(CH
2)
p-SR
2Most preferred Z group comprises-OR
2,-H ,-OCOR
2,-OCO
2R
3With-NHCOR
2
Preferred W and W ' group comprise H, R
3, aryl, replacement the aryl of aryl, heteroaryl and replacement.Preferably, W is identical group with W '.More preferably W and W ' are H.
On the one hand, the chemical compound of formula I and IA preferably has group Z, this group be H, alkyl, alcyl, hydroxyl, alkoxyl,
Or NHCOR.
Preferred such group Z, promptly this group reduces the tendentiousness that by-product ethenyl aromatic yl ketone carries out the Michael additive reaction.Preferred Z group is such group, can think that vinyl provides the group of electronics, and this is one knownly can reduce α, and beta-unsaturated carbonyl compound carries out the tendentious method of Michael additive reaction.For example, the methyl that exists on the similar position of acrylamide produces the active chemical compound of no mutagenesis, and unsubstituted vinyl analog has high mutagenicity.Other groups may have similar function, as Z=OR, NHAc etc.Other groups also can stop the Michael additive reaction, the group that particularly can cause two keys to be opened simultaneously, as Z=OH ,-OC (O) R ,-OCO
2R and NH
2, after eliminating reaction, the tautomerization reaction can take place in fast again.Because some W and W ' group can stop with the additive reaction of β-carbon and make unstable products, so these groups also help this effect.
Another kind of preferred Z group can be added to α for containing after eliminating reaction, and the group of the nucleophilic group on β-unsaturated double-bond is as (CH
2)
pSH or (CH
2)
pOH, wherein p is 2 or 3.Another kind of preferred group is the group that is connected to V, and this V group can be added to α after eliminating reaction, on β-unsaturated double-bond:
In yet another aspect, the prodrug of preferred formula 7-i:
Wherein
Z is selected from :-CHR
2OH ,-CHR
2OCOR
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3With-CHR
2OC (S) OR
3Preferred Y is-O-.Preferred group comprises-CHR
2OH ,-CHR
2OC (O) R
3With-CHR
2OCO
2R
3
In yet another aspect, the prodrug of preferred formula 8-i:
Wherein
Z ' is selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D
4And D
3Independently be selected from-H, alkyl, OR
2,-OH and-OC (O) R
3Prerequisite is D at least
4And D
3In one be-H.Preferred Y is-O-.
In a preferred embodiment, W ' and Z be-H, and W and V are the heteroaryl of aryl, heteroaryl or the replacement of identical aryl, replacement, so makes the phosphonate ester precursor portions:
Has symmetric plane.Preferred Y is-O-.
In another preferred embodiment, W and W ' are H, and V is selected from aryl, the heteroaryl of aryl, replacement, the heteroaryl of replacement, and Z is selected from-H, OR
2With-NHCOR
2More preferably such chemical compound, wherein Z is-H.
The p450 oxidation reaction may compare sensitivity to the phosphorus that has aromatic group or the spatial chemistry of carbon.With regard to phosphorus, prodrug of the present invention has two kinds of isomeric form.Preferred spatial chemistry is for making oxidation reaction and eliminating all generable spatial chemistry of reaction.On phosphorus, preferred spatial chemistry is a cis.
Preferred formula 8-i chemical compound has utilized the Z ' group that can carry out such oxidation reaction, promptly should reaction produce unsettled intermediate, and by eliminating reaction, these intermediate are decomposed into corresponding R
5-X-PO
3 2-, R
5-X-P (O) (NHR
6)
2Or R
5-X-P (O) is (NHR (O-)
6).Particularly preferred Z ' group is OH.Group D
4And D
3Be preferably hydrogen, alkyl and-OR
2,-OC (O) R
3, but D at least
4And D
3In one be necessary for H.
Preferred following formula I, the prodrug of II, III, IV, V-1, V-2, VI, VII-1, VII-2 and X:
The acyloxy Arrcostab;
The alkoxy-carbonyl oxy Arrcostab;
Aryl ester;
The benzyl ester of benzyl and replacement;
The disulphide that contains ester;
(1,3-dioxole-2-ketone (the dioxolen-2-one)) methyl ester that replaces;
3-benzo [c] furanonyl (3-phthalidyl) ester that replaces;
Ring-[5-hydroxyl cyclohexane extraction-1,3-two bases) diester and hydroxyl protection form;
Ring-[2-hydroxymethyl propane-1,3-two bases] diester and hydroxyl protection form;
Ring-(1-aryl propane-1,3-two bases);
The lactone that two ω position replaces; And the mixed ester of any possible combination of above-mentioned ester;
The more preferably chemical compound of following type:
Two-the oxy acid methyl neopentyl ester;
Two-isobutyl acyl-oxygen ylmethyl ester;
Ring-[2-hydroxymethyl propane-1,3-two bases] diester;
Ring-[2-acetoxy-methyl propane-1,3-two bases] diester;
Ring-[2-methoxycarbonyl oxygen ylmethyl propane-1,3-two bases] diester;
Ring-[1-phenyl-propane-1,3-two bases] diester;
Ring-[1-(2-pyridine radicals) propane-1,3-two bases)] diester;
Ring-[1-(3-pyridine radicals) propane-1,3-two bases] diester;
Ring-[1-(4-pyridine radicals) propane-1,3-two bases] diester;
Ring-[5-hydroxyl cyclohexane extraction-1,3-two bases] diester and hydroxyl protection form;
Two-benzoyl sulphomethyl ester;
Two-benzoyl thio-ethyl ester;
Two-benzoyl oxygen ylmethyl ester;
Two-p-fluorobenzene formoxyl oxygen ylmethyl ester;
Two-6-chloro nicotinylsalicylic oxygen methyl ester;
Two-5-bromo nicotinylsalicylic oxygen methyl ester;
Two-thiophene ketonic oxygen ylmethyl ester;
Two-2-furoyl oxygen ylmethyl ester;
Two-3-furoyl oxygen ylmethyl ester;
Diphenyl;
Two-(4-methoxyphenyl) ester;
Two-(2-methoxyphenyl) ester;
Two-(2-ethoxyl phenenyl) ester;
List-(2-ethoxyl phenenyl) ester;
Two-(4-acetylamino phenyl) ester;
Two-(4-acetoxyl group phenyl) ester;
Two-(4-hydroxy phenyl) ester;
Two-(2-acetoxyl group phenyl) ester;
Two-(3-acetoxyl group phenyl) ester;
Two-(4-morpholino phenyl) ester;
Two-[4-(1-triazole) phenyl] ester;
Two-(3-N, N-dimethylaminophenyl) ester;
Two-(1,2,3,4-tetralin-2-yl) ester;
Two-(3-chloro-4-methoxyl group) benzyl ester;
Two-(3-bromo-4-methoxyl group) benzyl ester;
Two-(3-cyano group-4-methoxyl group) benzyl ester;
Two-(3-chloro-4-acetoxyl group) benzyl ester;
Two-(3-bromo-4-acetoxyl group) benzyl ester;
Two-(3-cyano group-4-acetoxyl group) benzyl ester;
Two-(4-chloro) benzyl ester;
Two-(4-acetoxyl group) benzyl ester;
Two-(3,5-dimethoxy-4 '-acetoxyl group) benzyl ester;
Two-(3-methyl-4-acetoxyl group) benzyl ester;
Two-(benzyl) ester;
Two-(3-methoxyl group-4-acetoxyl group) benzyl ester;
Two-(6 '-hydroxyl-3 ', 4 '-dithia) hexyl ester;
Two-(6 '-acetoxy-3 ', 4 '-dithia) and hexyl ester;
(3,4-dithia hexane-1,6-two bases) ester;
Two-(5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methyl ester;
Two-(5-ethyl-1,3-dioxole-2-ketone-4-yl) methyl ester;
Two-(the 5-tert-butyl group-1,3-dioxole-2-ketone-4-yl) methyl ester;
Two-3-(5,6, the 7-trimethoxy) benzo [c] furanonyl ester;
Two-(cyclohexyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(isopropyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(ethyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(methyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(isopropylthio ketonic oxygen ylmethyl) ester;
Two-(phenyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(benzyloxycarbonyloxy methyl) ester;
Two-(phenyl thiocarbonyl oxygen ylmethyl) ester;
Two-(p-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(m-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(o-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(o-methylphenoxy ketonic oxygen ylmethyl) ester;
Two-(p-chloro phenoxy group ketonic oxygen ylmethyl) ester;
Two-(1,4-biphenylyloxy (biphenoxy) ketonic oxygen ylmethyl) ester;
Two-[(2-phthalimido ethyl) oxygen base ketonic oxygen ylmethyl] ester;
Two-(N-phenyl-N-methylamino formoxyl oxygen ylmethyl) ester;
Two-(2,2,2-three chloro ethyls) ester;
Two-(2-bromoethyl) ester;
Two-(2-iodo ethyl) ester;
Two-(2-azido ethyl) ester;
Two-(2-acetoxyl group ethyl) ester;
Two-(2-amino-ethyl) ester;
Two-(2-N, N-dimethyl aminoethyl) ester;
Two-(2-amino-ethyl) ester;
Two-(methoxycarbonyl methyl) ester;
Two-(2-amino-ethyl) ester;
Two-[N, N-two (2-hydroxyethyl)] carbamoyl methyl ester;
Two-(2-amino-ethyl) ester;
Two-(2-methyl-5-thiazole ylmethyl) ester;
Two-(two-2-hydroxyethyl carbamyl ylmethyl) ester.
The O-phenyl-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (N (H) CH (Me) CO (OPh) for phosphoramidate
2Et)
The O-phenyl-[N-(1-methoxycarbonyl) ethyl] (P (O) is (N (H) CH (Me) CO (OPh) for phosphoramidate
2Me)
O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NHCH (Me) CO (OPh-3-Cl) for phosphoramidate
2Et)
O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NHCH (Me) CO (OPh-2-Cl) for phosphoramidate
2Et)
O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NHCH (Me) CO (OPh-4-Cl) for phosphoramidate
2Et)
O-(4-acetylamino phenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-CH (Me) CO (OPh-4NHAc) for phosphoramidate
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl) ethyl] phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-CH (Me) CO
2Et)
The O-phenyl-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate
2CO
2Et)
The O-phenyl-[N-(1-methoxycarbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate
2CO
2Me)
O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-3-Cl) for phosphoramidate
2CO
2Et)
O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-2-Cl) for phosphoramidate
2CO
2Et)
O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-Cl) for phosphoramidate
2CO
2Et)
O-(4-acetylamino phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-NHAc) for phosphoramidate
2CO
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-C (Me)
2CO
2Et)
The O-phenyl-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate
2CO
2Et)
The O-phenyl-[N-(methoxycarbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate
2CO
2Me)
O-(3-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-3-Cl) for phosphoramidate
2CO
2Et)
O-(2-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-2-Cl) for phosphoramidate
2CO
2Et)
O-(4-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4-Cl) for phosphoramidate
2CO
2Et)
O-(4-acetylamino phenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4NHAc) for phosphoramidate
2CO
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(ethoxy carbonyl) methyl] phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-CH
2CO
2Et).
The chemical compound of following type most preferably:
Two-the oxy acid methyl neopentyl ester;
Two-isobutyl acyl-oxygen ylmethyl ester;
Ring-(2-hydroxymethyl propane-1,3-two bases) ester;
Ring-(2-acetoxy-methyl propane-1,3-two bases) ester;
Ring-(2-methyl oxygen base ketonic oxygen ylmethyl propane-1,3-two bases) ester;
Ring-(2-cyclohexyl-carbonyl oxygen ylmethyl propane-1,3-two bases) ester;
Ring-[phenyl-propane-1,3-two bases] diester;
Ring-[1-(2-pyridine radicals) propane-1,3-two bases)] diester;
Ring-[1-(3-pyridine radicals) propane-1,3-two bases] diester;
Ring-[1-(4-pyridine radicals) propane-1,3-two bases] diester;
Ring-[5-hydroxyl cyclohexane extraction-1,3-two bases] diester and hydroxyl protection form;
Two-benzoyl sulphomethyl ester;
Two-benzoyl thio-ethyl ester;
Two-benzoyl oxygen ylmethyl ester;
Two-p-fluorobenzene formoxyl oxygen ylmethyl ester;
Two-6-chloro nicotinylsalicylic oxygen methyl ester;
Two-5-bromo nicotinylsalicylic oxygen methyl ester;
Two-thiophene ketonic oxygen ylmethyl ester;
Two-2-furoyl oxygen ylmethyl ester;
Two-3-furoyl oxygen ylmethyl ester;
Diphenyl;
Two-(2-aminomethyl phenyl) ester;
Two-(2-methoxyphenyl) ester;
Two-(2-ethoxyl phenenyl) ester;
Two-(4-methoxyphenyl) ester;
Two-(3-bromo-4-methoxy-benzyl) ester;
Two-(4-acetoxyl group benzyl) ester;
Two-(3,5-dimethoxy-4 '-acetoxyl group benzyl) ester;
Two-(3-methyl-4-acetoxyl group benzyl) ester;
Two-(3-methoxyl group-4-acetoxyl group benzyl) ester;
Two-(3-chloro-4-acetoxyl group benzyl) ester;
Two-(cyclohexyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(isopropyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(ethyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(methyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(isopropylthio ketonic oxygen ylmethyl) ester;
Two-(phenyl oxygen base ketonic oxygen ylmethyl) ester;
Two-(benzyloxycarbonyloxy methyl) ester;
Two-(phenyl thiocarbonyl oxygen ylmethyl) ester;
Two-(p-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(m-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(o-methoxyl group phenoxy group ketonic oxygen ylmethyl) ester;
Two-(o-methylphenoxy ketonic oxygen ylmethyl) ester;
Two-(p-chloro phenoxy group ketonic oxygen ylmethyl) ester;
Two-(1,4-biphenylyloxy ketonic oxygen ylmethyl) ester;
Two-[(2-phthalimido ethyl) oxygen base ketonic oxygen ylmethyl] ester;
Two-(6-hydroxyl-3,4-dithia) hexyl ester;
Ring-(3,4-dithia hexane-1,6-two bases) ester;
Two-(2-bromoethyl) ester;
Two-(2-amino-ethyl) ester;
Two-(2-N, N-diamino ethyl) ester;
The O-phenyl-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh) for phosphoramidate
*CH (Me) CO
2Et)
The O-phenyl-[N-(1-methoxycarbonyl) ethyl] (P (O) is (NH-(OPh) for phosphoramidate
*CH (Me) CO
2Me)
O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-3-Cl) for phosphoramidate
*CH (Me) CO
2Et)
O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-2-Cl) for phosphoramidate
*CH (Me) CO
2Et)
O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl) ethyl] (p (O) is (NH-(OPh-4-Cl) for phosphoramidate
*CH (Me) CO
2Et)
O-(4-acetylamino phenyl)-[N-(1-ethoxy carbonyl) ethyl] (P (O) is (NH-(OPh-4-NHAc) for phosphoramidate
*CH (Me) CO
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl) ethyl] phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-
*CH (Me) CO
2Et)
The O-phenyl-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate
2CO
2Et)
The O-phenyl-[N-(1-methoxycarbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh) for phosphoramidate
2CO
2Me)
O-(3-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-3-Cl) for phosphoramidate
2CO
2Et)
O-(2-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-2-Cl) for phosphoramidate
2CO
2Et)
O-(4-chlorophenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-Cl) for phosphoramidate
2CO
2Et)
O-(4-acetylamino phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl] (P (O) is (NH-C (Me) (OPh-4-NHAc) for phosphoramidate
2CO
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(1-ethoxy carbonyl-1-methyl) ethyl]-phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-C (Me)
2CO
2Et).
In the prodrug of the above-mentioned type, the asterisk on the carbon (
*) refer to L-type configuration.
The O-phenyl-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate
2CO
2Et)
The O-phenyl-[N-(methoxycarbonyl) methyl] (P (O) is (NH-CH (OPh) for phosphoramidate
2CO
2Me)
O-(3-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-3-Cl) for phosphoramidate
2CO
2Et)
O-(2-chlorophenyl)-[N-(ethoxy carbonyl) methyl] phosphoramidate (P (O) (OPh-2-Cl)-(NH-CH
2CO
2Et)
O-(4-chlorophenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4-Cl) for phosphoramidate
2CO
2Et)
O-(4-acetylamino phenyl)-[N-(ethoxy carbonyl) methyl] (P (O) is (NH-CH (OPh-4-NHAc) for phosphoramidate
2CO
2Et)
O-(2-ethoxy carbonyl phenyl)-[N-(ethoxy carbonyl) methyl] phosphoramidate (P (O) (OPh-2-CO
2Et) (NH-CH
2CO
2Et).
Specified chemical compound is preferred formula I-A chemical compound in the table 1.Wherein M is R
5-X-, identical with definition among formula i, formula ii and the formula iii, Q wherein
1And Q
2NR corresponding to formula I-A
15N
16And N (R
18)-(CR
12R
13)
n-C (O)-R
14
Formula i formula ii formula iii
In above-mentioned formula i, ii and iii, R
5Can be replaced by A and B.Preferred formula i, ii and iii chemical compound are listed in the table 1, according to following convention Q
1, Q
2, R
5, B, A, to the radicals R among above-mentioned formula i, ii and the iii
5, A, B, Q
1And Q
2Specified respectively and represented numeral.For each several part, in the table below to radicals R
5, A, B, Q
1And Q
2Structure specified represent the numeral.
With variable radicals R
5Be divided into two groups, every group has four kinds of different structures.
The R of the formula i that provides in the table 1, ii and iii chemical compound
5The representative numeral of part is as follows:
The 1st group:
The 2nd group:
The representative numeral of variable group A part is as follows:
| ??1 | ??2 | ??3 | ??4 | |
| ??A＝ | ??MH 2 | ??H | ??Me | ??Cl |
The representative numeral of variable group B part is as follows:
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | |
| ??B＝ | ??-SCH 3 | ??-iBu | ??-cPr | ??-S-nPr | ??-SEt | ??-iPr | ??-nPr | ??-CH 2cPr |
With variable group Q
1And Q
2Be divided into three groups, every group has eight kinds of different substituent groups.
Q
1And Q
2The representative numeral of part is as follows:
The 1st group:
Q
1And Q
2
1.-NH-CH
2-C(O)R
14
2.-NH-CH(CH
3)-C(O)R
14
3.-NH-C(CH
3)
2-C(O)R
14
4.-NH-C(CH
3)
2CH
2-C(O)R
14
5.-NH-CH(CH(CH
3)
2))-C(O)R
14
6.-NH-CH(CH
2(CH(CH
3)
2)))-C(O)R
14
7.-NH-CH(CH
2CH
2SCH
3)-C(O)R
14
8.-NH-CH(CH
2SCH
2Ph)-C(O)R
14
The 2nd group:
Q
1And Q
2
1.-NH-CH
2CH
2-C(O)R
14
2.-NH-CH(CH
2CH
2COR
14)-C(O)R
14
3.-NH-CH(CH
2COR
14)-C(O)R
14
4.-NH-CH(CH
2CONH
2)-C(O)R
14
5.-NH-CH(COR
14)CH
2-C(O)R
14
6.-NH-CH(CH
2OR
17)-C(O)R
14
7.-NH-CH(CH
2CH
2COR
14)-C(O)R
14
8.-NH-CH(CH
2OH)-C(O)R
14
The 3rd group:
Q
1And Q
2
1.-NH-CH(CH
2-C
6H
5OH)-C(O)R
14
(2.-NH-C c-propyl group)-C (O) R
14
(3.-NH-C c-amyl group)-C (O) R
14
(4.-NH-C c-hexyl)-C (O) R
14
5.-NH-CH(CH
2Ph)-C(O)R
14
6.-N(CH
3)-CH
2-C(O)R
14
8.-NR
18R
19，
R wherein
14Be selected from: OMe, OEt, OBn, O-tBu, O-nPr, OPh ,-N (Me)
2, morpholine, SMe, SEt; R
17Be methyl, ethyl, benzyl and propyl group; R
18Be H, Me, Et, Bn, Pr and Ph, R
19Be Me, Et, Bn, Pr and Ph; R
18And R
19Be morpholinyl and pyrrolidinyl.
Therefore, work as R
5Be selected from the R in the 1st group
5, Q
1And Q
2Be selected from the Q in the 1st group
1With the 1st group in Q
2The time, represent numeral to be the structure of the chemical compound in the table 1 of 3.3.1.2.1 corresponding to following facial i:
Work as R
14During for ethyoxyl, this structure is as follows:
In addition, work as Q
1And Q
2Be selected from the Q in the 3rd group
1With the 3rd group in Q
2, R
5Be selected from the R in the 2nd group
5The time, represent numeral to be the structure of the chemical compound in the table 1 of 3.3.1.2.1 so corresponding to following facial i:
The chemical compound of the representative digitized representation in the table 1 also refers to benzothiazole and the benzoazole compounds of preferred formula X.These preferred chemical compounds are suc as formula shown in iv and the v:
Formula iv formula v
Preferred formula iv and formula v chemical compound are listed in the table 1, according to following convention: Q
1, Q
2, A, B, D, to group A, B, D, Q
1And Q
2Specified respectively and represented numeral.For each several part, in the table below to group A, B, D, Q
1And Q
2Structure specified represent the numeral.
With variable group Q
1And Q
2Be divided into three groups, every group has eight kinds of different substituent groups.Q
1And Q
2The representative numeral of part is as follows:
The 1st group:
Q
1And Q
2
1.-NH-CH
2-C(O)R
14
2.-NH-CH(CH
3)-C(O)R
14
3.-NH-C(CH
3)
2-C(O)R
14
4.-NH-C(CH
3)
2CH
2-C(O)R
14
5.-NH-CH(CH(CH
3)
2))-C(O)R
14
6.-NH-CH(CH
2(CH(CH
3)
2)))-C(O)R
14
7.-NH-CH(CH
2CH
2SCH
3)-C(O)R
14
8.-NH-CH(CH
2SCH
2Ph)-C(O)R
14
The 2nd group:
Q
1And Q
2
1.-NH-CH
2CH
2-C(O)R
14
2.-NH-CH(CH
2CH
2COR
14)-C(O)R
14
3.-NH-CH(CH
2COR
14)-C(O)R
14
4.-NH-CH(CH
2CONH
2)-C(O)R
14
5.-NH-CH(COR
14)CH
2-C(O)R
14
6.-NH-CH(CH
2OR
17)-C(O)R
14
7.-NH-CH(CH
2CH
2COR
14)-C(O)R
14
8.-NH-CH(CH
2OH)-C(O)R
14
The 3rd group:
Q
1And Q
2
1.-NH-CH(CH
2-C
6H
5OH)-C(O)R
14
(2.-NH-C c-propyl group)-C (O) R
14
(3.-NH-C c-amyl group)-C (O) R
14
(4.-NH-C c-hexyl)-C (O) R
14
5.-NH-CH(CH
2Ph)-C(O)R
14
6.-N(CH
3)-CH
2-C(O)R
14
8.-NR
18R
19
Variable group B is divided into three groups, and every group has eight kinds of different substituent groups.The representative numeral of B part is as follows:
The 1st group:
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | |
| ??B＝ | ??H | ??Me | ??Et | ??nPr | ??Br | ??iPr | ??Cl | ??cPr |
The 2nd group:
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | |
| ??B＝ | ??CN | ??F | ??OMe | ??OEt | ??SMe | ??SEt | The 2-furyl | ??C(O)OEt |
The 3rd group:
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | |
| ??B＝ | B links to each other with D and forms cyclohexyl ring | B links to each other with D and forms benzyl ring | B links to each other with D and forms furan basic ring (O is connected on the B) | B links to each other with D and forms furan basic ring (O is connected on the D) | B links to each other with D and forms cyclohexyl ring | B links to each other with D and forms benzyl ring | B links to each other with D and forms furan basic ring (O is connected on the B) | B links to each other with D and forms furan basic ring (O is connected on the D) |
The 3rd group of variable group B only can combine with the 3rd group of variable group D.
Variable group D is divided into three groups, and every group has four kinds of different substituent groups.
The 1st group:
| ??1 | ??2 | ??3 | ??4 | |
| ??D＝ | ??H | ??Me | ??Et | ??SCN |
The 2nd group:
Variable group D is replaced by the part of following digitized representation:
| ??1 | ??2 | ??3 | ??4 | |
| ??D＝ | ??SMe | ??SEt | ??CH 2OMe | ??OMe |
The 3rd group:
| ??1 | ??2 | ??3 | ??4 | |
| ??D＝ | Do not exist | Do not exist | Do not exist | Do not exist |
The representative numeral of the A part of formula iv that provides in the table 1 and v chemical compound is as follows:
| ??1 | ??2 | ??3 | ??4 | |
| ??A＝ | ??NH 2 | ??H | ??Me | ??Cl |
R wherein
14Be selected from OMe, OEt, OBn, O-tBu, O-nPr, OPh ,-N (Me)
2, morpholine, SMe, SEt; R
17Be methyl, ethyl, benzyl and propyl group; R
18Be H, Me, Et, Bn, Pr and Ph, R
19Be Me, Et, Bn, Pr and Ph, R
18And R
19Be morpholinyl and pyrrolidinyl.
Therefore, B, D, Q
1And Q
2The representative numeral that is the 1st group is the structure of the chemical compound of 2.2.1.7.4 corresponding to following facial iv:
And work as R
14During for ethyoxyl, this structure is:
Equally, when variable group B is the 3rd group, represent numeral for the chemical compound of 2.2.1.7.4 then corresponding to the structure of descending facial iv:
And work as R
14During for ethyoxyl, this structure is:
Table 1
1.1.1.1.1??1.1.1.1.2??1.1.1.1.3??1.1.1.1.4??1.1.1.2.1??1.1.1.2.2??1.1.1.2.3??1.1.1.2.4
1.1.1.3.1??1.1.1.3.2??1.1.1.3.3??1.1.1.3.4??1.1.1.4.1??1.1.1.4.2??1.1.1.4.3??1.1.1.4.4
1.1.1.5.1??1.1.1.5.2??1.1.1.5.3??1.1.1.5.4??1.1.1.6.1??1.1.1.6.2??1.1.1.6.3??1.1.1.6.4
1.1.1.7.1??1.1.1.7.2??1.1.1.7.3??1.1.1.7.4??1.1.1.8.1??1.1.1.8.2??1.1.1.8.3??1.1.1.8.4
1.1.2.1.1??1.1.2.1.2??1.1.2.1.3??1.1.2.1.4??1.1.2.2.1??1.1.2.2.2??1.1.2.2.3??1.1.2.2.4
1.1.2.3.1??1.1.2.3.2??1.1.2.3.3??1.1.2.3.4??1.1.2.4.1??1.1.2.4.2??1.1.2.4.3??1.1.2.4.4
1.1.2.5.1??1.1.2.5.2??1.1.2.5.3??1.1.2.5.4??1.1.2.6.1??1.1.2.6.2??1.1.2.6.3??1.1.2.6.4
1.1.2.7.1??1.1.2.7.2??1.1.2.7.3??1.1.2.7.4??1.1.2.8.1??1.1.2.8.2??1.1.2.8.3??1.1.2.8.4
1.1.3.1.1??1.1.3.1.2??1.1.3.1.3??1.1.3.1.4??1.1.3.2.1??1.1.3.2.2??1.1.3.2.3??1.1.3.2.4
1.1.3.3.1??1.1.3.3.2??1.1.3.3.3??1.1.3.3.4??1.1.3.4.1??1.1.3.4.2??1.1.3.4.3??1.1.3.4.4
1.1.3.5.1??1.1.3.5.2??1.1.3.5.3??1.1.3.5.4??1.1.3.6.1??1.1.3.6.2??1.1.3.6.3??1.1.3.6.4
1.1.3.7.1??1.1.3.7.2??1.1.3.7.3??1.1.3.7.4??1.1.3.8.1??1.1.3.8.2??1.1.3.8.3??1.1.3.8.4
1.1.4.1.1??1.1.4.1.2??1.1.4.1.3??1.1.4.1.4??1.1.4.2.1??1.1.4.2.2??1.1.4.2.3??1.1.4.2.4
1.1.4.3.1??1.1.4.3.2??1.1.4.3.3??1.1.4.3.4??1.1.4.4.1??1.1.4.4.2??1.1.4.4.3??1.1.4.4.4
1.1.4.5.1??1.1.4.5.2??1.1.4.5.3??1.1.4.5.4??1.1.4.6.1??1.1.4.6.2??1.1.4.6.3??1.1.4.6.4
1.1.4.7.1??1.1.4.7.2??1.1.4.7.3??1.1.4.7.4??1.1.4.8.1??1.1.4.8.2??1.1.4.8.3??1.1.4.8.4
1.2.1.1.1??1.2.1.1.2??1.2.1.1.3??1.2.1.1.4??1.2.1.2.1??1.2.1.2.2??1.2.1.2.3??1.2.1.2.4
1.2.1.3.1??1.2.1.3.2??1.2.1.3.3??1.2.1.3.4??1.2.1.4.1??1.2.1.4.2??1.2.1.4.3??1.2.1.4.4
1.2.1.5.1??1.2.1.5.2??1.2.1.5.3??1.2.1.5.4??1.2.1.6.1??1.2.1.6.2??1.2.1.6.3??1.2.1.6.4
1.2.1.7.1??1.2.1.7.2??1.2.1.7.3??1.2.1.7.4??1.2.1.8.1??1.2.1.8.2??1.2.1.8.3??1.2.1.8.4
1.2.2.1.1??1.2.2.1.2??1.2.2.1.3??1.2.2.1.4??1.2.2.2.1??1.2.2.2.2??1.2.2.2.3??1.2.2.2.4
1.2.2.3.1??1.2.2.3.2??1.2.2.3.3??1.2.2.3.4??1.2.2.4.1??1.2.2.4.2??1.2.2.4.3??1.2.2.4.4
1.2.2.5.1??1.2.2.5.2??1.2.2.5.3??1.2.2.5.4??1.2.2.6.1??1.2.2.6.2??1.2.2.6.3??1.2.2.6.4
1.2.2.7.1??1.2.2.7.2??1.2.2.7.3??1.2.2.7.4??1.2.2.8.1??1.2.2.8.2??1.2.2.8.3??1.2.2.8.4
1.2.3.1.1??1.2.3.1.2??1.2.3.1.3??1.2.3.1.4??1.2.3.2.1??1.2.3.2.2??1.2.3.2.3??1.2.3.2.4
1.2.3.3.1??1.2.3.3.2??1.2.3.3.3??1.2.3.3.4??1.2.3.4.1??1.2.3.4.2??1.2.3.4.3??1.2.3.4.4
1.2.3.5.1??1.2.3.5.2??1.2.3.5.3??1.2.3.5.4??1.2.3.6.1??1.2.3.6.2??1.2.3.6.3??1.2.3.6.4
1.2.3.7.1??1.2.3.7.2??1.2.3.7.3??1.2.3.7.4??1.2.3.8.1??1.2.3.8.2??1.2.3.8.3??1.2.3.8.4
1.2.4.1.1??1.2.4.1.2??1.2.4.1.3??1.2.4.1.4??1.2.4.2.1??1.2.4.2.2??1.2.4.2.3??1.2.4.2.4
1.2.4.3.1??1.2.4.3.2??1.2.4.3.3??1.2.4.3.4??1.2.4.4.1??1.2.4.4.2??1.2.4.4.3??1.2.4.4.4
1.2.4.5.1??1.2.4.5.2??1.2.4.5.3??1.2.4.5.4??1.2.4.6.1??1.2.4.6.2??1.2.4.6.3??1.2.4.6.4
1.2.4.7.1??1.2.4.7.2??1.2.4.7.3??1.2.4.7.4??1.2.4.8.1??1.2.4.8.2??1.2.4.8.3??1.2.4.8.4
1.3.1.1.1??1.3.1.1.2??1.3.1.1.3??1.3.1.1.4??1.3.1.2.1??1.3.1.2.2??1.3.1.2.3??1.3.1.2.4
Table 1-is continuous
1.3.1.3.1??1.3.1.3.2??1.3.1.3.3??1.3.1.3.4??1.3.1.4.1??1.3.1.4.2??1.3.1.4.3??1.3.1.4.4
1.3.1.5.1??1.3.1.5.2??1.3.1.5.3??1.3.1.5.4??1.3.1.6.1??1.3.1.6.2??1.3.1.6.3??1.3.1.6.4
1.3.1.7.1??1.3.1.7.2??1.3.1.7.3??1.3.1.7.4??1.3.1.8.1??1.3.1.8.2??1.3.1.8.3??1.3.1.8.4
1.3.2.1.1??1.3.2.1.2??1.3.2.1.3??1.3.2.1.4??1.3.2.2.1??1.3.2.2.2??1.3.2.2.3??1.3.2.2.4
1.3.2.3.1??1.3.2.3.2??1.3.2.3.3??1.3.2.3.4??1.3.2.4.1??1.3.2.4.2??1.3.2.4.3??1.3.2.4.4
1.3.2.5.1??1.3.2.5.2??1.3.2.5.3??1.3.2.5.4??1.3.2.6.1??1.3.2.6.2??1.3.2.6.3??1.3.2.6.4
1.3.2.7.1??1.3.2.7.2??1.3.2.7.3??1.3.2.7.4??1.3.2.8.1??1.3.2.8.2??1.3.2.8.3??1.3.2.8.4
1.3.3.1.1??1.3.3.1.2??1.3.3.1.3??1.3.3.1.4??1.3.3.2.1??1.3.3.2.2??1.3.3.2.3??1.3.3.2.4
1.3.3.3.1??1.3.3.3.2??1.3.3.3.3??1.3.3.3.4??1.3.3.4.1??1.3.3.4.2??1.3.3.4.3??1.3.3.4.4
1.3.3.5.1??1.3.3.5.2??1.3.3.5.3??1.3.3.5.4??1.3.3.6.1??1.3.3.6.2??1.3.3.6.3??1.3.3.6.4
1.3.3.7.1??1.3.3.7.2??1.3.3.7.3??1.3.3.7.4??1.3.3.8.1??1.3.3.8.2??1.3.3.8.3??1.3.3.8.4
1.3.4.1.1??1.3.4.1.2??1.3.4.1.3??1.3.4.1.4??1.3.4.2.1??1.3.4.2.2??1.3.4.2.3??1.3.4.2.4
1.3.4.3.1??1.3.4.3.2??1.3.4.3.3??1.3.4.3.4??1.3.4.4.1??1.3.4.4.2??1.3.4.4.3??1.3.4.4.4
1.3.4.5.1??1.3.4.5.2??1.3.4.5.3??1.3.4.5.4??1.3.4.6.1??1.3.4.6.2??1.3.4.6.3??1.3.4.6.4
1.3.4.7.1??1.3.4.7.2??1.3.4.7.3??1.3.4.7.4??1.3.4.8.1??1.3.4.8.2??1.3.4.8.3??1.3.4.8.4
1.4.1.1.1??1.4.1.1.2??1.4.1.1.3??1.4.1.1.4??1.4.1.2.1??1.4.1.2.2??1.4.1.2.3??1.4.1.2.4
1.4.1.3.1??1.4.1.3.2??1.4.1.3.3??1.4.1.3.4??1.4.1.4.1??1.4.1.4.2??1.4.1.4.3??1.4.1.4.4
1.4.1.5.1??1.4.1.5.2??1.4.1.5.3??1.4.1.5.4??1.4.1.6.1??1.4.1.6.2??1.4.1.6.3??1.4.1.6.4
1.4.1.7.1??1.4.1.7.2??1.4.1.7.3??1.4.1.7.4??1.4.1.8.1??1.4.1.8.2??1.4.1.8.3??1.4.1.8.4
1.4.2.1.1??1.4.2.1.2??1.4.2.1.3??1.4.2.1.4??1.4.2.2.1??1.4.2.2.2??1.4.2.2.3??1.4.2.2.4
1.4.2.3.1??1.4.2.3.2??1.4.2.3.3??1.4.2.3.4??1.4.2.4.1??1.4.2.4.2??1.4.2.4.3??1.4.2.4.4
1.4.2.5.1??1.4.2.5.2??1.4.2.5.3??1.4.2.5.4??1.4.2.6.1??1.4.2.6.2??1.4.2.6.3??1.4.2.6.4
1.4.2.7.1??1.4.2.7.2??1.4.2.7.3??1.4.2.7.4??1.4.2.8.1??1.4.2.8.2??1.4.2.8.3??1.4.2.8.4
1.4.3.1.1??1.4.3.1.2??1.4.3.1.3??1.4.3.1.4??1.4.3.2.1??1.4.3.2.2??1.4.3.2.3??1.4.3.2.4
1.4.3.3.1??1.4.3.3.2??1.4.3.3.3??1.4.3.3.4??1.4.3.4.1??1.4.3.4.2??1.4.3.4.3??1.4.3.4.4
1.4.3.5.1??1.4.3.5.2??1.4.3.5.3??1.4.3.5.4??1.4.3.6.1??1.4.3.6.2??1.4.3.6.3??1.4.3.6.4
1.4.3.7.1??1.4.3.7.2??1.4.3.7.3??1.4.3.7.4??1.4.3.8.1??1.4.3.8.2??1.4.3.8.3??1.4.3.8.4
1.4.4.1.1??1.4.4.1.2??1.4.4.1.3??1.4.4.1.4??1.4.4.2.1??1.4.4.2.2??1.4.4.2.3??1.4.4.2.4
1.4.4.3.1??1.4.4.3.2??1.4.4.3.3??1.4.4.3.4??1.4.4.4.1??1.4.4.4.2??1.4.4.4.3??1.4.4.4.4
1.4.4.5.1??1.4.4.5.2??1.4.4.5.3??1.4.4.5.4??1.4.4.6.1??1.4.4.6.2??1.4.4.6.3??1.4.4.6.4
1.4.4.7.1??1.4.4.7.2??1.4.4.7.3??1.4.4.7.4??1.4.4.8.1??1.4.4.8.2??1.4.4.8.3??1.4.4.8.4
1.5.1.1.1??1.5.1.1.2??1.5.1.1.3??1.5.1.1.4??1.5.1.2.1??1.5.1.2.2??1.5.1.2.3??1.5.1.2.4
Table 1-is continuous
1.5.1.3.1??1.5.1.3.2??1.5.1.3.3??1.5.1.3.4??1.5.1.4.1??1.5.1.4.2??1.5.1.4.3??1.5.1.4.4
1.5.1.5.1??1.5.1.5.2??1.5.1.5.3??1.5.1.5.4??1.5.1.6.1??1.5.1.6.2??1.5.1.6.3??1.5.1.6.4
1.5.1.7.1??1.5.1.7.2??1.5.1.7.3??1.5.1.7.4??1.5.1.8.1??1.5.1.8.2??1.5.1.8.3??1.5.1.8.4
1.5.2.1.1??1.5.2.1.2??1.5.2.1.3??1.5.2.1.4??1.5.2.2.1??1.5.2.2.2??1.5.2.2.3??1.5.2.2.4
1.5.2.3.1??1.5.2.3.2??1.5.2.3.3??1.5.2.3.4??1.5.2.4.1??1.5.2.4.2??1.5.2.4.3??1.5.2.4.4
1.5.2.5.1??1.5.2.5.2??1.5.2.5.3??1.5.2.5.4??1.5.2.6.1??1.5.2.6.2??1.5.2.6.3??1.5.2.6.4
1.5.2.7.1??1.5.2.7.2??1.5.2.7.3??1.5.2.7.4??1.5.2.8.1??1.5.2.8.2??1.5.2.8.3??1.5.2.8.4
1.5.3.1.1??1.5.3.1.2??1.5.3.1.3??1.5.3.1.4??1.5.3.2.1??1.5.3.2.2??1.5.3.2.3??1.5.3.2.4
1.5.3.3.1??1.5.3.3.2??1.5.3.3.3??1.5.3.3.4??1.5.3.4.1??1.5.3.4.2??1.5.3.4.3??1.5.3.4.4
1.5.3.5.1??1.5.3.5.2??1.5.3.5.3??1.5.3.5.4??1.5.3.6.1??1.5.3.6.2??1.5.3.6.3??1.5.3.6.4
1.5.3.7.1??1.5.3.7.2??1.5.3.7.3??1.5.3.7.4??1.5.3.8.1??1.5.3.8.2??1.5.3.8.3??1.5.3.8.4
1.5.4.1.1??1.5.4.1.2??1.5.4.1.3??1.5.4.1.4??1.5.4.2.1??1.5.4.2.2??1.5.4.2.3??1.5.4.2.4
1.5.4.3.1??1.5.4.3.2??1.5.4.3.3??1.5.4.3.4??1.5.4.4.1??1.5.4.4.2??1.5.4.4.3??1.5.4.4.4
1.5.4.5.1??1.5.4.5.2??1.5.4.5.3??1.5.4.5.4??1.5.4.6.1??1.5.4.6.2??1.5.4.6.3??1.5.4.6.4
1.5.4.7.1??1.5.4.7.2??1.5.4.7.3??1.5.4.7.4??1.5.4.8.1??1.5.4.8.2??1.5.4.8.3??1.5.4.8.4
1.6.1.1.1??1.6.1.1.2??1.6.1.1.3??1.6.1.1.4??1.6.1.2.1??1.6.1.2.2??1.6.1.2.3??1.6.1.2.4
1.6.1.3.1??1.6.1.3.2??1.6.1.3.3??1.6.1.3.4??1.6.1.4.1??1.6.1.4.2??1.6.1.4.3??1.6.1.4.4
1.6.1.5.1??1.6.1.5.2??1.6.1.5.3??1.6.1.5.4??1.6.1.6.1??1.6.1.6.2??1.6.1.6.3??1.6.1.6.4
1.6.1.7.1??1.6.1.7.2??1.6.1.7.3??1.6.1.7.4??1.6.1.8.1??1.6.1.8.2??1.6.1.8.3??1.6.1.8.4
1.6.2.1.1??1.6.2.1.2??1.6.2.1.3??1.6.2.1.4??1.6.2.2.1??1.6.2.2.2??1.6.2.2.3??1.6.2.2.4
1.6.2.3.1??1.6.2.3.2??1.6.2.3.3??1.6.2.3.4??1.6.2.4.1??1.6.2.4.2??1.6.2.4.3??1.6.2.4.4
1.6.2.5.1??1.6.2.5.2??1.6.2.5.3??1.6.2.5.4??1.6.2.6.1??1.6.2.6.2??1.6.2.6.3??1.6.2.6.4
1.6.2.7.1??1.6.2.7.2??1.6.2.7.3??1.6.2.7.4??1.6.2.8.1??1.6.2.8.2??1.6.2.8.3??1.6.2.8.4
1.6.3.1.1??1.6.3.1.2??1.6.3.1.3??1.6.3.1.4??1.6.3.2.1??1.6.3.2.2??1.6.3.2.3??1.6.3.2.4
1.6.3.3.1??1.6.3.3.2??1.6.3.3.3??1.6.3.3.4??1.6.3.4.1??1.6.3.4.2??1.6.3.4.3??1.6.3.4.4
1.6.3.5.1??1.6.3.5.2??1.6.3.5.3??1.6.3.5.4??1.6.3.6.1??1.6.3.6.2??1.6.3.6.3??1.6.3.6.4
1.6.3.7.1??1.6.3.7.2??1.6.3.7.3??1.6.3.7.4??1.6.3.8.1??1.6.3.8.2??1.6.3.8.3??1.6.3.8.4
1.6.4.1.1??1.6.4.1.2??1.6.4.1.3??1.6.4.1.4??1.6.4.2.1??1.6.4.2.2??1.6.4.2.3??1.6.4.2.4
1.6.4.3.1??1.6.4.3.2??1.6.4.3.3??1.6.4.3.4??1.6.4.4.1??1.6.4.4.2??1.6.4.4.3??1.6.4.4.4
1.6.4.5.1??1.6.4.5.2??1.6.4.5.3??1.6.4.5.4??1.6.4.6.1??1.6.4.6.2??1.6.4.6.3??1.6.4.6.4
1.6.4.7.1??1.6.4.7.2??1.6.4.7.3??1.6.4.7.4??1.6.4.8.1??1.6.4.8.2??1.6.4.8.3??1.6.4.8.4
1.7.1.1.1??1.7.1.1.2??1.7.1.1.3??1.7.1.1.4??1.7.1.2.1??1.7.1.2.2??1.7.1.2.3??1.7.1.2.4
Table 1-is continuous
1.7.1.3.1??1.7.1.3.2??1.7.1.3.3??1.7.1.3.4??1.7.1.4.1??1.7.1.4.2??1.7.1.4.3??1.7.1.4.4
1.7.1.5.1??1.7.1.5.2??1.7.1.5.3??1.7.1.5.4??1.7.1.6.1??1.7.1.6.2??1.7.1.6.3??1.7.1.6.4
1.7.1.7.1??1.7.1.7.2??1.7.1.7.3??1.7.1.7.4??1.7.1.8.1??1.7.1.8.2??1.7.1.8.3??1.7.1.8.4
1.7.2.1.1??1.7.2.1.2??1.7.2.1.3??1.7.2.1.4??1.7.2.2.1??1.7.2.2.2??1.7.2.2.3??1.7.2.2.4
1.7.2.3.1??1.7.2.3.2??1.7.2.3.3??1.7.2.3.4??1.7.2.4.1??1.7.2.4.2??1.7.2.4.3??1.7.2.4.4
1.7.2.5.1??1.7.2.5.2??1.7.2.5.3??1.7.2.5.4??1.7.2.6.1??1.7.2.6.2??1.7.2.6.3??1.7.2.6.4
1.7.2.7.1??1.7.2.7.2??1.7.2.7.3??1.7.2.7.4??1.7.2.8.1??1.7.2.8.2??1.7.2.8.3??1.7.2.8.4
1.7.3.1.1??1.7.3.1.2??1.7.3.1.3??1.7.3.1.4??1.7.3.2.1??1.7.3.2.2??1.7.3.2.3??1.7.3.2.4
1.7.3.3.1??1.7.3.3.2??1.7.3.3.3??1.7.3.3.4??1.7.3.4.1??1.7.3.4.2??1.7.3.4.3??1.7.3.4.4
1.7.3.5.1??1.7.3.5.2??1.7.3.5.3??1.7.3.5.4??1.7.3.6.1??1.7.3.6.2??1.7.3.6.3??1.7.3.6.4
1.7.3.7.1??1.7.3.7.2??1.7.3.7.3??1.7.3.7.4??1.7.3.8.1??1.7.3.8.2??1.7.3.8.3??1.7.3.8.4
1.7.4.1.1??1.7.4.1.2??1.7.4.1.3??1.7.4.1.4??1.7.4.2.1??1.7.4.2.2??1.7.4.2.3??1.7.4.2.4
1.7.4.3.1??1.7.4.3.2??1.7.4.3.3??1.7.4.3.4??1.7.4.4.1??1.7.4.4.2??1.7.4.4.3??1.7.4.4.4
1.7.4.5.1??1.7.4.5.2??1.7.4.5.3??1.7.4.5.4??1.7.4.6.1??1.7.4.6.2??1.7.4.6.3??1.7.4.6.4
1.7.4.7.1??1.7.4.7.2??1.7.4.7.3??1.7.4.7.4??1.7.4.8.1??1.7.4.8.2??1.7.4.8.3??1.7.4.8.4
1.8.1.1.1??1.8.1.1.2??1.8.1.1.3??1.8.1.1.4??1.8.1.2.1??1.8.1.2.2??1.8.1.2.3??1.8.1.2.4
1.8.1.3.1??1.8.1.3.2??1.8.1.3.3??1.8.1.3.4??1.8.1.4.1??1.8.1.4.2??1.8.1.4.3??1.8.1.4.4
1.8.1.5.1??1.8.1.5.2??1.8.1.5.3??1.8.1.5.4??1.8.1.6.1??1.8.1.6.2??1.8.1.6.3??1.8.1.6.4
1.8.1.7.1??1.8.1.7.2??1.8.1.7.3??1.8.1.7.4??1.8.1.8.1??1.8.1.8.2??1.8.1.8.3??1.8.1.8.4
1.8.2.1.1??1.8.2.1.2??1.8.2.1.3??1.8.2.1.4??1.8.2.2.1??1.8.2.2.2??1.8.2.2.3??1.8.2.2.4
1.8.2.3.1??1.8.2.3.2??1.8.2.3.3??1.8.2.3.4??1.8.2.4.1??1.8.2.4.2??1.8.2.4.3??1.8.2.4.4
1.8.2.5.1??1.8.2.5.2??1.8.2.5.3??1.8.2.5.4??1.8.2.6.1??1.8.2.6.2??1.8.2.6.3??1.8.2.6.4
1.8.2.7.1??1.8.2.7.2??1.8.2.7.3??1.8.2.7.4??1.8.2.8.1??1.8.2.8.2??1.8.2.8.3??1.8.2.8.4
1.8.3.1.1??1.8.3.1.2??1.8.3.1.3??1.8.3.1.4??1.8.3.2.1??1.8.3.2.2??1.8.3.2.3??1.8.3.2.4
1.8.3.3.1??1.8.3.3.2??1.8.3.3.3??1.8.3.3.4??1.8.3.4.1??1.8.3.4.2??1.8.3.4.3??1.8.3.4.4
1.8.3.5.1??1.8.3.5.2??1.8.3.5.3??1.8.3.5.4??1.8.3.6.1??1.8.3.6.2??1.8.3.6.3??1.8.3.6.4
1.8.3.7.1??1.8.3.7.2??1.8.3.7.3??1.8.3.7.4??1.8.3.8.1??1.8.3.8.2??1.8.3.8.3??1.8.3.8.4
1.8.4.1.1??1.8.4.1.2??1.8.4.1.3??1.8.4.1.4??1.8.4.2.1??1.8.4.2.2??1.8.4.2.3??1.8.4.2.4
1.8.4.3.1??1.8.4.3.2??1.8.4.3.3??1.8.4.3.4??1.8.4.4.1??1.8.4.4.2??1.8.4.4.3??1.8.4.4.4
1.8.4.5.1??1.8.4.5.2??1.8.4.5.3??1.8.4.5.4??1.8.4.6.1??1.8.4.6.2??1.8.4.6.3??1.8.4.6.4
1.8.4.7.1??1.8.4.7.2??1.8.4.7.3??1.8.4.7.4??1.8.4.8.1??1.8.4.8.2??1.8.4.8.3??1.8.4.8.4
2.1.1.1.1??2.1.1.1.2??2.1.1.1.3??2.1.1.1.4??2.1.1.2.1??2.1.1.2.2??2.1.1.2.3??2.1.1.2.4
Table 1-is continuous
2.1.1.3.1??2.1.1.3.2??2.1.1.3.3??2.1.1.3.4??2.1.1.4.1??2.1.1.4.2??2.1.1.4.3??2.1.1.4.4
2.1.1.5.1??2.1.1.5.2??2.1.1.5.3??2.1.1.5.4??2.1.1.6.1??2.1.1.6.2??2.1.1.6.3??2.1.1.6.4
2.1.1.7.1??2.1.1.7.2??2.1.1.7.3??2.1.1.7.4??2.1.1.8.1??2.1.1.8.2??2.1.1.8.3??2.1.1.8.4
2.1.2.1.1??2.1.2.1.2??2.1.2.1.3??2.1.2.1.4??2.1.2.2.1??2.1.2.2.2??2.1.2.2.3??2.1.2.2.4
2.1.2.3.1??2.1.2.3.2??2.1.2.3.3??2.1.2.3.4??2.1.2.4.1??2.1.2.4.2??2.1.2.4.3??2.1.2.4.4
2.1.2.5.1??2.1.2.5.2??2.1.2.5.3??2.1.2.5.4??2.1.2.6.1??2.1.2.6.2??2.1.2.6.3??2.1.2.6.4
2.1.2.7.1??2.1.2.7.2??2.1.2.7.3??2.1.2.7.4??2.1.2.8.1??2.1.2.8.2??2.1.2.8.3??2.1.2.8.4
2.1.3.1.1??2.1.3.1.2??2.1.3.1.3??2.1.3.1.4??2.1.3.2.1??2.1.3.2.2??2.1.3.2.3??2.1.3.2.4
2.1.3.3.1??2.1.3.3.2??2.1.3.3.3??2.1.3.3.4??2.1.3.4.1??2.1.3.4.2??2.1.3.4.3??2.1.3.4.4
2.1.3.5.1??2.1.3.5.2??2.1.3.5.3??2.1.3.5.4??2.1.3.6.1??2.1.3.6.2??2.1.3.6.3??2.1.3.6.4
2.1.3.7.1??2.1.3.7.2??2.1.3.7.3??2.1.3.7.4??2.1.3.8.1??2.1.3.8.2??2.1.3.8.3??2.1.3.8.4
2.1.4.1.1??2.1.4.1.2??2.1.4.1.3??2.1.4.1.4??2.1.4.2.1??2.1.4.2.2??2.1.4.2.3??2.1.4.2.4
2.1.4.3.1??2.1.4.3.2??2.1.4.3.3??2.1.4.3.4??2.1.4.4.1??2.1.4.4.2??2.1.4.4.3??2.1.4.4.4
2.1.4.5.1??2.1.4.5.2??2.1.4.5.3??2.1.4.5.4??2.1.4.6.1??2.1.4.6.2??2.1.4.6.3??2.1.4.6.4
2.1.4.7.1??2.1.4.7.2??2.1.4.7.3??2.1.4.7.4??2.1.4.8.1??2.1.4.8.2??2.1.4.8.3??2.1.4.8.4
2.2.1.1.1??2.2.1.1.2??2.2.1.1.3??2.2.1.1.4??2.2.1.2.1??2.2.1.2.2??2.2.1.2.3??2.2.1.2.4
2.2.1.3.1??2.2.1.3.2??2.2.1.3.3??2.2.1.3.4??2.2.1.4.1??2.2.1.4.2??2.2.1.4.3??2.2.1.4.4
2.2.1.5.1??2.2.1.5.2??2.2.1.5.3??2.2.1.5.4??2.2.1.6.1??2.2.1.6.2??2.2.1.6.3??2.2.1.6.4
2.2.1.7.1??2.2.1.7.2??2.2.1.7.3??2.2.1.7.4??2.2.1.8.1??2.2.1.8.2??2.2.1.8.3??2.2.1.8.4
2.2.2.1.1??2.2.2.1.2??2.2.2.1.3??2.2.2.1.4??2.2.2.2.1??2.2.2.2.2??2.2.2.2.3??2.2.2.2.4
2.2.2.3.1??2.2.2.3.2??2.2.2.3.3??2.2.2.3.4??2.2.2.4.1??2.2.2.4.2??2.2.2.4.3??2.2.2.4.4
2.2.2.5.1??2.2.2.5.2??2.2.2.5.3??2.2.2.5.4??2.2.2.6.1??2.2.2.6.2??2.2.2.6.3??2.2.2.6.4
2.2.2.7.1??2.2.2.7.2??2.2.2.7.3??2.2.2.7.4??2.2.2.8.1??2.2.2.8.2??2.2.2.8.3??2.2.2.8.4
2.2.3.1.1??2.2.3.1.2??2.2.3.1.3??2.2.3.1.4??2.2.3.2.1??2.2.3.2.2??2.2.3.2.3??2.2.3.2.4
2.2.3.3.1??2.2.3.3.2??2.2.3.3.3??2.2.3.3.4??2.2.3.4.1??2.2.3.4.2??2.2.3.4.3??2.2.3.4.4
2.2.3.5.1??2.2.3.5.2??2.2.3.5.3??2.2.3.5.4??2.2.3.6.1??2.2.3.6.2??2.2.3.6.3??2.2.3.6.4
2.2.3.7.1??2.2.3.7.2??2.2.3.7.3??2.2.3.7.4??2.2.3.8.1??2.2.3.8.2??2.2.3.8.3??2.2.3.8.4
2.2.4.1.1??2.2.4.1.2??2.2.4.1.3??2.2.4.1.4??2.2.4.2.1??2.2.4.2.2??2.2.4.2.3??2.2.4.2.4
2.2.4.3.1??2.2.4.3.2??2.2.4.3.3??2.2.4.3.4??2.2.4.4.1??2.2.4.4.2??2.2.4.4.3??2.2.4.4.4
2.2.4.5.1??2.2.4.5.2??2.2.4.5.3??2.2.4.5.4??2.2.4.6.1??2.2.4.6.2??2.2.4.6.3??2.2.4.6.4
2.2.4.7.1??2.2.4.7.2??2.2.4.7.3??2.2.4.7.4??2.2.4.8.1??2.2.4.8.2??2.2.4.8.3??2.2.4.8.4
2.3.1.1.1??2.3.1.1.2??2.3.1.1.3??2.3.1.1.4??2.3.1.2.1??2.3.1.2.2??2.3.1.2.3??2.3.1.2.4
Table 1-is continuous
2.3.1.3.1??2.3.1.3.2??2.3.1.3.3??2.3.1.3.4??2.3.1.4.1??2.3.1.4.2??2.3.1.4.3??2.3.1.4.4
2.3.1.5.1??2.3.1.5.2??2.3.1.5.3??2.3.1.5.4??2.3.1.6.1??2.3.1.6.2??2.3.1.6.3??2.3.1.6.4
2.3.1.7.1??2.3.1.7.2??2.3.1.7.3??2.3.1.7.4??2.3.1.8.1??2.3.1.8.2??2.3.1.8.3??2.3.1.8.4
2.3.2.1.1??2.3.2.1.2??2.3.2.1.3??2.3.2.1.4??2.3.2.2.1??2.3.2.2.2??2.3.2.2.3??2.3.2.2.4
2.3.2.3.1??2.3.2.3.2??2.3.2.3.3??2.3.2.3.4??2.3.2.4.1??2.3.2.4.2??2.3.2.4.3??2.3.2.4.4
2.3.2.5.1??2.3.2.5.2??2.3.2.5.3??2.3.2.5.4??2.3.2.6.1??2.3.2.6.2??2.3.2.6.3??2.3.2.6.4
2.3.2.7.1??2.3.2.7.2??2.3.2.7.3??2.3.2.7.4??2.3.2.8.1??2.3.2.8.2??2.3.2.8.3??2.3.2.8.4
2.3.3.1.1??2.3.3.1.2??2.3.3.1.3??2.3.3.1.4??2.3.3.2.1??2.3.3.2.2??2.3.3.2.3??2.3.3.2.4
2.3.3.3.1??2.3.3.3.2??2.3.3.3.3??2.3.3.3.4??2.3.3.4.1??2.3.3.4.2??2.3.3.4.3??2.3.3.4.4
2.3.3.5.1??2.3.3.5.2??2.3.3.5.3??2.3.3.5.4??2.3.3.6.1??2.3.3.6.2??2.3.3.6.3??2.3.3.6.4
2.3.3.7.1??2.3.3.7.2??2.3.3.7.3??2.3.3.7.4??2.3.3.8.1??2.3.3.8.2??2.3.3.8.3??2.3.3.8.4
2.3.4.1.1??2.3.4.1.2??2.3.4.1.3??2.3.4.1.4??2.3.4.2.1??2.3.4.2.2??2.3.4.2.3??2.3.4.2.4
2.3.4.3.1??2.3.4.3.2??2.3.4.3.3??2.3.4.3.4??2.3.4.4.1??2.3.4.2.2??2.3.4.4.3??2.3.4.4.4
2.3.4.5.1??2.3.4.5.2??2.3.4.5.3??2.3.4.5.4??2.3.4.6.1??2.3.4.6.2??2.3.4.6.3??2.3.4.6.4
2.3.4.7.1??2.3.4.7.2??2.3.4.7.3??2.3.4.7.4??2.3.4.8.1??2.3.4.8.2??2.3.4.8.3??2.3.4.8.4
2.4.1.1.1??2.4.1.1.2??2.4.1.1.3??2.4.1.1.4??2.4.1.2.1??2.4.1.2.2??2.4.1.2.3??2.4.1.2.4
2.4.1.3.1??2.4.1.3.2??2.4.1.3.3??2.4.1.3.4??2.4.1.4.1??2.4.1.4.2??2.4.1.4.3??2.4.1.4.4
2.4.1.5.1??2.4.1.5.2??2.4.1.5.3??2.4.1.5.4??2.4.1.6.1??2.4.1.6.2??2.4.1.6.3??2.4.1.6.4
2.4.1.7.1??2.4.1.7.2??2.4.1.7.3??2.4.1.7.4??2.4.1.8.1??2.4.1.8.2??2.4.1.8.3??2.4.1.8.4
2.4.2.1.1??2.4.2.1.2??2.4.2.1.3??2.4.2.1.4??2.4.2.2.1??2.4.2.2.2??2.4.2.2.3??2.4.2.2.4
2.4.2.3.1??2.4.2.3.2??2.4.2.3.3??2.4.2.3.4??2.4.2.4.1??2.4.2.4.2??2.4.2.4.3??2.4.2.4.4
2.4.2.5.1??2.4.2.5.2??2.4.2.5.3??2.4.2.5.4??2.4.2.6.1??2.4.2.6.2??2.4.2.6.3??2.4.2.6.4
2.4.2.7.1??2.4.2.7.2??2.4.2.7.3??2.4.2.7.4??2.4.2.8.1??2.4.2.8.2??2.4.2.8.3??2.4.2.8.4
2.4.3.1.1??2.4.3.1.2??2.4.3.1.3??2.4.3.1.4??2.4.3.2.1??2.4.3.2.2??2.4.3.2.3??2.4.3.2.4
2.4.3.3.1??2.4.3.3.2??2.4.3.3.3??2.4.3.3.4??2.4.3.4.1??2.4.3.4.2??2.4.3.4.3??2.4.3.4.4
2.4.3.5.1??2.4.3.5.2??2.4.3.5.3??2.4.3.5.4??2.4.3.6.1??2.4.3.6.2??2.4.3.6.3??2.4.3.6.4
2.4.3.7.1??2.4.3.7.2??2.4.3.7.3??2.4.3.7.4??2.4.3.8.1??2.4.3.8.2??2.4.3.8.3??2.4.3.8.4
2.4.4.1.1??2.4.4.1.2??2.4.4.1.3??2.4.4.1.4??2.4.4.2.1??2.4.4.2.2??2.4.4.2.3??2.4.4.2.4
2.4.4.3.1??2.4.4.3.2??2.4.4.3.3??2.4.4.3.4??2.4.4.4.1??2.4.4.4.2??2.4.4.4.3??2.4.4.4.4
2.4.4.5.1??2.4.4.5.2??2.4.4.5.3??2.4.4.5.4??2.4.4.6.1??2.4.4.6.2??2.4.4.6.3??2.4.4.6.4
2.4.4.7.1??2.4.4.7.2??2.4.4.7.3??2.4.4.7.4??2.4.4.8.1??2.4.4.8.2??2.4.4.8.3??2.4.4.8.4
2.5.1.1.1??2.5.1.1.2??2.5.1.1.3??2.5.1.1.4??2.5.1.2.1??2.5.1.2.2??2.5.1.2.3??2.5.1.2.4
Table 1-is continuous
2.5.1.3.1??2.5.1.3.2??2.5.1.3.3??2.5.1.3.4??2.5.1.4.1??2.5.1.4.2??2.5.1.4.3??2.5.1.4.4
2.5.1.5.1??2.5.1.5.2??2.5.1.5.3??2.5.1.5.4??2.5.1.6.1??2.5.1.6.2??2.5.1.6.3??2.5.1.6.4
2.5.1.7.1??2.5.1.7.2??2.5.1.7.3??2.5.1.7.4??2.5.1.8.1??2.5.1.8.2??2.5.1.8.3??2.5.1.8.4
2.5.2.1.1??2.5.2.1.2??2.5.2.1.3??2.5.2.1.4??2.5.2.2.1??2.5.2.2.2??2.5.2.2.3??2.5.2.2.4
2.5.2.3.1??2.5.2.3.2??2.5.2.3.3??2.5.2.3.4??2.5.2.4.1??2.5.2.4.2??2.5.2.4.3??2.5.2.4.4
2.5.2.5.1??2.5.2.5.2??2.5.2.5.3??2.5.2.5.4??2.5.2.6.1??2.5.2.6.2??2.5.2.6.3??2.5.2.6.4
2.5.2.7.1??2.5.2.7.2??2.5.2.7.3??2.5.2.7.4??2.5.2.8.1??2.5.2.8.2??2.5.2.8.3??2.5.2.8.4
2.5.3.1.1??2.5.3.1.2??2.5.3.1.3??2.5.3.1.4??2.5.3.2.1??2.5.3.2.2??2.5.3.2.3??2.5.3.2.4
2.5.3.3.1??2.5.3.3.2??2.5.3.3.3??2.5.3.3.4??2.5.3.4.1??2.5.3.4.2??2.5.3.4.3??2.5.3.4.4
2.5.3.5.1??2.5.3.5.2??2.5.3.5.3??2.5.3.5.4??2.5.3.6.1??2.5.3.6.2??2.5.3.6.3??2.5.3.6.4
2.5.3.7.1??2.5.3.7.2??2.5.3.7.3??2.5.3.7.4??2.5.3.8.1??2.5.3.8.2??2.5.3.8.3??2.5.3.8.4
2.5.4.1.1??2.5.4.1.2??2.5.4.1.3??2.5.4.1.4??2.5.4.2.1??2.5.4.2.2??2.5.4.2.3??2.5.4.2.4
2.5.4.3.1??2.5.4.3.2??2.5.4.3.3??2.5.4.3.4??2.5.4.4.1??2.5.4.4.2??2.5.4.4.3??2.5.4.4.4
2.5.4.5.1??2.5.4.5.2??2.5.4.5.3??2.5.4.5.4??2.5.4.6.1??2.5.4.6.2??2.5.4.6.3??2.5.4.6.4
2.5.4.7.1??2.5.4.7.2??2.5.4.7.3??2.5.4.7.4??2.5.4.8.1??2.5.4.8.2??2.5.4.8.3??2.5.4.8.4
2.6.1.1.1??2.6.1.1.2??2.6.1.1.3??2.6.1.1.4??2.6.1.2.1??2.6.1.2.2??2.6.1.2.3??2.6.1.2.4
2.6.1.3.1??2.6.1.3.2??2.6.1.3.3??2.6.1.3.4??2.6.1.4.1??2.6.1.4.2??2.6.1.4.3??2.6.1.4.4
2.6.1.5.1??2.6.1.5.2??2.6.1.5.3??2.6.1.5.4??2.6.1.6.1??2.6.1.6.2??2.6.1.6.3??2.6.1.6.4
2.6.1.7.1??2.6.1.7.2??2.6.1.7.3??2.6.1.7.4??2.6.1.8.1??2.6.1.8.2??2.6.1.8.3??2.6.1.8.4
2.6.2.1.1??2.6.2.1.2??2.6.2.1.3??2.6.2.1.4??2.6.2.2.1??2.6.2.2.2??2.6.2.2.3??2.6.2.2.4
2.6.2.3.1??2.6.2.3.2??2.6.2.3.3??2.6.2.3.4??2.6.2.4.1??2.6.2.4.2??2.6.2.4.3??2.6.2.4.4
2.6.2.5.1??2.6.2.5.2??2.6.2.5.3??2.6.2.5.4??2.6.2.6.1??2.6.2.6.2??2.6.2.6.3??2.6.2.6.4
2.6.2.7.1??2.6.2.7.2??2.6.2.7.3??2.6.2.7.4??2.6.2.8.1??2.6.2.8.2??2.6.2.8.3??2.6.2.8.4
2.6.3.1.1??2.6.3.1.2??2.6.3.1.3??2.6.3.1.4??2.6.3.2.1??2.6.3.2.2??2.6.3.2.3??2.6.3.2.4
2.6.3.3.1??2.6.3.3.2??2.6.3.3.3??2.6.3.3.4??2.6.3.4.1??2.6.3.4.2??2.6.3.4.3??2.6.3.4.4
2.6.3.5.1??2.6.3.5.2??2.6.3.5.3??2.6.3.5.4??2.6.3.6.1??2.6.3.6.2??2.6.3.6.3??2.6.3.6.4
2.6.3.7.1??2.6.3.7.2??2.6.3.7.3??2.6.3.7.4??2.6.3.8.1??2.6.3.8.2??2.6.3.8.3??2.6.3.8.4
2.6.4.1.1??2.6.4.1.2??2.6.4.1.3??2.6.4.1.4??2.6.4.2.1??2.6.4.2.2??2.6.4.2.3??2.6.4.2.4
2.6.4.3.1??2.6.4.3.2??2.6.4.3.3??2.6.4.3.4??2.6.4.4.1??2.6.4.4.2??2.6.4.4.3??2.6.4.4.4
2.6.4.5.1??2.6.4.5.2??2.6.4.5.3??2.6.4.5.4??2.6.4.6.1??2.6.4.6.2??2.6.4.6.3??2.6.4.6.4
2.6.4.7.1??2.6.4.7.2??2.6.4.7.3??2.6.4.7.4??2.6.4.8.1??2.6.4.8.2??2.6.4.8.3??2.6.4.8.4
2.7.1.1.1??2.7.1.1.2??2.7.1.1.3??2.7.1.1.4??2.7.1.2.1??2.7.1.2.2??2.7.1.2.3??2.7.1.2.4
Table 1-is continuous
2.7.1.3.1??2.7.1.3.2??2.7.1.3.3??2.7.1.3.4??2.7.1.4.1??2.7.1.4.2??2.7.1.4.3??2.7.1.4.4
2.7.1.5.1??2.7.1.5.2??2.7.1.5.3??2.7.1.5.4??2.7.1.6.1??2.7.1.6.2??2.7.1.6.3??2.7.1.6.4
2.7.1.7.1??2.7.1.7.2??2.7.1.7.3??2.7.1.7.4??2.7.1.8.1??2.7.1.8.2??2.7.1.8.3??2.7.1.8.4
2.7.2.1.1??2.7.2.1.2??2.7.2.1.3??2.7.2.1.4??2.7.2.2.1??2.7.2.2.2??2.7.2.2.3??2.7.2.2.4
2.7.2.3.1??2.7.2.3.2??2.7.2.3.3??2.7.2.3.4??2.7.2.4.1??2.7.2.4.2??2.7.2.4.3??2.7.2.4.4
2.7.2.5.1??2.7.2.5.2??2.7.2.5.3??2.7.2.5.4??2.7.2.6.1??2.7.2.6.2??2.7.2.6.3??2.7.2.6.4
2.7.2.7.1??2.7.2.7.2??2.7.2.7.3??2.7.2.7.4??2.7.2.8.1??2.7.2.8.2??2.7.2.8.3??2.7.2.8.4
2.7.3.1.1??2.7.3.1.2??2.7.3.1.3??2.7.3.1.4??2.7.3.2.1??2.7.3.2.2??2.7.3.2.3??2.7.3.2.4
2.7.3.3.1??2.7.3.3.2??2.7.3.3.3??2.7.3.3.4??2.7.3.4.1??2.7.3.4.2??2.7.3.4.3??2.7.3.4.4
2.7.3.5.1??2.7.3.5.2??2.7.3.5.3??2.7.3.5.4??2.7.3.6.1??2.7.3.6.2??2.7.3.6.3??2.7.3.6.4
2.7.3.7.1??2.7.3.7.2??2.7.3.7.3??2.7.3.7.4??2.7.3.8.1??2.7.3.8.2??2.7.3.8.3??2.7.3.8.4
2.7.4.1.1??2.7.4.1.2??2.7.4.1.3??2.7.4.1.4??2.7.4.2.1??2.7.4.2.2??2.7.4.2.3??2.7.4.3.4
2.7.4.3.1??2.7.4.3.2??2.7.4.3.3??2.7.4.3.4??2.7.4.4.1??2.7.4.4.2??2.7.4.4.3??2.7.4.4.4
2.7.4.5.1??2.7.4.5.2??2.7.4.5.3??2.7.4.5.4??2.7.4.6.1??2.7.4.6.2??2.7.4.6.3??2.7.4.6.4
2.7.4.7.1??2.7.4.7.2??2.7.4.7.3??2.7.4.7.4??2.7.4.8.1??2.7.4.8.2??2.7.4.8.3??2.7.4.8.4
2.8.1.1.1??2.8.1.1.2??2.8.1.1.3??2.8.1.1.4??2.8.1.2.1??2.8.1.2.2??2.8.1.2.3??2.8.1.2.4
2.8.1.3.1??2.8.1.3.2??2.8.1.3.3??2.8.1.3.4??2.8.1.4.1??2.8.1.4.2??2.8.1.4.3??2.8.1.4.4
2.8.1.5.1??2.8.1.5.2??2.8.1.5.3??2.8.1.5.4??2.8.1.6.1??2.8.1.6.2??2.8.1.6.3??2.8.1.6.4
2.8.1.7.1??2.8.1.7.2??2.8.1.7.3??2.8.1.7.4??2.8.1.8.1??2.8.1.8.2??2.8.1.8.3??2.8.1.8.4
2.8.2.1.1??2.8.2.1.2??2.8.2.1.3??2.8.2.1.4??2.8.2.2.1??2.8.2.2.2??2.8.2.2.3??2.8.2.2.4
2.8.2.3.1??2.8.2.3.2??2.8.2.3.3??2.8.2.3.4??2.8.2.4.1??2.8.2.4.2??2.8..24.3??2.8.2.4.4
2.8.2.5.1??2.8.2.5.2??2.8.2.5.3??2.8.2.5.4??2.8.2.6.1??2.8.2.6.2??2.8.2.6.3??2.8.2.6.4
2.8.2.7.1??2.8.2.7.2??2.8.2.7.3??2.8.2.7.4??2.8.2.8.1??2.8.2.8.2??2.8.2.8.3??2.8.2.8.4
2.8.3.1.1??2.8.3.1.2??2.8.3.1.3??2.8.3.1.4??2.8.3.2.1??2.8.3.2.2??2.8.3.2.3??2.8.3.2.4
2.8.3.3.1??2.8.3.3.2??2.8.3.3.3??2.8.3.3.4??2.8.3.4.1??2.8.3.4.2??2.8.3.4.3??2.8.3.4.4
2.8.3.5.1??2.8.3.5.2??2.8.3.5.3??2.8.3.5.4??2.8.3.6.1??2.8.3.6.2??2.8.3.6.3??2.8.3.6.4
2.8.3.7.1??2.8.3.7.2??2.8.3.7.3??2.8.3.7.4??2.8.3.8.1??2.8.3.8.2??2.8.3.8.3??2.8.3.8.4
2.8.4.1.1??2.8.4.1.2??2.8.4.1.3??2.8.4.1.4??2.8.4.2.1??2.8.4.2.2??2.8.4.2.3??2.8.4.2.4
2.8.4.3.1??2.8.4.3.2??2.8.4.3.3??2.8.4.3.4??2.8.4.4.1??2.8.4.4.2??2.8.4.4.3??2.8.4.4.4
2.8.4.5.1??2.8.4.5.2??2.8.4.5.3??2.8.4.5.4??2.8.4.6.1??2.8.4.6.2??2.8.4.6.3??2.8.4.6.4
2.8.4.7.1??2.8.4.7.2??2.8.4.7.3??2.8.4.7.4??2.8.4.8.1??2.8.4.8.2??2.8.4.8.3??2.8.4.8.4
3.1.1.1.1??3.1.1.1.2??3.1.1.1.3??3.1.1.1.4??3.1.1.2.1??3.1.1.2.2??3.1.1.2.3??3.1.1.2.4
Table 1-is continuous
3.1.1.3.1??3.1.1.3.2??3.1.1.3.3??3.1.1.3.4??3.1.1.4.1??3.1.1.4.2??3.1.1.4.3??3.1.1.4.4
3.1.1.5.1??3.1.1.5.2??3.1.1.5.3??3.1.1.5.4??3.1.1.6.1??3.1.1.6.2??3.1.1.6.3??3.1.1.6.4
3.1.1.7.1??3.1.1.7.2??3.1.1.7.3??3.1.1.7.4??3.1.1.8.1??3.1.1.8.2??3.1.1.8.3??3.1.1.8.4
3.1.2.1.1??3.1.2.1.2??3.1.2.1.3??3.1.2.1.4??3.1.2.2.1??3.1.2.2.2??3.1.2.2.3??3.1.2.2.4
3.1.2.3.1??3.1.2.3.2??3.1.2.3.3??3.1.2.3.4??3.1.2.4.1??3.1.2.4.2??3.1.2.4.3??3.1.2.4.4
3.1.2.5.1??3.1.2.5.2??3.1.2.5.3??3.1.2.5.4??3.1.2.6.1??3.1.2.6.2??3.1.2.6.3??3.1.2.6.4
3.1.2.7.1??3.1.2.7.2??3.1.2.7.3??3.1.2.7.4??3.1.2.8.1??3.1.2.8.2??3.1.2.8.3??3.1.2.8.4
3.1.3.1.1??3.1.3.1.2??3.1.3.1.3??3.1.3.1.4??3.1.3.2.1??3.1.3.2.2??3.1.3.2.3??3.1.3.2.4
3.1.3.3.1??3.1.3.3.2??3.1.3.3.3??3.1.3.3.4??3.1.3.4.1??3.1.3.4.2??3.1.3.4.3??3.1.3.4.4
3.1.3.5.1??3.1.3.5.2??3.1.3.5.3??3.1.3.5.4??3.1.3.6.1??3.1.3.6.2??3.1.3.6.3??3.1.3.6.4
3.1.3.7.1??3.1.3.7.2??3.1.3.7.3??3.1.3.7.4??3.1.3.8.1??3.1.3.8.2??3.1.3.8.3??3.1.3.8.4
3.1.4.1.1??3.1.4.1.2??3.1.4.1.3??3.1.4.1.4??3.1.4.2.1??3.1.4.2.2??3.1.4.2.3??3.1.4.2.4
3.1.4.3.1??3.1.4.3.2??3.1.4.3.3??3.1.4.3.4??3.1.4.4.1??3.1.4.4.2??3.1.4.4.3??3.1.4.4.4
3.1.4.5.1??3.1.4.5.2??3.1.4.5.3??3.1.4.5.4??3.1.4.6.1??3.1.4.6.2??3.1.4.6.3??3.1.4.6.4
3.1.4.7.1??3.1.4.7.2??3.1.4.7.3??3.1.4.7.4??3.1.4.8.1??3.1.4.8.2??3.1.4.8.3??3.1.4.8.4
3.2.1.1.1??3.2.1.1.2??3.2.1.1.3??3.2.1.1.4??3.2.1.2.1??3.2.1.2.2??3.2.1.2.3??3.2.1.2.4
3.2.1.3.1??3.2.1.3.2??3.2.1.3.3??3.2.1.3.4??3.2.1.4.1??3.2.1.4.2??3.2.1.4.3??3.2.1.4.4
3.2.1.5.1??3.2.1.5.2??3.2.1.5.3??3.2.1.5.4??3.2.1.6.1??3.2.1.6.2??3.2.1.6.3??3.2.1.6.4
3.2.1.7.1??3.2.1.7.2??3.2.1.7.3??3.2.1.7.4??3.2.1.8.1??3.2.1.8.2??3.2.1.8.3??3.2.1.8.4
3.2.2.1.1??3.2.2.1.2??3.2.2.1.3??3.2.2.1.4??3.2.2.2.1??3.2.2.2.2??3.2.2.2.3??3.2.2.2.4
3.2.2.3.1??3.2.2.3.2??3.2.2.3.3??3.2.2.3.4??3.2.2.4.1??3.2.2.4.2??3.2.2.4.3??3.2.2.4.4
3.2.2.5.1??3.2.2.5.2??3.2.2.5.3??3.2.2.5.4??3.2.2.6.1??3.2.2.6.2??3.2.2.6.3??3.2.2.6.4
3.2.2.7.1??3.2.2.7.2??3.2.2.7.3??3.2.2.7.4??3.2.2.8.1??3.2.2.8.2??3.2.2.8.3??3.2.2.8.4
3.2.3.1.1??3.2.3.1.2??3.2.3.1.3??3.2.3.1.4??3.2.3.2.1??3.2.3.2.2??3.2.3.2.3??3.2.3.2.4
3.2.3.3.1??3.2.3.3.2??3.2.3.3.3??3.2.3.3.4??3.2.3.4.1??3.2.3.4.2??3.2.3.4.3??3.2.3.4.4
3.2.3.5.1??3.2.3.5.2??3.2.3.5.3??3.2.3.5.4??3.2.3.6.1??3.2.3.6.2??3.2.3.6.3??3.2.3.6.4
3.2.3.7.1??3.2.3.7.2??3.2.3.7.3??3.2.3.7.4??3.2.3.8.1??3.2.3.8.2??3.2.3.8.3??3.2.3.8.4.
3.2.4.1.1??3.2.4.1.2??3.2.4.1.3??3.2.4.1.4??3.2.4.2.1??3.2.4.2.2??3.2.4.2.3??3.2.4.2.4
3.2.4.3.1??3.2.4.3.2??3.2.4.3.3??3.2.4.3.4??3.2.4.4.1??3.2.4.4.2??3.2.4.4.3??3.2.4.4.4
3.2.4.5.1??3.2.4.5.2??3.2.4.5.3??3.2.4.5.4??3.2.4.6.1??3.2.4.6.2??3.2.4.6.3??3.2.4.6.4
3.2.4.7.1??3.2.4.7.2??3.2.4.7.3??3.2.4.7.4??3.2.4.8.1??3.2.4.8.2??3.2.4.8.3??3.2.4.8.4
3.3.1.1.1??3.3.1.1.2??3.3.1.1.3??3.3.1.1.4??3.3.1.2.1??3.3.1.2.2??3.3.1.2.3??3.3.1.2.4
Table 1-is continuous
3.3.1.3.1??3.3.1.3.2??3.3.1.3.3??3.3.1.3.4??3.3.1.4.1??3.3.1.4.2??3.3.1.4.3??3.3.1.4.4
3.3.1.5.1??3.3.1.5.2??3.3.1.5.3??3.3.1.5.4??3.3.1.6.1??3.3.1.6.2??3.3.1.6.3??3.3.1.6.4
3.3.1.7.1??3.3.1.7.2??3.3.1.7.3??3.3.1.7.4??3.3.1.8.1??3.3.1.8.2??3.3.1.8.3??3.3.1.8.4
3.3.2.1.1??3.3.2.1.2??3.3.2.1.3??3.3.2.1.4??3.3.2.2.1??3.3.2.2.2??3.3.2.2.3??3.3.2.2.4
3.3.2.3.1??3.3.2.3.2??3.3.2.3.3??3.3.2.3.4??3.3.2.4.1??3.3.2.4.2??3.3.2.4.3??3.3.2.4.4
3.3.2.5.1??3.3.2.5.2??3.3.2.5.3??3.3.2.5.4??3.3.2.6.1??3.3.2.6.2??3.3.2.6.3??3.3.2.6.4
3.3.2.7.1??3.3.2.7.2??3.3.2.7.3??3.3.2.7.4??3.3.2.8.1??3.3.2.8.2??3.3.2.8.3??3.3.2.8.4
3.3.3.1.1??3.3.3.1.2??3.3.3.1.3??3.3.3.1.4??3.3.3.2.1??3.3.3.2.2??3.3.3.2.3??3.3.3.2.4
3.3.3.3.1??3.3.3.3.2??3.3.3.3.3??3.3.3.3.4??3.3.3.4.1??3.3.3.4.2??3.3.3.4.3??3.3.3.4.4
3.3.3.5.1??3.3.3.5.2??3.3.3.5.3??3.3.3.5.4??3.3.3.6.1??3.3.3.6.2??3.3.3.6.3??3.3.3.6.4
3.3.3.7.1??3.3.3.7.2??3.3.3.7.3??3.3.3.7.4??3.3.3.8.1??3.3.3.8.2??3.3.3.8.3??3.3.3.8.4
3.3.4.1.1??3.3.4.1.2??3.3.4.1.3??3.3.4.1.4??3.3.4.2.1??3.3.4.2.2??3.3.4.2.3??3.3.4.2.4
3.3.4.3.1??3.3.4.3.2??3.3.4.3.3??3.3.4.3.4??3.3.4.4.1??3.3.4.4.2??3.3.4.4.3??3.3.4.4.4
3.3.4.5.1??3.3.4.5.2??3.3.4.5.3??3.3.4.5.4??3.3.4.6.1??3.3.4.6.2??3.3.4.6.3??3.3.4.6.4
3.3.4.7.1??3.3.4.7.2??3.3.4.7.3??3.3.4.7.4??3.3.4.8.1??3.3.4.8.2??3.3.4.8.3??3.3.4.8.4
3.4.1.1.1??3.4.1.1.2??3.4.1.1.3??3.4.1.1.4??3.4.1.2.1??3.4.1.2.2??3.4.1.2.3??3.4.1.2.4
3.4.1.3.1??3.4.1.3.2??3.4.1.3.3??3.4.1.3.4??3.4.1.4.1??3.4.1.4.2??3.4.1.4.3??3.4.1.4.4
3.4.1.5.1??3.4.1.5.2??3.4.1.5.3??3.4.1.5.4??3.4.1.6.1??3.4.1.6.2??3.4.1.6.3??3.4.1.6.4
3.4.1.7.1??3.4.1.7.2??3.4.1.7.3??3.4.1.7.4??3.4.1.8.1??3.4.1.8.2??3.4.1.8.3??3.4.1.8.4
3.4.2.1.1??3.4.2.1.2??3.4.2.1.3??3.4.2.1.4??3.4.2.2.1??3.4.2.2.2??3.4.2.2.3??3.4.2.2.4
3.4.2.3.1??3.4.2.3.2??3.4.2.3.3??3.4.2.3.4??3.4.2.4.1??3.4.2.4.2??3.4.2.4.3??3.4.2.4.4
3.4.2.5.1??3.4.2.5.2??3.4.2.5.3??3.4.2.5.4??3.4.2.6.1??3.4.2.6.2??3.4.2.6.3??3.4.2.6.4
3.4.2.7.1??3.4.2.7.2??3.4.2.7.3??3.4.2.7.4??3.4.2.8.1??3.4.2.8.2??3.4.2.8.3??3.4.2.8.4
3.4.3.1.1??3.4.3.1.2??3.4.3.1.3??3.4.3.1.4??3.4.3.2.1??3.4.3.2.2??3.4.3.2.3??3.4.3.2.4
3.4.3.3.1??3.4.3.3.2??3.4.3.3.3??3.4.3.3.4??3.4.3.4.1??3.4.3.4.2??3.4.3.4.3??3.4.3.4.4
3.4.3.5.1??3.4.3.5.2??3.4.3.5.3??3.4.3.5.4??3.4.3.6.1??3.4.3.6.2??3.4.3.6.3??3.4.3.6.4
3.4.3.7.1??3.4.3.7.2??3.4.3.7.3??3.4.3.7.4??3.4.3.8.1??3.4.3.8.2??3.4.3.8.3??3.4.3.8.4
3.4.4.1.1??3.4.4.1.2??3.4.4.1.3??3.4.4.1.4??3.4.4.2.1??3.4.4.2.2??3.4.4.2.3??3.4.4.2.4
3.4.4.3.1??3.4.4.3.2??3.4.4.3.3??3.4.4.3.4??3.4.4.4.1??3.4.4.4.2??3.4.4.4.3??3.4.4.4.4
3.4.4.5.1??3.4.4.5.2??3.4.4.5.3??3.4.4.5.4??3.4.4.6.1??3.4.4.6.2??3.4.4.6.3??3.4.4.6.4
3.4.4.7.1??3.4.4.7.2??3.4.4.7.3??3.4.4.7.4??3.4.4.8.1??3.4.4.8.2??3.4.4.8.3??3.4.4.8.4
3.5.1.1.1??3.5.1.1.2??3.5.1.1.3??3.5.1.1.4??3.5.1.2.1??3.5.1.2.2??3.5.1.2.3??3.5.1.2.4
Table 1-is continuous
3.5.1.3.1??3.5.1.3.2??3.5.1.3.3??3.5.1.3.4??3.5.1.4.1??3.5.1.4.2??3.5.1.4.3??3.5.1.4.4
3.5.1.5.1??3.51..5.2??3.5.1.5.3??3.5.1.5.4??3.5.1.6.1??3.5.1.6.2??3.5.1.6.3??3.5.1.6.4
3.5.1.7.1??3.5.1.7.2??3.5.1.7.3??3.5.1.7.4??3.5.1.8.1??3.5.1.8.2??3.5.1.8.3??3.5.1.8.4
3.5.2.1.1??3.5.2.1.2??3.5.2.1.3??3.5.2.1.4??3.5.2.2.1??3.5.2.2.2??3.5.2.2.3??3.5.2.2.4
3.5.2.3.1??3.5.2.3.2??3.5.2.3.3??3.5.2.3.4??3.5.2.4.1??3.5.2.4.2??3.5.2.4.3??3.5.2.4.4
3.5.2.5.1??3.5.2.5.2??3.5.2.5.3??3.5.2.5.4??3.5.2.6.1??3.5.2.6.2??3.5.2.6.3??3.5.2.6.4
3.5.2.7.1??3.5.2.7.2??3.5.2.7.3??3.5.2.7.4??3.5.2.8.1??3.5.2.8.2??3.5.2.8.3??3.5.2.8.4
3.5.3.1.1??3.5.3.1.2??3.5.3.1.3??3.5.3.1.4??3.5.3.2.1??3.5.3.2.2??3.5.3.2.3??3.5.3.2.4
3.5.3.3.1??3.5.3.3.2??3.5.3.3.3??3.5.3.3.4??3.5.3.4.1??3.5.3.4.2??3.5.3.4.3??3.5.3.4.4
3.5.3.5.1??3.5.3.5.2??3.5.3.5.3??3.5.3.5.4??3.5.3.6.1??3.5.3.6.2??3.5.3.6.3??3.5.3.6.4
3.5.3.7.1??3.5.3.7.2??3.5.3.7.3??3.5.3.7.4??3.5.3.8.1??3.5.3.8.2??3.5.3.8.3??3.5.3.8.4
3.5.4.1.1??3.5.4.1.2??3.5.4.1.3??3.5.4.1.4??3.5.4.2.1??3.5.4.2.2??3.5.4.2.3??3.5.4.2.4
3.5.4.3.1??3.5.4.3.2??3.5.4.3.3??3.5.4.3.4??3.5.4.4.1??3.5.4.4.2??3.5.4.4.3??3.5.4.4.4
3.5.4.5.1??3.5.4.5.2??3.5.4.5.3??3.5.4.5.4??3.5.4.6.1??3.5.4.6.2??3.5.4.6.3??3.5.4.6.4
3.5.4.7.1??3.5.4.7.2??3.5.4.7.3??3.5.4.7.4??3.5.4.8.1??3.5.4.8.2??3.5.4.8.3??3.5.4.8.4
3.6.1.1.1??3.6.1.1.2??3.6.1.1.3??3.6.1.1.4??3.6.1.2.1??3.6.1.2.2??3.6.1.2.3??3.6.1.2.4
3.6.1.3.1??3.6.1.3.2??3.6.1.3.3??3.6.1.3.4??3.6.1.4.1??3.6.1.4.2??3.6.1.4.3??3.6.1.4.4
3.6.1.5.1??3.6.1.5.2??3.6.1.5.3??3.6.1.5.4??3.6.1.6.1??3.6.1.6.2??3.6.1.6.3??3.6.1.6.4
3.6.1.7.1??3.6.1.7.2??3.6.1.7.3??3.6.1.7.4??3.6.1.8.1??3.6.1.8.2??3.6.1.8.3??3.6.1.8.4
3.6.2.1.1??3.6.2.1.2??3.6.2.1.3??3.6.2.1.4??3.6.2.2.1??3.6.2.2.2??3.6.2.2.3??3.6.2.2.4
3.6.2.3.1??3.6.2.3.2??3.6.2.3.3??3.6.2.3.4??3.6.2.4.1??3.6.2.4.2??3.6.2.4.3??3.6.2.4.4
3.6.2.5.1??3.6.2.5.2??3.6.2.5.3??3.6.2.5.4??3.6.2.6.1??3.6.2.6.2??3.6.2.6.3??3.6.2.6.4
3.6.2.7.1??3.6.2.7.2??3.6.2.7.3??3.6.2.7.4??3.6.2.8.1??3.6.2.8.2??3.6.2.8.3??3.6.2.8.4
3.6.3.1.1??3.6.3.1.2??3.6.3.1.3??3.6.3.1.4??3.6.3.2.1??3.6.3.2.2??3.6.3.2.3??3.6.3.2.4
3.6.3.3.1??3.6.3.3.2??3.6.3.3.3??3.6.3.3.4??3.6.3.4.1??3.6.3.4.2??3.6.3.4.3??3.6.3.4.4
3.6.3.5.1??3.6.3.5.2??3.6.3.5.3??3.6.3.5.4??3.6.3.6.1??3.6.3.6.2??3.6.3.6.3??3.6.3.6.4
3.6.3.7.1??3.6.3.7.2??3.6.3.7.3??3.6.3.7.4??3.6.3.8.1??3.6.3.8.2??3.6.3.8.3??3.6.3.8.4
3.6.4.1.1??3.6.4.1.2??3.6.4.1.3??3.6.4.1.4??3.6.4.2.1??3.6.4.2.2??3.6.4.2.3??3.6.4.2.4
3.6.4.3.1??3.6.4.3.2??3.6.4.3.3??3.6.4.3.4??3.6.4.4.1??3.6.4.4.2??3.6.4.4.3??3.6.4.4.4
3.6.4.5.1??3.6.4.5.2??3.6.4.5.3??3.6.4.5.4??3.6.4.6.1??3.6.4.6.2??3.6.4.6.3??3.6.4.6.4
3.6.4.7.1??3.6.4.7.2??3.6.4.7.3??3.6.4.7.4??3.6.4.8.1??3.6.4.8.2??3.6.4.8.3??3.6.4.8.4
3.7.1.1.1??3.7.1.1.2??3.7.1.1.3??3.7.1.1.4??3.7.1.2.1??3.7.1.2.2??3.7.1.2.3??3.7.1.2.4
Table 1-is continuous
3.7.1.3.1??3.7.1.3.2??3.7.1.3.3??3.7.1.3.4??3.7.1.4.1??3.7.1.4.2??3.7.1.4.3??3.7.1.4.4
3.7.1.5.1??3.7.1.5.2??3.7.1.5.3??3.7.1.5.4??3.7.1.6.1??3.7.1.6.2??3.7.1.6.3??3.7.1.6.4
3.7.1.7.1??3.7.1.7.2??3.7.1.7.3??3.7.1.7.4??3.7.1.8.1??3.7.1.8.2??3.7.1.8.3??3.7.1.8.4
3.7.2.1.1??3.7.2.1.2??3.7.2.1.3??3.7.2.1.4??3.7.2.2.1??3.7.2.2.2??3.7.2.2.3??3.7.2.2.4
3.7.2.3.1??3.7.2.3.2??3.7.2.3.3??3.7.2.3.4??3.7.2.4.1??3.7.2.4.2??3.7.2.4.3??3.7.2.4.4
3.7.2.5.1??3.7.2.5.2??3.7.2.5.3??3.7.2.5.4??3.7.2.6.1??3.7.2.6.2??3.7.2.6.3??3.7.2.6.4
3.7.2.7.1??3.7.2.7.2??3.7.2.7.3??3.7.2.7.4??3.7.2.8.1??3.7.2.8.2??3.7.2.8.3??3.7.3.8.4
3.7.3.1.1??3.7.3.1.2??3.7.3.1.3??3.7.3.1.4??3.7.3.2.1??3.7.3.2.2??3.7.3.2.3??3.7.3.2.4
3.7.3.3.1??3.7.3.3.2??3.7.3.3.3??3.7.3.3.4??3.7.3.4.1??3.7.3.4.2??3.7.3.4.3??3.7.3.4.4
3.7.3.5.1??3.7.3.5.2??3.7.3.5.3??3.7.3.5.4??3.7.3.6.1??3.7.3.6.2??3.7.3.6.3??3.7.3.6.4
3.7.3.7.1??3.7.3.7.2??3.7.3.7.3??3.7.3.7.4??3.7.3.8.1??3.7.3.8.2??3.7.3.8.3??3.7.3.8.4
3.7.4.1.1??3.7.4.1.2??3.7.4.1.3??3.7.4.1.4??3.7.4.2.1??3.7.4.2.2??3.7.4.2.3??3.7.4.2.4
3.7.4.3.1??3.7.4.3.2??3.7.4.3.3??3.7.4.3.4??3.7.4.4.1??3.7.4.4.2??3.7.4.4.3??3.7.4.4.4
3.7.4.5.1??3.7.4.5.2??3.7.4.5.3??3.7.4.5.4??3.7.4.6.1??3.7.4.6.2??3.7.4.6.3??3.7.4.6.4
3.7.4.7.1??3.7.4.7.2??3.7.4.7.3??3.7.4.7.4??3.7.4.8.1??3.7.4.8.2??3.7.4.8.3??3.7.4.8.4
3.8.1.1.1??3.8.1.1.2??3.8.1.1.3??3.8.1.1.4??3.8.1.2.1??3.8.1.2.2??3.8.1.2.3??3.8.1.2.4
3.8.1.3.1??3.8.1.3.2??3.8.1.3.3??3.8.1.3.4??3.8.1.4.1??3.8.1.4.2??3.8.1.4.3??3.8.1.4.4
3.8.1.5.1??3.8.1.5.2??3.8.1.5.3??3.8.1.5.4??3.8.1.6.1??3.8.1.6.2??3.8.1.6.3??3.8.1.6.4
3.8.1.7.1??3.8.1.7.2??3.8.1.7.3??3.8.1.7.4??3.8.1.8.1??3.8.1.8.2??3.8.1.8.3??3.8.1.8.4
3.8.2.1.1??3.8.2.1.2??3.8.2.1.3??3.8.2.1.4??3.8.2.2.1??3.8.2.2.2??3.8.2.2.3??3.8.2.2.4
3.8.2.3.1??3.8.2.3.2??3.8.2.3.3??3.8.2.3.4??3.8.2.4.1??3.8.2.4.2??3.8.2.4.3??3.8.2.4.4
3.8.2.5.1??3.8.2.5.2??3.8.2.5.3??3.8.2.5.4??3.8.2.6.1??3.8.2.6.2??3.8.2.6.3??3.8.2.6.4
3.8.2.7.1??3.8.2.7.2??3.8.2.7.3??3.8.2.7.4??3.8.2.8.1??3.8.2.8.2??3.8.2.8.3??3.8.2.8.4
3.8.3.1.1??3.8.3.1.2??3.8.3.1.3??3.8.3.1.4??3.8.3.2.1??3.8.3.2.2??3.8.3.2.3??3.8.3.2.4
3.8.3.3.1??3.8.3.3.2??3.8.3.3.3??3.8.3.3.4??3.8.3.4.1??3.8.3.4.2??3.8.3.4.3??3.8.3.4.4
3.8.3.5.1??3.8.3.5.2??3.8.3.5.3??3.8.3.5.4??3.8.3.6.1??3.8.3.6.2??3.8.3.6.3??3.8.3.6.4
3.8.3.7.1??3.8.3.7.2??3.8.3.7.3??3.8.3.7.4??3.8.3.8.1??3.8.3.8.2??3.8.3.8.3??3.8.3.8.4
3.8.4.1.1??3.8.4.1.2??3.8.4.1.3??3.8.4.1.4??3.8.4.2.1??3.8.4.2.2??3.8.4.2.3??3.8.4.2.4
3.8.4.3.1??3.8.4.3.2??3.8.4.3.3??3.8.4.3.4??3.8.4.4.1??3.8.4.4.2??3.8.4.4.3??3.8.4.4.4
3.8.4.5.1??3.8.4.5.2??3.8.4.5.3??3.8.4.5.4??3.8.4.6.1??3.8.4.6.2??3.8.4.6.3??3.8.4.6.4
3.8.4.7.1??3.8.4.7.2??3.8.4.7.3??3.8.4.7.4??3.8.4.8.1??3.8.4.8.2??3.8.4.8.3??3.8.4.8.4
4.1.1.1.1??4.1.1.1.2??4.1.1.1.3??4.1.1.1.4??4.1.1.2.1??4.1.1.2.2??4.1.1.2.3??4.1.1.2.4
Table 1-is continuous
4.1.1.3.1??4.1.1.3.2??4.1.1.3.3??4.1.1.3.4??4.1.1.4.1??4.1.1.4.2??4.1.1.4.3??4.1.1.4.4
4.1.1.5.1??4.1.1.5.2??4.1.1.5.3??4.1.1.5.4??4.1.1.6.1??4.1.1.6.2??4.1.1.6.3??4.1.1.6.4
4.1.1.7.1??4.1.1.7.2??4.1.1.7.3??4.1.1.7.4??4.1.1.8.1??4.1.1.8.2??4.1.1.8.3??4.1.1.8.4
4.1.2.1.1??4.1.2.1.2??4.1.2.1.3??4.1.2.1.4??4.1.2.2.1??4.1.2.2.2??4.1.2.2.3??4.1.2.2.4
4.1.2.3.1??4.1.2.3.2??4.1.2.3.3??4.1.2.3.4??4.1.2.4.1??4.1.2.4.2??4.1.2.4.3??4.1.2.4.4
4.1.2.5.1??4.1.2.5.2??4.1.2.5.3??4.1.2.5.4??4.1.2.6.1??4.1.2.6.2??4.1.2.6.3??4.1.2.6.4
4.1.2.7.1??4.1.2.7.2??4.1.2.7.3??4.1.2.7.4??4.1.2.8.1??4.1.2.8.2??4.1.2.8.3??4.1.2.8.4
4.1.3.1.1??4.1.3.1.2??4.1.3.1.3??4.1.3.1.4??4.1.3.2.1??4.1.3.2.2??4.1.3.2.3??4.1.3.2.4
4.1.3.3.1??4.1.3.3.2??4.1.3.3.3??4.1.3.3.4??4.1.3.4.1??4.1.3.4.2??4.1.3.4.3??4.1.3.4.4
4.1.3.5.1??4.1.3.5.2??4.1.3.5.3??4.1.3.5.4??4.1.3.6.1??4.1.3.6.2??4.1.3.6.3??4.1.3.6.4
4.1.3.7.1??4.1.3.7.2??4.1.3.7.3??4.1.3.7.4??4.1.3.8.1??4.1.3.8.2??4.1.3.8.3??4.1.3.8.4
4.1.4.1.1??4.1.4.1.2??4.1.4.1.3??4.1.4.1.4??4.1.4.2.1??4.1.4.2.2??4.1.4.2.3??4.1.4.2.4
4.1.4.3.1??4.1.4.3.2??4.1.4.3.3??4.1.4.3.4??4.1.4.4.1??4.1.4.4.2??4.1.4.4.3??4.1.4.4.4
4.1.4.5.1??4.1.4.5.2??4.1.4.5.3??4.1.4.5.4??4.1.4.6.1??4.1.4.6.2??4.1.4.6.3??4.1.4.6.4
4.1.4.7.1??4.1.4.7.2??4.1.4.7.3??4.1.4.7.4??4.1.4.8.1??4.1.4.8.2??4.1.4.8.3??4.1.4.8.4
4.2.1.1.1??4.2.1.1.2??4.2.1.1.3??4.2.1.1.4??4.2.1.2.1??4.2.1.2.2??4.2.1.2.3??4.2.1.2.4
4.2.1.3.1??4.2.1.3.2??4.2.1.3.3??4.2.1.3.4??4.2.1.4.1??4.2.1.4.2??4.2.1.4.3??4.2.1.4.4
4.2.1.5.1??4.2.1.5.2??4.2.1.5.3??4.2.1.5.4??4.2.1.6.1??4.2.1.6.2??4.2.1.6.3??4.2.1.6.4
4.2.1.7.1??4.2.1.7.2??4.2.1.7.3??4.2.1.7.4??4.2.1.8.1??4.2.1.8.2??4.2.1.8.3??4.2.1.8.4
4.2.2.1.1??4.2.2.1.2??4.2.2.1.3??4.2.2.1.4??4.2.2.2.1??4.2.2.2.2??4.2.2.2.3??4.2.2.2.4
4.2.2.3.1??4.2.2.3.2??4.2.2.3.3??4.2.2.3.4??4.2.2.4.1??4.2.2.4.2??4.2.2.4.3??4.2.2.4.4
4.2.2.5.1??4.2.2.5.2??4.2.2.5.3??4.2.2.5.4??4.2.2.6.1??4.2.2.6.2??4.2.2.6.3??4.2.2.6.4
4.2.2.7.1??4.2.2.7.2??4.2.2.7.3??4.2.2.7.4??4.2.2.8.1??4.2.2.8.2??4.2.2.8.3??4.2.2.8.4
4.2.3.1.1??4.2.3.1.2??4.2.3.1.3??4.2.3.1.4??4.2.3.2.1??4.2.3.2.2??4.2.3.2.3??4.2.3.2.4
4.2.3.3.1??4.2.3.3.2??4.2.3.3.3??4.2.3.3.4??4.2.3.4.1??4.2.3.4.2??4.2.3.4.3??4.2.3.4.4
4.2.3.5.1??4.2.3.5.2??4.2.3.5.3??4.2.3.5.4??4.2.3.6.1??4.2.3.6.2??4.2.3.6.3??4.2.3.6.4
4.2.3.7.1??4.2.3.7.2??4.2.3.7.3??4.2.3.7.4??4.2.3.8.1??4.2.3.8.2??4.2.3.8.3??4.2.3.8.4
4.2.4.1.1??4.2.4.1.2??4.2.4.1.3??4.2.4.1.4??4.2.4.2.1??4.2.4.2.2??4.2.4.2.3??4.2.4.2.4
4.2.4.3.1??4.2.4.3.2??4.2.4.3.3??4.2.4.3.4??4.2.4.4.1??4.2.4.4.2??4.2.4.4.3??4.2.4.4.4
4.2.4.5.1??4.2.4.5.2??4.2.4.5.3??4.2.4.5.4??4.2.4.6.1??4.2.4.6.2??4.2.4.6.3??4.2.4.6.4
4.2.4.7.1??4.2.4.7.2??4.2.4.7.3??4.2.4.7.4??4.2.4.8.1??4.2.4.8.2??4.2.4.8.3??4.2.4.8.4
4.3.1.1.1??4.3.1.1.2??4.3.1.1.3??4.3.1.1.4??4.3.1.2.1??4.3.1.2.2??4.3.1.2.3??4.3.1.2.4
Table 1-is continuous
4.3.1.3.1??4.3.1.3.2??4.3.1.3.3??4.3.1.3.4??4.3.1.4.1??4.3.1.4.2??4.3.1.4.3??4.3.1.4.4
4.3.1.5.1??4.3.1.5.2??4.3.1.5.3??4.3.1.5.4??4.3.1.6.1??4.3.1.6.2??4.3.1.6.3??4.3.1.6.4
4.3.1.7.1??4.3.1.7.2??4.3.1.7.3??4.3.1.7.4??4.3.1.8.1??4.3.1.8.2??4.3.1.8.3??4.3.1.8.4
4.3.2.1.1??4.3.2.1.2??4.3.2.1.3??4.3.2.1.4??4.3.2.2.1??4.3.2.2.2??4.3.2.2.3??4.3.2.2.4
4.3.2.3.1??4.3.2.3.2??4.3.2.3.3??4.3.2.3.4??4.3.2.4.1??4.3.2.4.2??4.3.2.4.3??4.3.2.4.4
4.3.2.5.1??4.3.2.5.2??4.3.2.5.3??4.3.2.5.4??4.3.2.6.1??4.3.2.6.2??4.3.2.6.3??4.3.2.6.4
4.3.2.7.1??4.3.2.7.2??4.3.2.7.3??4.3.2.7.4??4.3.2.8.1??4.3.2.8.2??4.3.2.8.3??4.3.2.8.4
4.3.3.1.1??4.3.3.1.2??4.3.3.1.3??4.3.3.1.4??4.3.3.2.1??4.3.3.2.2??4.3.3.2.3??4.3.3.2.4
4.3.3.3.1??4.3.3.3.2??4.3.3.3.3??4.3.3.3.4??4.3.3.4.1??4.3.3.4.2??4.3.3.4.3??4.3.3.4.4
4.3.3.5.1??4.3.3.5.2??4.3.3.5.3??4.3.3.5.4??4.3.3.6.1??4.3.3.6.2??4.3.3.6.3??4.3.3.6.4
4.3.3.7.1??4.3.3.7.2??4.3.3.7.3??4.3.3.7.4??4.3.3.8.1??4.3.3.8.2??4.3.3.8.3??4.3.3.8.4
4.3.4.1.1??4.3.4.1.2??4.3.4.1.3??4.3.4.1.4??4.3.4.2.1??4.3.4.2.2??4.3.4.2.3??4.3.4.2.4
4.3.4.3.1??4.3.4.3.2??4.3.4.3.3??4.3.4.3.4??4.3.4.4.1??4.3.4.4.2??4.3.4.4.3??4.3.4.4.4
4.3.4.5.1??4.3.4.5.2??4.3.4.5.3??4.3.4.5.4??4.3.4.6.1??4.3.4.6.2??4.3.4.6.3??4.3.4.6.4
4.3.4.7.1??4.3.4.7.2??4.3.4.7.3??4.3.4.7.4??4.3.4.8.1??4.3.4.8.2??4.3.4.8.3??4.3.4.8.4
4.4.1.1.1??4.4.1.1.2??4.4.1.1.3??4.4.1.1.4??4.4.1.2.1??4.4.1.2.2??4.4.1.2.3??4.4.1.2.4
4.4.1.3.1??4.4.1.3.2??4.4.1.3.3??4.4.1.3.4??4.4.1.4.1??4.4.1.4.2??4.4.1.4.3??4.4.1.4.4
4.4.1.5.1??4.4.1.5.2??4.4.1.5.3??4.4.1.5.4??4.4.1.6.1??4.4.1.6.2??4.4.1.6.3??4.4.1.6.4
4.4.1.7.1??4.4.1.7.2??4.4.1.7.3??4.4.1.7.4??4.4.1.8.1??4.4.1.8.2??4.4.1.8.3??4.4.1.8.4
4.4.2.1.1??4.4.2.1.2??4.4.2.1.3??4.4.2.1.4??4.4.2.2.1??4.4.2.2.2??4.4.2.2.3??4.4.2.2.4
4.4.2.3.1??4.4.2.3.2??4.4.2.3.3??4.4.2.3.4??4.4.2.4.1??4.4.2.4.2??4.4.2.4.3??4.4.2.4.4
4.4.2.5.1??4.4.2.5.2??4.4.2.5.3??4.4.2.5.4??4.4.2.6.1??4.4.2.6.2??4.4.2.6.3??4.4.2.6.4
4.4.2.7.1??4.4.2.7.2??4.4.2.7.3??4.4.2.7.4??4.4.2.8.1??4.4.2.8.2??4.4.2.8.3??4.4.2.8.4
4.4.3.1.1??4.4.3.1.2??4.4.3.1.3??4.4.3.1.4??4.4.3.2.1??4.4.3.2.2??4.4.3.2.3??4.4.3.2.4
4.4.3.3.1??4.4.3.3.2??4.4.3.3.3??4.4.3.3.4??4.4.3.4.1??4.4.3.4.2??4.4.3.4.3??4.4.3.4.4
4.4.3.5.1??4.4.3.5.2??4.4.3.5.3??4.4.3.5.4??4.4.3.6.1??4.4.3.6.2??4.4.3.6.3??4.4.3.6.4
4.4.3.7.1??4.4.3.7.2??4.4.3.7.3??4.4.3.7.4??4.4.3.8.1??4.4.3.8.2??4.4.3.8.3??4.4.3.8.4
4.4.4.1.1??4.4.4.1.2??4.4.4.1.3??4.4.4.1.4??4.4.4.2.1??4.4.4.2.2??4.4.4.2.3??4.4.4.2.4
4.4.4.3.1??4.4.4.3.2??4.4.4.3.3??4.4.4.3.4??4.4.4.4.1??4.4.4.4.2??4.4.4.4.3??4.4.4.4.4
4.4.4.5.1??4.4.4.5.2??4.4.4.5.3??4.4.4.5.4??4.4.4.6.1??4.4.4.6.2??4.4.4.6.3??4.4.4.6.4
4.4.4.7.1??4.4.4.7.2??4.4.4.7.3??4.4.4.7.4??4.4.4.8.1??4.4.4.8.2??4.4.4.8.3??4.4.4.8.4
4.5.1.1.1??4.5.1.1.2??4.5.1.1.3??4.5.1.1.4??4.5.1.2.1??4.5.1.2.2??4.5.1.2.3??4.5.1.2.4
Table 1-is continuous
4.5.1.3.1??4.5.1.3.2??4.5.1.3.3??4.5.1.3.4??4.5.1.4.1??4.5.1.4.2??4.5.1.4.3??4.5.1.4.4
4.5.1.5.1??4.5.1.5.2??4.5.1.5.3??4.5.1.5.4??4.5.1.6.1??4.5.1.6.2??4.5.1.6.3??4.5.1.6.4
4.5.1.7.1??4.5.1.7.2??4.5.1.7.3??4.5.1.7.4??4.5.1.8.1??4.5.1.8.2??4.5.1.8.3??4.5.1.8.4
4.5.2.1.1??4.5.2.1.2??4.5.2.1.3??4.5.2.1.4??4.5.2.2.1??4.5.2.2.2??4.5.2.2.3??4.5.2.2.4
4.5.2.3.1??4.5.2.3.2??4.5.2.3.3??4.5.2.3.4??4.5.2.4.1??4.5.2.4.2??4.5.2.4.3??4.5.2.4.4
4.5.2.5.1??4.5.2.5.2??4.5.2.5.3??4.5.2.5.4??4.5.2.6.1??4.5.2.6.2??4.5.2.6.3??4.5.2.6.4
4.5.2.7.1??4.5.2.7.2??4.5.2.7.3??4.5.2.7.4??4.5.2.8.1??4.5.2.8.2??4.5.2.8.3??4.5.2.8.4
4.5.3.1.1??4.5.3.1.2??4.5.3.1.3??4.5.3.1.4??4.5.3.2.1??4.5.3.2.2??4.5.3.2.3??4.5.3.2.4
4.5.3.3.1??4.5.3.3.2??4.5.3.3.3??4.5.3.3.4??4.5.3.4.1??4.5.3.4.2??4.5.3.4.3??4.5.3.4.4
4.5.3.5.1??4.5.3.5.2??4.5.3.5.3??4.5.3.5.4??4.5.3.6.1??4.5.3.6.2??4.5.3.6.3??4.5.3.6.4
4.5.3.7.1??4.5.3.7.2??4.5.3.7.3??4.5.3.7.4??4.5.3.8.1??4.5.3.8.2??4.5.3.8.3??4.5.3.8.4
4.5.4.1.1??4.5.4.1.2??4.5.4.1.3??4.5.4.1.4??4.5.4.2.1??4.5.4.2.2??4.5.4.2.3??4.5.4.2.4
4.5.4.3.1??4.5.4.3.2??4.5.4.3.3??4.5.4.3.4??4.5.4.4.1??4.5.4.4.2??4.5.4.4.3??4.5.4.4.4
4.5.4.5.1??4.5.4.5.2??4.5.4.5.3??4.5.4.5.4??4.5.4.6.1??4.5.4.6.2??4.5.4.6.3??4.5.4.6.4
4.5.4.7.1??4.5.4.7.2??4.5.4.7.3??4.5.4.7.4??4.5.4.8.1??4.5.4.8.2??4.5.4.8.3??4.5.4.8.4
4.6.1.1.1??4.6.1.1.2??4.6.1.1.3??4.6.1.1.4??4.6.1.2.1??4.6.1.2.2??4.6.1.2.3??4.6.1.2.4
4.6.1.3.1??4.6.1.3.2??4.6.1.3.3??4.6.1.3.4??4.6.1.4.1??4.6.1.4.2??4.6.1.4.3??4.6.1.4.4
4.6.1.5.1??4.6.1.5.2??4.6.1.5.3??4.6.1.5.4??4.6.1.6.1??4.6.1.6.2??4.6.1.6.3??4.6.1.6.4
4.6.1.7.1??4.6.1.7.2??4.6.1.7.3??4.6.1.7.4??4.6.1.8.1??4.6.1.8.2??4.6.1.8.3??4.6.1.8.4
4.6.2.1.1??4.6.2.1.2??4.6.2.1.3??4.6.2.1.4??4.6.2.2.1??4.6.2.2.2??4.6.2.2.3??4.6.2.2.4
4.6.2.3.1??4.6.2.3.2??4.6.2.3.3??4.6.2.3.4??4.6.2.4.1??4.6.2.4.2??4.6.2.4.3??4.6.2.4.4
4.6.2.5.1??4.6.2.5.2??4.6.2.5.3??4.6.2.5.4??4.6.2.6.1??4.6.2.6.2??4.6.2.6.3??4.6.2.6.4
4.6.2.7.1??4.6.2.7.2??4.6.2.7.3??4.6.2.7.4??4.6.2.8.1??4.6.2.8.2??4.6.2.8.3??4.6.2.8.4
4.6.3.1.1??4.6.3.1.2??4.6.3.1.3??4.6.3.1.4??4.6.3.2.1??4.6.3.2.2??4.6.3.2.3??4.6.3.2.4
4.6.3.3.1??4.6.3.3.2??4.6.3.3.3??4.6.3.3.4??4.6.3.4.1??4.6.3.4.2??4.6.3.4.3??4.6.3.4.4
4.6.3.5.1??4.6.3.5.2??4.6.3.5.3??4.6.3.5.4??4.6.3.6.1??4.6.3.6.2??4.6.3.6.3??4.6.3.6.4
4.6.3.7.1??4.6.3.7.2??4.6.3.7.3??4.6.3.7.4??4.6.3.8.1??4.6.3.8.2??4.6.3.8.3??4.6.3.8.4
4.6.4.1.1??4.6.4.1.2??4.6.4.1.3??4.6.4.1.4??4.6.4.2.1??4.6.4.2.2??4.6.4.2.3??4.6.4.2.4
4.6.4.3.1??4.6.4.3.2??4.6.4.3.3??4.6.4.3.4??4.6.4.4.1??4.6.4.4.2??4.6.4.4.3??4.6.4.4.4
4.6.4.5.1??4.6.4.5.2??4.6.4.5.3??4.6.4.5.4??4.6.4.6.1??4.6.4.6.2??4.6.4.6.3??4.6.4.6.4
4.6.4.7.1??4.6.4.7.2??4.6.4.7.3??4.6.4.7.4??4.6.4.8.1??4.6.4.8.2??4.6.4.8.3??4.6.4.8.4
4.7.1.1.1??4.7.1.1.2??4.7.1.1.3??4.7.1.1.4??4.7.1.2.1??4.7.1.2.2??4.7.1.2.3??4.7.1.2.4
Table 1-is continuous
4.7.1.3.1??4.7.1.3.2??4.7.1.3.3??4.7.1.3.4??4.7.1.4.1??4.7.1.4.2??4.7.1.4.3??4.7.1.4.4
4.7.1.5.1??4.7.1.5.2??4.7.1.5.3??4.7.1.5.4??4.7.1.6.1??4.7.1.6.2??4.7.1.6.3??4.7.1.6.4
4.7.1.7.1??4.7.1.7.2??4.7.1.7.3??4.7.1.7.4??4.7.1.8.1??4.7.1.8.2??4.7.1.8.3??4.7.1.8.4
4.7.2.1.1??4.7.2.1.2??4.7.2.1.3??4.7.2.1.4??4.7.2.2.1??4.7.2.2.2??4.7.2.2.3??4.7.2.2.4
4.7.2.3.1??4.7.2.3.2??4.7.2.3.3??4.7.2.3.4??4.7.2.4.1??4.7.2.4.2??4.7.2.4.3??4.7.2.4.4
4.7.2.5.1??4.7.2.5.2??4.7.2.5.3??4.7.2.5.4??4.7.2.6.1??4.7.2.6.2??4.7.2.6.3??4.7.2.6.4
4.7.2.7.1??4.7.2.7.2??4.7.2.7.3??4.7.2.7.4??4.7.2.8.1??4.7.2.8.2??4.7.2.8.3??4.7.2.8.4
4.7.3.1.1??4.7.3.1.2??4.7.3.1.3??4.7.3.1.4??4.7.3.2.1??4.7.3.2.2??4.7.3.2.3??4.7.3.2.4
4.7.3.3.1??4.7.3.3.2??4.7.3.3.3??4.7.3.3.4??4.7.3.4.1??4.7.3.4.2??4.7.3.4.3??4.7.3.4.4
4.7.3.5.1??4.7.3.5.2??4.7.3.5.3??4.7.3.5.4??4.7.3.6.1??4.7.3.6.2??4.7.3.6.3??4.7.3.6.4
4.7.3.7.1??4.7.3.7.2??4.7.3.7.3??4.7.3.7.4??4.7.3.8.1??4.7.3.8.2??4.7.3.8.3??4.7.3.8.4
4.7.4.1.1??4.7.4.1.2??4.7.4.1.3??4.7.4.1.4??4.7.4.2.1??4.7.4.2.2??4.7.4.2.3??4.7.4.2.4
4.7.4.3.1??4.7.4.3.2??4.7.4.3.3??4.7.4.3.4??4.7.4.4.1??4.7.4.4.2??4.7.4.4.3??4.7.4.4.4
4.7.4.5.1??4.7.4.5.2??4.7.4.5.3??4.7.4.5.4??4.7.4.6.1??4.7.4.6.2??4.7.4.6.3??4.7.4.6.4
4.7.4.7.1??4.7.4.7.2??4.7.4.7.3??4.7.4.7.4??4.7.4.8.1??4.7.4.8.2??4.7.4.8.3??4.7.4.8.4
4.8.1.1.1??4.8.1.1.2??4.8.1.1.3??4.8.1.1.4??4.8.1.2.1??4.8.1.2.2??4.8.1.2.3??4.8.1.2.4
4.8.1.3.1??4.8.1.3.2??4.8.1.3.3??4.8.1.3.4??4.8.1.4.1??4.8.1.4.2??4.8.1.4.3??4.8.1.4.4
4.8.1.5.1??4.8.1.5.2??4.8.1.5.3??4.8.1.5.4??4.8.1.6.1??4.8.1.6.2??4.8.1.6.3??4.8.1.6.4
4.8.1.7.1??4.8.1.7.2??4.8.1.7.3??4.8.1.7.4??4.8.1.8.1??4.8.1.8.2??4.8.1.8.3??4.8.1.8.4
4.8.2.1.1??4.8.2.1.2??4.8.2.1.3??4.8.2.1.4??4.8.2.2.1??4.8.2.2.2??4.8.2.2.3??4.8.2.2.4
4.8.2.3.1??4.8.2.3.2??4.8.2.3.3??4.8.2.3.4??4.8.2.4.1??4.8.2.4.2??4.8.2.4.3??4.8.2.4.4
4.8.2.5.1??4.8.2.5.2??4.8.2.5.3??4.8.2.5.4??4.8.2.6.1??4.8.2.6.2??4.8.2.6.3??4.8.2.6.4
4.8.2.7.1??4.8.2.7.2??4.8.2.7.3??4.8.2.7.4??4.8.2.8.1??4.8.2.8.2??4.8.2.8.3??4.8.2.8.4
4.8.3.1.1??4.8.3.1.2??4.8.3.1.3??4.8.3.1.4??4.8.3.2.1??4.8.3.2.2??4.8.3.2.3??4.8.3.2.4
4.8.3.3.1??4.8.3.3.2??4.8.3.3.3??4.8.3.3.4??4.8.3.4.1??4.8.3.4.2??4.8.3.4.3??4.8.3.4.4
4.8.3.5.1??4.8.3.5.2??4.8.3.5.3??4.8.3.5.4??4.8.3.6.1??4.8.3.6.2??4.8.3.6.3??4.8.3.6.4
4.8.3.7.1??4.8.3.7.2??4.8.3.7.3??4.8.3.7.4??4.8.3.8.1??4.8.3.8.2??4.8.3.8.3??4.8.3.8.4
4.8.4.1.1??4.8.4.1.2??4.8.4.1.3??4.8.4.1.4??4.8.4.2.1??4.8.4.2.2??4.8.4.2.3??4.8.4.2.4
4.8.4.3.1??4.8.4.3.2??4.8.4.3.3??4.8.4.3.4??4.8.4.4.1??4.8.4.4.2??4.8.4.4.3??4.8.4.4.4
4.8.4.5.1??4.8.4.5.2??4.8.4.5.3??4.8.4.5.4??4.8.4.6.1??4.8.4.6.2??4.8.4.6.3??4.8.4.6.4
4.8.4.7.1??4.8.4.7.2??4.8.4.7.3??4.8.4.7.4??4.8.4.8.1??4.8.4.8.2??4.8.4.8.3??4.8.4.8.4
5.1.1.1.1??5.1.1.1.2??5.1.1.1.3??5.1.1.1.4??5.1.1.2.1??5.1.1.2.2??5.1.1.2.3??5.1.1.2.4
Table 1-is continuous
5.1.1.3.1??5.1.1.3.2??5.1.1.3.3??5.1.1.3.4??5.1.1.4.1??5.1.1.4.2??5.1.1.4.3??5.1.1.4.4
5.1.1.5.1??5.1.1.5.2??5.1.1.5.3??5.1.1.5.4??5.1.1.6.1??5.1.1.6.2??5.1.1.6.3??5.1.1.6.4
5.1.1.7.1??5.1.1.7.2??5.1.1.7.3??5.1.1.7.4??5.1.1.8.1??5.1.1.8.2??5.1.1.8.3??5.1.1.8.4
5.1.2.1.1??5.1.2.1.2??5.1.2.1.3??5.1.2.1.4??5.1.2.2.1??5.1.2.2.2??5.1.2.2.3??5.1.2.2.4
5.1.2.3.1??5.1.2.3.2??5.1.2.3.3??5.1.2.3.4??5.1.2.4.1??5.1.2.4.2??5.1.2.4.3??5.1.2.4.4
5.1.2.5.1??5.1.2.5.2??5.1.2.5.3??5.1.2.5.4??5.1.2.6.1??5.1.2.6.2??5.1.2.6.3??5.1.2.6.4
5.1.2.7.1??5.1.2.7.2??5.1.2.7.3??5.1.2.7.4??5.1.2.8.1??5.1.2.8.2??5.1.2.8.3??5.1.2.8.4
5.1.3.1.1??5.1.3.1.2??5.1.3.1.3??5.1.3.1.4??5.1.3.2.1??5.1.3.2.2??5.1.3.2.3??5.1.3.2.4
5.1.3.3.1??5.1.3.3.2??5.1.3.3.3??5.1.3.3.4??5.1.3.4.1??5.1.3.4.2??5.1.3.4.3??5.1.3.4.4
5.1.3.5.1??5.1.3.5.2??5.1.3.5.3??5.1.3.5.4??5.1.3.6.1??5.1.3.6.2??5.1.3.6.3??5.1.3.6.4
5.1.3.7.1??5.1.3.7.2??5.1.3.7.3??5.1.3.7.4??5.1.3.8.1??5.1.3.8.2??5.1.3.8.3??5.1.3.8.4
5.1.4.1.1??5.1.4.1.2??5.1.4.1.3??5.1.4.1.4??5.1.4.2.1??5.1.4.2.2??5.1.4.2.3??5.1.4.2.4
5.1.4.3.1??5.1.4.3.2??5.1.4.3.3??5.1.4.3.4??5.1.4.4.1??5.1.4.4.2??5.1.4.4.3??5.1.4.4.4
5.1.4.5.1??5.1.4.5.2??5.1.4.5.3??5.1.4.5.4??5.1.4.6.1??5.1.4.6.2??5.1.4.6.3??5.1.4.6.4
5.1.4.7.1??5.1.4.7.2??5.1.4.7.3??5.1.4.7.4??5.1.4.8.1??5.1.4.8.2??5.1.4.8.3??5.1.4.8.4
5.2.1.1.1??5.2.1.1.2??5.2.1.1.3??5.2.1.1.4??5.2.1.2.1??5.2.1.2.2??5.2.1.2.3??5.2.1.2.4
5.2.1.3.1??5.2.1.3.2??5.2.1.3.3??5.2.1.3.4??5.2.1.4.1??5.2.1.4.2??5.2.1.4.3??5.2.1.4.4
5.2.1.5.1??5.2.1.5.2??5.2.1.5.3??5.2.1.5.4??5.2.1.6.1??5.2.1.6.2??5.2.1.6.3??5.2.1.6.4
5.2.1.7.1??5.2.1.7.2??5.2.1.7.3??5.2.1.7.4??5.2.1.8.1??5.2.1.8.2??5.2.1.8.3??5.2.1.8.4
5.2.2.1.1??5.2.2.1.2??5.2.2.1.3??5.2.2.1.4??5.2.2.2.1??5.2.2.2.2??5.2.2.2.3??5.2.2.2.4
5.2.2.3.1??5.2.2.3.2??5.2.2.3.3??5.2.2.3.4??5.2.2.4.1??5.2.2.4.2??5.2.2.4.3??5.2.2.4.4
5.2.2.5.1??5.2.2.5.2??5.2.2.5.3??5.2.2.5.4??5.2.2.6.1??5.2.2.6.2??5.2.2.6.3??5.2.2.6.4
5.2.2.7.1??5.2.2.7.2??5.2.2.7.3??5.2.2.7.4??5.2.2.8.1??5.2.2.8.2??5.2.2.8.3??5.2.2.8.4
5.2.3.1.1??5.2.3.1.2??5.2.3.1.3??5.2.3.1.4??5.2.3.2.1??5.2.3.2.2??5.2.3.2.3??5.2.3.2.4
5.2.3.3.1??5.2.3.3.2??5.2.3.3.3??5.2.3.3.4??5.2.3.4.1??5.2.3.4.2??5.2.3.4.3??5.2.3.4.4
5.2.3.5.1??5.2.3.5.2??5.2.3.5.3??5.2.3.5.4??5.2.3.6.1??5.2.3.6.2??5.2.3.6.3??5.2.3.6.4
5.2.3.7.1??5.2.3.7.2??5.2.3.7.3??5.2.3.7.4??5.2.3.8.1??5.2.3.8.2??5.2.3.8.3??5.2.3.8.4
5.2.4.1.1??5.2.4.1.2??5.2.4.1.3??5.2.4.1.4??5.2.4.2.1??5.2.4.2.2??5.2.4.2.3??5.2.4.2.4
5.2.4.3.1??5.2.4.3.2??5.2.4.3.3??5.2.4.3.4??5.2.4.4.1??5.2.4.4.2??5.2.4.4.3??5.2.4.4.4
5.2.4.5.1??5.2.4.5.2??5.2.4.5.3??5.2.4.5.4??5.2.4.6.1??5.2.4.6.2??5.2.4.6.3??5.2.4.6.4
5.2.4.7.1??5.2.4.7.2??5.2.4.7.3??5.2.4.7.4??5.2.4.8.1??5.2.4.8.2.?5.2.4.8.3??5.2.4.8.4
5.3.1.1.1??5.3.1.1.2??5.3.1.1.3??5.3.1.1.4??5.3.1.2.1??5.3.1.2.2??5.3.1.2.3??5.3.1.2.4
Table 1-is continuous
5.3.1.3.1??5.3.1.3.2??5.3.1.3.3??5.3.1.3.4??5.3.1.4.1??5.3.1.4.2??5.3.1.4.3??5.3.1.4.4
5.3.1.5.1??5.3.1.5.2??5.3.1.5.3??5.3.1.5.4??5.3.1.6.1??5.3.1.6.2??5.3.1.6.3??5.3.1.6.4
5.3.1.7.1??5.3.1.7.2??5.3.1.7.3??5.3.1.7.4??5.3.1.8.1??5.3.1.8.2??5.3.1.8.3??5.3.1.8.4
5.3.2.1.1??5.3.2.1.2??5.3.2.1.3??5.3.2.1.4??5.3.2.2.1??5.3.2.2.2??5.3.2.2.3??5.3.2.2.4
5.3.2.3.1??5.3.2.3.2??5.3.2.3.3??5.3.2.3.4??5.3.2.4.1??5.3.2.4.2??5.3.2.4.3??5.3.2.4.4
5.3.2.5.1??5.3.2.5.2??5.3.2.5.3??5.3.2.5.4??5.3.2.6.1??5.3.2.6.2??5.3.2.6.3??5.3.2.6.4
5.3.2.7.1??5.3.2.7.2??5.3.2.7.3??5.3.2.7.4??5.3.2.8.1??5.3.2.8.2??5.3.2.8.3??5.3.2.8.4
5.3.3.1.1??5.3.3.1.2??5.3.3.1.3??5.3.3.1.4??5.3.3.2.1??5.3.3.2.2??5.3.3.2.3??5.3.3.2.4
5.3.3.3.1??5.3.3.3.2??5.3.3.3.3??5.3.3.3.4??5.3.3.4.1??5.3.3.4.2??5.3.3.4.3??5.3.3.4.4
5.3.3.5.1??5.3.3.5.2??5.3.3.5.3??5.3.3.5.4??5.3.3.6.1??5.3.3.6.2??5.3.3.6.3??5.3.3.6.4
5.3.3.7.1??5.3.3.7.2??5.3.3.7.3??5.3.3.7.4??5.3.3.8.1??5.3.3.8.2??5.3.3.8.3??5.3.3.8.4
5.3.4.1.1??5.3.4.1.2??5.3.4.1.3??5.3.4.1.4??5.3.4.2.1??5.3.4.2.2??5.3.4.2.3??5.3.4.2.4
5.3.4.3.1??5.3.4.3.2??5.3.4.3.3??5.3.4.3.4??5.3.4.4.1??5.3.4.4.2??5.3.4.4.3??5.3.4.4.4
5.3.4.5.1??5.3.4.5.2??5.3.4.5.3??5.3.4.5.4??5.3.4.6.1??5.3.4.6.2??5.3.4.6.3??5.3.4.6.4
5.3.4.7.1??5.3.4.7.2??5.3.4.7.3??5.3.4.7.4??5.3.4.8.1??5.3.4.8.2??5.3.4.8.3??5.3.4.8.4
5.4.1.1.1??5.4.1.1.2??5.4.1.1.3??5.4.1.1.4??5.4.1.2.1??5.4.1.2.2??5.4.1.2.3??5.4.1.2.4
5.4.1.3.1??5.4.1.3.2??5.4.1.3.3??5.4.1.3.4??5.4.1.4.1??5.4.1.4.2??5.4.1.4.3??5.4.1.4.4
5.4.1.5.1??5.4.1.5.2??5.4.1.5.3??5.4.1.5.4??5.4.1.6.1.?5.4.1.6.2??5.4.1.6.3??5.4.1.6.4
5.4.1.7.1??5.4.1.7.2??5.4.1.7.3??5.4.1.7.4??5.4.1.8.1??5.4.1.8.2??5.4.1.8.3??5.4.1.8.4
5.4.2.1.1??5.4.2.1.2??5.4.2.1.3??5.4.2.1.4??5.4.2.2.1??5.4.2.2.2??5.4.2.2.3??5.4.2.2.4
5.4.2.3.1??5.4.2.3.2??5.4.2.3.3??5.4.2.3.4??5.4.2.4.1??5.4.2.4.2??5.4.2.4.3??5.4.2.4.4
5.4.2.5.1??5.4.2.5.2??5.4.2.5.3??5.4.2.5.4??5.4.2.6.1??5.4.2.6.2??5.4.2.6.3??5.4.2.6.4
5.4.2.7.1??5.4.2.7.2??5.4.2.7.3??5.4.2.7.4??5.4.2.8.1??5.4.2.8.2??5.4.2.8.3??5.4.2.8.4
5.4.3.1.1??5.4.3.1.2??5.4.3.1.3??5.4.3.1.4??5.4.3.2.1??5.4.3.2.2??5.4.3.2.3??5.4.3.2.4
5.4.3.3.1??5.4.3.3.2??5.4.3.3.3??5.4.3.3.4??5.4.3.4.1??5.4.3.4.2??5.4.3.4.3??5.4.3.4.4
5.4.3.5.1??5.4.3.5.2??5.4.3.5.3??5.4.3.5.4??5.4.3.6.1??5.4.3.6.2??5.4.3.6.3??5.4.3.6.4
5.4.3.7.1??5.4.3.7.2??5.4.3.7.3??5.4.3.7.4??5.4.3.3.1??5.4.3.8.2??5.4.3.8.3??5.4.3.8.4
5.4.4.1.1??5.4.4.1.2??5.4.4.1.3??5.4.4.1.4??5.4.4.2.1??5.4.4.2.2??5.4.4.2.3??5.4.4.2.4
5.4.4.3.1??5.4.4.3.2??5.4.4.3.3??5.4.4.3.4??5.4.4.4.1??5.4.4.4.2??5.4.4.4.3??5.4.4.4.4
5.4.4.5.1??5.4.4.5.2??5.4.4.5.3??5.4.4.5.4??5.4.4.6.1??5.4.4.6.2??5.4.4.6.3??5.4.4.6.4
5.4.4.7.1??5.4.4.7.2??5.4.4.7.3??5.4.4.7.4??5.4.4.8.1??5.4.4.8.2??5.4.4.8.3??5.4.4.8.4
5.5.1.1.1??5.5.1.1.2??5.5.1.1.3??5.5.1.1.4??5.5.1.2.1??5.5.1.2.2??5.5.1.2.3??5.5.1.2.4
Table 1-is continuous
5.5.1.3.1??5.5.1.3.2??5.5.1.3.3??5.5.1.3.4??5.5.1.4.1??5.5.1.4.2??5.5.1.4.3??5.5.1.4.4
5.5.1.5.1??5.5.1.5.2??5.5.1.5.3??5.5.1.5.4??5.5.1.6.1??5.5.1.6.2??5.5.1.6.3??5.5.1.6.4
5.5.1.7.1??5.5.1.7.2??5.5.1.7.3??5.5.1.7.4??5.5.1.8.1??5.5.1.8.2??5.5.1.8.3??5.5.1.8.4
5.5.2.1.1??5.5.2.1.2??5.5.2.1.3??5.5.2.1.4??5.5.2.2.1??5.5.2.2.2??5.5.2.2.3??5.5.2.2.4
5.5.2.3.1??5.5.2.3.2??5.5.2.3.3??5.5.2.3.4??5.5.2.4.1??5.5.2.4.2??5.5.2.4.3??5.5.2.4.4
5.5.2.5.1??5.5.2.5.2??5.5.2.5.3??5.5.2.5.4??5.5.2.6.1??5.5.2.6.2??5.5.2.6.3??5.5.2.6.4
5.5.2.7.1??5.5.2.7.2??5.5.2.7.3??5.5.2.7.4??5.5.2.8.1??5.5.2.8.2??5.5.2.8.3??5.5.2.8.4
5.5.3.1.1??5.5.3.1.2??5.5.3.1.3??5.5.3.1.4??5.5.3.2.1??5.5.3.2.2??5.5.3.2.3??5.5.3.2.4
5.5.3.3.1??5.5.3.3.2??5.5.3.3.3??5.5.3.3.4??5.5.3.4.1??5.5.3.4.2??5.5.3.4.3??5.5.3.4.4
5.5.3.5.1??5.5.3.5.2??5.5.3.5.3??5.5.3.5.4??5.5.3.6.1??5.5.3.6.2??5.5.3.6.3??5.5.3.6.4
5.5.3.7.1??5.5.3.7.2??5.5.3.7.3??5.5.3.7.4??5.5.3.8.1??5.5.3.8.2??5.5.3.8.3??5.5.3.8.4
5.5.4.1.1??5.5.4.1.2??5.5.4.1.3??5.5.4.1.4??5.5.4.2.1??5.5.4.2.2??5.5.4.2.3??5.5.4.2.4
5.5.4.3.1??5.5.4.3.2??5.5.4.3.3??5.5.4.3.4??5.5.4.4.1??5.5.4.4.2??5.5.4.4.3??5.5.4.4.4
5.5.4.5.1??5.5.4.5.2??5.5.4.5.3??5.5.4.5.4??5.5.4.6.1??5.5.4.6.2??5.5.4.6.3??5.5.4.6.4
5.5.4.7.1??5.5.4.7.2??5.5.4.7.3??5.5.4.7.4??5.5.4.8.1??5.5.4.8.2??5.5.4.8.3??5.5.4.8.4
5.6.1.1.1??5.6.1.1.2??5.6.1.1.3??5.6.1.1.4??5.6.1.2.1??5.6.1.2.2??5.6.1.2.3??5.6.1.2.4
5.6.1.3.1??5.6.1.3.2??5.6.1.3.3??5.6.1.3.4??5.6.1.4.1??5.6.1.4.2??5.6.1.4.3??5.6.1.4.4
5.6.1.5.1??5.6.1.5.2??5.6.1.5.3??5.6.1.5.4??5.6.1.6.1??5.6.1.6.2??5.6.1.6.3??5.6.1.6.4
5.6.1.7.1??5.6.1.7.2??5.6.1.7.3??5.6.1.7.4??5.6.1.8.1??5.6.1.8.2??5.6.1.8.3??5.6.1.8.4
5.6.2.1.1??5.6.2.1.2??5.6.2.1.3??5.6.2.1.4??5.6.2.2.1??5.6.2.2.2??5.6.2.2.3??5.6.2.2.4
5.6.2.3.1??5.6.2.3.2??5.6.2.3.3??5.6.2.3.4??5.6.2.4.1??5.6.2.4.2??5.6.2.4.3??5.6.2.4.4
5.6.2.5.1??5.6.2.5.2??5.6.2.5.3??5.6.2.5.4??5.6.2.6.1??5.6.2.6.2??5.6.2.6.3??5.6.2.6.4
5.6.2.7.1??5.6.2.7.2??5.6.2.7.3??5.6.2.7.4??5.6.2.8.1??5.6.2.8.2??5.6.2.8.3??5.6.2.8.4
5.6.3.1.1??5.6.3.1.2??5.6.3.1.3??5.6.3.1.4??5.6.3.2.1??5.6.3.2.2??5.6.3.2.3??5.6.3.2.4
5.6.3.3.1??5.6.3.3.2??5.6.3.3.3??5.6.3.3.4??5.6.3.4.1??5.6.3.4.2??5.6.3.4.3??5.6.3.4.4
5.6.3.5.1??5.6.3.5.2??5.6.3.5.3??5.6.3.5.4??5.6.3.6.1??5.6.3.6.2??5.6.3.6.3??5.6.3.6.4
5.6.3.7.1??5.6.3.7.2??5.6.3.7.3??5.6.3.7.4??5.6.3.8.1??5.6.3.8.2??5.6.3.8.3??5.6.3.8.4
5.6.4.1.1??5.6.4.1.2??5.6.4.1.3??5.6.4.1.4??5.6.4.2.1??5.6.4.2.2??5.6.4.2.3??5.6.4.2.4
5.6.4.3.1??5.6.4.3.2??5.6.4.3.3??5.6.4.3.4??5.6.4.4.1??5.6.4.4.2??5.6.4.4.3??5.6.4.4.4
5.6.4.5.1??5.6.4.5.2??5.6.4.5.3??5.6.4.5.4??5.6.4.6.1??5.6.4.6.2??5.6.4.6.3??5.6.4.6.4
5.6.4.7.1??5.6.4.7.2??5.6.4.7.3??5.6.4.7.4??5.6.4.8.1??5.6.4.8.2??5.6.4.8.3??5.6.4.8.4
5.7.1.1.1??5.7.1.1.2??5.7.1.1.3??5.7.1.1.4??5.7.1.2.1??5.7.1.2.2??5.7.1.2.3??5.7.1.2.4
Table 1-is continuous
5.7.1.3.1??5.7.1.3.2??5.7.1.3.3??5.7.1.3.4??5.7.1.4.1??5.7.1.4.2??5.7.1.4.3??5.7.1.4.4
5.7.1.5.1??5.7.1.5.2??5.7.1.5.3??5.7.1.5.4??5.7.1.6.1??5.7.1.6.2??5.7.1.6.3??5.7.1.6.4
5.7.1.7.1??5.7.1.7.2??5.7.1.7.3??5.7.1.7.4??5.7.1.8.1??5.7.1.8.2??5.7.1.8.3??5.7.1.8.4
5.7.2.1.1??5.7.2.1.2??5.7.2.1.3??5.7.2.1.4??5.7.2.2.1??5.7.2.2.2??5.7.2.2.3??5.7.2.2.4
5.7.2.3.1??5.7.2.3.2??5.7.2.3.3??5.7.2.3.4??5.7.2.4.1??5.7.2.4.2??5.7.2.4.3??5.7.2.4.4
5.7.2.5.1??5.7.2.5.2??5.7.2.5.3??5.7.2.5.4??5.7.2.6.1??5.7.2.6.2??5.7.2.6.3??5.7.2.6.4
5.7.2.7.1??5.7.2.7.2??5.7.2.7.3??5.7.2.7.4??5.7.2.8.1??5.7.2.8.2??5.7.2.8.3??5.7.2.8.4
5.7.3.1.1??5.7.3.1.2??5.7.3.1.3??5.7.3.1.4??5.7.3.2.1??5.7.3.2.2??5.7.3.2.3??5.7.3.2.4
5.7.3.3.1??5.7.3.3.2??5.7.3.3.3??5.7.3.3.4??5.7.3.4.1??5.7.3.4.2??5.7.3.4.3??5.7.3.4.4
5.7.3.5.1??5.7.3.5.2??5.7.3.5.3??5.7.3.5.4??5.7.3.6.1??5.7.3.6.2??5.7.3.6.3??5.7.3.6.4
5.7.3.7.1??5.7.3.7.2??5.7.3.7.3??5.7.3.7.4??5.7.3.8.1??5.7.3.8.2??5.7.3.8.3??5.7.3.8.4
5.7.4.1.1??5.7.4.1.2??5.7.4.1.3??5.7.4.1.4??5.7.4.2.1??5.7.4.2.2??5.7.4.2.3??5.7.4.2.4
5.7.4.3.1??5.7.4.3.2??5.7.4.3.3??5.7.4.3.4??5.7.4.4.1??5.7.4.4.2??5.7.4.4.3??5.7.4.4.4
5.7.4.5.1??5.7.4.5.2??5.7.4.5.3??5.7.4.5.4??5.7.4.6.1??5.7.4.6.2??5.7.4.6.3??5.7.4.6.4
5.7.4.7.1??5.7.4.7.2??5.7.4.7.3??5.7.4.7.4??5.7.4.8.1??5.7.4.8.2??5.7.4.8.3??5.7.4.8.4
5.8.1.1.1??5.8.1.1.2??5.8.1.1.3??5.8.1.1.4??5.8.1.2.1??5.8.1.2.2??5.8.1.2.3??5.8.1.2.4
5.8.1.3.1??5.8.1.3.2??5.8.1.3.3??5.8.1.3.4??5.8.1.4.1??5.8.1.4.2??5.8.1.4.3??5.8.1.4.4
5.8.1.5.1??5.8.1.5.2??5.8.1.5.3??5.8.1.5.4??5.8.1.6.1??5.8.1.6.2??5.8.1.6.3??5.8.1.6.4
5.8.1.7.1??5.8.1.7.2??5.8.1.7.3??5.8.1.7.4??5.8.1.8.1??5.8.1.8.2??5.8.1.8.3??5.8.1.8.4
5.8.2.1.1??5.8.2.1.2??5.8.2.1.3??5.8.2.1.4??5.8.2.2.1??5.8.2.2.2??5.8.2.2.3??5.8.2.2.4
5.8.2.3.1??5.8.2.3.2??5.8.2.3.3??5.8.2.3.4??5.8.2.4.1??5.8.2.4.2??5.8.2.4.3??5.8.2.4.4
5.8.2.5.1??5.8.2.5.2??5.8.2.5.3??5.8.2.5.4??5.8.2.6.1??5.8.2.6.2??5.8.2.6.3??5.8.2.6.4
5.8.2.7.1??5.8.2.7.2??5.8.2.7.3??5.8.2.7.4??5.8.2.8.1??5.8.2.8.2??5.8.2.8.3??5.8.2.8.4
5.8.3.1.1??5.8.3.1.2??5.8.3.1.3??5.8.3.1.4??5.8.3.2.1??5.8.3.2.2??5.8.3.2.3??5.8.3.2.4
5.8.3.3.1??5.8.3.3.2??5.8.3.3.3??5.8.3.3.4??5.8.3.4.1??5.8.3.4.2??5.8.3.4.3??5.8.3.4.4
5.8.3.5.1??5.8.3.5.2??5.8.3.5.3??5.8.3.5.4??5.8.3.6.1??5.8.3.6.2??5.8.3.6.3??5.8.3.6.4
5.8.3.7.1??5.8.3.7.2??5.8.3.7.3??5.8.3.7.4??5.8.3.8.1??5.8.3.8.2??5.8.3.8.3??5.8.3.8.4
5.8.4.1.1??5.8.4.1.2??5.8.4.1.3??5.8.4.1.4??5.8.4.2.1??5.8.4.2.2??5.8.4.2.3??5.8.4.2.4
5.8.4.3.1??5.8.4.3.2??5.8.4.3.3??5.8.4.3.4??5.8.4.4.1??5.8.4.4.2??5.8.4.4.3??5.8.4.4.4
5.8.4.5.1??5.8.4.5.2??5.8.4.5.3??5.8.4.5.4??5.8.4.6.1??5.8.4.6.2??5.8.4.6.3??5.8.4.6.4
5.8.4.7.1??5.8.4.7.2??5.8.4.7.3??5.8.4.7.4??5.8.4.8.1??5.8.4.8.2??5.8.4.8.3??5.8.4.8.4
6.1.1.1.1??6.1.1.1.2??6.1.1.1.3??6.1.1.1.4??6.1.1.2.1??6.1.1.2.2??6.1.1.2.3??6.1.1.2.4
Table 1-is continuous
6.1.1.3.1??6.1.1.3.2??6.1.1.3.3??6.1.1.3.4??6.1.1.4.1??6.1.1.4.2??6.1.1.4.3??6.1.1.4.4
6.1.1.5.1??6.1.1.5.2??6.1.1.5.3??6.1.1.5.4??6.1.1.6.1??6.1.1.6.2??6.1.1.6.3??6.1.1.6.4
6.1.1.7.1??6.1.1.7.2??6.1.1.7.3??6.1.1.7.4??6.1.1.8.1??6.1.1.8.2??6.1.1.8.3??6.1.1.8.4
6.1.2.1.1??6.1.2.1.2??6.1.2.1.3??6.1.2.1.4??6.1.2.2.1??6.1.2.2.2??6.1.2.2.3??6.1.2.2.4
6.1.2.3.1??6.1.2.3.2??6.1.2.3.3??6.1.2.3.4??6.1.2.4.1??6.1.2.4.2??6.1.2.4.3??6.1.2.4.4
6.1.2.5.1??6.1.2.5.2??6.1.2.5.3??6.1.2.5.4??6.1.2.6.1??6.1.2.6.2??6.1.2.6.3??6.1.2.6.4
6.1.2.7.1??6.1.2.7.2??6.1.2.7.3??6.1.2.7.4??6.1.2.8.1??6.1.2.8.2??6.1.2.8.3??6.1.2.8.4
6.1.3.1.1??6.1.3.1.2??6.1.3.1.3??6.1.3.1.4??6.1.3.2.1??6.1.3.2.2??6.1.3.2.3??6.1.3.2.4
6.1.3.3.1??6.1.3.3.2??6.1.3.3.3??6.1.3.3.4??6.1.3.4.1??6.1.3.4.2??6.1.3.4.3??6.1.3.4.4
6.1.3.5.1??6.1.3.5.2??6.1.3.5.3??6.1.3.5.4??6.1.3.6.1??6.1.3.6.2??6.1.3.6.3??6.1.3.6.4
6.1.3.7.1??6.1.3.7.2??6.1.3.7.3??6.1.3.7.4??6.1.3.8.1??6.1.3.8.2??6.1.3.8.3??6.1.3.8.4
6.1.4.1.1??6.1.4.1.2??6.1.4.1.3??6.1.4.1.4??6.1.4.2.1??6.1.4.2.2??6.1.4.2.3??6.1.4.2.4
6.1.4.3.1??6.1.4.3.2??6.1.4.3.3??6.1.4.3.4??6.1.4.4.1??6.1.4.4.2??6.1.4.4.3??6.1.4.4.4
6.1.4.5.1??6.1.4.5.2??6.1.4.5.3??6.1.4.5.4??6.1.4.6.1??6.1.4.6.2??6.1.4.6.3??6.1.4.6.4
6.1.4.7.1??6.1.4.7.2??6.1.4.7.3??6.1.4.7.4??6.1.4.8.1??6.1.4.8.2??6.1.4.8.3??6.1.4.8.4
6.2.1.1.1??6.2.1.1.2??6.2.1.1.3??6.2.1.1.4??6.2.1.2.1??6.2.1.2.2??6.2.1.2.3??6.2.1.2.4
6.2.1.3.1??6.2.1.3.2??6.2.1.3.3??6.2.1.3.4??6.2.1.4.1??6.2.1.4.2??6.2.1.4.3??6.2.1.4.4
6.2.1.5.1??6.2.1.5.2??6.2.1.5.3??6.2.1.5.4??6.2.1.6.1??6.2.1.6.2??6.2.1.6.3??6.2.1.6.4
6.2.1.7.1??6.2.1.7.2??6.2.1.7.3??6.2.1.7.4??6.2.1.8.1??6.2.1.8.2??6.2.1.8.3??6.2.1.8.4
6.2.2.1.1??6.2.2.1.2??6.2.2.1.3??6.2.2.1.4??6.2.2.2.1??6.2.2.2.2??6.2.2.2.3??6.2.2.2.4
6.2.2.3.1??6.2.2.3.2??6.2.2.3.3??6.2.2.3.4??6.2.2.4.1??6.2.2.4.2??6.2.2.4.3??6.2.2.4.4
6.2.2.5.1??6.2.2.5.2??6.2.2.5.3??6.2.2.5.4??6.2.2.6.1??6.2.2.6.2??6.2.2.6.3??6.2.2.6.4
6.2.2.7.1??6.2.2.7.2??6.2.2.7.3??6.2.2.7.4??6.2.2.8.1??6.2.2.8.2??6.2.2.8.3??6.2.2.8.4
6.2.3.1.1??6.2.3.1.2??6.2.3.1.3??6.2.3.1.4??6.2.3.2.1??6.2.3.2.2??6.2.3.2.3??6.2.3.2.4
6.2.3.3.1??6.2.3.3.2??6.2.3.3.3??6.2.3.3.4??6.2.3.4.1??6.2.3.4.2??6.2.3.4.3??6.2.3.4.4
6.2.3.5.1??6.2.3.5.2??6.2.3.5.3??6.2.3.5.4??6.2.3.6.1??6.2.3.6.2??6.2.3.6.3??6.2.3.6.4
6.2.3.7.1??6.2.3.7.2??6.2.3.7.3??6.2.3.7.4??6.2.3.8.1??6.2.3.8.2??6.2.3.8.3??6.2.3.8.4
6.2.4.1.1??6.2.4.1.2??6.2.4.1.3??6.2.4.1.4??6.2.4.2.1??6.2.4.2.2??6.2.4.2.3??6.2.4.2.4
6.2.4.3.1??6.2.4.3.2??6.2.4.3.3??6.2.4.3.4??6.2.4.4.1??6.2.4.4.2??6.2.4.4.3??6.2.4.4.4
6.2.4.5.1??6.2.4.5.2??6.2.4.5.3??6.2.4.5.4??6.2.4.6.1??6.2.4.6.2??6.2.4.6.3??6.2.4.6.4
6.2.4.7.1??6.2.4.7.2??6.2.4.7.3??6.2.4.7.4??6.2.4.8.1??6.2.4.8.2??6.2.4.8.3??6.2.4.8.4
6.3.1.1.1??6.3.1.1.2??6.3.1.1.3??6.3.1.1.4??6.3.1.2.1??6.3.1.2.2??6.3.1.2.3??6.3.1.2.4
Table 1-is continuous
6.3.1.3.1??6.3.1.3.2??6.3.1.3.3??6.3.1.3.4??6.3.1.4.1??6.3.1.4.2??6.3.1.4.3??6.3.1.4.4
6.3.1.5.1??6.3.1.5.2??6.3.1.5.3??6.3.1.5.4??6.3.1.6.1??6.3.1.6.2??6.3.1.6.3??6.3.1.6.4
6.3.1.7.1??6.3.1.7.2??6.3.1.7.3??6.3.1.7.4??6.3.1.8.1??6.3.1.8.2??6.3.1.8.3??6.3.1.8.4
6.3.2.1.1??6.3.2.1.2??6.3.2.1.3??6.3.2.1.4??6.3.2.2.1??6.3.2.2.2??6.3.2.2.3??6.3.2.2.4
6.3.2.3.1??6.3.2.3.2??6.3.2.3.3??6.3.2.3.4??6.3.2.4.1??6.3.2.4.2??6.3.2.4.3??6.3.2.4.4
6.3.2.5.1??6.3.2.5.2??6.3.2.5.3??6.3.2.5.4??6.3.2.6.1??6.3.2.6.2??6.3.2.6.3??6.3.2.6.4
6.3.2.7.1??6.3.2.7.2??6.3.2.7.3??6.3.2.7.4??6.3.2.8.1??6.3.2.8.2??6.3.2.8.3??6.3.2.8.4
6.3.3.1.1??6.3.3.1.2??6.3.3.1.3??6.3.3.1.4??6.3.3.2.1??6.3.3.2.2??6.3.3.2.3??6.3.3.2.4
6.3.3.3.1??6.3.3.3.2??6.3.3.3.3??6.3.3.3.4??6.3.3.4.1??6.3.3.4.2??6.3.3.4.3??6.3.3.4.4
6.3.3.5.1??6.3.3.5.2??6.3.3.5.3??6.3.3.5.4??6.3.3.6.1??6.3.3.6.2??6.3.3.6.3??6.3.3.6.4
6.3.3.7.1??6.3.3.7.2??6.3.3.7.3??6.3.3.7.4??6.3.3.8.1??6.3.3.8.2??6.3.3.8.3??6.3.3.8.4
6.3.4.1.1??6.3.4.1.2??6.3.4.1.3??6.3.4.1.4??6.3.4.2.1??6.3.4.2.2??6.3.4.2.3??6.3.4.2.4
6.3.4.3.1??6.3.4.3.2??6.3.4.3.3??6.3.4.3.4??6.3.4.4.1??6.3.4.4.2??6.3.4.4.3??6.3.4.4.4
6.3.4.5.1??6.3.4.5.2??6.3.4.5.3??6.3.4.5.4??6.3.4.6.1??6.3.4.6.2??6.3.4.6.3??6.3.4.6.4
6.3.4.7.1??6.3.4.7.2??6.3.4.7.3??6.3.4.7.4??6.3.4.8.1??6.3.4.8.2??6.3.4.8.3??6.3.4.8.4
6.4.1.1.1??6.4.1.1.2??6.4.1.1.3??6.4.1.1.4??6.4.1.2.1??6.4.1.2.2??6.4.1.2.3??6.4.1.2.4
6.4.1.3.1??6.4.1.3.2??6.4.1.3.3??6.4.1.3.4??6.4.1.4.1??6.4.1.4.2??6.4.1.4.3??6.4.1.4.4
6.4.1.5.1??6.4.1.5.2??6.4.1.5.3??6.4.1.5.4??6.4.1.6.1??6.4.1.6.2??6.4.1.6.3??6.4.1.6.4
6.4.1.7.1??6.4.1.7.2??6.4.1.7.3??6.4.1.7.4??6.4.1.8.1??6.4.1.8.2??6.4.1.8.3??6.4.1.8.4
6.4.2.1.1??6.4.2.1.2??6.4.2.1.3??6.4.2.1.4??6.4.2.2.1??6.4.2.2.2??6.4.2.2.3??6.4.2.2.4
6.4.2.3.1??6.4.2.3.2??6.4.2.3.3??6.4.2.3.4??6.4.2.4.1??6.4.2.4.2??6.4.2.4.3??6.4.2.4.4
6.4.2.5.1??6.4.2.5.2??6.4.2.5.3??6.4.2.5.4??6.4.2.6.1??6.4.2.6.2??6.4.2.6.3??6.4.2.6.4
6.4.2.7.1??6.4.2.7.2??6.4.2.7.3??6.4.2.7.4??6.4.2.8.1??6.4.2.8.2??6.4.2.8.3??6.4.2.8.4
6.4.3.1.1??6.4.3.1.2??6.4.3.1.3??6.4.3.1.4??6.4.3.2.1??6.4.3.2.2??6.4.3.2.3??6.4.3.2.4
6.4.3.3.1??6.4.3.3.2??6.4.3.3.3??6.4.3.3.4??6.4.3.4.1??6.4.3.4.2??6.4.3.4.3??6.4.3.4.4
6.4.3.5.1??6.4.3.5.2??6.4.3.5.3??6.4.3.5.4??6.4.3.6.1??6.4.3.6.2??6.4.3.6.3??6.4.3.6.4
6.4.3.7.1??6.4.3.7.2??6.4.3.7.3??6.4.3.7.4??6.4.3.8.1??6.4.3.8.2??6.4.3.8.3??6.4.3.8.4
6.4.4.1.1??6.4.4.1.2??6.4.4.1.3??6.4.4.1.4??6.4.4.2.1??6.4.4.2.2??6.4.4.2.3??6.4.4.2.4
6.4.4.3.1??6.4.4.3.2??6.4.4.3.3??6.4.4.3.4??6.4.4.4.1??6.4.4.4.2??6.4.4.4.3??6.4.4.4.4
6.4.4.5.1??6.4.4.5.2??6.4.4.5.3??6.4.4.5.4??6.4.4.6.1??6.4.4.6.2??6.4.4.6.3??6.4.4.6.4
6.4.4.7.1??6.4.4.7.2??6.4.4.7.3??6.4.4.7.4??6.4.4.8.1??6.4.4.8.2??6.4.4.8.3??6.4.4.8.4
6.5.1.1.1??6.5.1.1.2??6.5.1.1.3??6.5.1.1.4??6.5.1.2.1??6.5.1.2.2??6.5.1.2.3??6.5.1.2.4
Table 1-is continuous
6.5.1.3.1??6.5.1.3.2??6.5.1.3.3??6.5.1.3.4??6.5.1.4.1??6.5.1.4.2??6.5.1.4.3??6.5.1.4.4
6.5.1.5.1??6.5.1.5.2??6.5.1.5.3??6.5.1.5.4??6.5.1.6.1??6.5.1.6.2??6.5.1.6.3??6.5.1.6.4
6.5.1.7.1??6.5.1.7.2??6.5.1.7.3??6.5.1.7.4??6.5.1.8.1??6.5.1.8.2??6.5.1.8.3??6.5.1.8.4
6.5.2.1.1??6.5.2.1.2??6.5.2.1.3??6.5.2.1.4??6.5.2.2.1??6.5.2.2.2??6.5.2.2.3??6.5.2.2.4
6.5.2.3.1??6.5.2.3.2??6.5.2.3.3??6.5.2.3.4??6.5.2.4.1??6.5.2.4.2??6.5.2.4.3??6.5.2.4.4
6.5.2.5.1??6.5.2.5.2??6.5.2.5.3??6.5.2.5.4??6.5.2.6.1??6.5.2.6.2??6.5.2.6.3??6.5.2.6.4
6.5.2.7.1??6.5.2.7.2??6.5.2.7.3??6.5.2.7.4??6.5.2.8.1??6.5.2.8.2??6.5.2.8.3??6.5.2.8.4
6.5.3.1.1??6.5.3.1.2??6.5.3.1.3??6.5.3.1.4??6.5.3.2.1??6.5.3.2.2??6.5.3.2.3??6.5.3.2.4
6.5.3.3.1??6.5.3.3.2??6.5.3.3.3??6.5.3.3.4??6.5.3.4.1??6.5.3.4.2??6.5.3.4.3??6.5.3.4.4
6.5.3.5.1??6.5.3.5.2??6.5.3.5.3??6.5.3.5.4??6.5.3.6.1??6.5.3.6.2??6.5.3.6.3??6.5.3.6.4
6.5.3.7.1??6.5.3.7.2??6.5.3.7.3??6.5.3.7.4??6.5.3.8.1??6.5.3.8.2??6.5.3.8.3??6.5.3.8.4
6.5.4.1.1??6.5.4.1.2??6.5.4.1.3??6.5.4.1.4??6.5.4.2.1??6.5.4.2.2??6.5.4.2.3??6.5.4.2.4
6.5.4.3.1??6.5.4.3.2??6.5.4.3.3??6.5.4.3.4??6.5.4.4.1??6.5.4.4.2??6.5.4.4.3??6.5.4.4.4
6.5.4.5.1??6.5.4.5.2??6.5.4.5.3??6.5.4.5.4??6.5.4.6.1??6.5.4.6.2??6.5.4.6.3??6.5.4.6.4
6.5.4.7.1??6.5.4.7.2??6.5.4.7.3??6.5.4.7.4??6.5.4.8.1??6.5.4.8.2??6.5.4.8.3??6.5.4.8.4
6.6.1.1.1??6.6.1.1.2??6.6.1.1.3??6.6.1.1.4??6.6.1.2.1??6.6.1.2.2??6.6.1.2.3??6.6.1.2.4
6.6.1.3.1??6.6.1.3.2??6.6.1.3.3??6.6.1.3.4??6.6.1.4.1??6.6.1.4.2??6.6.1.4.3??6.6.1.4.4
6.6.1.5.1??6.6.1.5.2??6.6.1.5.3??6.6.1.5.4??6.6.1.6.1??6.6.1.6.2??6.6.1.6.3??6.6.1.6.4
6.6.1.7.1??6.6.1.7.2??6.6.1.7.3??6.6.1.7.4??6.6.1.8.1??6.6.1.8.2??6.6.1.8.3??6.6.1.8.4
6.6.2.1.1??6.6.2.1.2??6.6.2.1.3??6.6.2.1.4??6.6.2.2.1??6.6.2.2.2??6.6.2.2.3??6.6.2.2.4
6.6.2.3.1??6.6.2.3.2??6.6.2.3.3??6.6.2.3.4??6.6.2.4.1??6.6.2.4.2??6.6.2.4.3??6.6.2.4.4
6.6.2.5.1??6.6.2.5.2??6.6.2.5.3??6.6.2.5.4??6.6.2.6.1??6.6.2.6.2??6.6.2.6.3??6.6.2.6.4
6.6.2.7.1??6.6.2.7.2??6.6.2.7.3??6.6.2.7.4??6.6.2.8.1??6.6.2.8.2??6.6.2.8.3??6.6.2.8.4
6.6.3.1.1??6.6.3.1.2??6.6.3.1.3??6.6.3.1.4??6.6.3.2.1??6.6.3.2.2??6.6.3.2.3??6.6.3.2.4
6.6.3.3.1??6.6.3.3.2??6.6.3.3.3??6.6.3.3.4??6.6.3.4.1??6.6.3.4.2??6.6.3.4.3??6.6.3.4.4
6.6.3.5.1??6.6.3.5.2??6.6.3.5.3??6.6.3.5.4??6.6.3.6.1??6.6.3.6.2??6.6.3.6.3??6.6.3.6.4
6.6.3.7.1??6.6.3.7.2??6.6.3.7.3??6.6.3.7.4??6.6.3.8.1??6.6.3.8.2??6.6.3.8.3??6.6.3.8.4
6.6.4.1.1??6.6.4.1.2??6.6.4.1.3??6.6.4.1.4??6.6.4.2.1??6.6.4.2.2??6.6.4.2.3??6.6.4.2.4
6.6.4.3.1??6.6.4.3.2??6.6.4.3.3??6.6.4.3.4??6.6.4.4.1??6.6.4.4.2??6.6.4.4.3??6.6.4.4.4
6.6.4.5.1??6.6.4.5.2??6.6.4.5.3??6.6.4.5.4??6.6.4.6.1??6.6.4.6.2??6.6.4.6.3??6.6.4.6.4
6.6.4.7.1??6.6.4.7.2??6.6.4.7.3??6.6.4.7.4??6.6.4.8.1??6.6.4.8.2??6.6.4.8.3??6.6.4.8.4
Table 1-is continuous
6.7.1.1.1??6.7.1.1.2??6.7.1.1.3??6.7.1.1.4??6.7.1.2.1??6.7.1.2.2??6.7.1.2.3??6.7.1.2.4
6.7.1.3.1??6.7.1.3.2??6.7.1.3.3??6.7.1.3.4??6.7.1.4.1??6.7.1.4.2??6.7.1.4.3??6.7.1.4.4
6.7.1.5.1??6.7.1.5.2??6.7.1.5.3??6.7.1.5.4??6.7.1.6.1??6.7.1.6.2??6.7.1.6.3??6.7.1.6.4
6.7.1.7.1??6.7.1.7.2??6.7.1.7.3??6.7.1.7.4??6.7.1.8.1??6.7.1.8.2??6.7.1.8.3??6.7.1.8.4
6.7.2.1.1??6.7.2.1.2??6.7.2.1.3??6.7.2.1.4??6.7.2.2.1??6.7.2.2.2??6.7.2.2.3??6.7.2.2.4
6.7.2.3.1??6.7.2.3.2??6.7.2.3.3??6.7.2.3.4??6.7.2.4.1??6.7.2.4.2??6.7.2.4.3??6.7.2.4.4
6.7.2.5.1??6.7.2.5.2??6.7.2.5.3??6.7.2.5.4??6.7.2.6.1??6.7.2.6.2??6.7.2.6.3??6.7.2.6.4
6.7.2.7.1??6.7.2.7.2??6.7.2.7.3??6.7.2.7.4??6.7.2.8.1??6.7.2.8.2??6.7.2.8.3??6.7.2.8.4
6.7.3.1.1??6.7.3.1.2??6.7.3.1.3??6.7.3.1.4??6.7.3.2.1??6.7.3.2.2??6.7.3.2.3??6.7.3.2.4
6.7.3.3.1??6.7.3.3.2??6.7.3.3.3??6.7.3.3.4??6.7.3.4.1??6.7.3.4.2??6.7.3.4.3??6.7.3.4.4
6.7.3.5.1??6.7.3.5.2??6.7.3.5.3??6.7.3.5.4??6.7.3.6.1??6.7.3.6.2??6.7.3.6.3??6.7.3.6.4
6.7.3.7.1??6.7.3.7.2??6.7.3.7.3??6.7.3.7.4??6.7.3.8.1??6.7.3.8.2??6.7.3.8.3??6.7.3.8.4
6.7.4.1.1??6.7.4.1.2??6.7.4.1.3??6.7.4.1.4??6.7.4.2.1??6.7.4.2.2??6.7.4.2.3??6.7.4.2.4
6.7.4.3.1??6.7.4.3.2??6.7.4.3.3??6.7.4.3.4??6.7.4.4.1??6.7.4.4.2??6.7.4.4.3??6.7.4.4.4
6.7.4.5.1??6.7.4.5.2??6.7.4.5.3??6.7.4.5.4??6.7.4.6.1??6.7.4.6.2??6.1.4.6.3??6.7.4.6.4
6.7.4.7.1??6.7.4.7.2??6.7.4.7.3??6.7.4.7.4??6.7.4.8.1??6.7.4.8.2??6.7.4.8.3??6.7.4.8.4
6.8.1.1.1??6.8.1.1.2??6.8.1.1.3??6.8.1.1.4??6.8.1.2.1??6.8.1.2.2??6.8.1.2.3??6.8.1.2.4
6.8.1.3.1??6.8.1.3.2??6.8.1.3.3??6.8.1.3.4??6.8.1.4.1??6.8.1.4.2??6.8.1.4.3??6.8.1.4.4
6.8.1.5.1??6.8.1.5.2??6.8.1.5.3??6.8.1.5.4??6.8.1.6.1??6.8.1.6.2??6.8.1.6.3??6.8.1.6.4
6.8.1.7.1??6.8.1.7.2??6.8.1.7.3??6.8.1.7.4??6.8.1.8.1??6.8.1.8.2??6.8.1.8.3??6.8.1.8.4
6.8.2.1.1??6.8.2.1.2??6.8.2.1.3??6.8.2.1.4??6.8.2.2.1??6.8.2.2.2??6.8.2.2.3??6.8.2.2.4
6.8.2.3.1??6.8.2.3.2??6.8.2.3.3??6.8.2.3.4??6.8.2.4.1??6.8.2.4.2??6.8.2.4.3??6.8.2.4.4
6.8.2.5.1??6.8.2.5.2??6.8.2.5.3??6.8.2.5.4??6.8.2.6.1??6.8.2.6.2??6.8.2.6.3??6.8.2.6.4
6.8.2.7.1??6.8.2.7.2??6.8.2.7.3??6.8.2.7.4??6.8.2.8.1??6.8.2.8.2??6.8.2.8.3??6.8.2.8.4
6.8.3.1.1??6.8.3.1.2??6.8.3.1.3??6.8.3.1.4??6.8.3.2.1??6.8.3.2.2??6.8.3.2.3??6.8.3.2.4
6.8.3.3.1??6.8.3.3.2??6.8.3.3.3??6.8.3.3.4??6.8.3.4.1??6.8.3.4.2??6.8.3.4.3??6.8.3.4.4
6.8.3.5.1??6.8.3.5.2??6.8.3.5.3??6.8.3.5.4??6.8.3.6.1??6.8.3.6.2??6.8.3.6.3??6.8.3.6.4
6.8.3.7.1??6.8.3.7.2??6.8.3.7.3??6.8.3.7.4??6.8.3.8.1??6.8.3.8.2??6.8.3.8.3??6.8.3.8.4
6.8.4.1.1??6.8.4.1.2??6.8.4.1.3??6.8.4.1.4??6.8.4.2.1??6.8.4.2.2??6.8.4.2.3??6.8.4.2.4
6.8.4.3.1??6.8.4.3.2??6.8.4.3.3??6.8.4.3.4??6.8.4.4.1??6.8.4.4.2??6.8.4.4.3??6.8.4.4.4
6.8.4.5.1??6.8.4.5.2??6.8.4.5.3??6.8.4.5.4??6.8.4.6.1??6.8.4.6.2??6.8.4.6.3??6.8.4.6.4
6.8.4.7.1??6.8.4.7.2??6.8.4.7.3??6.8.4.7.4??6.8.4.8.1??6.8.4.8.2??6.8.4.8.3??6.8.4.8.4
Table 1-is continuous
7.1.1.1.1??7.1.1.1.2??7.1.1.1.3??7.1.1.1.4??7.1.1.2.1??7.1.1.2.2??7.1.1.2.3??7.1.1.2.4
7.1.1.3.1??7.1.1.3.2??7.1.1.3.3??7.1.1.3.4??7.1.1.4.1??7.1.1.4.2??7.1.1.4.3??7.1.1.4.4
7.1.1.5.1??7.1.1.5.2??7.1.1.5.3??7.1.1.5.4??7.1.1.6.1??7.1.1.6.2??7.1.1.6.3??7.1.1.6.4
7.1.1.7.1??7.1.1.7.2??7.1.1.7.3??7.1.1.7.4??7.1.1.8.1??7.1.1.8.2??7.1.1.8.3??7.1.1.8.4
7.1.2.1.1??7.1.2.1.2??7.1.2.1.3??7.1.2.1.4??7.1.2.2.1??7.1.2.2.2??7.1.2.2.3??7.1.2.2.4
7.1.2.3.1??7.1.2.3.2??7.1.2.3.3??7.1.2.3.4??7.1.2.4.1??7.1.2.4.2??7.1.2.4.3??7.1.2.4.4
7.1.2.5.1??7.1.2.5.2??7.1.2.5.3??7.1.2.5.4??7.1.2.6.1??7.1.2.6.2??7.1.2.6.3??7.1.2.6.4
7.1.2.7.1??7.1.2.7.2??7.1.2.7.3??7.1.2.7.4??7.1.2.8.1??7.1.2.8.2??7.1.2.8.3??7.1.2.8.4
7.1.3.1.1??7.1.3.1.2??7.1.3.1.3??7.1.3.1.4??7.1.3.2.1??7.1.3.2.2??7.1.3.2.3??7.1.3.2.4
7.1.3.3.1??7.1.3.3.2??7.1.3.3.3??7.1.3.3.4??7.1.3.4.1??7.1.3.4.2??7.1.3.4.3??7.1.3.4.4
7.1.3.5.1??7.1.3.5.2??7.1.3.5.3??7.1.3.5.4??7.1.3.6.1??7.1.3.6.2??7.1.3.6.3??7.1.3.6.4
7.1.3.7.1??7.1.3.7.2??7.1.3.7.3??7.1.3.7.4??7.1.3.8.1??7.1.3.8.2??7.1.3.8.3??7.1.3.8.4
7.1.4.1.1??7.1.4.1.2??7.1.4.1.3??7.1.4.1.4??7.1.4.2.1??7.1.4.2.2??7.1.4.2.3??7.1.4.2.4
7.1.4.3.1??7.1.4.3.2??7.1.4.3.3??7.1.4.3.4??7.1.4.4.1??7.1.4.4.2??7.1.4.4.3??7.1.4.4.4
7.1.4.5.1??7.1.4.5.2??7.1.4.5.3??7.1.4.5.4??7.1.4.6.1??7.1.4.6.2??7.1.4.6.3??7.1.4.6.4
7.1.4.7.1??7.1.4.7.2??7.1.4.7.3??7.1.4.7.4??7.1.4.8.1??7.1.4.8.2??7.1.4.8.3??7.1.4.8.4
7.2.1.1.1??7.2.1.1.2??7.2.1.1.3??7.2.1.1.4??7.2.1.2.1??7.2.1.2.2??7.2.1.2.3??7.2.1.2.4
7.2.1.3.1??7.2.1.3.2??7.2.1.3.3??7.2.1.3.4??7.2.1.4.1??7.2.1.4.2??7.2.1.4.3??7.2.1.4.4
7.2.1.5.1??7.2.1.5.2??7.2.1.5.3??7.2.1.5.4??7.2.1.6.1??7.2.1.6.2??7.2.1.6.3??7.2.1.6.4
7.2.1.7.1??7.2.1.7.2??7.2.1.7.3??7.2.1.7.4??7.2.1.8.1??7.2.1.8.2??7.2.1.8.3??7.2.1.8.4
7.2.2.1.1??7.2.2.1.2??7.2.2.1.3??7.2.2.1.4??7.2.2.2.1??7.2.2.2.2??7.2.2.2.3??7.2.2.2.4
7.2.2.3.1??7.2.2.3.2??7.2.2.3.3??7.2.2.3.4??7.2.2.4.1??7.2.2.4.2??7.2.2.4.3??7.2.2.4.4
7.2.2.5.1??7.2.2.5.2??7.2.2.5.3??7.2.2.5.4??7.2.2.6.1??7.2.2.6.2??7.2.2.6.3??7.2.2.6.4
7.2.2.7.1??7.2.2.7.2??7.2.2.7.3??7.2.2.7.4??7.2.2.8.1??7.2.2.8.2??7.2.2.8.3??7.2.2.8.4
7.2.3.1.1??7.2.3.1.2??7.2.3.1.3??7.2.3.1.4??7.2.3.2.1??7.2.3.2.2??7.2.3.2.3??7.2.3.2.4
7.2.3.3.1??7.2.3.3.2??7.2.3.3.3??7.2.3.3.4??7.2.3.4.1??7.2.3.4.2??7.2.3.4.3??7.2.3.4.4
7.2.3.5.1??7.2.3.5.2??7.2.3.5.3??7.2.3.5.4??7.2.3.6.1??7.2.3.6.2??7.2.3.6.3??7.2.3.6.4
7.2.3.7.1??7.2.3.7.2??7.2.3.7.3??7.2.3.7.4??7.2.3.8.1??7.2.3.8.2??7.2.3.8.3??7.2.3.8.4
7.2.4.1.1??7.2.4.1.2??7.2.4.1.3??7.2.4.1.4??7.2.4.2.1??7.2.4.2.2??7.2.4.2.3??7.2.4.2.4
7.2.4.3.1??7.2.4.3.2??7.2.4.3.3??7.2.4.3.4??7.2.4.4.1??7.2.4.4.2??7.2.4.4.3??7.2.4.4.4
7.2.4.5.1??7.2.4.5.2??7.2.4.5.3??7.2.4.5.4??7.2.4.6.1??7.2.4.6.2??7.2.4.6.3??7.2.4.6.4
7.2.4.7.1??7.2.4.7.2??7.2.4.7.3??7.2.4.7.4??7.2.4.8.1??7.2.4.8.2??7.2.4.8.3??7.2.4.8.4
Table 1-is continuous
7.3.1.1.1??7.3.1.1.2??7.3.1.1.3??7.3.1.1.4??7.3.1.2.1??7.3.1.2.2??7.3.1.2.3??7.3.1.2.4
7.3.1.3.1??7.3.1.3.2??7.3.1.3.3??7.3.1.3.4??7.3.1.4.1??7.3.1.4.2??7.3.1.4.3??7.3.1.4.4
7.3.1.5.1??7.3.1.5.2??7.3.1.5.3??7.3.1.5.4??7.3.1.6.1??7.3.1.6.2??7.3.1.6.3??7.3.1.6.4
7.3.1.7.1??7.3.1.7.2??7.3.1.7.3??7.3.1.7.4??7.3.1.8.1??7.3.1.8.2??7.3.1.8.3??7.3.1.8.4
7.3.2.1.1??7.3.2.1.2??7.3.2.1.3??7.3.2.1.4??7.3.2.2.1??7.3.2.2.2??7.3.2.2.3??7.3.2.2.4
7.3.2.3.1??7.3.2.3.2??7.3.2.3.3??7.3.2.3.4??7.3.2.4.1??7.3.2.4.2??7.3.2.4.3??7.3.2.4.4
7.3.2.5.1??7.3.2.5.2??7.3.2.5.3??7.3.2.5.4??7.3.2.6.1??7.3.2.6.2??7.3.2.6.3??7.3.2.6.4
7.3.2.7.1??7.3.2.7.2??7.3.2.7.3??7.3.2.7.4??7.3.2.8.1??7.3.2.8.2??7.3.2.8.3??7.3.2.8.4
7.3.3.1.1??7.3.3.1.2??7.3.3.1.3??7.3.3.1.4??7.3.3.2.1??7.3.3.2.2??7.3.3.2.3??7.3.3.2.4
7.3.3.3.1??7.3.3.3.2??7.3.3.3.3??7.3.3.3.4??7.3.3.4.1??7.3.3.4.2??7.3.3.4.3??7.3.3.4.4
7.3.3.5.1??7.3.3.5.2??7.3.3.5.3??7.3.3.5.4??7.3.3.6.1??7.3.3.6.2??7.3.3.6.3??7.3.3.6.4
7.3.3.7.1??7.3.3.7.2??7.3.3.7.3??7.3.3.7.4??7.3.3.8.1??7.3.3.8.2??7.3.3.8.3??7.3.3.8.4
7.3.4.1.1??7.3.4.1.2??7.3.4.1.3??7.3.4.1.4??7.3.4.2.1??7.3.4.2.2??7.3.4.2.3??7.3.4.2.4
7.3.4.3.1??7.3.4.3.2??7.3.4.3.3??7.3.4.3.4??7.3.4.4.1??7.3.4.4.2??7.3.4.4.3??7.3.4.4.4
7.3.4.5.1??7.3.4.5.2??7.3.4.5.3??7.3.4.5.4??7.3.4.6.1??7.3.4.6.2??7.3.4.6.3??7.3.4.6.4
7.3.4.7.1??7.3.4.7.2??7.3.4.7.3??7.3.4.7.4??7.3.4.8.1??7.3.4.8.2??7.3.4.8.3??7.3.4.8.4
7.4.1.1.1??7.4.1.1.2??7.4.1.1.3??7.4.1.1.4??7.4.1.2.1??7.4.1.2.2??7.4.1.2.3??7.4.1.2.4
7.4.1.3.1??7.4.1.3.2??7.4.1.3.3??7.4.1.3.4??7.4.1.4.1??7.4.1.4.2??7.4.1.4.3??7.4.1.4.4
7.4.1.5.1??7.4.1.5.2??7.4.1.5.3??7.4.1.5.4??7.4.1.6.1??7.4.1.6.2??7.4.1.6.3??7.4.1.6.4
7.4.1.7.1??7.4.1.7.2??7.4.1.7.3??7.4.1.7.4??7.4.1.8.1??7.4.1.8.2??7.4.1.8.3??7.4.1.8.4
7.4.2.1.1??7.4.2.1.2??7.4.2.1.3??7.4.2.1.4??7.4.2.2.1??7.4.2.2.2??7.4.2.2.3??7.4.2.2.4
7.4.2.3.1??7.4.2.3.2??7.4.2.3.3??7.4.2.3.4??7.4.2.4.1??7.4.2.4.2??7.4.2.4.3??7.4.2.4.4
7.4.2.5.1??7.4.2.5.2??7.4.2.5.3??7.4.2.5.4??7.4.2.6.1??7.4.2.6.2??7.4.2.6.3??7.4.2.6.4
7.4.2.7.1??7.4.2.7.2??7.4.2.7.3??7.4.2.7.4??7.4.2.8.1??7.4.2.8.2??7.4.2.8.3??7.4.2.8.4
7.4.3.1.1??7.4.3.1.2??7.4.3.1.3??7.4.3.1.4??7.4.3.2.1??7.4.3.2.2??7.4.3.2.3??7.4.3.2.4
7.4.3.3.1??7.4.3.3.2??7.4.3.3.3??7.4.3.3.4??7.4.3.4.1??7.4.3.4.2??7.4.3.4.3??7.4.3.4.4
7.4.3.5.1??7.4.3.5.2??7.4.3.5.3??7.4.3.5.4??7.4.3.6.1??7.4.3.6.2??7.4.3.6.3??7.4.3.6.4
7.4.3.7.1??7.4.3.7.2??7.4.3.7.3??7.4.3.7.4??7.4.3.8.1??7.4.3.8.2??7.4.3.8.3??7.4.3.8.4
7.4.4.1.1??7.4.4.1.2??7.4.4.1.3??7.4.4.1.4??7.4.4.2.1??7.4.4.2.2??7.4.4.2.3??7.4.4.2.4
7.4.4.3.1??7.4.4.3.2??7.4.4.3.3??7.4.4.3.4??7.4.4.4.1??7.4.4.4.2??7.4.4.4.3??7.4.4.4.4
7.4.4.5.1??7.4.4.5.2??7.4.4.5.3??7.4.4.5.4??7.4.4.6.1??7.4.4.6.2??7.4.4.6.3??7.4.4.6.4
7.4.4.7.1??7.4.4.7.2??7.4.4.7.3??7.4.4.7.4??7.4.4.8.1??7.4.4.8.2??7.4.4.8.3??7.4.4.8.4
Table 1-is continuous
7.5.1.1.1??7.5.1.1.2??7.5.1.1.3??7.5.1.1.4??7.5.1.2.1??7.5.1.2.2??7.5.1.2.3??7.5.1.2.4
7.5.1.3.1??7.5.1.3.2??7.5.1.3.3??7.5.1.3.4??7.5.1.4.1??7.5.1.4.2??7.5.1.4.3??7.5.1.4.4
7.5.1.5.1??7.5.1.5.2??7.5.1.5.3??7.5.1.5.4??7.5.1.6.1??7.5.1.6.2??7.5.1.6.3??7.5.1.6.4
7.5.1.7.1??7.5.1.7.2??7.5.1.7.3??7.5.1.7.4??7.5.1.8.1??7.5.1.8.2??7.5.1.8.3??7.5.1.8.4
7.5.2.1.1??7.5.2.1.2??7.5.2.1.3??7.5.2.1.4??7.5.2.2.1??7.5.2.2.2??7.5.2.2.3??7.5.2.2.4
7.5.2.3.1??7.5.2.3.2??7.5.2.3.3??7.5.2.3.4??7.5.2.4.1??7.5.2.4.2??7.5.2.4.3??7.5.2.4.4
7.5.2.5.1??7.5.2.5.2??7.5.2.5.3??7.5.2.5.4??7.5.2.6.1??7.5.2.6.2??7.5.2.6.3??7.5.2.6.4
7.5.2.7.1??7.5.2.7.2??7.5.2.7.3??7.5.2.7.4??7.5.2.8.1??7.5.2.8.2??7.5.2.8.3??7.5.2.8.4
7.5.3.1.1??7.5.3.1.2??7.5.3.1.3??7.5.3.1.4??7.5.3.2.1??7.5.3.2.2??7.5.3.2.3??7.5.3.2.4
7.5.3.3.1??7.5.3.3.2??7.5.3.3.3??7.5.3.3.4??7.5.3.4.1??7.5.3.4.2??7.5.3.4.3??7.5.3.4.4
7.5.3.5.1??7.5.3.5.2??7.5.3.5.3??7.5.3.5.4??7.5.3.6.1??7.5.3.6.2??7.5.3.6.3??7.5.3.6.4
7.5.3.7.1??7.5.3.7.2??7.5.3.7.3??7.5.3.7.4??7.5.3.8.1??7.5.3.8.2??7.5.3.8.3??7.5.3.8.4
7.5.4.1.1??7.5.4.1.2??7.5.4.1.3??7.5.4.1.4??7.5.4.2.1??7.5.4.2.2??7.5.4.2.3??7.5.4.2.4
7.5.4.3.1??7.5.4.3.2??7.5.4.3.3??7.5.4.3.4??7.5.4.4.1??7.5.4.4.2??7.5.4.4.3??7.5.4.4.4
7.5.4.5.1??7.5.4.5.2??7.5.4.5.3??7.5.4.5.4??7.5.4.6.1??7.5.4.6.2??7.5.4.6.3??7.5.4.6.4
7.5.4.7.1??7.5.4.7.2??7.5.4.7.3??7.5.4.7.4??7.5.4.8.1??7.5.4.8.2??7.5.4.8.3??7.5.4.8.4
7.6.1.1.1??7.6.1.1.2??7.6.1.1.3??7.6.1.1.4??7.6.1.2.1??7.6.1.2.2??7.6.1.2.3??7.6.1.2.4
7.6.1.3.1??7.6.1.3.2??7.6.1.3.3??7.6.1.3.4??7.6.1.4.1??7.6.1.4.2??7.6.1.4.3??7.6.1.4.4
7.6.1.5.1??7.6.1.5.2??7.6.1.5.3??7.6.1.5.4??7.6.1.6.1??7.6.1.6.2??7.6.1.6.3??7.6.1.6.4
7.6.1.7.1??7.6.1.7.2??7.6.1.7.3??7.6.1.7.4??7.6.1.8.1??7.6.1.8.2??7.6.1.8.3??7.6.1.8.4
7.6.2.1.1??7.6.2.1.2??7.6.2.1.3??7.6.2.1.4??7.6.2.2.1??7.6.2.2.2??7.6.2.2.3??7.6.2.2.4
7.6.2.3.1??7.6.2.3.2??7.6.2.3.3??7.6.2.3.4??7.6.2.4.1??7.6.2.4.2??7.6.2.4.3??7.6.2.4.4
7.6.2.5.1??7.6.2.5.2??7.6.2.5.3??7.6.2.5.4??7.6.2.6.1??7.6.2.6.2??7.6.2.6.3??7.6.2.6.4
7.6.2.7.1??7.6.2.7.2??7.6.2.7.3??7.6.2.7.4??7.6.2.8.1??7.6.2.8.2??7.6.2.8.3??7.6.2.8.4
7.6.3.1.1??7.6.3.1.2??7.6.3.1.3??7.6.3.1.4??7.6.3.2.1??7.6.3.2.2??7.6.3.2.3??7.6.3.2.4
7.6.3.3.1??7.6.3.3.2??7.6.3.3.3??7.6.3.3.4??7.6.3.4.1??7.6.3.4.2??7.6.3.4.3??7.6.3.4.4
7.6.3.5.1??7.6.3.5.2??7.6.3.5.3??7.6.3.5.4??7.6.3.6.1??7.6.3.6.2??7.6.3.6.3??7.6.3.6.4
7.6.3.7.1??7.6.3.7.2??7.6.3.7.3??7.6.3.7.4??7.6.3.8.1??7.6.3.8.2??7.6.3.8.3??7.6.3.8.4
7.6.4.1.1??7.6.4.1.2??7.6.4.1.3??7.6.4.1.4??7.6.4.2.1??7.6.4.2.2??7.6.4.2.3??7.6.4.2.4
7.6.4.3.1??7.6.4.3.2??7.6.4.3.3??7.6.4.3.4??7.6.4.4.1??7.6.4.4.2??7.6.4.4.3??7.6.4.4.4
7.6.4.5.1??7.6.4.5.2??7.6.4.5.3??7.6.4.5.4??7.6.4.6.1??7.6.4.6.2??7.6.4.6.3??7.6.4.6.4
7.6.4.7.1??7.6.4.7.2??7.6.4.7.3??7.6.4.7.4??7.6.4.8.1??7.6.4.8.2??7.6.4.8.3??7.6.4.8.4
Table 1-is continuous
7.7.1.1.1??7.7.1.1.2??7.7.1.1.3??7.7.1.1.4??7.7.1.2.1??7.7.1.2.2??7.7.1.2.3??7.7.1.2.4
7.7.1.3.1??7.7.1.3.2??7.7.1.3.3??7.7.1.3.4??7.7.1.4.1??7.7.1.4.2??7.7.1.4.3??7.7.1.4.4
7.7.1.5.1??7.7.1.5.2??7.7.1.5.3??7.7.1.5.4??7.7.1.6.1??7.7.1.6.2??7.7.1.6.3??7.7.1.6.4
7.7.1.7.1??7.7.1.7.2??7.7.1.7.3??7.7.1.7.4??7.7.1.8.1??7.7.1.8.2??7.7.1.8.3??7.7.1.8.4
7.7.2.1.1??7.7.2.1.2??7.7.2.1.3??7.7.2.1.4??7.7.2.2.1??7.7.2.2.2??7.7.2.2.3??7.7.2.2.4
7.7.2.3.1??7.7.2.3.2??7.7.2.3.3??7.7.2.3.4??7.7.2.4.1??7.7.2.4.2??7.7.2.4.3??7.7.2.4.4
7.7.2.5.1??7.7.2.5.2??7.7.2.5.3??7.7.2.5.4??7.7.2.6.1??7.7.2.6.2??7.7.2.6.3??7.7.2.6.4
7.7.2.7.1??7.7.2.7.2??7.7.2.7.3??7.7.2.7.4??7.7.2.8.1??7.7.2.8.2??7.7.2.8.3??7.7.2.8.4
7.7.3.1.1??7.7.3.1.2??7.7.3.1.3??7.7.3.1.4??7.7.3.2.1??7.7.3.2.2??7.7.3.2.3??7.7.3.2.4
7.7.3.3.1??7.7.3.3.2??7.7.3.3.3??7.7.3.3.4??7.7.3.4.1??7.7.3.4.2??7.7.3.4.3??7.7.3.4.4
7.7.3.5.1??7.7.3.5.2??7.7.3.5.3??7.7.3.5.4??7.7.3.6.1??7.7.3.6.2??7.7.3.6.3??7.7.3.6.4
7.7.3.7.1??7.7.3.7.2??7.7.3.7.3??7.7.3.7.4??7.7.3.8.1??7.7.3.8.2??7.7.3.8.3??7.7.3.8.4
7.7.4.1.1??7.7.4.1.2??7.7.4.1.3??7.7.4.1.4??7.7.4.2.1??7.7.4.2.2??7.7.4.2.3??7.7.4.2.4
7.7.4.3.1??7.7.4.3.2??7.7.4.3.3??7.7.4.3.4??7.7.4.4.1??7.7.4.4.2??7.7.4.4.3??7.7.4.4.4
7.7.4.5.1??7.7.4.5.2??7.7.4.5.3??7.7.4.5.4??7.7.4.6.1??7.7.4.6.2??7.7.4.6.3??7.7.4.6.4
7.7.4.7.1??7.7.4.7.2??7.7.4.7.3??7.7.4.7.4??7.7.4.8.1??7.7.4.8.2??7.7.4.8.3??7.7.4.8.4
7.8.1.1.1??7.8.1.1.2??7.8.1.1.3??7.8.1.1.4??7.8.1.2.1??7.8.1.2.2??7.8.1.2.3??7.8.1.2.4
7.8.1.3.1??7.8.1.3.2??7.8.1.3.3??7.8.1.3.4??7.8.1.4.1??7.8.1.4.2??7.8.1.4.3??7.8.1.4.4
7.8.1.5.1??7.8.1.5.2??7.8.1.5.3??7.8.1.5.4??7.8.1.6.1??7.8.1.6.2??7.8.1.6.3??7.8.1.6.4
7.8.1.7.1??7.8.1.7.2??7.8.1.7.3??7.8.1.7.4??7.8.1.8.1??7.8.1.8.2??7.8.1.8.3??7.8.1.8.4
7.8.2.1.1??7.8.2.1.2??7.8.2.1.3??7.8.2.1.4??7.8.2.2.1??7.8.2.2.2??7.8.2.2.3??7.8.2.2.4
7.8.2.3.1??7.8.2.3.2??7.8.2.3.3??7.8.2.3.4??7.8.2.4.1??7.8.2.4.2??7.8.2.4.3??7.8.2.4.4
7.8.2.5.1??7.8.2.5.2??7.8.2.5.3??7.8.2.5.4??7.8.2.6.1??7.8.2.6.2??7.8.2.6.3??7.8.2.6.4
7.8.2.7.1??7.8.2.7.2??7.8.2.7.3??7.8.2.7.4??7.8.2.8.1??7.8.2.8.2??7.8.2.8.3??7.8.2.8.4
7.8.3.1.1??7.8.3.1.2??7.8.3.1.3??7.8.3.1.4??7.8.3.2.1??7.8.3.2.2??7.8.3.2.3??7.8.3.2.4
7.8.3.3.1??7.8.3.3.2??7.8.3.3.3??7.8.3.3.4??7.8.3.4.1??7.8.3.4.2??7.8.3.4.3??7.8.3.4.4
7.8.3.5.1??7.8.3.5.2??7.8.3.5.3??7.8.3.5.4??7.8.3.6.1??7.8.3.6.2??7.8.3.6.3??7.8.3.6.4
7.8.3.7.1??7.8.3.7.2??7.8.3.7.3??7.8.3.7.4??7.8.3.8.1??7.8.3.8.2??7.8.3.8.3??7.8.3.8.4
7.8.4.1.1??7.8.4.1.2??7.8.4.1.3??7.8.4.1.4??7.8.4.2.1??7.8.4.2.2??7.8.4.2.3??7.8.4.2.4
7.8.4.3.1??7.8.4.3.2??7.8.4.3.3??7.8.4.3.4??7.8.4.4.1??7.8.4.4.2??7.8.4.4.3??7.8.4.4.4
7.8.4.5.1??7.8.4.5.2??7.8.4.5.3??7.8.4.5.4??7.8.4.6.1??7.8.4.6.2??7.8.4.6.3??7.8.4.6.4
7.8.4.7.1??7.8.4.7.2??7.8.4.7.3??7.8.4.7.4??7.8.4.8.1??7.8.4.8.2??7.8.4.8.3??7.8.4.8.4
Table 1-is continuous
8.1.1.1.1??8.1.1.1.2??8.1.1.1.3??8.1.1.1.4??8.1.1.2.1??8.1.1.2.2??8.1.1.2.3??8.1.1.2.4
8.1.1.3.1??8.1.1.3.2??8.1.1.3.3??8.1.1.3.4??8.1.1.4.1??8.1.1.4.2??8.1.1.4.3??8.1.1.4.4
8.1.1.5.1??8.1.1.5.2??8.1.1.5.3??8.1.1.5.4??8.1.1.6.1??8.1.1.6.2??8.1.1.6.3??8.1.1.6.4
8.1.1.7.1??8.1.1.7.2??8.1.1.7.3??8.1.1.7.4??8.1.1.8.1??8.1.1.8.2??8.1.1.8.3??8.1.1.8.4
8.1.2.1.1??8.1.2.1.2??8.1.2.1.3??8.1.2.1.4??8.1.2.2.1??8.1.2.2.2??8.1.2.2.3??8.1.2.2.4
8.1.2.3.1??8.1.2.3.2??8.1.2.3.3??8.1.2.3.4??8.1.2.4.1??8.1.2.4.2??8.1.2.4.3??8.1.2.4.4
8.1.2.5.1??8.1.2.5.2??8.1.2.5.3??8.1.2.5.4??8.1.2.6.1??8.1.2.6.2??8.1.2.6.3??8.1.2.6.4
8.1.2.7.1??8.1.2.7.2??8.1.2.7.3??8.1.2.7.4??8.1.2.8.1??8.1.2.8.2??8.1.2.8.3??8.1.2.8.4
8.1.3.1.1??8.1.3.1.2??8.1.3.1.3??8.1.3.1.4??8.1.3.2.1??8.1.3.2.2??8.1.3.2.3??8.1.3.2.4
8.1.3.3.1??8.1.3.3.2??8.1.3.3.3??8.1.3.3.4??8.1.3.4.1??8.1.3.4.2??8.1.3.4.3??8.1.3.4.4
8.1.3.5.1??8.1.3.5.2??8.1.3.5.3??8.1.3.5.4??8.1.3.6.1??8.1.3.6.2??8.1.3.6.3??8.1.3.6.4
8.1.3.7.1??8.1.3.7.2??8.1.3.7.3??8.1.3.7.4??8.1.3.8.1??8.1.3.8.2??8.1.3.8.3??8.1.3.8.4
8.1.4.1.1??8.1.4.1.2??8.1.4.1.3??8.1.4.1.4??8.1.4.2.1??8.1.4.2.2??8.1.4.2.3??8.1.4.2.4
8.1.4.3.1??8.1.4.3.2??8.1.4.3.3??8.1.4.3.4??8.1.4.4.1??8.1.4.4.2??8.1.4.4.3??8.1.4.4.4
8.1.4.5.1??8.1.4.5.2??8.1.4.5.3??8.1.4.5.4??8.1.4.6.1??8.1.4.6.2??8.1.4.6.3??8.1.4.6.4
8.1.4.7.1??8.1.4.7.2??8.1.4.7.3??8.1.4.7.4??8.1.4.8.1??8.1.4.8.2??8.1.4.8.3??8.1.4.8.4
8.2.1.1.1??8.2.1.1.2??8.2.1.1.3??8.2.1.1.4??8.2.1.2.1??8.2.1.2.2??8.2.1.2.3??8.2.1.2.4
8.2.1.3.1??8.2.1.3.2??8.2.1.3.3??8.2.1.3.4??8.2.1.4.1??8.2.1.4.2??8.2.1.4.3??8.2.1.4.4
8.2.1.5.1??8.2.1.5.2??8.2.1.5.3??8.2.1.5.4??8.2.1.6.1??8.2.1.6.2??8.2.1.6.3??8.2.1.6.4
8.2.1.7.1??8.2.1.7.2??8.2.1.7.3??8.2.1.7.4??8.2.1.8.1??8.2.1.8.2??8.2.1.8.3??8.2.1.8.4
8.2.2.1.1??8.2.2.1.2??8.2.2.1.3??8.2.2.1.4??8.2.2.2.1??8.2.2.2.2??8.2.2.2.3??8.2.2.2.4
8.2.2.3.1??8.2.2.3.2??8.2.2.3.3??8.2.2.3.4??8.2.2.4.1??8.2.2.4.2??8.2.2.4.3??8.2.2.4.4
8.2.2.5.1??8.2.2.5.2??8.2.2.5.3??8.2.2.5.4??8.2.2.6.1??8.2.2.6.2??8.2.2.6.3??8.2.2.6.4
8.2.2.7.1??8.2.2.7.2??8.2.2.7.3??8.2.2.7.4??8.2.2.8.1??8.2.2.8.2??8.2.2.8.3??8.2.2.8.4
8.2.3.1.1??8.2.3.1.2??8.2.3.1.3??8.2.3.1.4??8.2.3.2.1??8.2.3.2.2??8.2.3.2.3??8.2.3.2.4
8.2.3.3.1??8.2.3.3.2??8.2.3.3.3??8.2.3.3.4??8.2.3.4.1??8.2.3.4.2??8.2.3.4.3??8.2.3.4.4
8.2.3.5.1??8.2.3.5.2??8.2.3.5.3??8.2.3.5.4??8.2.3.6.1??8.2.3.6.2??8.2.3.6.3??8.2.3.6.4
8.2.3.7.1??8.2.3.7.2??8.2.3.7.3??8.2.3.7.4??8.2.3.8.1??8.2.3.8.2??8.2.3.8.3??8.2.3.8.4
8.2.4.1.1??8.2.4.1.2??8.2.4.1.3??8.2.4.1.4??8.2.4.2.1??8.2.4.2.2??8.2.4.2.3??8.2.4.2.4
8.2.4.3.1??8.2.4.3.2??8.2.4.3.3??8.2.4.3.4??8.2.4.4.1??8.2.4.4.2??8.2.4.4.3??8.2.4.4.4
8.2.4.5.1??8.2.4.5.2??8.2.4.5.3??8.2.4.5.4??8.2.4.6.1??8.2.4.6.2??8.2.4.6.3??8.2.4.6.4
8.2.4.7.1??8.2.4.7.2??8.2.4.7.3??8.2.4.7.4??8.2.4.8.1??8.2.4.8.2??8.2.4.8.3??8.2.4.8.4
Table 1-is continuous
8.3.1.1.1??8.3.1.1.2??8.3.1.1.3??8.3.1.1.4??8.3.1.2.1??8.3.1.2.2??8.3.1.2.3??8.3.1.2.4
8.3.1.3.1??8.3.1.3.2??8.3.1.3.3??8.3.1.3.4??8.3.1.4.1??8.3.1.4.2??8.3.1.4.3??8.3.1.4.4
8.3.1.5.1??8.3.1.5.2??8.3.1.5.3??8.3.1.5.4??8.3.1.6.1??8.3.1.6.2??8.3.1.6.3??8.3.1.6.4
8.3.1.7.1??8.3.1.7.2??8.3.1.7.3??8.3.1.7.4??8.3.1.8.1??8.3.1.8.2??8.3.1.8.3??8.3.1.8.4
8.3.2.1.1??8.3.2.1.2??8.3.2.1.3??8.3.2.1.4??8.3.2.2.1??8.3.2.2.2??8.3.2.2.3??8.3.2.2.4
8.3.2.3.1??8.3.2.3.2??8.3.2.3.3??8.3.2.3.4??8.3.2.4.1??8.3.2.4.2??8.3.2.4.3??8.3.2.4.4
8.3.2.5.1??8.3.2.5.2??8.3.2.5.3??8.3.2.5.4??8.3.2.6.1??8.3.2.6.2??8.3.2.6.3??8.3.2.6.4
8.3.2.7.1??8.3.2.7.2??8.3.2.7.3??8.3.2.7.4??8.3.2.8.1??8.3.2.8.2??8.3.2.8.3??8.3.2.8.4
8.3.3.1.1??8.3.3.1.2??8.3.3.1.3??8.3.3.1.4??8.3.3.2.1??8.3.3.2.2??8.3.3.2.3??8.3.3.2.4
8.3.3.3.1??8.3.3.3.2??8.3.3.3.3??8.3.3.3.4??8.3.3.4.1??8.3.3.4.2??8.3.3.4.3??8.3.3.4.4
8.3.3.5.1??8.3.3.5.2??8.3.3.5.3??8.3.3.5.4??8.3.3.6.1??8.3.3.6.2??8.3.3.6.3??8.3.3.6.4
8.3.3.7.1??8.3.3.7.2??8.3.3.7.3??8.3.3.7.4??8.3.3.8.1??8.3.3.8.2??8.3.3.8.3??8.3.3.8.4
8.3.4.1.1??8.3.4.1.2??8.3.4.1.3??8.3.4.1.4??8.3.4.2.1??8.3.4.2.2??8.3.4.2.3??8.3.4.2.4
8.3.4.3.1??8.3.4.3.2??8.3.4.3.3??8.3.4.3.4??8.3.4.4.1??8.3.4.4.2??8.3.4.4.3??8.3.4.4.4
8.3.4.5.1??8.3.4.5.2??8.3.4.5.3??8.3.4.5.4??8.3.4.6.1??8.3.4.6.2??8.3.4.6.3??8.3.4.6.4
8.3.4.7.1??8.3.4.7.2??8.3.4.7.3??8.3.4.7.4??8.3.4.8.1??8.3.4.8.2??8.3.4.8.3??8.3.4.8.4
8.4.1.1.1??8.4.1.1.2??8.4.1.1.3??8.4.1.1.4??8.4.1.2.1??8.4.1.2.2??8.4.1.2.3??8.4.1.2.4
8.4.1.3.1??8.4.1.3.2??8.4.1.3.3??8.4.1.3.4??8.4.1.4.1??8.4.1.4.2??8.4.1.4.3??8.4.1.4.4
8.4.1.5.1??8.4.1.5.2??8.4.1.5.3??8.4.1.5.4??8.4.1.6.1??8.4.1.6.2??8.4.1.6.3??8.4.1.6.4
8.4.1.7.1??8.4.1.7.2??8.4.1.7.3??8.4.1.7.4??8.4.1.8.1??8.4.1.8.2??8.4.1.8.3??8.4.1.8.4
8.4.2.1.1??8.4.2.1.2??8.4.2.1.3??8.4.2.1.4??8.4.2.2.1??8.4.2.2.2??8.4.2.2.3??8.4.2.2.4
8.4.2.3.1??8.4.2.3.2??8.4.2.3.3??8.4.2.3.4??8.4.2.4.1??8.4.2.4.2??8.4.2.4.3??8.4.2.4.4
8.4.2.5.1??8.4.2.5.2??8.4.2.5.3??8.4.2.5.4??8.4.2.6.1??8.4.2.6.2??8.4.2.6.3??8.4.2.6.4
8.4.2.7.1??8.4.2.7.2??8.4.2.7.3??8.4.2.7.4??8.4.2.8.1??8.4.2.8.2??8.4.2.8.3??8.4.2.8.4
8.4.3.1.1??8.4.3.1.2??8.4.3.1.3??8.4.3.1.4??8.4.3.2.1??8.4.3.2.2??8.4.3.2.3??8.4.3.2.4
8.4.3.3.1??8.4.3.3.2??8.4.3.3.3??8.4.3.3.4??8.4.3.4.1??8.4.3.4.2??8.4.3.4.3??8.4.3.4.4
8.4.3.5.1??8.4.3.5.2??8.4.3.5.3??8.4.3.5.4??8.4.3.6.1??8.4.3.6.2??8.4.3.6.3??8.4.3.6.4
8.4.3.7.1??8.4.3.7.2??8.4.3.7.3??8.4.3.7.4??8.4.3.8.1??8.4.3.8.2??8.4.3.8.3??8.4.3.8.4
8.4.4.1.1??8.4.4.1.2??8.4.4.1.3??8.4.4.1.4??8.4.4.2.1??8.4.4.2.2??8.4.4.2.3??8.4.4.2.4
8.4.4.3.1??8.4.4.3.2??8.4.4.3.3??8.4.4.3.4??8.4.4.4.1??8.4.4.4.2??8.4.4.4.3??8.4.4.4.4
8.4.4.5.1??8.4.4.5.2??8.4.4.5.3??8.4.4.5.4??8.4.4.6.1??8.4.4.6.2??8.4.4.6.3??8.4.4.6.4
8.4.4.7.1??8.4.4.7.2??8.4.4.7.3??8.4.4.7.4??8.4.4.8.1??8.4.4.8.2??8.4.4.8.3??8.4.4.8.4
Table 1-is continuous
8.5.1.1.1??8.5.1.1.2??8.5.1.1.3??8.5.1.1.4??8.5.1.2.1??8.5.1.2.2??8.5.1.2.3??8.5.1.2.4
8.5.1.3.1??8.5.1.3.2??8.5.1.3.3??8.5.1.3.4??8.5.1.4.1??8.5.1.4.2??8.5.1.4.3??8.5.1.4.4
8.5.1.5.1??8.5.1.5.2??8.5.1.5.3??8.5.1.5.4??8.5.1.6.1??8.5.1.6.2??8.5.1.6.3??8.5.1.6.4
8.5.1.7.1??8.5.1.7.2??8.5.1.7.3??8.5.1.7.4??8.5.1.8.1??8.5.1.8.2??8.5.1.8.3??8.5.1.8.4
8.5.2.1.1??8.5.2.1.2??8.5.2.1.3??8.5.2.1.4??8.5.2.2.1??8.5.2.2.2??8.5.2.2.3??8.5.2.2.4
8.5.2.3.1??8.5.2.3.2??8.5.2.3.3??8.5.2.3.4??8.5.2.4.1??8.5.2.4.2??8.5.2.4.3??8.5.2.4.4
8.5.2.5.1??8.5.2.5.2??8.5.2.5.3??8.5.2.5.4??8.5.2.6.1??8.5.2.6.2??8.5.2.6.3??8.5.2.6.4
8.5.2.7.1??8.5.2.7.2??8.5.2.7.3??8.5.2.7.4??8.5.2.8.1??8.5.2.8.2??8.5.2.8.3??8.5.2.8.4
8.5.3.1.1??8.5.3.1.2??8.5.3.1.3??8.5.3.1.4??8.5.3.2.1??8.5.3.2.2??8.5.3.2.3??8.5.3.2.4
8.5.3.3.1??8.5.3.3.2??8.5.3.3.3??8.5.3.3.4??8.5.3.4.1??8.5.3.4.2??8.5.3.4.3??8.5.3.4.4
8.5.3.5.1??8.5.3.5.2??8.5.3.5.3??8.5.3.5.4??8.5.3.6.1??8.5.3.6.2??8.5.3.6.3??8.5.3.6.4
8.5.3.7.1??8.5.3.7.2??8.5.3.7.3??8.5.3.7.4??8.5.3.8.1??8.5.3.8.2??8.5.3.8.3??8.5.3.8.4
8.5.4.1.1??8.5.4.1.2??8.5.4.1.3??8.5.4.1.4??8.5.4.2.1??8.5.4.2.2??8.5.4.2.3??8.5.4.2.4
8.5.4.3.1??8.5.4.3.2??8.5.4.3.3??8.5.4.3.4??8.5.4.4.1??8.5.4.4.2??8.5.4.4.3??8.5.4.4.4
8.5.4.5.1??8.5.4.5.2??8.5.4.5.3??8.5.4.5.4??8.5.4.6.1??8.5.4.6.2??8.5.4.6.3??8.5.4.6.4
8.5.4.7.1??8.5.4.7.2??8.5.4.7.3??8.5.4.7.4??8.5.4.8.1??8.5.4.8.2??8.5.4.8.3??8.5.4.8.4
8.6.1.1.1??8.6.1.1.2??8.6.1.1.3??8.6.1.1.4??8.6.1.2.1??8.6.1.2.2??8.6.1.2.3??8.6.1.2.4
8.6.1.3.1??8.6.1.3.2??8.6.1.3.3??8.6.1.3.4??8.6.1.4.1??8.6.1.4.2??8.6.1.4.3??8.6.1.4.4
8.6.1.5.1??8.6.1.5.2??8.6.1.5.3??8.6.1.5.4??8.6.1.6.1??8.6.1.6.2??8.6.1.6.3??8.6.1.6.4
8.6.1.7.1??8.6.1.7.2??8.6.1.7.3??8.6.1.7.4??8.6.1.8.1??8.6.1.8.2??8.6.1.8.3??8.6.1.8.4
8.6.2.1.1??8.6.2.1.2??8.6.2.1.3??8.6.2.1.4??8.6.2.2.1??8.6.2.2.2??8.6.2.2.3??8.6.2.2.4
8.6.2.3.1??8.6.2.3.2??8.6.2.3.3??8.6.2.3.4??8.6.2.4.1??8.6.2.4.2??8.6.2.4.3??8.6.2.4.4
8.6.2.5.1??8.6.2.5.2??8.6.2.5.3??8.6.2.5.4??8.6.2.6.1??8.6.2.6.2??8.6.2.6.3??8.6.2.6.4
8.6.2.7.1??8.6.2.7.2??8.6.2.7.3??8.6.2.7.4??8.6.2.8.1??8.6.2.8.2??8.6.2.8.3??8.6.2.8.4
8.6.3.1.1??8.6.3.1.2??8.6.3.1.3??8.6.3.1.4??8.6.3.2.1??8.6.3.2.2??8.6.3.2.3??8.6.3.2.4
8.6.3.3.1??8.6.3.3.2??8.6.3.3.3??8.6.3.3.4??8.6.3.4.1??8.6.3.4.2??8.6.3.4.3??8.6.3.4.4
8.6.3.5.1??8.6.3.5.2??8.6.3.5.3??8.6.3.5.4??8.6.3.6.1??8.6.3.6.2??8.6.3.6.3??8.6.3.6.4
8.6.3.7.1??8.6.3.7.2??8.6.3.7.3??8.6.3.7.4??8.6.3.8.1??8.6.3.8.2??8.6.3.8.3??8.6.3.8.4
8.6.4.1.1??8.6.4.1.2??8.6.4.1.3??8.6.4.1.4??8.6.4.2.1??8.6.4.2.2??8.6.4.2.3??8.6.4.2.4
8.6.4.3.1??8.6.4.3.2??8.6.4.3.3??8.6.4.3.4??8.6.4.4.1??8.6.4.4.2??8.6.4.4.3??8.6.4.4.4
8.6.4.5.1??8.6.4.5.2??8.6.4.5.3??8.6.4.5.4??8.6.4.6.1??8.6.4.6.2??8.6.4.6.3??8.6.4.6.4
8.6.4.7.1??8.6.4.7.2??8.6.4.7.3??8.6.4.7.4??8.6.4.8.1??8.6.4.8.2??8.6.4.8.3??8.6.4.8.4
Table 1-is continuous
8.7.1.1.1??8.7.1.1.2??8.7.1.1.3??8.7.1.1.4??8.7.1.2.1??8.7.1.2.2??8.7.1.2.3??8.7.1.2.4
8.7.1.3.1??8.7.1.3.2??8.7.1.3.3??8.7.1.3.4??8.7.1.4.1??8.7.1.4.2??8.7.1.4.3??8.7.1.4.4
8.7.1.5.1??8.7.1.5.2??8.7.1.5.3??8.7.1.5.4??8.7.1.6.1??8.7.1.6.2??8.7.1.6.3??8.7.1.6.4
8.7.1.7.1??8.7.1.7.2??8.7.1.7.3??8.7.1.7.4??8.7.1.8.1??8.7.1.8.2??8.7.1.8.3??8.7.1.8.4
8.7.2.1.1??8.7.2.1.2??8.7.2.1.3??8.7.2.1.4??8.7.2.2.1??8.7.2.2.2??8.7.2.2.3??8.7.2.2.4
8.7.2.3.1??8.7.2.3.2??8.7.2.3.3??8.7.2.3.4??8.7.2.4.1??8.7.2.4.2??8.7.2.4.3??8.7.2.4.4
8.7.2.5.1??8.7.2.5.2??8.7.2.5.3??8.7.2.5.4??8.7.2.6.1??8.7.2.6.2??8.7.2.6.3??8.7.2.6.4
8.7.2.7.1??8.7.2.7.2??8.7.2.7.3??8.7.2.7.4??8.7.2.8.1??8.7.2.8.2??8.7.2.8.3??8.7.2.8.4
8.7.3.1.1??8.7.3.1.2??8.7.3.1.3??8.7.3.1.4??8.7.3.2.1??8.7.3.2.2??8.7.3.2.3??8.7.3.2.4
8.7.3.3.1??8.7.3.3.2??8.7.3.3.3??8.7.3.3.4??8.7.3.4.1??8.7.3.4.2??8.7.3.4.3??8.7.3.4.4
8.7.3.5.1??8.7.3.5.2??8.7.3.5.3??8.7.3.5.4??8.7.3.6.1??8.7.3.6.2??8.7.3.6.3??8.7.3.6.4
8.7.3.7.1??8.7.3.7.2??8.7.3.7.3??8.7.3.7.4??8.7.3.8.1??8.7.3.8.2??8.7.3.8.3??8.7.3.8.4
8.7.4.1.1??8.7.4.1.2??8.7.4.1.3??8.7.4.1.4??8.7.4.2.1??8.7.4.2.2??8.7.4.2.3??8.7.4.2.4
8.7.4.3.1??8.7.4.3.2??8.7.4.3.3??8.7.4.3.4??8.7.4.4.1??8.7.4.4.2??8.7.4.4.3??8.7.4.4.4
8.7.4.5.1??8.7.4.5.2??8.7.4.5.3??8.7.4.5.4??8.7.4.6.1??8.7.4.6.2??8.7.4.6.3??8.7.4.6.4
8.7.4.7.1??8.7.4.7.2??8.7.4.7.3??8.7.4.7.4??8.7.4.8.1??8.7.4.8.2??8.7.4.8.3??8.7.4.8.4
8.8.1.1.1??8.8.1.1.2??8.8.1.1.3??8.8.1.1.4??8.8.1.2.1??8.8.1.2.2??8.8.1.2.3??8.8.1.2.4
8.9.1.3.1??8.8.1.3.2??8.8.1.3.3??8.8.1.3.4??8.8.1.4.1??8.8.1.4.2??8.8.1.4.3??8.8.1.4.4
8.8.1.5.1??8.8.1.5.2??8.8.1.5.3??8.8.1.5.4??8.8.1.6.1??8.8.1.6.2??8.8.1.6.3??8.8.1.6.4
8.8.1.7.1??8.8.1.7.2??8.8.1.7.3??8.8.1.7.4??8.8.1.8.1??8.8.1.8.2??8.8.1.8.3??8.8.1.8.4
8.8.2.1.1??8.8.2.1.2??8.8.2.1.3??8.8.2.1.4??8.8.2.2.1??8.8.2.2.2??8.8.2.2.3??8.8.2.2.4
8.8.2.3.1??8.8.2.3.2??8.8.2.3.3??8.8.2.3.4??8.8.2.4.1??8.8.2.4.2??8.8.2.4.3??8.8.2.4.4
8.8.2.5.1??8.8.2.5.2??8.8.2.5.3??8.8.2.5.4??8.8.2.6.1??8.8.2.6.2??8.8.2.6.3??8.8.2.6.4
8.8.2.7.1??8.8.2.7.2??8.8.2.7.3??8.8.2.7.4??8.8.2.8.1??8.8.2.8.2??8.8.2.8.3??8.8.2.8.4
8.8.3.1.1??8.8.3.1.2??8.8.3.1.3??8.8.3.1.4??8.8.3.2.1??8.8.3.2.2??8.8.3.2.3??8.8.3.2.4
8.8.3.3.1??8.8.3.3.2??8.8.3.3.3??8.8.3.3.4??8.8.3.4.1??8.8.3.4.2??8.8.3.4.3??8.8.3.4.4
8.8.3.5.1??8.8.3.5.2??8.8.3.5.3??8.8.3.5.4??8.8.3.6.1??8.8.3.6.2??8.8.3.6.3??8.8.3.6.4
8.8.3.7.1??8.8.3.7.2??8.8.3.7.3??8.8.3.7.4??8.8.3.8.1??8.8.3.8.2??8.8.3.8.3??8.8.3.8.4
8.8.4.1.1??8.8.4.1.2??8.8.4.1.3??8.8.4.1.4??8.8.4.2.1??8.8.4.2.2??8.8.4.2.3??8.8.4.2.4
8.8.4.3.1??8.8.4.3.2??8.8.4.3.3??8.8.4.3.4??8.8.4.4.1??8.8.4.4.2??8.8.4.4.3??8.8.4.4.4
8.8.4.5.1??8.8.4.5.2??8.8.4.5.3??8.8.4.5.4??8.8.4.6.1??8.8.4.6.2??8.8.4.6.3??8.8.4.6.4
8.8.4.7.1??8.8.4.7.2??8.8.4.7.3??8.8.4.7.4??8.8.4.8.1??8.8.4.8.2??8.8.4.8.3??8.8.4.8.4
The example of formula VII chemical compound includes, but is not limited to following table viia and listed chemical compound and pharmaceutically acceptable salt and the prodrug of table viib:
Table viia
Table viib
Insulin secretagogue
On the one hand, preferably use at least a FBP enzyme inhibitor and at least a insulin secretagogue.The effect target of insulin secretagogue is for eliminating one of three major defects relevant with diabetes, i.e. pancreatic beta cell dysfunction.Insulin secretagogue is the chemical compound that stimulates insulin to be discharged by pancreatic beta cell, thus can be by improving glucose tolerance and/or reduce the fasting blood glucose, and/or reduce hematochrome Alc level and improve Blood glucose control.These effects may relate to minimizing, the insulin-mediated of the whole improvement that glucose is handled, liver glucose output glycogenesis increase, reduce the index of steatolysis and/or the reaction of other raising insulin secretion.In some cases, insulin secretagogue of the present invention also can reduce circulation triglyceride and/or free fatty acid, also can increase the HDL cholesterol levels, can the hypercholesterolemia reducing level, can reduce fasting insulin and insulin C-peptide level, can reduce appetite and/or can postpone gastric emptying.
Insulin secretagogue be exemplified as such chemical compound, promptly they can combine with the ATP dependency potassium channel on the pancreatic beta cell, make the closed justacrine insulin of this passage thus.These chemical compounds comprise as sulphanylureas chemical compound and non-sulphanylureas chemical compound.
Sulphanylureas
Since the mid-1960s, sulphanylureas has been widely used in clinical.Although sulphanylureas has been represented treatment NIDDM patient's main Therapeutic Method,, four kinds of effects limit their development.
First, in diabetics, have many patients sulphanylureas treatment not to be produced enough reactions (promptly this kind Therapeutic Method produces preliminary failure (primaryfailure) in the patient of about 20-25%), perhaps with the diabetics of sulphanylureas treatment to treatment generation resistance (promptly this kind Therapeutic Method produces secondary fail (secondary failure) every year in the patient of about 5-10%).It is believed that secondary failure is to be subjected to due to the undue stimulation of sulphanylureas by pancreas, is toxic action comprehensive of high lipid level on high blood glucose and the β cell.
The second, the sulphanylureas treatment causes that the danger of serious hypoglycemic episodes increases.As everyone knows, serious hypoglycemic episodes causes affected individual dangerous increasing.
The 3rd, chronic hyperinsulinemia can cause cardiovascular disease.But this dependency is not also specifically confirmed.
At last, sulphanylureas causes weight increase.Weight increase is that people do not wish to take place, because weight increase causes periphery that the sensitivity of insulin is worsened, thereby quickens the deterioration of this disease.
The mechanism of action of sulphanylureas relates to the ad hoc structure territory of adenosine triphosphate (the ATP)-dependency potassium channel of β cell, and is promptly so-called " sulfonylureas receptor " or SUR1.By combination like this, sulphanylureas suppresses the efflux of potassium ion.
Domain by second key of the potassium channel of isolating protein subunit coding forms part, Kir6.x for the ion hole.Referring to as Groop LC
Diabetes Care6:737-754 (1992); Luna B et al.
Diabetes26:895-915 (1999); Babenk AP, Aguilar Bryan L, Bryan J
Annu.Rev.Physiol60:667-87 (1998) and Aguilar-Bryan L et al Science 268:423-6 (1995).
Combine with SUR1 cell membrane depolarization and calcium ion are flowed into.Calcium and calmodulin, CaM form complex, stimulate the granule exocytosis that contains insulin as the second message,second messenger then, take this uelralante and enter blood circulation.The metabolism of two keys of insulin is consequently improved the Blood glucose control effect for increasing tissue (as muscular tissue) to the processing of glucose and the inhibition that liver glucose is exported.
The example of sulphanylureas comprises chemical compound, as glibenclamide, glimepiride and glipizide.Sulphanylureas is known, as U.S. patent the 2nd, 968,158; 3,097,242; 3,454,635; 3,501,495; 3,654,357; 3,668,215; 3,669,966 and 3.708.486 in address.
Particularly preferred sulphanylureas is the chemical compound of formula XV:
Wherein:
A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl; And B is selected from alkyl, cycloalkyl and Heterocyclylalkyl.
Preferred especially following sulphanylureas: glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
Non--sulphanylureas
The fugitive non-sulphanylureas Nateglinide (nateglinide) of benzyl (benzoic) and phenyl propyl (phenylproprionic) series and repaglinide by with the similar machine-processed stimulating pancreas uelralante of the mechanism of action of sulphanylureas.Referring to Panten U etc.
Biochem.Pharmacol.38:1217-1229 (1989); Grell W etc.
J.Med.Chem41:5219-5246 (1998); Priscilla A. etc.
Diabetes49 (suppl.1), 449 P (2000).But the effect of repaglinide is to combine mediation by the binding site with sulphur urea receptor, and is significantly different with the effect of glibenclamide.Referring to Diabetes 47:345-351 (1998) such as FuhlendorffJ.Another kind of is imidazoline (as Midaglizole, BTS-67582, isaglidole, deriglidole, idazoxan, efaroxan and fluparoxan) by making the closed non-sulphanylureas that insulin is discharged of potassium channel.Referring to Rustenbeck I etc.
Ann.NY Acad.Sci.881:229-240 (1999); Br.J.Pharmacol.127:1279-1287 such as MourtadaM (1999); Le Brigand L etc.
Br.J. Pharmacol128:1021-1026 (1999).Known these chemical compounds form part (Kir6.x) with the hole of passage and combine, rather than combine with sulphanylureas binding site (SURl).
The example of non-sulphanylureas comprises chemical compound, as benzoic acid derivative (as mitiglinide and repaglinide), benzyl propionate derivant (as Nateglinide) and imidazolidine derivatives (as BTS-67582 (Knoll Pharmaceuticals, Co.), Midaglizole, isaglidole, deriglidole, idazoxan, efaroxan and fluparoxan).Multiple in these non-sulphanylureas addressed in following patent literature and publication: WO 91/03247; WO 93/0337; WO 96/34870; WO 97/31019; WO 98/27078; WO 98/56378; WO 98/07681; WO00/71117; WO 01/26639; U.S.5,631,224 and U.S.5,741,926.
Particularly preferred non-sulphanylureas comprises mitiglinide, BTS-67582, repaglinide and Nateglinide.
The GLP-1 receptor stimulating agent
Another kind of insulin secretagogue is GLP-1 (comprise GLP-1 and GLP-1 fragment, comprise their an analog and functional derivatives and peptide mimics) receptor stimulating agent.These chemical compounds by with pancreatic beta cell on the GLP-1 receptors bind work, increase the release of the insulin that glucose stimulates thus by cAMP-dependency mechanism.This para-insulin sercretogogue is addressed in as the U.S. patent No. 5,118,666; 5,120,712; 5,545,618; 5,512,549; 5,574,008; 5,614,492; 5,631,224; 5,705,483; 5,766,620; 5,908,830; 5,958,909; 5,977,071; 5,981,488 and PCT publication number WO 87/06941 and WO99/25728 in.The example of the insulin secretagogue of these types comprises NN-2211 (SciosInc./Novo Nordisk A/S), exendin and exedin agonist.
DPP IV inhibitor
The insulin secretagogue of the third type can prolong the medicine of GLP-1 plasma half-life for those.These medicines comprise dipeptidyl peptidase (DPP)-IV inhibitor (as NVP-DPP728, P32/98 (Probiodrug) and valine pyrrolidide), and they stop the inactivation of the GLP-1 of DPP-IV mediation, thus the biological agent that prolongs GLP-1.These chemical compounds are addressed in following patent literature and publication, as: the open DE 2 9909208 of Deutsche Bundespatent; DE2 9909210; With DE 2 9909211; U.S. the patent No. 6,011, and 155; 6,107,317; 6,110,949; With 6,124,305; And PCT publication number WO 97/40832; WO98/19998; WO 99/61431; WO 99/67279; In WO 00/34241.
Other insulin secretagogue comprises glucagon-like peptide (GLP-1) receptor stimulating agent, as GLP-1, its fragment and analog and GLP-1 or its segmental functional derivatives.GLP-1 is an incretin, is by the L cell in the lower digestive tract feed generation response to be transcribed the back cracking to Proglucagon to be produced.The main action site of these insulin secretagogues is the β cell of pancreas, with the GLP-1 receptors bind after, can increase the release of the insulin that glucose stimulates by the mechanism of cAMP mediation.Referring to Diabetes Care 21:1925-31 (1998) such as Nauck MA.Because DPP-IV is to the tachymetabolism effect of GLP-1, so its action time is very short.
Once the someone addressed, and the analog of GLP-1 can increase above-mentioned metabolic toleration, therefore can increase its half-life in vivo.Referring to, as Diabetes40 (suppl.1) 943-P (2000) such as Sturis J.Also known GLP-1 analog increases the affinity of GLP-1 receptor.Referring to as Xiao Q etc.
Diabetes 46(Suppl.1) 941-P (2000).The example of GLP-1 agonist comprises NN-2211 (Scios Inc./Novo Nordisk A/S) and exendin.
The 3rd para-insulin sercretogogue comprises that those increase the chemical compound of GLP-1 drug effect half-life.For example, show that on evidence DPP-IV inhibitor (as NVP-DPP728) increases the blood plasma level of GLP-1, thereby prolong its stimulation insulin secretion.Referring to, as HolstJJ, Deacon CF
Diabetes47:1663-70 (1998) and Hughes TE etc.
Biochemistry38:11597-603 (1999).
The example of preferred DPP-IV inhibitor comprises valine pyrrolidide, NVP-DPP728 and P32/98 (Probiodrug).
Preferred insulin secretagogue is those disclosed in following publication and patent.Sulphanylureas:
U.S. the patent No. 2,968, and 158; 3,097,242; 3,454,635; 3,501,495; 3,654,357; 3,668,215; 3,669,966 and 3,708,486.
2. non-sulphanylureas:
U.S. the patent No. 5,631, and 224 and 5,741,926; PCT publication number WO 91/03247; WO 93/00337; WO 96/34870; WO 97/31019; WO 98/07681; WO98/27078; WO 98/56378; WO 00/71117 and WO 01/26639.
3.GLP-1 receptor stimulating agent:
U.S. the patent No. 5,118, and 666; 5,120,712; 5,512,549; 5,545,618; 5,574,008; 5,614,492; 5,631,224; 5,705,483; 5,766,620; 5,908,830; 5,958,909; 5,977,071 and 5,981,488 and PCT publication number WO 87/06941 and WO99/25728.
4.DPP-IV inhibitor:
German patent publication No. DE 2 9909208; DE 2 9909210; With DE 2 9909211; The U.S patent No. 6,011,155; 6,107,317; 6,110,949 and 6,124,305; And PCT publication number WO 97/40832; WO 98/19998; WO 99/61431; WO 99/67278; WO 99/67279; With WO 00/34241.
Although these disclosures comprise a large amount of insulin secretagogues, the present invention is not so limited, and can adopt any insulin secretagogue chemical compound.
Being used for insulin secretagogue of the present invention generally all shows active in the known evaluation that is used for the chemical compound of insulin secretagogue.This class measure include, but is not limited to identify following active those: (a) lead by the pancreas of pancreas or β cell uelralante (embodiment H), (b) secretion of insulin (embodiment L) in the rat, (c) the rat glucose reduces (example I) on an empty stomach, (d) vein of empty stomach rat or the toleration (embodiment J and K) that per os gives glucose, (e) inhibition (embodiment M) of the ATP-dependency potassium channel of pancreatic beta cell, (f) with combine (the embodiment N) of sulphur urea receptor, (g) with the combining and (h) inhibition of DPP-IV (embodiment O) of GLP-1 receptor.Mensuration in addition is included in those that describe in the following document: J.Biol.Chem.269:1041-45 (1994) such as Bergsten P; J.Biol.Chem.270:788289 (1995) such as Frodin M; Eur.J.Pharmacol.339:69-76 (1997) such as Dickinson K; Eur.J.Pharmacol.335:227-234 (1997) such as Ladriere L; Edwards G.Weston AH Ann.Rev.Pharmacol.Toxicol.33:597-637 (1993); Science 268:423-6 (1995) such as Aguilar-Bryan L; Diabetes 42:1678-82 (1993) such as Thorens B; Deacon CF, Hughes TE, Holst JJ Diabetes 47:764-9 (1998).Particularly preferred insulin secretagogue is glibenclamide, glipizide and glimepiride, mitiglinide, BTS-67582, repaglinide and Nateglinide.
As desired according to their mechanism of action, insulin secretagogue mainly acts on the early stage of NIDDM, and in this stage, the insulin secretion activity of all or part pancreas also keeps.As, the usefulness of sulphanylureas just can significantly reduce at NIDDM late period, and this is serious disturbed relevant with the β cell function, reduces insulin secretion thus.Referring to Groop LCDiabetes Care 15:737-54 (1992).These medicines can reflect (being about 20-25% and 5-10% every year respectively) by their high first property and Secondary cases mortality to the dependency of functional β cell.Referring to Gerich JE N.Engl?J?Med。321：1231-45(1989)。
Generally speaking, insulin secretagogue treatment deficiency is so that patient's blood sugar recovery is normal or make the horizontal normalization of hematochrome Alc (HbAlc).For example, second filial generation sulphanylureas is 0.8-1.7% to the meansigma methods that hematochrome Alc value reduces, and is 50-70mg/dL to the reduction level of fasting blood glucose.Referring to, Horm.Metab.Res.28:426-9 (1996) such as Dills DJ for example; Diabetes Care 19:883-4 (1996) such as Mooradian AD; Diabetes Care 20:597-606 (1997) such as Simonson DC.But, among the NIDDM patient, make these parameters return to the general needs assessment reduction＞140mg/dl of normal level and＞3% late.
Opposite with insulin secretagogue, the FBP enzyme inhibitor to early diabetes and late period diabetes all effective.Zooscopy shows, the FBP enzyme inhibitor ' hyperinsulinemia db/db mice (early diabetes model (EXAMPLE V) and late period diabetes model: the inductive diabetes rat of streptozocin that insulin secretion reduces) can significantly reduce blood glucose levels.A kind of model in back is widely used as the type i diabetes model, and this shows that the FBP enzyme inhibitor has potential application aspect this.In the ZDF rat, FBP enzyme inhibitor ' all effective in diabetes (8-9 age in week, embodiment W) and the diabetes in late period (16 all ages) in early days.
Based on the pharmacological action pattern of above-mentioned insulin secretagogue and FBP enzyme inhibitor, the Therapeutic Method that insulin secretagogue combines with the FBP enzyme inhibitor can effectively be treated the patient of wide region.For early diabetes, FBP enzyme inhibitor and insulin secretagogue are all in full force and effect.Although people have been fully recognized that the effect of insulin to liver glucose output, but the Therapeutic Method that insulin secretagogue and FBP enzyme inhibitor combine not only can be improved Blood glucose control (embodiment X) to early diabetes, but also can reduce the incidence rate that secondary is failed, this often is observed (embodiment Y) in the monotherapy that adopts insulin secretagogue.In the diabetes, insulin secretagogue has first high property mortality late, and only part is effective, and the FBP enzyme inhibitor then keeps very high usefulness.To the advantage that late period, diabetes were carried out therapeutic alliance is to make the not aitiogenic patient's number of treatment is significantly reduced and the overall degree of glycemic control is improved.Although the initial reaction of therapeutic alliance of diabetes may major part be because the FBP enzyme inhibitor to late period ' due to the treatment, but blood-glucose reduces and can improve the function of pancreas and make insulin secretagogue prolongation in time more effective, and therefore can improve reaction and increase Blood glucose control to insulin secretagogue for a long time.
To be them have unexpected effect to carbohydrate and/or lipid and/or Proteometabolism to another significant advantage of insulin secretagogue and the therapeutic alliance of FBP enzyme inhibitor.
Another advantage of described therapeutic alliance is the side effect that the FBP enzyme inhibitor can alleviate insulin secretagogue, and vice versa.A serious consequence of insulin secretagogue treatment is a hyperinsulinemia, causes promoting weight increase thus, and causes the unwanted side effect of insulin resistance deterioration and patient's hypoglycemic episodes successively.Hyperinsulinemia also causes the increase of trunk disease risks.Insulin secretagogue is possibility overstimulation pancreas also, and therefore accelerate the failure of β cytopathy and secondary.Equally, the FBP enzyme inhibitor may have unwanted side effect to the people.For example, the FPB inhibitor may cause the of short duration rising of blood glucose lactate levels.As described in embodiment X, FBP enzyme inhibitor ' and the therapeutic alliance of insulin secretagogue (glibenclamide) can raise to the blood lactic acid salt level that causes by FBP enzyme inhibitor monotherapy and produce the unexpected effect that alleviates.
Insulin/insulin analog
On the other hand, preferably use FBP enzyme inhibitor and insulin or insulin analog.Insulin is peptide hormone (molecular weight is about 6000), it be pancreatic beta cell to the metabolisable energy material of key such as aminoacid, triose such as glyceraldehyde, the most important thing is glucose take place response generation and discharge into blood circulation.The major physiological of insulin act as the dynamic equilibrium of regulating glucose.Once secretion, insulin promptly combines with specific receptor on the cell surface, and amplify the various processes of regulating by the signal cascade of complexity, comprise that tissue (as muscular tissue and fatty tissue) is to the picked-up of glucose and the inhibition of liver glucose generation (" liver glucose generation ", i.e. HGO).It is believed that insulin mainly is to be that the flux of the approach of gluconeogenesis reaches by reducing by producing glucose again to the inhibitory action of HGO.Insulin is mediated by number of mechanisms the inhibitory action of gluconeogenesis, comprise: (a) reduce key precursor such as glycerol, lactate and amino acid whose supply, (b) increase liver fructose 2, the level of 6-diphosphonic acid, be fructose 1,6-diphosphatase inhibitor and (c) to reduce by 3 kinds of main gluconeogenesis enzymes be phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase.Referring to Diabetes Mellitus, eds.LeRoith?D，Taylor?SI，Olefsky?GM，LippincottRaven?Publishers，Philadelphia(1996)。
Insulin is generally the basis of treatment IDDM.And insulin also is one of best approach of treatment NIDDM normally.It is applied in several main expection randomized clinical trials and is estimated.For example, the result to early diabetes (UKPDS test) and diabetes in late period (VACSDM test) treatment shows that it is effective adopting the insulin monotherapy.Referring to UK Prospective Diabetes Study group, Diabetes 44:1249 (1995); Colwell JA, Ann.Intern.Med 124:131 (1996).The UKPDS result of the test shows, in early days insulin is regulated and can be reduced microvascular complication and significantly reduce the trunk complication.Yet because the continuous increase of insulin resistance, regular or intensive employing insulinize can not stably keep the Blood glucose control effect during the research in 6 years.In the VACSDM test, included the patient of sulphur urea treatment failure in, 1/3rd patient's blood glucose can not be controlled, and, in general, also need the insulin of heavy dose of and multiple dose could control the level of glucose in the blood for remaining patient.Insulinize causes that body weight significantly increases (this increases relevant with insulin resistance), hypertension and lipidosis, and all these all are to bring out the cardiovascular disease risk factor.
Traditionally, insulin obtains from cattle and the separation and purification of Pancreas Sus domestica gland.Nearest development owing to recombinant technique just makes can be at the produced in vitro insulin human.In the U.S., the general practice is all to adopt the insulin human of reorganization in carrying out all patients of insulinize at present, also adopts the insulin and the insulin analog of various purification.Can obtain the various mixture of various quick actings, middle effect or long lasting preparation and described preparation.Being used for insulin preparation of the present invention comprises: Humulin N, Humulin N NPH, Humulin N NPHPen, Novolin N Human Insulin Vial, Novolin N PenFill Cartridges, Novolin N Prefilled Syringe Disposable Insulin Delivery System, Humulin R Regular, Humulin R, Humulin R Regular Cartridge, NovolinR Human Insulin Vial, Novolin R PenFill Cartridges, Novolin R PrefilledSyringe Disposable Insulin Delivery System, Velosulin BR HumanInsulin Vials, NovoPen, Humulin 50/50, Humulin 70/30, Humulin 70/30Cartridge, Humulin 70/30 Pen, Novolin 70/30 Human Insulin Vials, Novolin 70/30 Penfill Cartridges, Novolin 70/30 Prefilled DisposableInsulin Delivery System, Humulin L, Humulin U, Novolin L humanInsulin Vials, Iletin II, NPH (Pork), Purified Pork NPH Isophane Insulin, Iletin II Regular (Pork), Purified Pork Regular Insulin, Iletin II, Lente (Pork), Purified Pork Lente Insulin.Be used for other insulin types of the present invention and be set forth in US 5,149,716; WO 92/00321 and WO 99/65941.The invention is not restricted to these specific formulation, but can adopt any insulin or the insulin analog that gives by injection, suction, subcutaneous, oral, implantable pump or any other mode.Be used for insulin analog of the present invention and include, but is not limited to following material: insulin lispro, insulin aspart and insulin glargine.Some new analog/preparation comprises suction insulin (as AERx, Spiros and Aerodose) and oral insulin (as Oralin, Macrulin and M2).These analog are set forth in following publication/patent documentation: Heller SR, Amiel SA, Mansell P Diabetes Care 22:1607-1611 (1999); Raskin P, Guthrie RA, Leiter L, RiisA, Jovanovic L Diabetes Care 23:583-588 (2000); Heinemann L, Linkeschova R, Rave K et al Diabetes Care 23:644-649 (2000); EP-00622376; US 5,681, and 811 and US 5,438,040.
According to Kristensen C, Wiberg FC, Schaffer L.Andersen AS measures in method described in the J.Biol.Chem 273:1778-1786 (1998), and the dissociation constant of preferred insulin and solubility Recombulin receptors bind is 0.03nM-300nM.More preferably dissociation constant is 0.3nM-30nM.
FBP enzyme inhibitor of the present invention also can be used to implant " artificial pancreas " patient of (that is, having can be in response to the raise pancreas of the cell that produces insulin of glucose level as recombined human pancreatic beta cell or other).The method that is used to the insulin analog identifying insulin or have ILA is known, for example comprise combine with Insulin receptor INSR, the activation of insulin receptor tyrosine kinase, the phosphorylation of IRS and the interaction of these substrates and downstream signaling molecule.
Although known insulin is inhibited to gluconeogenesis, the therapeutic alliance of FBP enzyme inhibitor and insulin or insulin analog significantly remains surprisingly greater than the effect that any medicine uses separately the effect that glycemic control produces.This can be proved (embodiment Z, AA, BB and CC) in fat NIDDM patient's crucial model (db/db mice) and fragile NIDDM patient's model (Goto-Kakizaki rat).In addition, by drug combination, reduce insulin dose and get final product blood sugar control.Therefore, the invention enables and to treat diabetes in safer and more effective mode.
Another advantage of therapeutic alliance is the side effect that the FBP enzyme inhibitor can alleviate insulin or insulin analog treatment generation, and vice versa.A serious consequence of insulin or insulin analog treatment is a hyperinsulinemia, causes promoting weight increase thus.Known weight increase makes the insulin resistance situation worsen (thereby causing hyperinsulinism), hypertension and lipidosis.Hyperinsulinemia also causes the increase of trunk disease risks.The presentation of results of embodiment A A and BB, therapeutic alliance significantly reduce the weight increase that adopts the insulin monotherapy to cause.The result of embodiment A A and BB also illustrates, gives the FBP enzyme inhibitor simultaneously and makes the dosage of insulin reduce greatly, and the glycemic control effect that can keep the insulin monotherapy to be produced simultaneously, this result is surprisingly.
This insulinize may reduce the risk of the above-mentioned side effect due to the insulinize.
Another significant advantage of FBP enzyme and insulin combination treatment is that carbohydrate and/or lipid and/or protein metabolism are had unexpected beneficial effect.
Biguanide
Biguanides is a series of chemical compound, comprises metformin, phenformin and buformin.These chemical compounds have following general formula: (R
1R
2) NC (NH) NHC (NH) NH
2, R wherein
1And R
2Comprise H, alkyl, aryl, aralkyl etc., and comprise the salt and the standard prodrug of these chemical compounds.Since nineteen ninety-five, metformin has been put on market in the U.S. and has been used for the treatment of NIDDM.People it be unclear that the mechanism of action of this compounds, but it is believed that its significant feature mode is to suppress liver to produce glucose.Referring to Inzucchi SE, MaggsDG, N.Engl.J.Med.338:867-872 (1998) such as Spollett GR.All have this type of active biguanide compound that can easily prove and all can be used among the present invention.According to Wollen N, Bailey CJ measures in method described in the Biochem.Pharmacol.37:4353-4358 (1998), and in the presence of insulin, it is the IC of glucose that preferred biguanides suppresses rat hepatocytes gluconeogenesis lactate
50Be 10nM-100 μ M.More preferably IC
50Be 1 μ M-30 μ M.Preferred biguanides also can be offset glucagon (glucacon) stimulation in rats hepatocyte makes lactate be converted into glucose.Referring to Yu B, Pugazhenthi S, Khandlewal RL, Biochem.Pharmacol.48:949-954 (1994).The IC of preferred chemical compound
50Be 0.1-5000 μ M.More preferably IC
50Be 0.1-500 μ M.
In yet another aspect, preferably use FBP enzyme inhibitor and biguanide.Metformin is for being used for the treatment of the biguanide of NIDDM since nineteen fifty-seven.For many years, it is believed that metformin is derived from it to the raising of periphery insulin sensitivity with to the reduction of carbohydrate absorption after the meal to the reduction effect of glucose.At present, it is believed that metformin mainly is to work by the generation that reduces endogenous glucose.Referring to Inzucchi SE, Maggs DG, Spollett GR etc. are in N.Engl.J.Med.338:867-872 (1998).A large amount of evidences show, the effect that metformin produces the drug resistance glucose is because it is to due to the inhibition of liver gluconeogenesis.To studies show that isolating perfusion (perfused) liver and hepatocyte from animal carry out, metformin reduces the gluconeogenesis that is produced by multiple substrate (comprising lactate, pyruvate, alanine, glutamine and glycerol) by producing synergistic mechanism of action with insulin.Referring to Wiernsperger NF and Bailey CJ Drugs 58 (suppl.1): 31-39 (1999).The research of recently type 2 diabetes mellitus being carried out shows that also metformin is by reducing the generation that gluconeogenesis suppresses endogenous glucose.Referring to Hundal RS, Krassak M, Diabetes 49 (suppl.1) 154 OR (2000) such as Laurent D.People it be unclear that the inhibiting mechanism of action of this kind, but infer the stimulation of the reduction of absorbing with the liver of gluconeogenesis precursor and/or gluconokinase and the stimulation of glycolytic pathway is relevant in contrast to this.
Metformin is one of medicine that is studied in U.K.Prospective Diabetes Study (UKPDS), and the blood glucose that the research has been analyzed the type 2 diabetes mellitus patient tightens control whether to reduce the sickness rate of clinical complication.Reported result of study in 1998, although show metformin abundant blood sugar control at first, the forfeiture effect gradually of the treatment stage in 6 years, metformin to this big multiple center trial; When the research finishes, only there is 41% patient's blood glucose can access enough control.Result of study for insulin and the treatment of sulphur urea is disappointing equally.This research has been strengthened people to the new antidiabetic treatment method and the needs of medicine.Referring to U.K.Prospective Diabetes Study GroupDiabetes 44:1249-1258 (1995).
At present, at U.S.'s metformin (hydrochlorate) be the prescription drug (" Glucophage ", Bristol-Myers Squibb) of oral tablet form.Metformin is preferred biguanides.Be used for other biguanides of the present invention and comprise phenformin and buformin.Those that are used for that other metformin preparations of the present invention include, but is not limited to that following patent literature/publication describes:
U.S. Patent number 3,174,901 disclose phosphate, sulfate, hydrobromate, Salicylate, maleate, benzoate, succinate, esilate, fumarate and the glycol hydrochlorate of metformin;
U.S. Patent number 4,835,184 disclose the p-chlorobenzene ethoxyacetic acid salt of metformin;
U.S. Patent number 6,031,004 discloses the fumarate of metformin;
U.S. Patent number 4,028,402 disclose metformin dichloro-acetate.
French Patent (FRP) numbers 2320735 and 2037002 discloses the pamoate of metformin;
French Patent (FRP) numbers 2264539 and Japanese Patent No. 66008075 disclose the Orotate of metformin;
French Patent (FRP) numbers 2275199 discloses (4-chloro phenoxy group) isobutyrate of metformin;
U.S. Patent number 4,080,472 disclose the clofibric acid salt of metformin;
U.S. Patent number 3,957,853 disclose the acetylsalicylic acid salt of metformin;
French Patent (FRP) numbers 2220256 discloses the theophylline-7-acetate of metformin;
German patent 2357864 and 1967138 discloses the nicotinate of metformin;
U.S. Patent number 3,903,141 disclose the adamantoate of metformin;
Japanese Patent No. 69008566 discloses the CHLOROPHYLLINE zinc salt of metformin;
Japanese Patent No. 64008237 discloses the hydroxy acid salt of metformin, comprises the salt of hydroxyl aliphatic dicarboxylic acid such as mesotartaric acid, tartaric acid, mesoxalic acid and the maleate of oxidation;
Japanese Patent No. 63014942 discloses the tannate of metformin;
Japanese Patent No. 87005905 and 61022071 discloses 3-methyl-pyrazoles-5-carboxylic acid (or other 5-unit heterocyclic radical carboxylic acid) salt of metformin;
Romanian Patent No.82052 discloses the sulfoamino-group aryloxy alkyl carboxylate of metformin;
Soviet Union Patent No.992512 discloses the trimethoxybenzoic acid salt of metformin;
WO?99/29314A1
WO?99/47128Al
WO?98/10786A2
EP-00976395
WO?99/55320
WO?96/08243
Although it is believed that metformin mainly is to show its glucose reduction effect to the type 2 diabetes mellitus patient by suppressing gluconeogenesis, the independent employing effect that any medicine produced of the control action ratio that when FBP enzyme inhibitor and metformin therapeutic alliance blood glucose is produced is big (embodiment DD) surprisingly.
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another important benefit of FBP enzyme inhibitor and metformin therapeutic alliance.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the metformin treatment produces, and vice versa.A main metabolism complication of metformin treatment is a lactic acidosis.The sickness rate of this kind side effect is about 0.03 example/1000 patient's years.It is found that the biguanide medicine phenformin of structurally associated increases the risk of cardiovascular complication in the test that the UGDP research group carries out.The FBP enzyme inhibitor also has unwanted side effect to the people.
Alpha-glucosidase inhibitor
In yet another aspect, preferably adopt FBP enzyme inhibitor and Alpha-glucosidase inhibitor.Alpha-Glucosidase is one group and is responsible for the enzyme that carbohydrate digests in gastrointestinal tract.Referring to ElbeinAD FASEB J.5:3055 (1991).People are fully definite, suppress the rapid rising that alpha-Glucosidase can reduce the GLPP level of NIDDM, therefore can improve the toleration of glucose.Referring to Reaven GM, Lardinois CK, the DiabetesCare 13:32-36 (1990) of Greenfield MS etc.Under normal circumstances, complex carbohydrate is in the digestion of small intestinal near-end, and little complex carbohydrate then arrives the intestinal far-end.Can stop the digestion of carbohydrate with the Alpha-glucosidase inhibitor treatment, therefore can delay the absorption of carbohydrate, be digested by glucosidase at intestinal far-end (ileum) until complex carbohydrate at the intestinal near-end.The delaying of this carbohydrate digestion the peak value of post-prandial blood glucose after the dining and insulin is weakened and make day glucose and insulin level steady.Referring to Hillebrand I, BoehmeK, the Res.Exp.Med 175:81 (1979) of Frank G etc.
The most perfect Alpha-glucosidase inhibitor of people's exploitation is acarbose (Bayer), and this medicine is the pseudotetasaccharide of microbial source, and this medicine worldwide is approved for clinical at present.Most preferred Alpha-glucosidase inhibitor is acarbose, miglitol and voglibose.
Other preferred Alpha-glucosidase inhibitors comprise: miglitol, voglibose, emiglitate, MDL-25,637, camiglibose and MDL-73,945.
Preferred Alpha-glucosidase inhibitor can suppress saccharase and maltase, its IC
50Be 1nM-10 μ M (embodiment P).More preferably IC
50Be 1nM-1 μ M.
Be used for preferred Alpha-glucosidase inhibitor of the present invention in addition and be following patent literature describes those:
WO?98/57635
WO?99/29327
WO?98/09981
WO?97/09040
EP?0713873?A2
EP-00056194
DE-02758025
EP-410953-A
EP-427694-A
EP-406211-A
EP-409812-A
US?5,017,563
US?5,025,098
US?4,013,510
US?5,028,614
US?5,097,023
US?5,157,116
US?5,504,078
US?5,840,705
US?5,844,102
JP08040998A2
JP08289783A2
JP09048735A2
JP11236337A2
JP11286449A2
JP11029472A2
JP10045588A2
JP09104624A2
Although described a large amount of Alpha-glucosidase inhibitors in these publications, the present invention is not subjected to the restriction of these publications, can adopt any Alpha-glucosidase inhibitor in the present invention.Be used to identify that the method for Alpha-glucosidase inhibitor is known, and description is arranged in various kinds of document.
In fragile type (lean) the model Goto-Kakizaki of NIDDM rat, with respect to the treatment of adopting any independent medicine, FBP enzyme inhibitor and Alpha-glucosidase inhibitor therapeutic alliance have produced unexpected post-prandial glycemia control action (embodiment E E).Data show that the absorption of carbohydrate and gluconeogenesis are the key factors that influences level of postprandial blood sugar in the intestinal.
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of therapeutic alliance.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the Alpha-glucosidase inhibitor treatment produces, and vice versa.Known Alpha-glucosidase inhibitor has gastrointestinal side effect to the people and causes that serum transaminase raises.Equally, the FBP enzyme inhibitor also has side effect to the people.
The hepatic glucose output inhibitor
In yet another aspect, preferably adopt FBP enzyme inhibitor and hepatic glucose output inhibitor (as glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, dextrin agonist or fatty acid oxidation inhibitors).Hepatic glucose produces by two kinds of approach: gluconeogenesis (synthesis of glucose again) and glycogenolysis (storage glycogenolysis).Although gluconeogenesis is the main cause that glucose excessively is produced as the NIDDM hyperglycemia, glycogenolysis remains the key factor of HGO, so also be an important rake point of hyperglycemia treatment.A rate-limiting step in the glycogenolysis is catalytic by glycogen phosphorylase α, and this enzyme is that people study very sufficient a kind of enzyme, and it is a kind of enzyme of being regulated by multivalence substrate allosteric effector.Referring to Newgard CB, Hwang PK, Fletterick RJ Crit.Rev.Biochem.Mol.Biol.24:6999 (1989).Glycogen phosphorylase catalysis glycogen is cracked into glucose-1-phosphate.Two other enzyme that makes glucose be released into blood circulation is G-6-P isomerase and G-6-Pase.
People have reported two types glycogen phosphorylase: with near the glucalogue that combines the enzyme active sites and with the bonded caffeine in regulatory site I-site and other heteroaromatic analogue.It is reported that indole-2-carboxylic acid amides can be used as people's liver glycogen phosphorylase enzyme inhibitor and can reduce blood glucose levels behind orally give diabetes ob/ob mice.Referring to Hoover DJ, Lefkowitz-Snow S, the J.Med.Chem.41:2934-2938 (1998) of Burgess-Henry JL etc.People also describe piperidines and pyrrolidine inhibitors can reduce baseline and reduce the rat hepatocytes generation glucose (WO97/09040) that glucagon stimulates.
Measure in (embodiment Q) IC of preferred glycogen phosphorylase inhibitors at the recombined human glycogen phosphorylase
50Be 1nM-10 μ M.More preferably IC
50Be 1nM-1 μ M.
Be used for preferred glycogen phosphorylase inhibitors of the present invention and comprise CP91149, CP-316819 and CP-368296.Various inhibitor are addressed in following publication and patent documentation:
Hoover DJ, Lefkowitz-Snow S, the J.Med.Chem.41:2934-2938 (1998) of Burgess-Henry JL etc.
Martin JL, Veluraja K, the Biochemistry 30:10101-10116 (1991) of Ross K etc.
Watson KA, Mitchell EP, the Biochemistry 33:5745-5758 (1994) of Johnson LN etc.
Bichard CJF, Mitchell EP, the Tetrahedron Lett.36:2145-2148 (1995) of Wormald MR etc.
Krulle TM, Watson KA, the Tetrahedron Lett 36:8291-8294 (1995) of Gregorious M etc.
Kasvinsky PJ, Madsen NB, the J.Biol Chem 253:3343-3351 (1978) of Sygusch J
The J.Pharmacol.Exp.Ther 280:1312-1318 (1997) of Ercan-Fang N and Nuttall FQ
Kasvinsky PJ, Fletterick RJ, the Can.J.Biochem.59:387-395 of Madsen NB (1981)
Waagpetersen?HS，Westergaard?N，Schousboe?A?Neurochem.Int.36：435-440(2000)
Oikonomakos NG, Tsitsanou KE, the Protein Sci.8:1930-1945 (1999) of Zographos SE etc.
WO?95/24391
WO?97/09040
WO?98/50359
WO?96/03984
WO?96/03985
WO-98/40353
WO-97/09040
WO-96/39384
WO-96/39385
WO-98/50359
US?5,998,463
US-05998463
EP00978279
EP00832066
EP00832065
EP-01088824
EP-00978279
Although described a large amount of glycogen phosphorylase inhibitors in these publications, the present invention is not subjected to the restriction of these publications, can adopt any glycogen phosphorylase inhibitors in the present invention.Be used to identify that the method for glycogen phosphorylase inhibitors is known, and description is arranged in various kinds of document.
Although glycogen phosphorylase inhibitors is to show their reduction effects to glucose by the output that suppresses hepatic glucose, but with respect to the treatment of adopting any independent medicine, FBP enzyme inhibitor and glycogen phosphorylase inhibitors therapeutic alliance have produced unexpected glycemic control effect (embodiment F F).
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of FBP enzyme inhibitor and glycogen phosphorylase inhibitors therapeutic alliance.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the glycogen phosphorylase inhibitors treatment produces, and vice versa.
G-6-Pase catalysis G-6-P ester dephosphorylation, thus glucose produced.Because the G-6-P ester is liver gluconeogenesis and glycogenolytic common end-product, therefore suppresses this enzyme and can directly reduce hepatic glucose output.G-6-Pase is relevant with the multienzyme complex in the endocytoplasmic reticulum.Described multienzyme complex is made up of the specificity translocase in the endoplasmic reticulum, the phosphatase that is positioned at film chamber side and phosphoric acid translocase.Biochim.Biophys Acta 1092:129-137 (1990) referring to Burchell A and Waddell ID.Under all study conditions that carry out in animal, the activity of this multienzyme complex increases, and this causes blood glucose levels rising (as the streptozotocin treatment).In addition, clinical research shows that also observed glucose produces to increase in NIDDM increases relevant with the G-6-Pase activity.Referring to Clore JN, Stillman J, the Diabetes 49 (6) of Sugerman H: 969-74 (2000).
The IC of preferred G-6-Pase inhibitor
50Be 0.1nM-10 μ M (embodiment R).More preferably IC
50Be 0.1nM-300nM.
Being used for preferred G-6-Pase inhibitor of the present invention comprises by interacting with other necessary components (being translocase or phosphatase) of G-6-Pase itself or G-6-Pase multienzyme complex and suppresses the dephosphorylized chemical compound of G-6-P ester.The method of identifying the G-6-Pase inhibitor is known and addresses in various kinds of document.Hoecht report chlorogenic acid and benzoic acid derivative can suppress G-6-Pase, and Novo Nordisk has reported to have active tetrahydrotheinol pyridine derivate, and Pfizer has reported selectivity chlorogenic acid derivant.The example of these chemical compounds comprises S-0034 and S-4048.Representational G-6-Pase inhibitor is addressed in following publication and patent documentation:
Arion WJ, Canfield WK, the Arch.Biochem.Biophys.15:279-285 (1998) of Ramos FC etc.
Herling AW, Burger HJ, the Am.J.Physiol.274:G1087-1093 (1998) of Schwab D etc.
Parker JC, Van Volkenburg MA, the Diabetes 47:1630-1636 (1998) of Levy CB etc.
EP93114260.0
EP93114261.6
US?5,567,725
EP816329
EP0682024A1
WO?98/40385
Although described a large amount of G-6-Pase inhibitor in these publications, the present invention is not subjected to the restriction of these publications, can adopt any G-6-Pase inhibitor in the present invention.
Although the G-6-Pase inhibitor is to show their reduction effects to glucose by the output that suppresses hepatic glucose, but with respect to the treatment of adopting any independent medicine, FBP enzyme inhibitor and the therapeutic alliance of G-6-Pase inhibitor have produced unexpected glycemic control effect (embodiment YGG).
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of FBP enzyme inhibitor and the therapeutic alliance of G-6-Pase inhibitor.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the G-6-Pase inhibitor for treating produces, and vice versa.
Glucagon is by Proglucagon being transcribed the polypeptide hormone that post-treatment produces in the α of pancreas cell.The major physiological effect that glucagon produces jointly with insulin is to guarantee the short-term of blood glucose levels and long-term stability.Low plasma glucose excites the secretion of glucagon, and this chemical compound improves hepatic glucose output by the speed that increases glycogenolysis and gluconeogenesis.These effects are that described receptor can produce the positivity coupling by Gs albumen and adenyl cyclase by the mediation that combines of glucagon with specific receptor.This is to show that too high glucagon level is to cause on an empty stomach and a strong evidence of the hyperglycemia of the NIDDM of the state of feed.Prove that also the glucagon that adopts antibodies selective to remove in the blood circulation can improve glucemia.These observed results are also for adopting glucagon antagonist treatment NIDDM that strong theoretical foundation is provided.Drugs 54:355-368 (1997) referring to Scheen AJ; Brand CL, Jorgensen PN, the Am.J.Physiol.269:E469-477 of KniggeU etc. (1995); Johnson DG, Goebel CU, the Science 215:1115-1116 (1982) of Hruby VJ etc.; Baron AD, Schaeffer L, Shragg P, the Diabetes 36:274-283 (1987) of Kolterman OG.
Except that glucagon receptor antibodies, also have two class antagonisies: peptide source antagonist and non-peptide compound.The example of peptide source glucagon antagonist is addressed as following U.S.Patent Nos.:4,879,273; 5,143,902; 5,480,867; 5,665,705; 5,408,037; With 5,510,459.
The example of non-peptide antagonists is addressed as in following publication and the patent documentation:
Collins?JL，Dambek?PJ，Goldstein?SW，Faraci?WS?Bioorg.Med.Chem.Lett?2：915-918(1992)；
Guillon J.Dallemagne P, Eur.J.Med.Chem.33:293-308 (1998) such as Pfeiffer B;
De Laszlo SE, Hacker C, Bioorg.Med.Chem.Lett.9:641-646 (1999) such as Li B;
Cook JH, Doherty EM, ACS National Meeting.Boston such as Ladouceur G, MA, USA,
Poster?No.MEDI?285(August?1998)；
WO?97/16442；
WO?97/35598；
WO?98/04528；
WO?98/21957；
WO?98/22108；
WO?98/22109；
WO?98/24780；
WO?99/01423；
U.S.5,508,304; With
U.S.5,677,334。
Although described a large amount of glucagon antagonists in these publications, the present invention is not subjected to the restriction of these publications, can adopt any glucagon antagonist in the present invention.The example of known glucagon comprise ALT-3000 (Alteon, Inc.), BAY-27-9955 (Bayer, AG), CP-99711, Skyrin and NNC-92-1687.The method that is used for identifying glucagon antagonist is known (as referring to embodiment S) and address in various kinds of document.
Glucagon antagonist can glucagon suppression and combine (the embodiment S) of the baby hamster kidney cell that infects with human glucagon receptor.The IC of preferred antagonist
50Be 0.1nM-100 μ M.The IC of preferred chemical compound
50Be 0.1nM-1 μ M.
Although glucagon antagonist is to work by the generation that suppresses hepatic glucose, with respect to the treatment of any independent medicine of employing, FBP enzyme inhibitor and glucagon antagonist therapeutic alliance have produced unexpected glycemic control effect.
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of FBP enzyme inhibitor and glucagon antagonist therapeutic alliance.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the glucagon antagonist treatment produces, and vice versa.
As mentioned above, glucagon is the important regulator that hepatic glucose produces.Although (known they for the excretory two kinds of factors of glucagon suppression) takes place simultaneously for hyperglycemia and hyperinsulinemia, in NIDDM, basic glucagon level is higher than matched group.Referring to Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB, J ClinEndocrinol Metab 64:106-110 (1987).It is found that there are direct relation in blood plasma glucagon concentration and blood glucose levels among the NIDDM.In addition, find that also it 60% is by due to the glucagon that in NIDDM patient hepatic glucose produces what raise.Referring to BaronAD, Schaeffer L, Shragg P, Kolterman OG, Diabetes 36:274-283 (1987).Pancreatic beta cell can suppress pancreas α emiocytosis glucagon.
Dextrin/dextrin agonist
Dextrin is 37 amino acid whose peptides, by stimulation and insulin common storage and the generation of pancreatic beta cell in response to nutrient substance.The effect of dextrin includes, but is not limited to the control of food intake, gastric peristalsis and the inhibition of glucagon secretion after the meal, and it can reduce the generation of hepatic glucose after the meal.As if among the NIDDM, the secretion of dextrin is delayed and is reduced late.Dextrin agonist (comprising dextrin itself) is applied in US Patent No.5 in treatment in the diabetes, addresses in 175,145.Amylin is a kind of synthetic people's dextrin analog, has shown that this material can increase insulin to the metabolic control of NIDDM patient.Referring to RGThompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Care 21:987-993 (1998).In multiple center clinical study, two the serum mark fructosamines and the hemoglobin A lc of glycemic control significantly reduce.The method of identifying the dextrin agonist is known, and at various kinds of document such as WO92/11863 and US Patent No.5, addresses in 264,372.
Dextrin that the dextrin agonist suppresses the 125I labelling and combine (embodiment T) by the isolating film preparation thing in nuclear accumbens district of rat forebrain substrate.The Ki of preferred agonist is 0.001nM-1 μ M.The Ki of preferred chemical compound is 0.001nM-10nM.The dextrin agonist shows that active other assay method comprises rat soleus muscle mensuration, is set forth among the Nature 335:632-635 (1988) by Leighton B and Cooper GJS.In this is measured, dextrin or the dextrin agonist exists and not in the presence of, measure insulin to the synthetic stimulation of glycogen.The EC of preferred agonist
50Be 0.1nM-1 μ M.The EC of most preferred dextrin agonist
50Be 0.1nM-100nM.
Dextrin is that stimulation in response to nutrient substance is with the excretory spouse of insulin (partner) hormone.Proved that dextrin is the effective inhibitors of glucagon secretion.Referring to GedulinBR, Rink TJ, Young AA, Metabolism 46:67-70 (1997).Therefore, people expect that dextrin and dextrin agonist can reduce the generation of hepatic glucose, and therefore can be used for the treatment of hyperglycemia, and hyperglycemia is a feature of diabetes.Amylin is the dextrin agonist that is in the clinical research, and verified this material can improve the Blood glucose control to NIDDM patient.Referring to RG Thompson, L Pearson, SL Schoenfeld, OG Kolterman, Diabetes Care 21:987-993 (1998).In WO 99/34822, claimed dextrin agonist peptide class pharmaceutical formulation (comprising amylin).But, be not limited to amylin in the present invention, but can adopt any dextrin agonist.
Although the dextrin agonist is to work by the generation that suppresses hepatic glucose, with respect to the treatment of any independent medicine of employing, FBP enzyme inhibitor and the therapeutic alliance of dextrin agonist have produced unexpected glycemic control effect (embodiment HH).
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of FBP enzyme inhibitor and the therapeutic alliance of dextrin agonist.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the dextrin agonist treatment produces, and vice versa.
Fatty acid oxidation inhibitors
Under normal operation, the liver that is reduced to of free fatty (FFA) level provides a signal that reduces the glucose generation after the meal.In NIDDM patient, the FFA level raises, and the oxidation of known FFA produces forward to gluconeogenesis and regulates, and therefore increases the output of hepatic glucose.Referring to Reberin K, Steil GM, Getty L, Bergman RN Diabetes 44:1038-1045 (1995); Foley JE Diabetes Care 15:773-784 (1992).Therefore, an approach that reduces NIDDM blood samples of patients glucose level is to reduce the excess fat acid oxidase, and this is that a fatty acid is produced reduction equivalent and acetyl group CoA by metabolism in mitochondrial matrix.A rate-limiting step in the long-chain fat acid oxidase is by Carnitine palmitoyltransferase I (CPT I) FFA to be transported to mitochondrion.Show, suppress hepatic glucose generation and blood glucose levels that CPT I can reduce NIDDM patient.Referring to Ratheiser K, Schneeweiss B, Metabolism 40:1185-90 (1991) such as Waldhausl W.
Being used for CPT I inhibitor of the present invention comprises 2-myristyl-glycidic acid (methylpalmoxirate), relies on not department, clomoxir, ST1326 and SDZ-CPI-975.Various inhibitor are set forth in the following publication:
Tutwiler?GF，Kirsch?T，Bridi?G，Washington?F?Diabetes?27：856(1978)
Tutwiler?GF，Dellevigne?P?J.Biol.Chem.254：2935(1979)
Koundakjian?PP，Turnbull?DM，Bone?AJ?Biochem?Pharmacol?33：465(1984)
Deems?RO，Anderson?RC，Foley?JE?Am.J.Physiol.274：R524-528(1998)。
The invention is not restricted to above-mentioned CPT I inhibitor, but can adopt other chemical compounds of any CPT I inhibitor or inhibition fatty acid oxidation.The method of identifying fatty acid oxidation inhibitors is known, and addresses in various kinds of document.
In the cetylate oxidimetry that in rat hepatocytes, carries out, the IC of preferred fatty acid oxidation inhibitors
50Be 10nM-300 μ M (embodiment U).More preferably IC
50Be 10nM-30 μ M.
Although known fatty acid oxidation inhibitors can suppress the generation of hepatic glucose, but with respect to the treatment of adopting any independent medicine, FBP enzyme inhibitor and fatty acid oxidation inhibitors therapeutic alliance have produced unexpected glycemic control effect (embodiment JJ).
To be them have unexpected benefit to carbohydrate and/or lipid and/or Proteometabolism to another benefit of FBP enzyme inhibitor and fatty acid oxidation inhibitors therapeutic alliance.
Another benefit of therapeutic alliance is that the FBP enzyme inhibitor can alleviate the side effect that the fatty acid oxidation inhibitors treatment produces, and vice versa.For example, known fatty acid oxidation inhibitors treatment causing cardiac hypertrophy.Referring to Bressler R, Gay R, Life Sci 44:1897-1906 (1989) such as Copeland G.
The FBP enzyme inhibitor can reduce on an empty stomach state (embodiment E-G) and ad lib state (embodiment W) and the blood glucose levels of state (embodiment X) after the meal.This chance widely for providing with insulin secretagogue, insulin, biguanide, Alpha-glucosidase inhibitor, glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, dextrin agonist or fatty acid oxidation inhibitors use in conjunction.For example, in the time of on the feed, administering drug combinations so can improve the Blood glucose control effect with respect to giving any medicine separately.Another kind of possible dosage regimen is to give insulin secretagogue, insulin, biguanide, glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, dextrin agonist or fatty acid oxidation inhibitors in the daytime, and gives the FBP enzyme inhibitor separately at night.Multiple other dosage regimen also is feasible.
Although FBP enzyme inhibitor and insulin secretagogue, insulin, biguanide, Alpha-glucosidase inhibitor, glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, dextrin agonist or fatty acid oxidation inhibitors associating mainly are to be used for the treatment of NIDDM and relevant kidney, neuron, retina, blood capillary and trunk and metabolism complication, they for treatment other improve with glycemic control and/insulin sensitivity increase diseases associated also is possible.Under normal conditions, the patient's of glucose tolerance impaired (IGT) hyperglycemia has been reduced to minimum, but can become hyperglycemia after a large amount of glucose load digestion.IGT is a leading indicators of diabetes, and therefore, the patient who has IGT has in recent years become the target of diabetes mellitus prevention test.These patients are carried out therapeutic alliance (particularly time) on the feed can recover them to the normal reaction of glucose and reduce the pathogenetic danger of glycosuria.Another group has the host of high NIDDM incidence rate for suffering from the women of polycystic ovarian syndrome (POCS).It is helpful equally to carry out therapeutic alliance for this class patient, because these patients generally have insulin resistance and suffer from IGT.Therapeutic alliance also can be used for treating renal function imbalance and hypertension, the particularly Fei Pang insulin resistance patient who suffers from IGT.Other application of therapeutic alliance comprise gastrointestinal diabetes, IDM, obesity and lipidosis out of control.
Preparation
According to the present invention, provide diabetes new combinational therapeutic methods, comprise oral or inject giving FBP enzyme inhibitor and another kind of medicine.
The FBP enzyme inhibitor of the present invention that adopts ' be about 1000 with the weight ratio of sulphur urea or non-sulphur urea insulin secretagogue: 1-50: 1, preferred about 250: 1-75: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 10 with the weight ratio of metformin: 1-0.01: 1, preferred about 3: 1-0.1: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 300 with the weight ratio of Alpha-glucosidase inhibitor: 1-2: 1, preferred about 200: 1-25: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 100 with the weight ratio of glycogen phosphorylase inhibitors: 1-0.01: 1, preferred about 10: 1-0.1: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 1000 with the weight ratio of G-6-Pase inhibitor: 1-0.01: 1, preferred 100: 1-0.1: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 1000 with the weight ratio of glucagon antagonist: 1-0.01: 1, preferred 100: 1-0.1: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 1000 with the weight ratio of dextrin agonist: 1-0.01: 1, preferred 100: 1-0.1: 1.
The FBP enzyme inhibitor of the present invention that adopts ' be about 1000 with the weight ratio of fatty acid oxidation inhibitors: 1-0.1: 1, preferred 100: 1-0.1: 1.
In addition,, also provide the method for treatment diabetes and relevant disease, wherein need the FBP enzyme inhibitor of the patient treatment effective dose of this type of treatment, choose wantonly and combine with other antidiabetic medicine according to the present invention.
If adopt, preparation, consumption and the administration of sulfonylurea drugs (as glibenclamide, glimepride, glipyride, glipizide, chlorpropamide and glicazide) and Alpha-glucosidase inhibitor (acarbose or miglitol) and biguanides (as metformin) can be referring to Physician ' s Desk Reference.
If adopt, can be oral, intranasal or parenteral give GLP-1 or GLP-1 analog, referring to US 5,346,701, US 5,614,492 and US 5,631,224.
If adopt, the preparation of insulin, consumption and administration can be referring to Physician ' sDesk Reference.
If adopt, the daily dose of glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, dextrin agonist or fatty acid oxidation inhibitors is 0.5mg-2500mg, preferred 10mg-1000mg.Can give the described inhibitor of daily dose, perhaps daily dose is divided into several parts of suitable gradation and give (as bid or tid).
No matter be with FBP enzyme inhibitor of the present invention individually dosed or with other antidiabetic medicine administering drug combinations, all it can be formulated as conventional dosage form, as tablet, capsule, elixir or ejection preparation.Above-mentioned dosage form can also comprise necessary physiologically acceptable carrier mass, excipient, lubricant, buffer agent, antibacterial, filler (as mannitol), antioxidant (ascorbic acid or sodium sulfite) etc.Although it is very satisfied that parenteral dosage form is also made us, the preferred oral dosage form.
Must the dosage that give carefully be adjusted according to patient's age, body weight and health status, route of administration, dosage form and scheme and required effect.Generally speaking, FBP enzyme inhibitor ' daily dose be about 5mg-2500mg, preferred 100mg-1000mg.Can give the FBP enzyme inhibitor of daily dose, perhaps daily dose is divided into several parts of suitable gradation and give (as bid or tid).Give the FBP enzyme inhibitor in the time of on the feed or on the feed ', other antidiabetic medicine can give also can give at other times simultaneously.
Can adopt conventional formulation method, other antidiabetic medicines of FBP enzyme inhibitor of the present invention and therapeutic alliance are prepared separately, perhaps when possibility, they are formulated as single dosage form.
Optional one or more fillers or the excipient of comprising of various preparation of the present invention, its consumption is about 0-90% weight, preferably be about 1-80% weight, as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salt such as calcium carbonate and/or cellulose derivative, as lignocellulose and microcrystalline Cellulose.
Except that above-mentioned filler, can adopt one or more binding agents, perhaps replace above-mentioned filler with these binding agents, its consumption is about the 0-35% of composition weight, preferably is about 0.5-30%.The example of the binding agent that is fit to comprises that (molecular weight is about 5000-80 to polyvinylpyrrolidone, 000, preferably be about 40,000), wax adhesive such as Brazil wax, paraffin, whale oil, polyethylene or the microwax of lactose, starch such as corn starch, modified corn starch, sugar, arabic gum etc. and fine powder form (less than 500 μ m).
If described compositions is a tablet, it can comprise one or more tablet disintegrants so, its consumption is about 0.5-10% of composition weight, preferred about 2-8%, as cross-linking sodium carboxymethyl cellulose, polyvidone, polyvinylpolypyrrolidone, sodium starch glycolate, corn starch or microcrystalline Cellulose, also can comprise one or more tablet lubricants, its consumption is about 0.2-8% of composition weight, preferred about 0.5-2% is as magnesium stearate, stearic acid, Palmic acid, calcium stearate, Pulvis Talci, Brazil wax etc.Other the conventional components that can choose existence wantonly comprise that antiseptic, stabilizing agent, antitack agent or silica gel flowing regulator are fluidizer, as Syloid board silicon dioxide and FD ﹠amp; The C coloring agent.
Also can contain coatings in the tablet of the present invention, this coatings can account for the 0-about 15% of tablet composition weight.The coatings that is coated on the label can comprise any coated preparation, generally include one or more films and form agent or binding agent, as hydrophilic polymer (as hydroxypropyl emthylcellulose) and hydrophobic fiber element (as the glyceride of ethyl cellulose, cellulose acetate, polyvinyl alcohol-copolymer-maleic anhydride, beta-pinene polymer, wood gum etc. etc.) and one or more plasticizers (as triethyl citrate, phthalic acid diethyl ester, propylene glycol, glycerol, phthalic acid butyl ester, Semen Ricini wet goods).Core tablet and coated tablet all can contain the aluminum color lake and carry out painted.
Can adopt the solvent system that contains one or more solvents to form the film coating, described solvent comprises that water, alcohol (as methylol, ethyl alcohol or isopropyl alcohol), ketone (as acetone or ethyl methyl ketone), chlorohydrocarbon are (as dichloromethane, dichloroethanes and 1,1, the 1-trichloroethane).
If the use coloring agent can use itself and film formation agent, plasticizer and solvent compositions simultaneously.
The preferred tablet composition of the present invention comprises the polyvidone of the FBP enzyme inhibitor of about 90-97.5% weight, about 2-8% weight and the magnesium stearate of about 0.5-2% weight.
Can prepare Pharmaceutical composition of the present invention according to following method.The mixture (contain coloring agent or do not contain coloring agent) of medicine and part (less than 50%) filler (if adopt, as lactose) is mixed, cross the #12-#40 mesh sieve.Add filler-binding agent (if adopt, as microcrystalline Cellulose), disintegrating agent (as polyvidone), and mix.Add lubricant (as magnesium stearate), be mixed to the thing that is uniformly mixed simultaneously.Then the mixture that obtains is compressed to tablet up to the 2g size.When needing, also can be according to U.S. Patent number 5,030, disclosed wet granulation method prepares tablet of the present invention in 447, and it is for referencial use to be incorporated herein this patent documentation.
Embodiment-synthetic schemes
According to the method for describing in the document, and improvement that it will be appreciated by those skilled in the art that and increase, can preparation formula VI chemical compound.Generally speaking, the method that can describe in document J.Med.Chem. (1976) according to Srivastava prepares these chemical compounds.Additive method is addressed: the J.Med.Chem.28:1198-1203 of Wood etc. (1985); The J.Med.Chem.35:4549-4556 of Sagi etc. (1992); Paul, Jr.J.Med.Chem.28:1704-1716 (1985); J.Am.Chem.Soc.95:4619-4624 such as Cohen (1973).According to the method for describing among PCT publication number WO 98/39344, WO 98/39343 and the WO 98/39342, preparation formula II-IV chemical compound.
Part 1
Synthesizing of formula I chemical compound
The synthetic part steps or the Overall Steps that generally comprises in the following general step of chemical compound of the present invention: 1) preparation phosphonate ester precursor; (2) phosphonate ester go the protection; (3) heterocyclic modification; (4) coupling of heterocycle and phosphonate ester part; (5) heterocyclic structure; (6) the closed formation of ring has the heterocycle of phosphonic acids part and the preparation of (7) useful as intermediates.The synthetic below wherein R of these steps
5Describe in the flow process for formula 2 chemical compounds of 5-unit hetero-aromatic ring.R wherein
5For formula 2 chemical compounds of 6-unit hetero-aromatic ring or other hetero-aromatic rings can adopt similar method preparation.
(1a) preparation of phosphonate ester precursor
Can introduce prodrug in the different phase of building-up process.Because their unstability, so under most of situation, these prodrug are by the phosphonic acids preparation of formula 2.The reaction condition of the step that as long as these prodrug can tolerate subsequently to be carried out, introducing prodrug so in early days is eaily.
Under the nucleophilic substitution condition, make formula 2 alkylations with electrophilic reagent (as alkyl halide, alkyl sulfonic ester etc.), obtain phosphonate ester.For example, exist down at alkali (as N, N '-dicyclohexyl-4-morpholine carbonamidine, Hunigs alkali etc.), the solvent that is fit to (as 1,1-dimethyl formamide " DMF " (Starrett etc., J.Med.Chem., 1994,1857)), with suitable acyloxy alkyl halide (as Cl, Br, I; Elhaddadi etc., Phosphorus Sulfur, 1990,54 (1-4): 143; Hoffmann, Synthesis, 1988,62) formula 2 chemical compounds are carried out direct alkylation, synthetic wherein R
1Formula I chemical compound for the acyloxy alkyl.The carboxylate of these acyloxy alkyl halides includes, but is not limited to acetas, propionic ester, isobutyrate, pivalate, benzoate and other carboxylate.In the time of suitably, can after forming, these acyloxy phosphonate esters, carry out further modification as behind nitroreduction.For example, (Dickson etc., J.Med.Chem., 1996,39:661 under suitable reducing condition; Lyer etc., Tetrahedron Lett., 1989,30:7141; Srivastva etc., Bioorg.Chem., 1984,12:118), be that formula 3 chemical compounds of nitro are converted into wherein that A is amino formula 3 chemical compounds with A.These methods can be expanded the prodrug that is used for synthetic other types, as R wherein
1Be 3-benzo [c] furanonyl, 2-oxo-4,5-dihydro-1, the formula I chemical compound of 3-dioxolanes methyl or 2-oxo-tetrahydrofuran-5-base (Biller etc., US 5,157, and 027; Serafinowska etc., J.Med.Chem.1995,38:1372; Starrett etc., J.Med.Chem.1994,37:1857; Martin etc., J.Pharm.Sci.1987,76:180; Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; EPO 0632048A1).N, dinethylformamide dialkyl acetal (NN-dimethylformamide dialkyl acetals) also can be used to make phosphonic acids alkylation (Alexander, P etc., Collect.Czech.Chem.Commun., 1994,59,1853).
Perhaps, by make alcohol and corresponding dichloro phosphonate ester reflect to synthesize these phosphonate ester precursors (Alexander etc., Collect.Czech.Chem.Commun., 1994,59:1853).For example, in the presence of alkali (as pyridine, triethylamine etc.), make the phenol and the aralkyl alcohol reaction of dichloro phosphonate ester and replacement, obtaining wherein, R1 is formula V chemical compound (Khamnei etc., J.Med.Chem., 1996, the 39:4109 of aryl; Serafinowska etc., J.Med.Chem., 1995,38:1372; De Lombaert etc., J.Med.Chem., 1994,37:498) or R1 be aralkyl formula V chemical compound (Mitchell etc., J.Chem.Soc.Perkin Trans.1,1992,38:2345).Contain disulphide prodrug (Puech etc., Antiviral Res., 1993,22:155) also can under standard conditions, prepare by dichloro phosphonate ester and 2-hydroxyethyl disulphide.
This type of reactive dichloro phosphonate ester can be produced (as thionyl chloride: Starrett etc. by corresponding phosphonic acids and chlorinating agent, J.Med.Chem., 1994,1857, oxalyl chloride: Stowell etc., Tetrahedron Lett., 1990,31:3261 and phosphorus pentachloride: Quast etc., Synthesis, 1974,490).Perhaps, also can by corresponding phosphonic acids dimethyl silanyl ester (Bhongle etc., Synth.Commun., 1987,17:1071) or dialkyl alkylphosphonate (Still etc., TetrahedronLett., 1983,24:4405; Patois etc., Bull.Soc.Chim.Fr., 1993,130:485) preparation dichloro phosphonate ester.
In addition, can also adopt Mitsunobu reaction (Mitsunobu, Synthesis, 1981,1; Campbell, J.Org.Chem., 1992,52:6331) and other corresponding coupling reactions (as using carbodiimides:Alexander etc., Collect.Czech.Chem.Commun., 1994,59:1853; Casara etc., Bioorg.Med.Chem.Lett., 1992,2:145; Ohashi etc., Tetrahedron Lett., 1988,29:1189 and benzotriazolyloxytris (dimethylamino) phosphonium salts:Campagne etc., Tetrahedron Lett., 1993,34:6743) prepare these prodrug.Suitable alkali (as NaH or diisopropylethylamine, Biller etc., US 5,157,027; Serafinowska etc., J.Med.Chem.1995,38:1372; Starrett etc., J.Med.Chem.1994,37:1857; Martin etc., J.Pharm.Sci.1987,76:180; Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; EPO 0632048A1) exists down, adopt suitable halogenide,, also can synthesize wherein R by the direct alkylated reaction of free phosphonic acids
1Formula I chemical compound for cyclic carbonate, lactone or benzo [c] furanonyl.
R
1Also can be in the early stage introducing of this building-up process, as long as it can tolerate the subsequent reaction step.For example, by making 2-furyl heterocycle metallization (as adopting LDA), catching anion with the clodronic acid diaryl ester subsequently, can prepare wherein R
1Formula I chemical compound for aryl.
Be appreciated that formula V chemical compound can be blended phosphonate ester (as phenyl and benzyl ester, or phenyl and acyloxy Arrcostab), comprise the bonded precursor of chemically combined mixed ester such as phenyl and benzyl,, wait at Bioorg.Med.Chem.Lett. referring to Meier, 1997, the report among the 7:99.
(1b) preparation of bisamide phosphonate ester (bisamidate phosphonate)
The universal synthesis method of two amido phosphonate precursors (bis-phosphoroamidate)
Generally speaking, can be by two amido phosphonates of activatory phosphonate ester (as the dichloro phosphonate ester) and amino-acid ester (as the glycine ethyl ester) coupling preparation formula I, wherein-NR
15R
16With-N (R
18)-(CR
12R
13)
n-C (O)-R
14All, in this reaction, can not add alkali and also can add alkali, as the N-Methylimidazole. from amino acid residue.Can be according to the described preparation feedback dichloride of the general prodrug composite part in front.
Perhaps, at PPh
3With in pyridine 2,2 '-pyridyl disulfide exists down, prepares these pairs amido phosphonate by corresponding phosphonic acids and amino-acid ester (as the glycine ethyl ester) are reacted, referring to WO 95/07920 or Mukaiyama, T. etc., J.Am.Chem.Soc., 1972,94,8528.
As mentioned above, directly transform (order addition), separate required product by column chromatography or HPLC subsequently through dichloride, the two amido phosphonates of mixing that can preparation formula IA, wherein-NR
15R
16With-N (R18)-(CR
12R
13)
nC (O)-R
14Combination for the amine of different amino-acid esters or amino-acid ester and replacement.Perhaps, adopt suitable phosphonate monoester (as phenylester or benzyl ester), obtain blended phosphono esteramides, under the stable condition of amido link, carry out the hydrolysis of ester subsequently by chloride, thereby prepare blended pair of amido phosphonate as raw material.As mentioned above, by with the amine condensation of second kind of amino ester or replacement, via chloride the monoamides of above-mentioned generation is converted into blended bisamide.Adopt document (EP481214) reported method to prepare the synthetic of this type of monoesters.
By making 1 of corresponding dichloro phosphonate ester and replacement, the ammediol reaction can be synthesized the ring-type propyl phosphonous acid ester of replacement.Be used to prepare 1 of replacement, the method for ammediol is discussed below.
1, ammediol synthetic
It is polytype 1 that various synthetic methods can be used to prepare, ammediol: (i) 1-replaces, and (ii) 2-replaces, and (iii) 1,2-or 1,1 of 3-ring formation, ammediol.The substituent group of formula I chemical compound prodrug part (promptly 1, ammediol substituent group partly) can be introduced in these glycol building-up processes or after these glycol couplings obtain formula 2 chemical compounds or it is carried out modification.
(i) 1 of the 1-replacement, ammediol
Be used for that the present invention contains 1, ammediol can adopt various synthetic methods preparations.Add the aryl Grignard reagent in 1-hydroxyl-third-3-aldehyde, obtain 1 of 1-aryl-replacement, (approach a) for ammediol.This method is suitable for various aryl halides and is converted into-1 of 1-aryl replacement, ammediol (Coppi etc., J.Org.Chem., 1988,53,911).Adopt Heck reaction (as with 1, the 3-diox-4-ene coupling), then reduce and hydrolysis subsequently (Sakamoto etc., Tetrahedron Lett., 1992,33,6845), with aryl halide be converted into that 1-replaces 1, ammediol.Adopt alkenyl Ge Liya additive reaction, carry out hydroboration subsequently, also various aromatic aldehydes can be converted into-1 of 1-replacement, ammediol (approach b).The metallization tert-butyl group and aromatic aldehyde addition, ester reduction (approach e) also can be used for synthesizing 1, ammediol (Turner., J.Org.Chem., 1990,55 4744) subsequently.In another method, adopt known method (as the asymmetric epoxidation reaction of Sharpless epoxidation and other) to carry out the epoxidation of cinnamyl alcohol, carry out reduction reaction (as adopting Red-Al) subsequently, obtain various 1, ammediol (approach c).Perhaps, adopt the chirality borine that hydroxyethyl aryl ketones derivant is carried out reduction reaction, can obtain 1 of enantiomer-pure, ammediol (Ramachandran etc., TetrahedronLett., 1997,38 761).Adopt the N-oxide to form and react, under the acetic anhydride condition, carry out subsequently rearrangement reaction, third-3-the alcohol that can oxidation has 1-heteroaryl substituent group (as pyridine radicals, quinolyl or isoquinolyl), obtain 1 of 1-replacement, ammediol (approach d) (Yamamoto etc., Tetrahedron, 1981,37,1871).
(ii) 2-replace 1, ammediol
Adopt known chemical method, by 2-(methylol)-1, ammediol can prepare and be used for 1 of the synthetic various 2-replacements of formula I chemical compound, ammediol (Larock, ComprehensiveOrganic Transformations, VCH, New York, 1989).For example, the reduction of carrying out tri-alkoxy carbonyl methane by reduction fully under known condition obtains triol (approach a), perhaps by one of ester group being carried out selective hydrolysis, subsequently remaining two ester group being reduced and two methylol acetic acid are reduced.Also knownly can eliminate reaction and obtain triol (approach b) (Latour etc., Synthesis, 1987,8,742) by the nitro triol is reduced.In addition, according to known chemical method, adopt acyl chlorides or alkyl chloroformate (as chloroacetic chloride or methylchloroformate), can be with 2-methylol-1, ammediol is converted into single acylated derivatives (as acetyl group, methoxycarbonyl derivant) (approach d) (Greene etc., Protective Groups InOrganic Synthesis; Wiley, New York, 1990).Other functional group's processing method also can be used to prepare 1, ammediol, and as with 2-methylol-1, a methylol in the ammediol is oxidized to aldehyde, carries out additive reaction (approach c) with the aryl Grignard reagent subsequently.Also aldehyde can be converted into alkylamine (approach e) by reduction amination.
(iii) 1 of ring formation, ammediol
By 1, the 3-cyclohexanediol can prepare wherein V and Z or V and link to each other by four carbon with W and form the formula I chemical compound of ring.For example, as replace at 2-1, described in the ammediol preparation, to cis, cis-1,3, the 5-phloroglucite carries out modification.Be appreciated that these modifications can be at cyclic phosphonic acid 1, the ammediol ester carries out before forming, and also can carry out after forming.Adopt the Diels-Alder reaction (as with pyrone as diene: Posner etc., Tetrahedron Lett., 1991,32,5295), also can prepare various 1, the 3-cyclohexanediol.1, the 3-Cyclohexanediole derivatives also can be by other cycloaddition reaction preparation.For example, adopt known chemical method, make nitrile oxide carry out cycloaddition reaction and form alkene, then make the cycloaddition thing of generation be converted into 2-ketone group alcohol derivative, can be converted into 1,3-cyclohexanediol (Curran etc., J.Am.Chem.Soc., 1985,107,6023).Perhaps, by quinic acid preparation 1, the precursor of 3-cyclohexanediol (Rao etc., Tetrahedron Lett., 1991,32,547.).
2) phosphonate ester go the protection
Adopt known phosphate ester and phosphonate ester cracking condition, prepare wherein R by phosphonate ester
1Formula I chemical compound for H.Usually adopt silyl halides to come the various phosphonate esters of cracking, subsequently the phosphonic acids silyl ester that produces is carried out mild hydrolysis, obtain required phosphonic acids product.When needing, when synthesizing sour unstable compounds, can use acid scavenger (as 1,1,1,3,3,3-hexamethyldisiloxane, 2,6-lutidines etc.).This type of silyl halides comprises chloro trimethyl silane (Rabinowitz, J.Org.Chem., 1963,28:2975) with bromo trimethyl silane (McKenna etc., Tetrahedron Lett., 1977,155) and iodo trimethyl silane (Blackburn etc., J.Chem.Soc., Chem.Commun., 1978,870).Perhaps, cracking phosphonate ester (as HBr or HCl:Moffatt etc., U.S.Patent 3,524,846,1970) under strong acidic condition.These esters also can use halogenating agent (as phosphorus pentachloride, thionyl chloride, BBr by the cracking of dichloro phosphonate ester
3: Pelchowicz etc., J.Chem.Soc., 1961,238) handle described ester, be hydrolyzed subsequently, obtain phosphonic acids.Can be under the hydrogenolysis condition (Lejczak etc., Synthesis, 1982,412; Elliott etc., J.Med.Chem., 1985,28:1208; Baddiley etc., Nature, 1953,171:76) or under the metallic reducing condition (Shafer etc., J.Am.Chem.Soc., 1977,99:5118), the phosphonate ester of cracking aryl and benzyl.Electrochemical conditions (Shono etc., J.Org.Chem., 1979,44:4508) and pyrolytical condition (Gupta etc., Synth.Commun., 1980,10:299) also can be used for the various phosphonate esters of cracking.
(3) existing heterocyclic modification
In multiple summary, (referring to the 4th part) discussed and described to the heterocyclic synthetic method that contains in the disclosed chemical compound fully.Although it is relatively good to contain required substituent group before formula 4 chemical compounds are synthetic in these heterocycles, but in some cases, required substituent group may not tolerate subsequent reaction, therefore, need to adopt conventional chemical method existing heterocycle to be carried out modification (Larock, Comprehensive organictransformations, VCH in the later stage of synthetic schemes, New York, 1989; Trost, Comprehensive organicsynthesis; Pergamon press, New York, 1991).For example, by be converted into diazonium groups and with various copper (I) salt (as CuI, CuBr, CuCl, CuCN) reaction, can prepare wherein A, A by corresponding amine " or B be the formula I chemical compound of halo or cyano group.By various heterocycles are carried out direct halogenation, can introduce halogen.For example, adopt all ingredients (as NIS, NBS, NCS), can be converted into 2-amino-5-halo thiazole by 5-is unsubstituted-thiazolamine.Heteroaryl halogenide also is useful as intermediates, by the auxiliary coupling reaction of transition metal, as Suzuki, Heck or Stille reaction (Farina etc., Organic Reactions, Vol.50; Wiley, New York, 1997; Mitchell, Synthesis, 1992,808; Suzuki, Pure App.Chem., 1991,63,419; Heck Palladium Reagents in OrganicSynthesis; Academic Press:San Diego, 1985), can easily they be converted into other substituent group (as A, A ", B, B ", C ", D, D ", E and E ").Via ammonolysis reaction, can prepare wherein that A is the formula I chemical compound of carbamoyl by the corresponding alkyl carboxylic acid ester of formula I chemical compound and various amine, described alkyl carboxylic acid ester is carried out conventional functional group modification can be used for synthetic wherein A and be-CH
2OH or-CH
2-halogenated formula I chemical compound.The displacement reaction of carrying out halogenated heterocyclic (as 2-bromo thiazole and 5-bromo thiazole) with various nucleopilic reagents (as HSMe, HOMe etc.) is for introducing substituent group such as A, A ", B and B " another kind of method.For example, make methanthiol and 2-diuril azoles generation displacement reaction, obtain corresponding 2-methyl mercapto thiazole.
Be appreciated that, can be easily to heterocycle (as imidazoles, 1,2,4-triazole and 1,2,3,4-tetrazolium) nitrogen-atoms in carries out necessary alkylation, as adopt the alkylated reaction (with alkyl halide, aralkyl halide, alkyl sulfonic ester or sweet-smelling alkyl sulfonic acid ester) of standard, and perhaps the Mitsunobu reaction is with pure) carry out described reaction.
(4) coupling of heterocycle and phosphonate ester part
If feasible, comprise that by employing the route of synthesis of heterocycle and the coupling of phosphonic acid diester part can prepare chemical compound disclosed by the invention easily.
Transition metal-catalyzed coupling reaction (as Stille or Suzuki reaction) is particularly suitable for synthetic compound of formula i.(Farina etc., OrganicReactions, Vol.50 under the catalytic reaction condition of palladium; Wiley, New York, 1997; Mitchell, Synthesis, 1992,808; Suzuki, Pure App.Chem., 1991,63,419), make heteroaryl halogenide or triflate (as the 2-bromopyridine) and M-PO
3R ' (wherein M is 2-(5-tributyl tin alkyl (stannyl)) furyl or 2-(5-boryl (boronyl)) furyl) coupling obtains wherein that X is a furan-2, the formula I chemical compound of 5-two bases.The character that is appreciated that coupling part in these coupling reactions also can (as make trialkyltin alkyl or boryl heterocycle and halo-X-P (O) (O-alkyl) conversely
2Coupling).For other coupling reactions between organic stannane and alkenyl halide or alkenyl triflate report is arranged also, these reactions can be used to prepare wherein that X is the formula I chemical compound of alkenyl.The Heck reaction can be used to prepare wherein, and X is formula V chemical compound (the Heck Palladium Reagents in Organic Synthesis of alkynyl; AcademicPress:San Diego, 1985).These reactions are particularly suitable for synthetic R
5Be the formula I chemical compound of various heteroaromatics, as long as various halogenated heterocyclics have practicality, these reactions be particularly suitable for parallel synthesizing (as in solid phase (Bunin, B.A., The Combinatorial Index; Academic press:San Diego, 1998) (Flynn, D.L etc., Curr.Op.Drug.Disc.Dev., 1998,1,1367) merge synthetic or in liquid phase), produce a large amount of merging synthetic product (combinatorial libraries).For example, under suitable coupling reaction condition, make 5-iodo-2-furyl phosphinic acid ethyl ester and the coupling of Wang resin.Then in a similar fashion; adopt organo-borane and organotin to make 5-iodo-2-[5-(O-ethyl-O-Wang resin) phosphono of resin coupling] transition metal-catalyzed Suzuki and the Stille reaction (as mentioned above) of furan experience; obtain wherein that X is a furan-2, formula 3 chemical compounds of 5-two bases.
Displacement reaction can be used for the coupling of heterocycle and phosphonic acid diester part.For example cyanuric chloride can with mercaptoalkyl dialkyl alkylphosphonate or aminoalkyl dialkyl alkylphosphonate generation displacement reaction, obtain wherein R
5For 1,3,5-triazines, X is formula 2 chemical compounds of alkylthio group or alkylamino.Alkylated reaction also can be used for the coupling of heterocycle and phosphonic acid diester part.For example, adopt the dialkyl methyl phosphonate derivant (as ICH
2P (O) (OEt)
2, TsOCH
2P (O) (OEt)
2, TfOCH
2P (O) (OEt)
2) make heteroaromatic mercaptan (as 1,3,4-thiadiazoles-2-mercaptan) alkylation, obtaining wherein, X is the formula I chemical compound of alkylthio group.On the other hand, adopt the dialkyl methyl phosphonate derivant (as ICH
2P (O) (OEt)
2, TsOCH
2P (O) (OEt)
2, TfOCH
2P (O) (OEt)
2) make heteroaromatic carboxylic acids (as the thiazole-4-carboxylic acid) alkylation, can obtain wherein that X is the formula I chemical compound of alkoxy carbonyl, adopt the dialkyl methyl phosphonate derivant (as ICH
2P (O) (OEt)
2, TsOCH
2P (O) (OEt)
2, TfOCH
2P (O) (OEt)
2) make heteroaromatic thiocarboxylic acid (as thiazole-4-thiocarboxylic acid) alkylation, can obtaining wherein, X is the formula I chemical compound of alkylthio group carbonyl.Haloalkyl heterocycle (as 4-haloalkyl thiazole) can be used to prepare wherein with the displacement reaction that contains the nucleopilic reagent (as the hydroxymethyl phosphonic acid diethyl ester) of phosphonate ester, and X is the formula I chemical compound of alkoxyalkyl or alkylthio alkyl.For example, adopt hydroxymethyl phosphonic acid dialkyl and suitable alkali (as sodium hydride), can preparing wherein by 2-chloromethylpyridine or 4-5-chloromethyl thiazole, X is-CH
2OCH
2-formula I chemical compound.The character that also can make the nucleopilic reagent of displacement reaction and electrophilic reagent conversely, even haloalkyl-and/or the sulfonyl phosphonate ester displacement reaction takes place with the heterocycle (as 2-hydroxy alkyl pyridine, 2-mercaptoalkylpyridin or 4-hydroxyl base alkane base oxazole) that contains nucleopilic reagent.
Known amido link forms the coupling that reaction (as carboxylic acid halides method, mixed anhydride method, carbodlimide method) also can be used for heteroaromatic carboxylic acids and phosphonic acid diester part, and obtaining wherein, X is formula 4 chemical compounds of alkyl amino-carbonyl or alkoxy carbonyl.For example, thiazole-4-carboxylic acid and aminoalkyl dialkyl alkylphosphonate or the coupling of hydroxy alkyl dialkyl alkylphosphonate obtain wherein R
5For thiazole, X is formula 4 chemical compounds of alkyl amino-carbonyl or alkoxy carbonyl.Perhaps, also can be conversely with the character of coupling component, obtaining wherein, X is formula 4 chemical compounds of alkyl-carbonyl-amino.For example, under these reaction conditions, make thiazolamine with (RO)
2P (O)-alkyl-CO
2H (as diethyl phosphonyl acetic acid) coupling obtains wherein R
5For thiazole, X is formula 4 chemical compounds of alkyl-carbonyl-amino.Merge chemical reaction by solid phase or liquid phase, adopt these reactions to carry out the parallel synthetic of chemical compound.For example, adopt above-mentioned reaction method, make HOCH
2P (O) is (O-resin), H (OEt)
2NCH
2P (O) is (O-resin) and HOOCCH (OEt)
2P (O) is (O-resin) (adopting known method preparation) and various heterocycle couplings (OEt), and obtaining wherein, X is-C (O) OCH
2-or-C (O) NHCH
2-or-NHC (O) CH
2-formula 3 chemical compounds.
Rearrangement reaction also can be used to prepare chemical compound of the present invention.For example, in the presence of hydroxy alkyl dialkyl alkylphosphonate or aminoalkyl dialkyl alkylphosphonate, make the thiazole-4-carboxylic acid carry out the Curtius rearrangement reaction, obtaining wherein, X is formula 4 chemical compounds of alkyl amino-carbonyl amino or alkoxycarbonyl amino.These reactions also can be used for the merging of various formula 3 chemical compounds and synthesize.For example, make heterocyclic carboxylic acid and HOCH
2P (O) is (O-resin) or H (OEt)
2NCH
2P (O) (OEt) (O-resin) carries out the Curtius rearrangement reaction, and obtaining wherein, X is-NHC (O) OCH
2-or-NHC (O)
nHCH
2-formula 1 chemical compound.
For X wherein is the formula V chemical compound of alkyl, can adopt other common phosphonate ester formation methods, as Michaelis-Arbuzov reaction (Bhattacharya etc., Chem.Rev., 1981,8l:415), Michaelis-Becker reacts (Blackburn etc., J.Organomet.Chem., 1988,348:55) introduce the phosphonate ester part with the additive reaction of phosphorus and electrophilic reagent (as aldehyde, ketone, carboxylic acid halides, imines and other carbonyl derivative).
Also can introduce the phosphonate ester part by lithiation.For example, adopt suitable alkali that the 2-ethynyl pyridine is carried out lithiumation, follows the anion of catching acquisition like this with the chloro dialkyl alkylphosphonate, obtain wherein R
5For pyridine radicals, X is formula 3 chemical compounds of 1-(2-phosphono) acetenyl.
(5) heterocyclic structure
Although existing heterocycle can be used for synthesis type V chemical compound, when needed, also can make up heterocycle obtaining chemical compound of the present invention, and in some cases, preferably make up heterocycle with the preparation part of compounds.In many pieces of documents, fully described and under various reaction conditions, made up heterocyclic method (Joule etc., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology InOrganic Synthesis; Academic press, San Diego, 1987; Padwa, 1,3-DipolarCycloaddition Chemistry; Wiley, New York, 1984; Katritzsky etc., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome etc., Contemporary Heterocyclic Chemistry:Syntheses, Reactionand Applications; Wiley, New York, 1982; Syntheses of HeterocyclicCompounds; Consultants Bureau, New York).Wherein the part method that is used to prepare chemical compound of the present invention provides as example in the following discussion.
(i) structure of thiazole ring system
Adopt the ring of various detailed descriptions to form reaction, can easily prepare the thiazole (Metzger, Thiazole and its derivatives, the part land part 2 that are used for the present invention; Wiley﹠amp; Sons, New York, 1979).In the structure of thiazole ring system, useful especially is the cyclization of thioamides (as thioacetamide, thiourea) and α-Lu Daitangjihuahewu (as α-Lu Daitong, alpha-halogen aldehyde).For example, thiourea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] furan generation cyclization can be used for synthetic wherein R
5For thiazole, A are furan-2 for amino, X, formula 2 chemical compounds of 5-two bases; And thiourea and bromo acetone acid Arrcostab generation cyclization can obtain 2-amino-4-alkoxy carbonyl thiazole, and this chemical compound can be used to prepare wherein R
5For thiazole, X is formula 2 chemical compounds of alkyl amino-carbonyl, alkoxy carbonyl, alkyl amino-carbonyl amino or alkoxycarbonyl amino.Adopt reported method in the document, can prepare thioamides (Trost, Comprehensive organic synthesis, the 6th volume; Pergamon publishing house, New York, 1991, the 419-434 pages or leaves), and α-Lu Daitangjihuahewu can easily obtain (Larock, Comprehensive organic transformations, VCH, New York, 1989) by popular response.For example, adopt Lawesson reagent or P
2S
5Amide can be converted into thioamides, adopt various halide reagents (as NBS, CuBr
2) can be with various ketone halogenations.
(the structure of) oxazole ring system ii
Adopt the whole bag of tricks of describing in the document, can prepare the oxazole (Turchi, the Oxazoles that are used for Ben Faming; Wiley ﹠amp; Sons, New York, 1986).Isocyanide (as tosyl ylmethyl isocyanide) and carbonyl compound (as aldehyde and acyl chlorides) reaction can be used for structure and build oxazole ring system (van Leusen etc., Tetrahedron Lett., 1972,2369).Perhaps, amide (as urea, carboxylic acid amides) and α-Lu Daitangjihuahewu generation cyclization can be used for structure usually and build the oxazole ring system.For example, urea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] furan generation cyclization can be used for synthetic wherein R
5Wei oxazole, A be furan-2 for amino, X, formula 2 chemical compounds of 5-two bases.Amine and imino-ester (imidate) reaction also can be used for Gou Jian oxazole ring system (Meyers etc., J.Org.Chem., 1986,51 (26), 5111).
*The (iii) structure of pyridine ring system
Adopt various known synthetic methods, can prepare and be used for formula I chemical compound synthetic pyridine (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984).1,5-dicarbonyl compound or its homologue and ammonia or the chemical compound reaction that can produce ammonia obtain 1, the 4-dihydropyridine, and this compounds easily dehydrogenation obtains pyridine.Undersaturated 1 when making, 5-dicarbonyl compound or their homologue (as the pyrans ion) can directly produce pyridine during with ammonia react.Adopt conventional chemical method can prepare 1,5-dicarbonyl compound or their homologue.For example, can obtain 1 by number of ways, the 5-diketone for example makes enolate and ketenes (or Mannich alkali precursor (Gill etc., J.Am.Chem.Soc., 1952,74,4923)) carry out the Michael additive reaction, make the cyclopentenes precursor carry out ozonolysis reaction or make silicyl enol ether and 3-methoxyl group allyl alcohol react (Duhamel etc., Tetrahedron, 1986,42,4777).When one of carbonyl carbon was the acid oxidase attitude, this class reaction produced the 2-pyridone so, after this can easily they be converted into 2-haloperidid (Isler etc., Helv.Chim.Acta, 1955,38,1033) or 2-aminopyridine (Vorbruggen etc., Chem.Ber., 1984,117,1523).Perhaps, by the Hantzsch synthetic reaction (Bossart etc., Angew.Chem.Int.Ed.Engl., 1981,20,762) of routine, can be by aldehyde, 1,3-dicarbonyl compound and ammonia prepare pyridine.Also can be by making 1,3-dicarbonyl compound (or their homologue) and 3-amino-ketenes or 3-amino-nitrile prepared in reaction pyridine (as Guareschi synthesis, Mariella, Org.Synth., Coll.Vol.IV, 1963,210).Can be by to corresponding 1,3-glycol or aldol reaction product carry out oxidation reaction preparation 1,3-dicarbonyl compound (Mukaiyama, Org, Reactions, 1982,28,203).Cycloaddition reaction also can be used for pyridine synthesis, cycloaddition reaction between Li such as oxazole and the alkene (Naito etc., Chem.Pharm.Bull., 1965,13,869) and 1,2, the reaction of the Diels-Alder between 4-triazine and the enamine (Boger etc., J.Org.Chem., 1981,46,2179).
The (iv) structure of pyrimidine ring system
Can easily obtain to be used for formula V-2 chemical compound synthetic pyrimidine ring system (Brown, ThePyrimidines; Wiley, New York, 1994).The synthetic a kind of method of pyrimidine comprises makes 1,3-dicarbapentaborane part (or its homologue) and N-C-N fragment generation coupling.N-C-N part-urea (Sherman etc., Org.Synth., Coll.Vol.IV, 1963,247), amidine (Kenner etc., J.Chem.Soc., 1943,125) or guanidine (Burgess, J.Org.Chem., 1956,21,97; VanAllan, Org.Synth., Coll.Vol.IV, 1963,245) the C-2 of selection decision pyrimidine product replace.This method is particularly suitable for synthetic formula V-2 chemical compound with various A groups.In another approach, can prepare pyrimidine, for example by 1 by cycloaddition reaction, 3, aza-Diels-Alder prepared in reaction pyrimidine (Boger etc., J.Org.Chem. between 5-triazine and enamine or the ynamine, 1992,57,4331 reach the list of references of wherein quoting).
(the v) structure of imidazo ring systems
Adopt various synthetic reaction, can easily prepare and be used for the synthetic imidazoles of formula V-1 chemical compound.The various cyclizations of general employing synthesize imidazoles, as amidine and α-Lu Daitong reaction (Mallick etc., J.Am.Chem.Soc., 1984,106 (23), 7252) or alpha-alcohol ketone (Shi etc., Synthetic Comm., 1993,23 (18), 2623) reaction between the reaction between, urea and the α-Lu Daitong and aldehyde and 1, the reaction that the 2-dicarbonyl compound carries out in the presence of amine.
(vi) structure of isoxazole ring system
Adopt the whole bag of tricks easily to synthesize and be used for the synthetic isoxazole of formula V-1 chemical compound (as the cycloaddition, 1 of nitrile oxide and alkynes or activity methene compound, 3-dicarbonyl compound or α, β-acetylene series carbonyl compound or α, the oximation reaction of β-dihalo carbonyl compound etc.), can be used for synthesizing isoxazole ring system (Grunanger etc., isoxazoles; Wiley ﹠amp; Sons, New York, 1991)).For example, in the presence of alkali (as triethylamine, Hunig alkali, pyridine), make alkynes and 5-diethyl phosphonyl-2-chlorine oximido furan reaction, can be used for synthetic wherein R
5Wei isoxazole, X are furan-2, formula 2 chemical compounds of 5-two bases.
(the vii) structure of pyrazoles ring system
Adopt the whole bag of tricks easily to synthesize and be used for formula V-1 chemical compound synthetic pyrazoles (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and CondensedRings; Interscience Publishers, New York, 1967), as hydrazine and 1,3-dicarbonyl compound or 1, the additive reaction of (masked as carbonyl is enamine, ketal or the acetal) reaction of 3-dicarbapentaborane homologue or hydrazine and acrylonitrile and cyclisation (Dorn etc. subsequently, Org.Synth., 1973, Coll.Vol.V, 39).2-(2-alkyl-3-N, N-dimethylamino) acryloyl group-5-diethyl phosphonyl furan and hydrazine reaction can be used for synthetic wherein R
5For pyrazoles, X are furan-2,5-two bases and B " be the formula I chemical compound of alkyl.
(viii) 1,2, the structure of 4-triazole ring system
Adopt the whole bag of tricks, can easily prepare be used for formula V-1 chemical compound synthetic 1,2,4-triazole (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981).For example, make the reaction of hydrazides and imino-ester or sulfo-imino-ester (Sui etc., Bioorg.Med.Chem.Lett., 1998,8,1929; Catarzi etc., J.Med.Chem., 1995,38 (2), 2196), 1,3,5-triazine and hydrazine reaction (Grundmann etc., J.Org.Chem., 1956,21,1037) and Aminoguanidine carboxylates (Ried etc., Chem.Ber., 1968,101,2117) reaction can be used for synthesizing 1,2, the 4-triazole.
(6) the closed heterocycle that has phosphonate ester that makes up of ring
Adopt the ring closed reaction, making up heterocycle by the precursor that contains the phosphonate ester part also can preparation formula 4 chemical compound.For example, make thiourea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] furan generation cyclization, can be used for synthetic wherein R
5For thiazole, A are that amino and X are furan-2, formula 2 chemical compounds of 5-two bases.Adopt the ring closed reaction also can prepare the oxazole of Ben Faming.In this case, make urea and 5-diethyl phosphonyl-2-[(2-bromo-1-oxo) alkyl] the furan reaction, can be used for synthetic wherein R
5Wei oxazole, A are that amino and X are furan-2, the formula I chemical compound of 5-two bases.5-diethyl phosphonyl-2-furfural, alkylamine, 1,2-diketone and ammonium acetate reaction, can be used for synthetic wherein R5 is that imidazoles and X are furan-2, formula 2 chemical compounds of 5-two bases.The ring closed reaction of these types also can be used for synthetic the present invention's pyridine or pyrimidine.For example; make 5-diethyl phosphonyl-2-[3-dimethylamino-2-alkyl) acryloyl group] furan and cyanoacetamide react in the presence of alkali; obtain 5-alkyl-3-cyano group-6-[2-(5-diethyl phosphonyl) furyl]-2-pyridone (Jain etc.; Tetrahedron Lett.; 1995; 36,3307).Subsequently these 2-pyridones are converted into corresponding 2-haloperidid (list of references of quoting in heterocyclic modified referring to the 3rd part), thereby obtain wherein R
5For pyridine, A are that halo, X are furan-2,5-two bases and B are the formula I chemical compound of alkyl.Make 5-diethyl phosphonyl-2-[3-dimethylamino-2-alkyl) acryloyl group] furan and amidine react in the presence of alkali, obtains 5-alkyl-6-[2-(5-diethyl phosphonyl)-furyl] pyrimidine, obtain wherein R thus
5For pyrimidine, X are furan-2,5-two bases and B are formula 2 chemical compounds of alkyl.
(7) be used for the preparation of the various precursors of cyclization
Usually improved to prepare by existing method in the document or to existing method and be used for the synthetic required intermediate of The compounds of this invention.In this article, the synthetic method that is used for the synthetic part intermediate of The compounds of this invention has been described.
Various arylphosphonic acid dialkyls are particularly useful for synthetic compound of formula i.For example, can by various furyl precursor preparation wherein X be furan-2, formula 3 chemical compounds of 5-two bases.The synthetic of precursor that is appreciated that other can be adopted part steps or all steps in these reactions steps, improves and may need that for different precursors part is carried out in these reactions.It is furan-2 that 5-dialkyl phosphine acyl group-2-furan carbonyl compound (as 5-diethyl phosphonyl-2-furfural, 5-diethyl phosphonyl-2-acetyl furan) is particularly suitable for synthetic wherein X, the formula I chemical compound of 5-two bases.Adopt the conventional chemical method, for example the protection of lithiation, carbonyl and carbonyl go protection, can prepare these intermediate by furan or furan derivatives.For example, (Gschwend Org.React.1979 adds phosphoric acid agent 26:1), subsequently (as ClPO to adopt known method to carry out the furan lithiumation
3R
2), obtain 2-dialkyl phosphine acyl group-furan (as 2-diethyl phosphonyl furan).This method also can be used for the furan (as the 2-furancarboxylic acid) that 2-replaces, thereby obtains the furan (as 5-diethyl phosphonyl-2-furancarboxylic acid) that 5-dialkyl phosphine acyl group-2-replaces.Be appreciated that and adopt this method or this method is improved, also can be used to prepare other phosphonic acids aryl ester.Perhaps, the method that adopts other is as adopting the transition metal-catalyzed aryl halide or the reaction of triflate (J.Org.Chem. such as Balthazar, 1980,45:5425; J.Am.Chem.Soc. such as Petrakis, 1987,109:2831; Synthesis such as Lu, 1987,726), can prepare the phosphonic acids aryl ester.The phosphonic acids aryl ester also can prepare (Melvin, Tetrahedron Lett., 1981,22:3375 by aryl phosphate under the anionoid rearrangement reaction condition; Synthesis such as Casteel, 1991,691).The reaction of the alkali metal derivant of N-alkoxy aryl salt and dialkyl alkylphosphonate for the another kind of universal method of synthesis of heteroaryl-2-phosphonate ester (Redmore J.Org.Chem., 1970,35:4114).
Although also can adopt other method (as being used for synthetic Vilsmeier-Hack reaction of aldehyde or Reimar-Teimann reaction) to produce functional group's (as aldehyde), adopt the second lithiumation step in phosphonic acids dialkyl aryl ester, to introduce second group such as aldehyde, trialkyltin alkyl or halo group usually.In the second lithiumation step, with the reagent that can directly produce required functional group (as, for aldehyde, adopt DMF, HCO
2R etc.) or adopt the aromatic ring that can be converted into reagent (can be converted into aldehyde) the processing lithiumation of required functional group subsequently by known chemical method as alcohol, ester, nitrile, alkene.For example; under normal operation; 2-dialkyl phosphine acyl group furan (as 2-diethyl phosphonyl furan) is carried out lithiumation (as the LDA in THF); use electrophilic reagent (as tributyltin chloride or tributyl Tin tetraiodide. (tributyltin chloride or iodine)) to catch the anion of generation like this subsequently, thus obtain the 5-functionalization-2-dialkyl phosphine acyl group furan (as 5-tributyl tin alkyl-2-diethyl phosphonyl furan or 5-iodo-2-diethyl phosphonyl furan).The order that is appreciated that these reactions can promptly at first be introduced aldehyde and carry out phosphorylation reaction partly, subsequently conversely.The order of reaction depends on reaction condition and blocking group.Be further appreciated that before carrying out phosphorylation reaction, preferably adopt various known method that wherein part functional group is protected (as the aldehyde protection is acetal, aminal, the ketone protection being ketal).Then behind phosphorylation reaction, remove the blocking group in the functional group of protection.Referring to ProtectiveGroup in Organic Synthesis, Greene, T.W., 1991, Wiley, New York.For example; with 1; ammediol protection 2-furfural, subsequently carry out lithiumation step (as adopting LDA), catch anion and go under the protective condition acetal degree of functionality to be gone to protect in routine subsequently with chloro dialkyl alkylphosphonate (as chloro phosphonic acids diethyl ester), obtain 5-dialkyl phosphine acyl group-2-furfural (as 5-diethyl phosphonyl-2-furfural).Another is exemplified as the preparation of 5-ketone group-2-dialkyl phosphine acyl group furan; comprising following step: the acylation reaction of under the Friedel-Crafts reaction condition, carrying out furan; obtain 2-ketone group furan; be that ketal is (as 1 with the ketone protection subsequently; the ammediol cyclic ketal); then carry out the lithiumation step as mentioned above; obtain 5-dialkyl phosphine acyl group-2-furanone; ketone wherein is protected to be 1; the ammediol cyclic ketal; as carrying out the protection of going of ketal under the acid condition, obtain 2-ketone group-5-dialkyl phosphine acyl group furan (as 2-acetyl group-5-diethyl phosphonyl furan) at last.Perhaps, come Synthetic 2-ketone group furan by the catalytic 2-trialkyltin of the palladium alkyl furan (as 2-tributyl tin alkyl furan) and the reaction of acyl chlorides (as chloroacetic chloride, isobutyryl chloride).Be preferably in and have phosphonate ester part (as 2-tributyl tin alkyl-5-diethyl phosphonyl furan) in the 2-trialkyltin alkyl furan.By acid being converted into corresponding acyl chlorides and adding Grignard reagent subsequently, also can be by 5-dialkyl phosphine acyl group-2-furancarboxylic acid (as 5-diethyl phosphonyl-2-furancarboxylic acid) preparation 2-ketone group-5-dialkyl phosphine acyl group furan.
The part intermediate of foregoing description also can be used for synthetic other useful as intermediates.For example, 2-ketone group-5-dialkyl phosphine acyl group furan can be converted into 1,3-two-carbonyl derivative, these derivants can be used to prepare pyrazoles, pyridine or pyrimidine.2-ketone group-5-dialkyl phosphine acyl group furan (as 2-acetyl group-5-diethyl phosphonyl furan) and dialkylformamide dialkyl acetal (as dimethyl formamide dimethyl acetal (dimethylformamide dimethyl acetal)) reaction; obtain 1; 3-dicarbapentaborane homologue, 2-(3-dialkylamino-2-alkyl-acryloyl group)-5-dialkyl phosphine acyl group furan (as 2-(3-dimethylamino acryloyl group)-5-diethyl phosphonyl furan).
Be appreciated that the above-mentioned method that is used for synthetic furan derivatives can be directly used in or it improved to be used for synthetic various other useful as intermediates, as phosphonic acids aryl ester (as phosphonic acids thienyl ester, phosphonic acids phenylester or phosphonic acids pyridyl ester).
Be appreciated that and adopt when suitable above-mentioned synthetic method to carry out solid phase or liquid phase is parallel synthetic, with the research of the SAR (structure activity relationship) that carries out FBP enzyme inhibitor of the present invention fast, as long as the developmental research of these reactions can be successfully.
Part 2
Synthesizing of formula X chemical compound
The synthetic part steps or the Overall Steps that generally comprises in the following general step of chemical compound of the present invention: 1) preparation phosphonate ester precursor; (2) phosphonate ester go the protection; (3) heterocyclic structure; (4) introduce the phosphonic acids part; (5) synthetic anil.Step (1) and step (2) are discussed in part 1, below step (3), step (4) and step (5) are discussed.These methods also are applicable to formula X chemical compound usually.
(3) heterocyclic structure
(i) benzothiazole ring system
Adopt the various synthetic methods of reporting in the document, can prepare wherein G "=formula 3 chemical compounds of S, i.e. benzothiazole compound.Wherein two kinds the method for providing in the following discussion is as example.A kind of method is that the benzothiazole derivant that commerce obtains is carried out modification, obtains having on the benzothiazole ring chemical compound of suitable degree of functionality.Another kind method is to make various aniline (suc as formula 4 chemical compounds) ring formation make up the thiazole part of benzothiazole ring.For example, G wherein "=S, A=NH
2, L
2, E
2, J
2=H, X
2=CH
2Formula 3 chemical compounds of O and R '=Et can adopt the commercial 4-methoxyl group-thiazolamine that obtains to obtain through two-step reaction: adopt reagent such as BBr
3(Node, M. etc., J.Org.Chem.45,2243-2246,1980) or in the presence of mercaptan, adopt AlCl
3(as EtSH) (McOmie, J.F.W etc., Org.Synth., Collect.Vol.V, 412,1973) 4-methoxyl group-2-aminobenzothiazole is converted into 4-hydroxyl-2-aminobenzothiazole, subsequently in the presence of the suitable alkali (as sodium hydride), in polar non-solute (as DMF), make the phenol alkylation with trifluoromethanesulfonic acid diethyl phosphonyl methyl ester, obtain required compound (Phillion, D.P.; Deng Tetrahedron Lett.27,1477-1484,1986).
Can adopt several methods that various aniline are converted into benzothiazole (Sprague, J.M.; Land, A.H.Heterocycle.Compd.5,506-13,1957).For example, adopt various common methods, by making wherein W
2The formula 4 chemical compound ring formation of=H prepare 2-aminobenzothiazole (A=NH wherein
2Formula 3 chemical compounds).A kind of method comprises with KSCN and CuSO
4Carbinol mixture handle the aniline that suitably replaces, the 2-aminobenzothiazole (Ismail, the I.A. that obtain replacing; Sharp, D.E; Chedekel, M.R.J.Org.Chem.45,2243-2246,1980).Perhaps, also can in the presence of KSCN, in acetic acid, use Br
2Handle and prepare 2-aminobenzothiazole (Patil, D.G.; Chedekel, M.R.J.Org.Chem.49,997-1000,1984).This method also can be finished in two steps.For example, in chloroform, handle the phenylthiourea that replaces, the 2-aminobenzothiazole (Patil, the D.G. that obtain replacing with Br2; Chedekel, M.R.J.Org.Chem.49,997-1000,1984).Also can be by making neighbour's (ortho) Iodoaniline and thiourea at Ni catalyst (NiCl
2(PPH
3)
2) the following condensation prepared 2-aminobenzothiazole (Takagi, K.Chem.Lett.265-266,1986) of existence.
Benzothiazole can experience close electric aromatics displacement reaction, obtains benzothiazole (Sprague, J.M. that 6-replaces; Land, A.H.Heterocycle.Compd.5,606-13,1957).For example, with bromine in polar solvent such as AcOH to G wherein "=S, A=NH
2, L
2, E
2, J
2=H, X
2=CH
2Formula 3 chemical compounds of O and R=Et carry out bromination, obtain wherein E
2Formula 3 chemical compounds of=Br.
In addition, wherein A is that formula 3 chemical compounds of halo, H, alkoxyl, alkylthio group or alkyl can be by the preparation of corresponding amino-compound (Larock, Comprehensive organictransformations, VCH, New York, 1989; Trost, Comprehensive organicsynthesis; Pergamon press, New York, 1991).
(ii) benzoxazole
G wherein "=formula 3 chemical compounds of O, promptly benzoxazole can by with suitable reagent (as cyanogen halides (A=NH
2Alt, K.O. etc., J.Heterocyclic Chem.12,775,1975) or acetic acid (A=CH
3Saa, J.M.; J.Org.Chem.57,589-594,1992) or alkyl orthoformate (A=H; Org.Prep.Proced.Iht., 22,613,1990)) make the preparation of o-aminophenol ring formation.
(4) introduce the phosphonate ester part
Can adopt diverse ways (as alkylation and nucleophilic displacement reaction) preparation formula 4 chemical compounds (X wherein
2=CH
2O, R '=alkyl).Generally speaking; can adopt suitable alkali (as NaH) at polar non-solute (as DMF; DMSO) handle wherein formula 5 chemical compounds of M '=OH in; use suitable electrophilic reagent (preferably containing the phosphonate ester part) to make the phenol anion alkylation of generation subsequently as iodomethyl phosphonic acids diethyl ester, trifluoromethyl sulfonyl (sulphono) methylphosphonic acid diethyl ester, right-Methyl benzenesulfonyl ylmethyl phosphonic acids diethyl ester.This alkylation also is applicable to the precursor compound of formula 5 chemical compounds that have phenol moieties, can make its alkylation with the chemical compound that contains the phosphonic acids part.Perhaps, also can be by nucleophilic displacement reaction preparation formula 4 chemical compounds of the precursor compound of formula 5 chemical compounds (wherein halo, be preferably the ortho position that fluoro or chloro are present in nitro).For example, by using NaOCH
2P (O) (OEt)
2In DMF, handle 2-chloro-1-nitrobenzene derivative, can preparation formula 4 chemical compounds (X wherein
2=CH
2O, R '=Et).Equally, also can prepare wherein X
2=-alkyl-S-or-formula 4 chemical compounds of alkyl-N-.
(5) anil is synthetic
People have reported the multiple synthetic method of anil that is used for, and these methods can be used for the synthetic of useful as intermediates, obtain formula X chemical compound by these intermediate then.For example, by transition metal-catalyzed reaction (Kasibhatla, S.R., WO 98/39343 that waits and the list of references of wherein quoting), can introduce various alkenyls or aryl to phenyl ring; By reduction reaction, can prepare aniline by corresponding nitro-derivative and (in the presence of at 10%Pd/C, carry out hydrogenation, perhaps in HCl, adopt SnCl
2Carry out reduction reaction (Patil, D.G.; Chedekel, M.R.J.Org.Chem.49,997-1000,1984)).
The 3rd part
Synthesizing of formula VII chemical compound
The synthetic part steps or the Overall Steps that generally comprises in the general step shown in the following flow process of chemical compound of the present invention: (a) coupling of phosphonic acids part (1a or 1b) and aryl or heteroaryl moieties (being respectively 2a or 2b); When (b) needing, the coupling molecule is carried out modification; (c) phosphonic acid diester part (3) go protection, obtain phosphonic acids (4) and (d) preparation phosphonate ester precursor.
(a) coupling of phosphonate ester part (1) and aryl moiety (2)
If possible, chemical compound disclosed by the invention is preferably by preparing the phosphonate ester part and the route of synthesis of aryl or the coupling of heteroaryl ring part.
Transition metal-catalyzed coupling reaction such as Stille and Suzuki reaction are particularly suitable for synthetic (Farina etc., Organic Reactions, the Vol.50 of formula VII chemical compound; Wiley, New York, 1997; Suzuki in Metal Catalyzed Cross Coupling Reactions; WileyVCH, 1998, pp 49-97).Under the catalytic reaction condition of palladium, (wherein B is preferably Bu to chemical compound 1
3Sn) and chemical compound 2 (wherein A is as iodo, bromo or trifluoromethanesulfonic acid root) coupling, obtain formula 3 chemical compounds, wherein X
4For as 2, the 5-furyl.Chemical compound 1 (wherein B is preferably iodo) and chemical compound 2 (A=B (OH) wherein
2Or Bu
3Sn) carry out the coupling reaction of same type, also can obtain formula 3 chemical compounds, wherein X
4For as 2, the 5-furyl.
For the aryl that replaces and the reactant 2 of heteroaryl compound can be obtained by commerce, perhaps can adopt known method easily synthetic.Coupling reagent 1 also can adopt known chemical method preparation.For example, work as X
4Be 2, during the 5-furyl, coupling reagent 1 can adopt the organolithium method to be prepared by furan.(as n-BuLi/TMEDA, Gschwend Org.React.1979 adds phosphorylation agent 26:1), subsequently (as ClPO to adopt known method that furan is carried out lithiumation
3R
2), obtain 2-dialkyl phosphine acyl group-furan (as 2-diethyl phosphonyl furan).Other 2; the structure of the dibasic furan of 5-can be by adding 2-dialkyl phosphine acyl group furan (as 2-diethyl phosphonyl furan) and suitable alkali (as LDA) carries out lithiumation, the anion of using electrophilic reagent (as tributyltin chloride, triisopropyl borate or iodine) to catch generation is subsequently finished; obtain thus 5-functionalized-2-dialkyl phosphine acyl group furan (as being respectively 5-tributyl tin alkyl-2-diethyl phosphonyl furan, 2-diethyl phosphonyl furan-5-boric acid and 5-iodo-2-diethyl phosphonyl furan).
Be appreciated that the above-mentioned method that is used for synthetic furan derivatives can be directly used in or it carried out part improve and be used further to synthetic various other useful as intermediates, as phosphonic acids aryl ester (as phosphonic acids thienyl ester, phosphonic acids phenylester or phosphonic acids pyridyl ester).
Known amido link forms reaction also can be used to make phosphonic acid diester raw material 1 and aryl or 2 couplings of heteroaryl ring intermediate, thereby obtains wherein X
4Formula VII chemical compound for alkyl amino-carbonyl or alkyl-carbonyl-amino.For example, make aryl carboxylic acid (preferably having aminomethylphosphonic acid diethyl ester part) coupling, can obtain formula VII chemical compound, the ring portion of wherein drawing from intermediate 2 is divided into aryl, X
4For-CH
2NHC (O)-.Equally, in the method, alkyl amino alkyl phosphonic acids diethyl ester generation displacement reaction can produce wherein X
4For-R ' C (R ") N (R) C (O)-chemical compound.In addition, can also as make arylamine (preferably having diethyl phosphonyl acetic acid part) that coupling takes place, obtain formula VII chemical compound, the ring portion of wherein drawing from intermediate 2 is divided into aryl, X
4For-CH
2C (O) NH-.According to the extended method of this method, can prepare X
4Chemical compound for-R ' C (R ") C (O) NR-.
Known ester bond forms reaction also can be used to prepare wherein X
4For alkyl carboxyl or alkoxy carbonyl (as-CH
2C (O) O-or-CH
2OC (O)-) formula VII chemical compound.For example, when chemical compound 2 parts are the aryl (as amphyl) of hydroxyl replacement, can in the presence of bulky amine (as triethylamine), with its acidylate, obtain wherein X with the diethyl phosphonyl chloroacetic chloride
4For-CH
2The chemical compound of C (O) O-.In addition, can make aryl-carboxylic acid halides (as aryl-acyl chlorides) and (hydroxyalkyl) dialkyl alkylphosphonate (as (hydroxyl) methylphosphonic acid diethyl ester) coupling, obtain wherein X
4For-alkoxy carbonyl-(as-CH
2OC (O)-) chemical compound.
Known ehter bond forms reaction also can be used to prepare wherein X
4Formula VII chemical compound for alkylidene-O or alkylidene-O-alkylidene.For example, with iodomethyl phosphonic acids diethyl ester or preferably make the sodium salt alkylation of phenol, obtain wherein X with trifluoromethanesulfonic acid diethyl phosphonyl methyl ester
4Formula VII chemical compound for-alkylidene-O.Equally, with iodomethyl phosphonic acids diethyl ester or preferably make the sodium salt alkylation of aryl methyl alcohol, can obtain wherein X with trifluoromethanesulfonic acid diethyl phosphonyl methyl ester
4For-alkylidene-O-alkylidene-formula VII chemical compound.Perhaps, handle the hydroxymethyl phosphonic acid diethyl ester and the sodium salt of generation and haloalkyl aryl compound are reacted, can obtain wherein X with sodium hydride
4For-alkylidene-O-alkylidene-formula VII chemical compound.
For X wherein
4Formula VII chemical compound for alkyl, can adopt other common phosphonate ester formation methods to introduce the phosphonate ester part, as adopt Michaelis-Arbuzov to react (Bhattacharya etc., Chem.Rev., 1981,81:415), Michaelis-Becker reacts (Blackburn etc., J.Organomet.Chem., 1988,348:55) and the additive reaction of phosphorus and electrophilic reagent (as aldehyde, ketone, carboxylic acid halides, imines and other carbonyl derivatives) preparation.
If feasible and words easily in some cases also can be come preparation formula 3 chemical compounds by aryl compound (2b) by introducing the phosphonate ester part as dialkyl phosphine acyl group (such as diethyl phosphonyl).For example, by terminal aryl alkynes being carried out lithiumation, then making the anion that obtains and phosphorus esterification reagent (as ClPO
3R
2) reaction produces the aromatic yl polysulfide yl phosphonate ester and prepare wherein X
4Formula VII chemical compound for ethynylene.Required aryl alkynes can adopt conventional chemical method preparation.For example; adopt Sonogashira reaction (Sonogashira in ComprehensiveOrganic Synthesis; Pergamon Press:New York; 1991; Vol.3; pp521-549), make aryl halide (as iodide, bromide) or triflate and trimethyl silyl acetylene reaction, go protection to obtain terminal aryl alkynes and prepare the aryl alkine compounds to trimethyl silyl subsequently.
(b) modification of coupling molecule
Can adopt the whole bag of tricks that coupling molecule 3 is carried out modification.Aryl halide (J
3-J
7Optional respectively is as Br, I or O-trifluoromethanesulfonic acid root) be useful as intermediates, can easily be converted into other substituent group by following reaction, as aryl, alkene, alkyl, alkynes, arylamine and aryloxy group, described reaction comprises transition metal-catalyzed coupling reaction, as Stille, Suzuki, Heck, Sonogashira and other reactions (Farina etc., OrganicReactions, Vol.50; Wiley, New York, 1997; Mitchell, Synthesis, 1992,808; Suzuki in Metal Catalyzed Cross-Coupling Reactions; Wiley VCH, 1998, pp 49-97; Heck Palladium Reagents in Organic Synthesis; Academic Press:San Diego, 1985; Sonogashira in ComprehensiveOrganic Synthesis, Pergamon Press; New York, 1991, Vol.3, pp521-549, BuchwaldJ.Am.Chem.Soc.1999,121,4369-4378; Hartwig, J.Am.Chem.Soc.1999,121,3224-3225; Buchwald Acc.Chem.Res.1998,31,805).
J wherein
3-J
7The optional respectively formula VII chemical compound for formamido group can be by following method preparation: by corresponding alkyl carboxylic acid ester by adopting various amine and carry out aminolysis or forming by amido link that (amido link that mediates as DIC/HOBt forms reaction) reacts carboxylic acid and amine under the reaction condition in standard.
J wherein
3-J
7The optional respectively formula VII chemical compound for carboxylate can prepare by following method: the esterification by standard is (as DIEA/DMF/ alkiodide or EDCI, DMAP and alcohol) by the corresponding carboxylic acid preparation, perhaps prepare by corresponding aryl halide/triflate by transition metal-catalyzed carbonylation.
J wherein
3-J
7The optional respectively formula VII chemical compound for alkyl amino alkyl or arylamino alkyl can be by standard reduction amination (as aryl or alkylamine, TMOF, AcOH, DMSO, NaBH
4) by its corresponding aldehyde preparation.
(c) phosphonate ester or phosphoramidate go the protection
As described in part 1, adopt known phosphate ester and phosphonate ester cracking condition, can preparation formula 4 chemical compounds by phosphonate ester.
(d) preparation of phosphonate ester or phosphoramidate precursor
Can introduce described substituent group precursor in the different phase of building-up process.The most conventional way is that the phosphonic acids by formula 4 prepares described precursor, and this is because due to the unstability of part precursor.Preferably at the described precursor of early stage introducing of synthesis phase, as long as this precursor can tolerate the reaction condition in the reactions steps subsequently.
The bis-amino phosphate ester, wherein two Y are nitrogen, R
1Be formula VII chemical compound derived from amino acid whose identical group, can add alkali (as N-Methylimidazole., 4-N, the N-dimethyl aminopyridine) or not add under the situation of alkali, prepare by formula 4 chemical compounds by making suitable activatory phosphonate ester (as the dichloro phosphonate ester) and amino-acid ester (as the alanine ethyl ester) coupling.Perhaps, as WO 95/07920 or Mukaiyama, T etc., J.Am.Chem.Soc., 1972,94,8528 is described, can be by the triphenyl phasphine and 2 in pyridine, 2 '-pyridyl disulfide exists down, makes formula 4 chemical compounds and amino-acid ester (glycine ethyl ester) prepared in reaction bis-amino phosphate ester.
Blended bis-amino phosphonate ester, wherein two Y are nitrogen, R
1Be different groups (one of them R
1For derived from amino acid whose group, another R
1For derived from amino acid whose group or be other group (as alkyl, aryl, aralkyl, amine)) formula VII chemical compound also can adopt as described in the method preparation, but make suitable activatory phosphonate ester (as the dichloro phosphonate ester) and different amine (glycine ethyl ester and alanine ethyl ester) order of occurrence additive reaction.Be appreciated that and adopt suitable purification technique such as column chromatography, MPLC or method for crystallising, blended bis-amino phosphate ester and other products (can be nitrogen, R as two Y wherein
1Formula VII chemical compound for identical group) separates.Perhaps, can adopting in the following method, preparation mixes the bis-amino phosphate ester: by above-mentioned chlorination, make suitable phosphonate monoester (as phenylester or benzyl ester) and amine (as alanine ethyl ester or morpholine) coupling, (as suitable hydrogenation conditions) removes phosphonate ester (as phenylester or benzyl ester) under the stable condition of phosphoramidic acid ester bond subsequently, by above-mentioned chlorination, make list-phosphoramidate and second kind of amine (as the glycine ethyl ester) coupling of generation, obtain blended bis-amino phosphate ester.Phosphate monoester can adopt conventional method preparation (as the hydrolysis of phosphonic acid diester or according to the method described in the EP 481 214).
Mono amino phosphate ester, one of them Y are that O, another Y are that the formula VII chemical compound of N also can adopt the preparation of said sequence addition method.For example, handle the dichloride product that is produced by formula 4 chemical compounds with the normal alcohol of 0.7-1 (as phenol, benzylalcohol, 2,2,2-trifluoroethanol), this reaction is preferably carried out under suitable alkali (as Hunig alkali, triethylamine) exists.After above-mentioned reaction is finished, add the normal amine of 2-10 (as the alanine ethyl ester) in reactant, obtain formula VII chemical compound, one of them Y is O, and another Y is N.Perhaps, phosphonic acid diester (as the phosphonic acids diphenyl) is carried out selective hydrolysis (as adopting Lithium hydrate) also can obtain phosphonate monoester (as phosphonic acids list phenylester), make described phosphonate monoester and amine (as the alanine ethyl ester) coupling by the chlorination described in the above-mentioned mixing bis-amino phosphate ester preparation then.
Under the nucleophilic displacement reaction condition, make formula 4 alkylations with electrophilic reagent (as alkyl halide, alkyl sulfonate esters etc.), can obtain phosphonate ester.For example, by existing down at suitable alkali (as N, N '-dicyclohexyl-4-morpholine carbonamidine, Hunig alkali etc.), adopt suitable acyloxy alkyl halide (as Cl, Br, I; Elhaddadi etc., Phosphorus Sulfur, 1990,54 (1-4): 143; Hoffmann, Synthesis, 1988,62) make the direct alkylation of formula 4 chemical compounds, can synthesis type VII chemical compound, wherein R
1Be acyloxy alkyl (Starrett, etc., J.Med.Chem., 1994,1857).The carboxylate radical part of these acyloxy alkyl halides can be (but being not limited to) acetate, propionate, 2 Methylpropionic acid root, neopentanoic acid root, benzoate anion and other carboxylate radical.In the time of suitably, after forming, the acyloxy phosphonate ester can carry out further modification, as the reduction of nitro.For example, can under suitable reducing condition, incite somebody to action wherein J
3-J
7Optionally respectively be converted into wherein J for formula 5 chemical compounds of nitro
3-J
7Optional respectively formula 5 chemical compounds for amino (Dickson, etc., J.Med.Chem., 1996,39:661; Lyer, etc., Tetrahedron Lett., 1989,30:7141; Srivastva, etc., Bioorg.Chem., 1984,12:118).R wherein
1For the formula VII chemical compound of cyclic carbonate root, lactone or phthalidyl also can be by directly making formula 4 alkylations synthesize with suitable electrophilic reagent (as halogenide), this is reflected under the suitable alkali existence and carries out (as NaH or diisopropylethylamine, Biller etc., US 5,157,027; Serafinowska etc., J.Me d.Chem.1995,38:1372; Starrett etc., J.Med.Chem.1994,37:1857; Martin etc., J.Pharm.Sci.1987,76:180; Alexander etc., Collect.Czech.Chem.Commun, 1994,59:1853; EPO 0632048A1).Also can make formula 4 alkylations (as adopting N, N-diformazan Methanamide dialkyl acetal is as alkylating reagent: Alexander, P etc., Collect.Czech.Chem.Commun., 1994,59,1853) with additive method.
In addition, can also by make corresponding dichloro phosphonate ester and alcohol reaction synthesize these phosphonate ester precursors (Alexander etc., Collect.Czech.Chem.Commun., 1994,59:1853).For example, make the dichloro phosphonate ester in the presence of suitable alkali (as pyridine, triethylamine etc.) with suitable phenol, aralkyl alcohol reaction, obtain formula VII chemical compound, wherein R
1Be aryl (Khamnei etc., J.Med.Chem., 1996,39:4109; Serafmowska etc., J.Med.Chem., 1995,38:1372; De Lombaert etc., J.Med.Chem., 1994,37:498) or be aryl alkyl (Mitchell etc., J.Chem.Soc.Perkin Trahs.1,1992,38:2345) and Y be oxygen.Under standard conditions, by dichloro phosphonate ester and 2-ethoxy disulphide also can prepare the precursor that contains disulphide (Puech etc., Antiviral Res., 1993,22:155).In the time of suitably, these methods expansions can be used to prepare the precursor of other types, as R wherein
1Be 3-benzo [c] furanonyl, 2-oxo-4,5-two dehydrogenations-1, the formula VII chemical compound of 3-dioxolanes methyl or 2-oxo-tetrahydrofuran-5-base.
Adopt chlorination reagent (as thionyl chloride: Starrett etc., J.Med.Chem., 1994,1857, oxalyl chloride: Stowell etc., Tetrahedron Lett., 1990,31:3261, and phosphorus pentachloride: Quast etc., Synthesis, 1974,490), by corresponding phosphoric acid can preparation formula 4 chemical compounds a dichloro phosphonate ester or a clodronic acid ester derivant.Perhaps, also can by its corresponding phosphonic acids dimethyl silanyl ester (Bhonle etc., Synth.Commun., 1987,17:1071) or dialkyl alkylphosphonate (Still etc., Tetrahedron Lett., 1983,24:4405; Patois etc., Bull.Soc.Chim.Fr., 1993,130:485) preparation dichloro phosphonate ester.
In addition, if feasible, the part precursor also can adopt Mitsunobu reaction (Mitsunobu, Synthesis, 1981,1; Campbell, J.Org.Chem., 1992,52:6331) and other coupling reaction (as adopting carbodiimide: Alexander etc., Collect.Czech.Chem.Commun., 1994,59:1853; Casara etc., Bioorg.Med.Chem.Lett., 1992,2:145; Ohashi etc., Tetrahedron Lett., 1988,29:1189 and three (dimethylamino) phosphonium salt: Campagne etc., TetrahedronLett., 1993, the 34:6743) preparations of employing benzotriazole oxygen base.In some cases, can introduce R at the commitment of building-up process
1, as long as this group can tolerate the subsequent reaction step.For example, the heterocycle that the 2-furyl is replaced metallizes (as adopting LDA), catches with chloro phosphonic acids diaryl ester subsequently the anion of generation, can prepare wherein R
1Formula VII chemical compound for aryl.
Be appreciated that formula VII chemical compound can be blended phosphonate ester (as phenyl and benzyl ester, or phenyl and acyloxy Arrcostab), comprise the bonded precursor of chemically combined mixed ester such as phenyl and benzyl,, wait at Bioorg.Med.Chem.Lett. referring to Meier, 1997, the report among the 7:99.
By making 1 of corresponding dichloro phosphonate ester and replacement, ammediol, 1,3-hydroxyl propylamine or 1, the reaction of 3-propane diamine can be synthesized the ring-type propyl phosphonous acid ester or the phosphoramidate of replacement.Be used for preparation example as 1 of replacement, the method for ammediol is discussed below.
1, ammediol, 1,3-hydroxyl propylamine or 1,3-propane diamine synthetic
It is polytype 1 that various synthetic methods can be used to prepare, ammediol: (i) 1-replaces, and (ii) 2-replaces, and (iii) 1,2-or 1,1 of 3-ring formation, ammediol, (iv) 1,3-hydroxyl propylamine and 1,3-propane diamine.In the above the universal method that is used for these compound is discussed.
Chirality replace 1,3-hydroxylamine and 1,3-diamidogen synthetic
By making 3-chlorphenyl ethyl ketone carry out CBS enantioselectivity catalytic reaction, preparing required secondary amine with the halo group displacement subsequently or primary amine synthesizes 3-aryl-3-hydroxyl third-1-amine (Corey etc. of enantiomer-pure, Tetrahedron Lett., 1989,30,5207).Make the nitrone of the replacement of the alkene of chiral purity and aryl aldehyde carry out 1,3-dipolar addition, reduction subsequently produce the De isoxazole alkyl, can obtain chirality 3-aryl-3-amino third-1-alcohol type precursor (Koizumi etc., J.Org.Chem., 1982,47,4005).Form δ-amino alcohol by chirality phosphine palladium complex enantioselectivity, also can be 1, chiral induction forms and replaces De isoxazole alkyl (Hori etc., J.Org.Chem., 1999,64,5017) in the 3-polarity addition (polar additions).Perhaps, can adopt required amine to make corresponding chiral epoxy alcohol selective opening obtain the amino alcohol (Canas etc., Tetrahedron Lett., 1991,32,6931) that optically pure 1-aryl replaces.
Known several methods can be used for 1, and the cis-selectivity of the dibasic amino alcohol of 3-is synthetic.For example, under high cis-selectivity condition, handle (E)-N-cinnamyl three chloro acetamides with hypochlorous acid and can produce trans-two hydrogen oxazines, this chemical compound can easily be hydrolyzed to red-β-chloro-Alpha-hydroxy-δ-phenylpropylamine (Commercon etc., Tetrahedron Lett., 1990,31,3871).1, the cis-selectivity of 3-amino alcohol forms also can obtain (Haddad etc., Tetrahedron Lett., 1997,38,5981) by making optically pure 3-hydroxy-ketone reduction amination.In another approach, under the highly-solid selectively condition,, the 3-amino ketones is converted into 1, the dibasic amino alcohol of 3-(Barluenga etc., J.Org Chem., 1992,57,1219) by the reduction of selective hydration thing.
All said methods also can be used to prepare corresponding V-Z, V-W or V
2-Z
2The chiral amino alcohol of ring formation.In addition, by the described method of a preceding part, also can obtain optically pure diamidogen by the optically pure amino alcohol of this class.
The 4th part
Ring-type 1,3-propyl diester (propanyl ester) prodrug cracking mechanism
In the presence of rat and people's hepatomicrosome, the rat hepatocytes of fresh separated and cytochrome P 450 inhibitors can fast cracking ring-types 1,3-propyl diester prodrug.It is believed that, isozyme cytochrome C YP3A4 oxidation reaction, this reaction is based on the ketoconozole inhibition that medicine forms.As if the inhibitor of Cytochrome P450 family 1 and/or family 2 do not suppress the cracking of prodrug.In addition, as if although these specificity prodrug can be by the CYP3A4 cracking, other prodrug in this compounds may be other P450 substrate.
Although ring-type 1 of the present invention, the 3-propyl diester is not subjected to the restriction of above-mentioned mechanism, but as a rule, every kind of ester all contains group or the atom (as alcohol, benzylic methine protons) that is subject to the mitochondrion oxidation, and their β-elimination reactions by phosphonate ester or phosphoramidate diacid in aqueous solution produce the intermediate that can be decomposed into parent compound.
The 1st class prodrug can easily carry out the P450 oxidation reaction, and this is because of they Z '=hydroxyl or corresponding groups of hydroxyl at the ortho position (together with the position) of acid proton.D ' is a hydrogen, makes that therefore can eliminate reaction obtains phenol.
The V of the 2nd class prodrug is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkenyl and the 1-alkynyl of replacement usually.This class prodrug can easily carry out the P450 oxidation on benzylic methine protons (proton on the carbon that the V group connects).If the allylic proton is 1-alkenyl and 1-alkynyl type, its model of action is similar so.If experience this oxidation mechanism, then must be at V have hydrogen together with the position.Because Z, W and W ' are not the oxidation site that is positioned at this class prodrug, so can there be multiple different substituent group.On the one hand, Z can be electron-donating group, and it can reduce the mutagenicity or the toxicity of aryl vinyl ketone, and this ketone is the by-product of this class prodrug oxidation reaction.Therefore, at this Z be-OR
2,-SR
2Or-NR
2 2
In this class prodrug, V is with W can cis also can be for trans each other mutually.
The mechanism of the 2nd class is generally ring-type 1, the oxidation mechanism of 3-propyl diester, and wherein V links to each other by an other 3-5 atom with Z and forms cyclic group together, optionally contains 1 hetero atom, and described cyclic group is in β and the γ position and aryl-condensed of the Y adjacent with V.
The 3rd class comprises such chemical compound, i.e. Z wherein
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C α CR
2) OH and-CH
2The NH aryl.
The 3rd class prodrug can easily carry out the P450 oxidation, and this is because of they Z at the ortho position (together with the position) of acid proton
2Contain the corresponding group of hydroxyl or hydroxyl (as-CHR
2OC (O) R
3,-CHR
2N
3).Z
2Group can easily experience the P450 oxidation reaction, because they have benzylic methine protons or corresponding group (as-CH
2Aryl ,-CH (CH=CR
2 2) OH).It is believed that, work as Z
2For-SR
2The time, it can be oxidized to sulfoxide or sulfone, and this helps β-removal process.Work as Z
2For-CH
2During the NH aryl, the carbon adjacent with nitrogen is oxidized to hemiacetal amine, and this compound hydrolysis is aldehyde (C (O) H), as shown in the 3rd class.Because V
2, W
2And W " not the oxidation site that is positioned at this class prodrug, so can there be multiple different V
2, W
2And W " substituent group.
The 3rd class mechanism of foregoing description is generally ring-type 1, the oxidation mechanism of 3-propyl diester, wherein V
2And Z
2Contain 5-7 atom, choose wantonly and contain 1 heteroatomic cyclic group by the continuous formation of an other 3-5 atom, can be replaced by hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group is connected on the carbon of 3 atoms of two Y groups of distance, and described Y group is connected on the phosphorus.This class prodrug experience P450 oxidation reaction, and with similarly machine-processed oxidized with the mechanism of above-mentioned the 3rd class.The scope of W ' and W group is wider.
Cracking mechanism may be carried out in the following manner.These machine-processed evidences can show by the by-product of analytical pyrolysis.Wherein Y be-the 1st class prodrug of O-produces phenol, and wherein Y be-the 2nd class prodrug generation phenyl vinyl ketone of O-.
Wherein Y is that the cyclic amino phosphate ester of nitrogen rather than oxygen can be used as prodrug, because these phosphoramidate intermediate can produce phosphonate ester intermediate or phosphoramidate intermediate via similar mechanism.Then, described phosphoramidate (P (O) (NH
2) O
-) can be converted into phosphonate ester (PO
3 2-).
Embodiment
Except that specializing, all chemical compounds mentioned in the application's (comprising among the embodiment) and reagent generally all derive from Aldrich Chemical Company; Milwaukee, WI.
Part 1
Embodiment 1
Preparation 5-diethyl phosphonyl-2 furan carboxyaldehyde (1)
Steps A. in-78 ℃, handle 2-furfural diethyl acetal (2-furaldehyde diethyl acetal) THF (oxolane) solution (1mmol) with nBuLi (1mmol).After 1 hour, add chloro diethyl phosphate (1.2mmol), reactant was stirred 40 minutes.After extraction and the evaporation, obtain brown oil.
Step B. is in 90 ℃, the brown oil that obtains with 80% acetic acid treatment.Behind extraction and the chromatography, obtain chemical compound 1 into clarified yellow oil shape thing.Perhaps, prepare this aldehyde by furan according to following described method.
Step C. is in-78 ℃, with TMEDA (N, N, N ', N '-tetramethylethylenediamine) (1mmol) and the diethyl ether solution of nBuLi (2mmol) processing furan (1mmol) 0.5 hour.In reactant mixture, add chloro diethyl phosphate (1.2mmol), restir 1 hour.After extraction and the distillation, obtain 2-furan diethyl phosphonate, be clarification grease.
Step D. is in-78 ℃, handles the THF solution 20 minutes of 2-furan diethyl phosphonate (1mmol) with LDA (1.12mmol, N, N-diisopropyl lithamide).Add methyl formate (1.5mmol), reactant was stirred 1 hour.Behind extraction and the chromatography, obtain chemical compound 1 into clarified yellow oil shape thing.Preferably, prepare this aldehyde by the 2-furfural according to following method.
Step e. reflux 2-furfural (1mmol) and N, the toluene solution of N '-dimethyl-ethylenediamine (1mmol) is collected the water that produces by dean stark trap simultaneously.After 2 hours, vacuum is removed solvent, and distillation leftover obtains the furan-2-(N, N '-methylimidazole alkane) into clear colorless oil shape thing.bp?59-61℃(3mmHg)。
Step F. in-40 to-48 ℃, handle furan-2-(N, N '-methylimidazole alkane) (1mmol) and the THF solution of TMEDA (1mmol) with nBuLi (1.3mmol).Stirred this reactant 1.5 hours in 0 ℃, be cooled to-55 ℃ then, with the THF solution-treated of chloro diethyl phosphonate (1.1mmol).After 12 hours, evaporation reaction mixture obtains the 5-diethyl phosphonyl furan-2-(N, N '-methylimidazole alkane) into brown oil after the extraction in 25 ℃ of stirrings.
Step G. handles 5-diethyl phosphonyl furan-2-(N, N '-dimethyl-imidazolidine) aqueous solution (1mmol) to pH=1 with concentrated sulphuric acid.Behind extraction and the chromatography, obtain chemical compound 1, be clarified yellow oil shape thing.
Embodiment 2
Preparation 5-diethyl phosphonyl-2-[(1-oxo) alkyl] furan and 6-diethyl phosphonyl-2[(1-oxo) alkyl] pyridine
Steps A. in 56 ℃, the toluene solution of furan (1.3mmol) was handled 3.5 hours with 4-methylvaleric acid (1mmol), trifluoroacetic anhydride (1.2mmol) and boron trifluoride etherate (0.1mmol).With sodium bicarbonate aqueous solution (1.9mmol) quenching reactant mixture, filter by Celite pad.The extraction, the evaporation and the distillation after, obtain 2-[(4-methyl isophthalic acid-oxo) amyl group] furan, for brown oil (bp 65-77 ℃, 0.1mmHg).
Step B. is in refluxing down, with 2-[(4-methyl-l-oxo) amyl group] the benzole soln spent glycol (2.1mmol) and the p-toluenesulfonic acid (0.05mmol) of furan (1mmol) handle 60h, simultaneously by dean stark trap removal water.Add triethyl orthoformate (0.6mmol), the mixture restir that will produce down 1 hour in refluxing.After extraction and the evaporation, obtain 2-(2-furyl)-2-[(3-methyl) butyl]-1, the 3-dioxolanes is orange liquid.
Step C. is in-45 ℃, with 2-(2-furyl)-2-[(3-methyl) butyl]-l, the THF solution of 3-dioxolanes (1mmol) is handled with TMEDA (1mmol) and nBuLi (1.1mmol), the reactant mixture of in-5 to 0 ℃ of stirring generations 1 hour.The reactant mixture that produces is cooled to-45 ℃, under-45 ℃, adds in the THF solution of chloro diethyl phosphate by conduit.With 1.25 hours, make reactant mixture be warmed to room temperature gradually.After extraction and the evaporation, obtain 2-[2-(5-diethyl phosphonyl) furyl]-the 2-[(3-methyl) butyl]-1, the 3-dioxolanes is dark grease.
Step D. uses 1N hydrochloric acid (0.2mmol) with 2-[2-(5-diethyl phosphonyl) furyl in 60 ℃]-the 2-[(3-methyl) butyl]-1, the methanol solution of 3-dioxolanes (1mmol) was handled 18 hours.The extraction and the distillation after, obtain 5-diethyl phosphonyl-2-[(4-methyl isophthalic acid-oxo) amyl group] furan (2.1), for greenish orange color grease (bp 152-156 ℃, 0.1mmHg).
According to this method, the preparation following compounds:
(2.2) 5-diethyl phosphonyl-2-acetyl furan: bp 125-136 ℃, 0.1mmHg.
(2.3) 5-diethyl phosphonyl-2-[(1-oxo) butyl] furan: bp 130-145 ℃, 0.08mmHg.
In addition, these chemical compounds also can be adopted preparation in the following method:
Step e. in refluxing down, with 2-[(4-methyl-l-oxo) amyl group] the benzole soln N of furan (1mmol is according to the steps A preparation), N-dimethylhydrazine (2.1mmol) and trifluoroacetic acid (0.05mmol) processing 6 hours.After extraction and the evaporation, obtain 2-[(4-methyl isophthalic acid-oxo) amyl group] furan N, N-dimethyl hydrazone is brown liquid.
Step F. make 2-[(4-methyl isophthalic acid-oxo) amyl group] furan N; the reaction of N-dimethyl hydrazone experience step C; obtain 2-[(4-methyl isophthalic acid-oxo) amyl group]-5-diethyl phosphonyl furan N; N-dimethyl hydrazone; be brown liquid, then its ethanol-water solution with copper chloride (II) (1.1 equivalent) handled 6 hours down at 25 ℃.After extraction and the distillation, obtain chemical compound 2.1, be greenish orange color grease.
Adopt following method, prepare some 5-diethyl phosphonyl-2-[(1-oxo) alkyl] furan compound:
Step G. handles chemical compound 1 (1mmol) and 1, the chloroformic solution of 3-dimercaptopropane (1.1mmol) 24 hours with boron trifluoride etherate (0.1mmol) under 25 ℃.Behind evaporation and the chromatography, obtain 2-(2-(5-diethyl phosphonyl) furyl)-1, the 3-dithiane is faint yellow oily thing.
With 2-(2-(5-diethyl phosphonyl) furyl)-1, the THF solution of 3-dithiane (1mmol) is cooled to-78 ℃, and handles with nBuLi (1.2mmol).Behind the 1h, under-78 ℃, with cyclopropane methyl bromide reaction mixture, in-78 ℃ of restir reactants 1 hour.Behind extraction and the chromatography, obtain 2-(2-(5-diethyl phosphonyl) furyl)-2-cyclopropane methyl isophthalic acid, the 3-dithiane is grease.
In 25 ℃, with 2-(2-(5-diethyl phosphonyl) furyl)-2-cyclopropane methyl isophthalic acid, the acetonitrile-aqueous solution of 3-dithiane (1mmol) was handled 24 hours with [two (trifluoroacetyl oxygen base) iodo] benzene (2mmol).Behind extraction and the chromatography, obtain 5-diethyl phosphonyl-2-(2-cyclopropyl acetyl group) furan, be greenish orange color grease.
Prepare following compounds according to this method:
(2.4) 5-diethyl phosphonyl-2-(2-ethoxy carbonyl acetyl group) furan
(2.5) 5-diethyl phosphonyl-2-(2-methylmercaptan ethyl acyl group) furan
(2.6) 6-diethyl phosphonyl-2-acetylpyridine
Embodiment 3
Preparation 4-[2-(5-phosphono) furyl] thiazole, 4-[2-(6-phosphono) pyridine radicals] thiazole and 4-[2-(5-phosphono) furyl] selenazoles
Steps A. in refluxing down, (2.2mmol) handle the alcoholic solution 3 hours of chemical compound 2.1 (1mmol) with copper bromide (II).Filter refrigerative reactant mixture, filtrate is evaporated to dried.Produce dark grease through chromatography purification, obtain 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] furan, be orange.
Step B. is in refluxing down, with 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] alcoholic solution of furan (1mmol) and thiourea (2mmol) heated 2 hours.Transpiration-cooled reactant mixture is suspended in the yellow foam that produces in saturated sodium bicarbonate and the water (pH=8) to doing.Filter and collect the yellow solid that produces, obtain 2-amino-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] thiazole.
Step C. is in 25 ℃, with 2-amino-5-isobutyl group-4-[2-(5-diethyl phosphonyl)-furyl] dichloromethane solution of thiazole (1mmol) handled 8 hours with bromo trimethyl silane (10mmol).Reactant mixture is evaporated to dried, residue is suspended in water.Filter and collect the solid that produces, obtain 2-amino-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole (3.1), be pale solid.mp＞250℃。C
11H
15N
2O
4PS+1.25HBr value of calculation: C:32.75; H:4.06; N:6.94.Measured value: C:32.39; H:4.33; N:7.18.
According to said method or adopt the conventional chemical method that these methods are improved in some cases, the preparation following compounds:
(3.2) 2-methyl-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
12H
16NO
4PS+HBr+0.1CH
2Cl
2Value of calculation: C:37.20; H:4.44; N:3.58.Measured value: C:37.24; H:4.56; N:3.30.
(3.3) 4-[2-(5-phosphono) furyl] thiazole.C
7H
6NO
4PS+0.65HBr value of calculation: C:29.63; H:2.36; N:4.94.Measured value: C:29.92; H:2.66; N:4.57.
(3.4) 2-methyl-4-[2-(5-phosphono) furyl] thiazole.mp235-236℃。C
8H
8NO
4PS+0.25H
2O value of calculation: C:38.48; H:3.43; N:5.61.Measured value: C:38.68; H:3.33; N:5.36.
(3.5) 2-phenyl-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
17H
18NO
4PS+HBr value of calculation: C:45.96; H:4.31; N:3.15.Measured value: C:45.56; H:4.26; N:2.76.
(3.6) 2-isopropyl-4-[2-(5-phosphono) furyl] thiazole.mp?194-197℃。C
10H
12NO
4PS value of calculation: C:43.96; H:4.43; N:5.13.Measured value: C:43.70; H:4.35; N:4.75.
(3.7) 5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.mp164-166℃。Value of calculation C
11H
14NO
4PS:C:45.99; H:4.91; N:4.88.Measured value: C:45.63; H:5.01; N:4.73.
(3.8) amino thiocarbonyl-4-[2-(5-phosphono) furyl of 2-] thiazole.mp189-191℃。Value of calculation C
8H
7N
2O
4PS
2: C:33.10; H:2.43; N:9.65.Measured value: C:33.14; H:2.50; N:9.32.
(3.9) 2-(piperidino)-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
16H
23N
2O
4PS+1.3HBr value of calculation: C:40.41; H:5.15; N:5.89.Measured value: C:40.46; H:5.36; N:5.53.
(3.10) 2-(2-thienyl)-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
15H
16NO
4PS
2+ 0.75H
2O value of calculation: C:47.05; H:4.61; N:3.66.Measured value: C:47.39; H:4.36; N:3.28.
(3.11) 2-(3-pyridine radicals)-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
16H
17N
2O
4PS+3.75HBr value of calculation: C:28.78; H:3.13; N:4.20.Measured value: C:28.73; H:2.73; N:4.53.
(3.12) 2-acetylaminohydroxyphenylarsonic acid 5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.mp179-181℃。C
13H
17N
2O
5PS+0.25H
2O value of calculation: C:44.76; H:5.06; N:8.03.Measured value: C:44.73; H:5.07; N:7.89.
(3.13) 2-amino-4-[2-(5-phosphono) furyl] thiazole.C
7H
7N
2O
4PS value of calculation: C:34.15; H:2.87; N:11.38.Measured value: C:33.88; H:2.83; N:11.17.
(3.14) 2-methylamino-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.mp202-205℃。C
12H
17N
2O
4PS+0.5H
2O value of calculation: C:44.30; H:5.58; N:8.60.Measured value: C:44.67; H:5.27; N:8.43.
(3.15) 2-(N-amino-N-methyl) amino-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.mp179-181℃。C
12H
18N
3O
4PS+1.25HBr value of calculation: C:33.33; H:4.49; N:9.72.Measured value: C:33.46; H:4.81; N:9.72.
(3.16) 2-amino-5-methyl-4-[2-(5-phosphono) furyl] thiazole.mp200-220℃。C
8H
9N
2O
4PS+0.65HBr value of calculation: C:30.72; H:3.11; N:8.96.Measured value: C:30.86; H:3.33; N:8.85.
(3.17) 2,5-dimethyl-4-[2-(5-phosphono) furyl] thiazole.Mp195 ℃ (decomposition).C
9H
10NO
4PS+0.7HBr value of calculation: C:34.22; H:3.41; N:4.43.Measured value: C:34.06; H:3.54; N:4.12.
(3.18) the amino thiocarbonyl of 2--5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
12H
15N
2O
4PS
2+ 0.1HBr+0.3EtOAc value of calculation: C:41.62; H:4.63; N:7.35.Measured value: C:41.72; H:4.30; N:7.17.
(3.19) 2-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.mp163-165℃。C
10H
10NO
6PS+0.5H
2O value of calculation: C:38.47; H:3.55; N:4.49.Measured value: C:38.35; H:3.30; N:4.42.
(3.20) 2-amino-5-isopropyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
13N
2O
4The PS+1HBr:C:32.53 value of calculation; H:3.82; N:7.59.Measured value: C:32.90; H:3.78; N:7.65.
(3.21) 2-amino-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.mp＞250℃。C
9H
11N
2O
4PS value of calculation: C:39.42; H:4.04; N:10.22.Measured value: C:39.02; H:4.15; N:9.92.
(3.22) 2-cyano methyl-4-[2-(5-phosphono) furyl] thiazole.mp204-206℃。C
9H
7N
2O
4PS value of calculation: C:40.01; H:2.61; N:10.37.Measured value: C:39.69; H:2.64; N:10.03.
(3.23) the amino thio-carbonyl-amino of 2--5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.mp177-182℃。C
12H
16N
3O
4PS
2+ 0.2 hexane+0.3HBr value of calculation: C:39.35; H:4.78; N:10.43.Measured value: C:39.61; H:4.48; N:10.24.
(3.24) 2-amino-5-propyl group-4-[2-(5-phosphono) furyl] thiazole.mp235-237℃。C
10H
13N
2O
4PS+0.3H
2O value of calculation: C:40.90; H:4.67; N:9.54.Measured value: C:40.91; H:4.44; N:9.37.
(3.25) 2-amino-5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.mp248-250℃。C
10H
11N
2O
6PS+0.1HBr value of calculation: C:36.81; H:3.43; N:8.58.Measured value: C:36.99; H:3.35; N:8.84.
(3.26) 2-amino-5-methyl mercapto-4-[2-(5-phosphono) furyl] thiazole.mp181-184℃。C
8H
9N
12O
4PS
2+ 0.4H
2O value of calculation: C:32.08; H:3.30; N:9.35.Measured value: C:32.09; H:3.31; N:9.15.
(3.27) 2-amino-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
11N
2O
4PS+1H
2O+0.75HBr value of calculation: C:32.91; H:3.80; N:7.68.Measured value: C:33.10; H:3.80; N:7.34.
(3.28) 2-amino-5-methanesulfinyl-4-[2-(5-phosphono) furyl] thiazole.mp＞250℃。C
8H
9N
2O
5PS
2+ 0.35NaCl value of calculation: C:29.23; H:2.76; N:8.52.Measured value: C:29.37; H:2.52; N:8.44.
(3.29) 2-amino-5-benzyl oxygen base carbonyl-4-[2-(5-phosphono) furyl] thiazole.C
15H
13N
2O
6PS+0.2H
2O value of calculation: C:46.93; H:3.52; N:7.30.Measured value: C:46.64; H:3.18; N:7.20.
(3.30) 2-amino-5-cyclobutyl-4-[2-(5-phosphono) furyl] thiazole.C
11H
13N
2O
4PS+0.15HBr+0.15H
2O value of calculation: C:41.93; H:4.30; N:8.89.Measured value: C:42.18; H:4.49; N:8.53.
(3.31) 2-amino-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C
10H
11N
2O
4PSBr+0.73HBr+0.15MeOH+0.5H
2O value of calculation: C:33.95; H:3.74; N:7.80; S:8.93; Br:16.24.Measured value: C:33.72; H:3.79; N:7.65; S:9.26; Br:16.03.
(3.32) 2-amino-5-[(N, the N-dimethyl) amino methyl]-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.Value of calculation C
10H
16N
3O
4Br
2PS+0.8CH
2Cl
2: C:24.34; H:3.33; N:7.88.Measured value: C:24.23; H:3.35; N:7.64.
(3.33) 2-amino-5-methoxycarbonyl-4-[2-(5-phosphono) furyl] thiazole.Mp227 ℃ (decomposition).C
9H
9N
2O
6PS+0.1H
2O+0.2HBr value of calculation: C:33.55; H:2.94; N:8.69.Measured value: C:33.46; H:3.02; N:8.49.
(3.34) 2-amino-5-ethylenebis dithiocarbamate carbonyl-4-[2-(5-phosphono) furyl] thiazole.Mp245 ℃ (decomposition).C
10H
11N
2O
5PS
2Value of calculation: C:35.93; H:3.32; N:8.38.Measured value: C:35.98; H:3.13; N:8.17.
(3.35) 2-amino-5-propyl group oxygen base carbonyl-4-[2-(5-phosphono) furyl] thiazole.Mp245 ℃ (decomposition).C
11H
13N
2O
6PS value of calculation: C:39.76; H:3.94; N:8.43.Measured value: C:39.77; H:3.72; N:8.19.
(3.36) 2-amino-5-benzyl-4-[2-(5-phosphono) furyl] thiazole.C
14H
13N
2O
4PS+H
2O value of calculation: C:47.46; H:4.27; N:7.91.Measured value: C:47.24; H:4.08; N:7.85.
(3.37) 2-amino-5-[(N, the N-diethyl) amino methyl]-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.C
12H
2ON
3O
4Br
2PS+0.1HBr+1.4MeOH value of calculation: C:29.47; H:4.74; N:7.69.Measured value: C:29.41; H:4.60; N:7.32.
(3.38) 2-amino-5-[(N, the N-dimethyl) carbamoyl]-4-[2-(5-phosphono) furyl] thiazole.C
10H
12N
3O
5PS+1.3HBr+1.0H
2O+0.3 acetone value of calculation: C:28.59; H:3.76; N:9.18.Measured value: C:28.40; H:3.88; N:9.01.
(3.39) 2-amino-5-carboxyl-4-[2-(5-phosphono) furyl] thiazole.C
8H
7N
2O
6PS+0.2HBr+0.1H
2O value of calculation: C:31.18; H:2.42; N:9.09.Measured value: C:31.11; H:2.42; N:8.83.
(3.40) 2-amino-5-isopropyl oxygen base carbonyl-4-[2-(5-phosphono) furyl] thiazole.Mp240 ℃ (decomposition).C
11H
13N
2O
6PS value of calculation: C:39.76; H:3.94; N:8.43。Measured value: C:39.42; H:3.67; N:8.09.
(3.41) 2-methyl-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
12O
4PNS+0.75HBr+0.35H
2O value of calculation: C:36.02; H:4.13; N:4.06.Measured value: C:36.34; H:3.86; N:3.69.
(3.42) 2-methyl-5-cyclopropyl-4-[2-(5-phosphono) furyl] thiazole.C
11H
12NO
4PS+0.3HBr+0.5CHCl
3Value of calculation: C:37.41; H:3.49; N:3.79.Measured value: C:37.61; H:3.29; N:3.41.
(3.43) 2-methyl-5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.C
11H
12NO
6PS value of calculation: C:41.64; H:3.81; N:4.40.Measured value: C:41.61; H:3.78; N:4.39.
(3.44) amino 2-[(N-acetyl group)]-5-methoxy-4-[2-(5-phosphono) furyl] thiazole.C
11H
13N
2O
6PS+0.15HBr value of calculation: C:38.36; H:3.85; N:8.13.Measured value: C:38.74; H:3.44; N:8.13.
(3.45) 2-amino-5-(4-morpholinyl) methyl-4-[2-(5-phosphono) furyl] the thiazolyl-dihydro bromate.C
12H
18Br
2N
3O
5PS+0.25HBr value of calculation: C:27.33; H:3.49; N:7.97.Measured value: C:27.55; H:3.75; N:7.62.
(3.46) 2-amino-5-cyclo propyl methoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.238 ℃ of Mp (decomposition).C
12H
13N
2O
6PS value of calculation: C:41.86; H:3.81; N:8.14.Measured value: C:41.69; H:3.70; N:8.01.
(3.47) 2-amino-5-methyl mercapto-4-[2-(5-phosphono) furyl] thiazole N, N-dicyclohexyl ammonium salt.Mp＞250℃。C
8H
9N
2O
4PS
2+ 1.15C
12H
23N value of calculation: C:52.28; H:7.13; N:8.81.Measured value: C:52.12; H:7.17; N:8.81.
(3.48) amino 2-[(N-dansyl base)]-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
23H
26N
3O
6PS
2+ 0.5HBr value of calculation: C:47.96; H:4.64; N:7.29.Measured value: C:48.23; H:4.67; N:7.22.
(3.49) 2-amino-5-(2,2,2-three fluoro ethyls)-4-[2-(5-phosphono) furyl] thiazole.C
9H
8N
2F
3O
4PS value of calculation: C:32.94, H:2.46, N:8.54.Measured value: C:32.57, H:2.64, N:8.14.
(3.50) 2-methyl-5-methyl mercapto-4-[2-(5-phosphono) furyl] thiazole.C
9H
10NO
4PS
2Value of calculation: C:37.11; H:3.46; N:4.81.Measured value: C:36.72; H:3.23; N:4.60.
(3.51) 2-amino-5-methyl mercapto-4-[2-(5-phosphono) furyl] the thiazole ammonium salt.C
8H
12N
3O
4PS
2Value of calculation: C:31.07; H:3.91; N:13.59.Measured value: C:31.28; H:3.75; N:13.60.
(3.52) 2-cyano group-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
9N
2O
4PS value of calculation: C:42.26; H:3.19; N:9.86.Measured value: C:41.96; H:2.95; N:9.76.
(3.53) 2-amino-5-hydroxymethyl-4-[2-(5-phosphono) furyl] thiazole.C
8H
9N
2O
5PS value of calculation: C:34.79; H:3.28; N:10.14.Measured value: C:34.57; H:3.00; N:10.04.
(3.54) 2-cyano group-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
12H
13N
2O4SP+0.09HBr value of calculation: C:46.15; H:4.20; N:8.97.Measured value: C:44.81; H:3.91; N:8.51.
(3.55) 2-amino-5-isopropylthio-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C
10H
14BrN
2O
4PS
2Value of calculation: C:29.94; H:3.52; N:6.98.Measured value: C:30.10; H:3.20; N:6.70.
(3.56) 2-amino-5-phenyl sulfo--4-[2-(5-phosphono) furyl] thiazole.C
13H
11N
2O
4PS
2Value of calculation: C:44.07; H:3.13; N:.91.Measured value: C:43.83; H:3.07; N:7.74.
(3.57) 2-amino-5-t-butylthio-4-[2-(5-phosphono) furyl] thiazole.C
11H
15N
2O
4PS
2+ 0.6CH
2Cl
2Value of calculation: C:36.16; H:4.24; N:7.27.Measured value: C:36.39; H:3.86; N:7.21.
(3.58) 2-amino-5-propyl dithiocarbamate-4-[2-(5-phosphono) furyl] thiazole hydrobromide salt.C
10H
14BrN
2O
4PS
2Value of calculation: C:29.94; H:3.52; N:6.98.Measured value: C:29.58; H:3.50; N:6.84.
(3.59) 2-amino-5-ethylenebis dithiocarbamate-4-[2-(5-phosphono) furyl] thiazole.C
9H
11N
2O
4PS
2+ 0.25HBr value of calculation: C:33.11; H:3.47; N:8.58.Measured value: C:33.30; H:3.42; N:8.60.
(3.60) amino 2-[(N-tert-butyl group oxygen base carbonyl)]-5-methoxy-4-[2-(5-phosphono) furyl] thiazole.C
14H
19N
2O
7PS value of calculation: C:43.08; H:4.91; N:7.18.Measured value: C:42.69; H:4.58; N:7.39.
(3.61) 2-hydroxyl-4-[2-(5-phosphono) furyl] thiazole.C
7H
6NO
5PS value of calculation: C:34.02; H:2.45; N:5.67.Measured value: C:33.69; H:2.42; N:5.39.
(3.62) 2-hydroxyl-5-ethyl-4-[2-(5-phosphono) furyl] thiazole.C
9H
10NO
5PS value of calculation: C:39.28; H:3.66; N:5.09.Measured value: C:39.04; H:3.44; N:4.93.
(3.63) 2-hydroxyl-5-isopropyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
12NO
5PS+0.1HBr value of calculation: C:40.39; H:4.10; N:4.71.Measured value: C:40.44; H:4.11; N:4.68.
(3.64) 2-hydroxyl-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
11H
14NO
5PS value of calculation: C:43.57; H:4.65; N:4.62.Measured value: C:43.45; H:4.66; N:4.46.
(3.65) 5-ethoxy carbonyl-4-[2-(5-phosphono) furyl] thiazole.C
10H
10NO
6PS value of calculation: C:39.61; H:3.32; N:4.62.Measured value: C:39.60; H:3.24; N:4.47.
(3.66) 2-amino-5-vinyl-4-[2-(5-phosphono) furyl] thiazole.C
9H
9N
2O
4PS+0.28HCl value of calculation: C:37.66; H:3.26; N:9.46.Measured value: C:37.96; H:3.37:N:9.10.
(3.67) 2-amino-4-[2-(6-phosphono) pyridine radicals] thiazole hydrobromide salt
(3.68) 2-methyl mercapto-5-isobutyl group-4-[2-(5-phosphono) furyl] thiazole.C
12H
16NO
4PS
2Value of calculation: C:43.24; H:4.84; N:4.20.Measured value: C:43.55; H:4.63; N:4.46.
(3.69) 2-amino-5-isobutyl group-4-[2-(3-phosphono) furyl] thiazole.C
11H
15N
2O
4PS+0.1H
2O value of calculation: C:43.45; H:5.04; N:9.21.Measured value: C:43.68; H:5.38; N:8.98.
(3.70) 2-amino-5-isobutyl group-4-[2-(5-phosphono) furyl] selenazoles.C
11H
15N
2O
4PSe+0.14HBr+0.6EtOAc value of calculation: C:38.93; H:4.86; N:6.78.Measured value: C:39.18; H:4.53; N:6.61.
(3.71) 2-amino-5-methyl mercapto-4-[2-(5-phosphono) furyl] selenazoles.C
8H
9N
2O
4PSSe+0.7HBr+0.2EtOAc value of calculation: C:25.57; H:2.75; N:6.78.Measured value: C:25.46; H:2.49; N:6.74.
(3.72) 2-amino-5-ethyl-4-[2-(5-phosphono) furyl] selenazoles.C
9H
11N
2O
4PSe+HBr value of calculation: C:26.89; H:3.01; N:6.97.Measured value: C:26.60; H:3.16; N:6.81.
Embodiment 4
Prepare 4-[2-(5-phosphono) furyl that various 2-and 5-replace] thiazole
Steps A. under 100 ℃, nitrogen environment; handle 2-bromo-5-isobutyl group-4-[2-(5-diethyl phosphonyl)-furyl with tributyl (vinyl) stannum (5mmol) and two (triphenyl phasphine) palladium chloride (0.05mmol)] thiazole (1mmol, by in 0 ℃ with copper bromide (II) (1.2mmol) and isopentyl nitrile (1.2mmol) handle 2-amino-5-isobutyl group-4-[2-(5-diethyl phosphonyl)-furyl] (1mmol) acetonitrile solution 1h of thiazole (in embodiment 3 step B, preparing), with after extraction and chromatography obtain the brown solid preparation).Behind the 5h, transpiration-cooled reactant mixture, residue obtain 2-vinyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl into yellow solid through chromatography] thiazole.
Step B. makes 2-vinyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] thiazole experience embodiment 3 step C, obtain 2-vinyl-5-isobutyl group-4-[2-(5-phosphono)-furyl into yellow solid] thiazole (4.1).C
13H
16NO
4PS+1HBr+0.1H
2O value of calculation: C:39.43; H:4.38; N:3.54.Measured value: C:39.18; H:4.38; N:3.56.
This method also can be used for preparing 4-[2-(5-phosphono) furyl that various 5-replace by corresponding halogenide] thiazole.
Step C. adopts 2-tributyl tin alkyl furan as another kind of coupling component; make 2-amino-5-bromo-4-[2-(5-diethyl phosphonyl) furyl] thiazole experience steps A, obtain 2-amino-5-(2-furyl)-4-[2-(5-diethyl phosphonyl) furyl] thiazole.
Step D. makes 2-amino-5-(2-furyl)-4-[2-(5-diethyl phosphonyl) furyl] thiazole experience embodiment 3 step C, obtain 2-amino-5-(2-furyl)-4-[2-(5-phosphono) furyl] thiazole (4.2).mp190-210℃。C
11H
9N
2O
5PS+0.25HBr value of calculation: C:39.74; H:2.80; N:8.43.Measured value: C:39.83; H:2.92; N:8.46.
Prepare following compounds according to this method:
(4.3) 2-amino-5-(2-thienyl)-4-[2-(5-diethyl phosphonyl) furyl] thiazole.C
11H
9N
2O
4PS
2+ 0.3EtOAc+0.11HBr value of calculation: C:40.77; H:3.40; N:7.79.Measured value: C:40.87; H:3.04; N:7.45.
Embodiment 5
Preparation 4-[2-(5-phosphono) furyl] oxazole and 4-[2-(5-phosphono) furyl] imidazoles
Steps A. in refluxing down, handle 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo with urea (10mmol)) amyl group] the t-BuOH solution 72 hours of furan (1mmol).Behind filtration, evaporation and the chromatography, obtain 2-amino-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] oxazole and 2-hydroxyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] imidazoles.
Step is amino-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] oxazole experience embodiment 3 step C B.2-, obtain 2-amino-5-isobutyl group-4-[2-(5-phosphono) furyl] oxazole (5.1).Mp250 ℃ (decomposition).C
11H
15N
2O
5P value of calculation: C:46.16; H:5.28; N:9.79.Measured value: C:45.80; H:5.15; N:9.55.
Step is hydroxyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl C.2-] imidazoles experience embodiment 3 step C, obtain 2-hydroxyl-5-isobutyl group-4-[2-(5-phosphono) furyl] imidazoles (5.14).Mp205 ℃ (decomposition).C
11H
15N
2O
5P value of calculation: C:46.16; H:5.28; N:9.79.Measured value: C:45.80; H:4.90; N:9.73.
Perhaps, prepare 4-[2-(5-phosphono) furyl] oxazole and 4-[2-(5-phosphono) furyl according to following method] imidazoles:
Step D. is in 100 ℃, with sodium acetate (2mmol) and ammonium acetate (2mmol) with 5-diethyl phosphonyl-2-[(2-bromo-4-methyl isophthalic acid-oxo) amyl group] the acetic acid solution processing 4 hours of furan (1mmol).Behind evaporation and the chromatography, obtain 2-methyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl]-oxazoles, 2-methyl-4-isobutyl group-5-[2-(5-diethyl phosphonyl) furyl] oxazole and 2-methyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] imidazoles.
Step e. make 2-methyl-5-isobutyl group-4-[2-(5-diethyl phosphonyl) furyl] oxazole, 2-methyl-4-isobutyl group-5-[2-(5-diethyl phosphonyl) furyl] oxazole and 2-methyl-5-isobutyl group-4-[2-(5 diethyl phosphonyl) furyl] imidazoles experience embodiment 3 step C, obtain following compounds:
(5.18) 2-methyl-4-isobutyl group-5-[2-(5-phosphono) furyl] oxazole hydrobromate.Mp＞230 ℃; C
12H
17BrNO
5P+0.4H
2O value of calculation: C:38.60; H:4.81; N:3.75.Measured value: C:38.29; H:4.61; N:3.67.
(5.19) 2-methyl-5-isobutyl group-4-[2-(5-phosphono) furyl] oxazole hydrobromate.C
12H
17BrNO
5P value of calculation: C:39.36; H:4.68; N:3.83.Measured value: C:39.33; H:4.56; N:3.85.
(5.21) 2-methyl-5-isobutyl group-4-[2-(5-phosphono) furyl] the imidazoles hydrobromate.
C
12H
18BrN
2O
4P+0.2NH
4Br value of calculation: C:37.46; H:4.93; N:8.01.Measured value: C:37.12; H:5.11; N:8.28.
Perhaps, prepare 4-[2-(5-phosphono) furyl according to following method] imidazoles:
Step F. in 80 ℃, the alcoholic solution of 5-diethyl phosphonyl-2-(bromo acetyl group) furan (1mmol) was handled 4 hours with trifluoro ethanamidine (2mmol).Behind evaporation and the chromatography, obtain 2-trifluoromethyl-4-[2-(5-diethyl phosphonyl) furyl] imidazoles, be grease.
Step is trifluoromethyl-4-[2-(5-diethyl phosphonyl) furyl G.2-] imidazoles experience embodiment 3 step C, obtain 2-trifluoromethyl-4-[2-(5-phosphono)-furyl] imidazoles (5.22).Mp188 ℃ (dec.); C
8H
6F
3N
2O
4P+0.5HBr value of calculation: C:29.79; H:2.03; N:8.68.Measured value: C:29.93; H:2.27; N:8.30.
Perhaps, according to following method preparation 4,5-dimethyl-1-isobutyl group-2-[2-(5-phosphono) furyl]-imidazoles:
Step H. is in 100 ℃, and with 5-diethyl phosphonyl-2-furfural (1mmol), ammonium acetate (1.4mmol), 3, the glacial acetic acid solution of 4-diacetyl (3mmol) and isobutyl amine (3mmol) heated 24 hours.Behind evaporation and the chromatography, obtain 4,5-dimethyl-1-isobutyl group-2-[2-(5-diethyl phosphonyl) furyl] imidazoles, be yellow solid.
Step I.4,5-dimethyl-1-isobutyl group-2-[2-(5-diethyl phosphonyl) furyl]-imidazoles experience embodiment 3 step C, obtain 4,5-dimethyl-1-isobutyl group-2-[2-(5-phosphono) furyl] imidazoles (5.23); C
13H
19N
2O
4P+1.35HBr value of calculation: C:38.32; H:5.03; N:6.87.Measured value: C:38.09; H:5.04; N:7.20.
According to said method or in some cases said method is carried out some and improve preparation following compounds:
(5.2) 2-amino-5-propyl group-4-[2-(5-phosphono) furyl] oxazole.Mp250 ℃ (decomposition); C
10H
13N
2O
5P value of calculation: C:44.13; H:4.81; N:10.29.Measured value: C:43.74; H:4.69; N:9.92.
(5.3) 2-amino-5-ethyl-4-[2-(5-phosphono) furyl] oxazole.C
9H
11N
2O
5P+0.4H
2O value of calculation: C:40.73; H:4.48; N:10.56.Measured value: C:40.85; H:4.10; N:10.21.
(5.4) 2-amino-5-methyl-4-[2-(5-phosphono) furyl] oxazole.C
8H
9N
2O
5P+0.1H
2O value of calculation: C:39.07; H:3.77; N:11.39.Measured value: C:38.96; H:3.59; N:11.18.
(5.5) 2-amino-4-[2-(5-phosphono) furyl] oxazole.C
7H
7N
2O
5P+0.6H
2O value of calculation: C:34.90; H:3.43; N:11.63.Measured value: C:34.72; H:3.08; N:11.35.
(5.6) 2-amino-5-isobutyl group-4-[2-(5-phosphono) furyl] oxazole hydrobromate.C
11H
16N
2O
5BrP+0.4H
2O value of calculation: C:35.29; H:4.52; N:7.48.Measured value: C:35.09; H:4.21; N:7.34.
Embodiment 6
A. prepare various phosphamide prodrug
Steps A. in refluxing down, with 2-methyl-5-isobutyl group-4-[2-(5-phosphono) furyl] thionyl chloride (5mL) the suspension heating of thiazole (1mmol) 4 hours.Transpiration-cooled reactant mixture is dissolved in the yellow residue that produces in the dichloromethane to doing, and handles with the dichloromethane solution of corresponding benzyl alcohol (4mmol) and pyridine (2.5mmol).After 24 hours, extract this reactant mixture and chromatography in 25 ℃ of stirrings, obtain target compound.
Step B. is with 2-methyl-5-isopropyl-4-[2-(5-phosphono)-furyl] thiazole dihydrochloride (preparing in steps A) dichloromethane (5mL) solution (1mmol) is cooled to 0 ℃, with benzyl alcohol (0.9mmol) dichloromethane (0.5mL) and pyridine (0.3mL) solution-treated.The reaction solution that produces was stirred 1 hour in 0 ℃, add the THF solution of ammonia (excessive) then.After stirring 16 hours under the room temperature; the evaporation reaction thing is to doing; residue obtains 2-methyl-5-isopropyl-4-[2-(5-phosphono list acylamino-(the phosphonomonoamido)) furyl into the hard jelly of yellow behind chromatography] thiazole (6.1) and be 2-methyl-5 isopropyls-4-[2-(5-phosphoro diamido (phosphorodiamido)) furyl of yellow hard jelly]-thiazole (6.2).
(6.1) 2-methyl-5-isopropyl-4-[2-(5-phosphono list acylamino-) furyl] thiazole: MSm/e 299 (M-H).
(6.2) 2-methyl-5-isopropyl-4-[2-(5-phosphoro diamido) furyl] thiazole: MSm/e 298 (M-H).
In addition, can prepare other phosphamide with diverse ways according to the method for following example:
Step C. is with 2-amino-5-methyl mercapto-4-[2-(5-phosphono) furyl] thiazole dichloride (preparing in steps A) dichloromethane (5mL) suspension (1mmol) is cooled to 0 ℃, blasts ammonia (excessive) 10min in reactant.After stirring 16 hours under the room temperature, the evaporation reaction thing is to doing, and residue obtains 2-amino-5-methyl mercapto-4-[2-(5-phosphoro diamido) furyl through chromatography purification] thiazole (6.3), be foam.C
8H
11N
4O
2PS
2+ 1.5HCl+0.2EtOH value of calculation: C:28.48; H:3.90; N:15.82.Measured value: o:28.32; H:3.76; N:14.21.
According to said method or in some cases said method is carried out some and improve preparation following compounds:
(6.4) 2-amino-5-isobutyl group-4-[2-(5-phosphono list acylamino-) furyl] thiazole.Mp77-81℃。
C
11H
16N
3O
3PS+H
2O+0.8Et
3N value of calculation: C:47.41; H:7.55; N:13.30.Measured value: C:47.04; H:7.55; N:13.67.
(6.5) 2-amino-5-isobutyl group-4-[2-(5-phosphoro diamido) furyl] thiazole.C
11H
17N
4O
2PS+0.5H
2O+0.75HCl value of calculation: C:39.24; H:5.61; N:16.64.Measured value: C:39.05; H:5.43; N:15.82.
(6.28) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-diisobutyl) phosphoro diamido] furyl } thiazole.Mp182-183℃。C
19H
33N
4O
2PS value of calculation: C:55.32; H:8.06; N:13.58.Measured value: C:54.93; H:7.75; N:13.20.
(6.29) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-(1, two (the ethoxy carbonyl)-1-propyl group of 3-)-phosphoro) diamido] furyl } thiazole.C
29H
45N
4O
10PS value of calculation: C:51.78:H:6.74; N:8.33.Measured value: C:51.70; H:6.64; N:8.15.
(6.30) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-(1-benzyl oxygen base carbonyl)-1-ethyl)-phosphoro diamido] furyl } thiazole.C
31H
37N
4O
6PS value of calculation: C:59.60; H:5.97; N:8.97.Measured value: C:59.27; H:5.63; N:8.74.
(6.31) two (2-methoxycarbonyl-1-the aziridinyl)-phosphoro diamidos of 2-amino-5-isobutyl group-4-{2-[5-] furyl } thiazole.C
19H
25N
4O
6PS+0.3CH
2Cl
2Value of calculation: C:46.93; H:5.22; N:11.34.Measured value: C:58.20; H:5.26; N:9.25.
(6.39) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-2-(1-ethoxy carbonyl) propyl group) phosphoro diamido] furyl } thiazole.C
23H
37N
4O
6PS+0.6EtOAc+0.1CH
2Cl
2Value of calculation: C:51.91; H:7.18; N:9.50.Measured value: C:51.78; H:7.17; N:9.26.
According to said method, single phenyl-single phosphamide derivant that also can preparation formula I:
Step D. under room temperature, with Lithium hydrate (1N 1.5mmol) handles 2-amino-5-isobutyl group-4-[2-(5-diphenylphosphine acyl group)-furyl] acetonitrile (9mL) of thiazole (1mmol) and water (4mL) solution 4 hours.Reaction solution is evaporated to dried, in residue water-soluble (10mL), is cooled to 0 ℃, add 6N HCl the pH of solution is transferred to 4.Filter and collect the white solid that produces, obtain 2-amino-5-isobutyl group-4-[2-(5-Phenylphosphine acyl group) furyl] thiazole.
Step e. with 2-amino-5-isobutyl group-4-[2-(5-Phenylphosphine acyl group) furyl] thionyl chloride (3mL) suspension of thiazole (1mmol) is heated to and refluxed 2 hours.Reaction solution is evaporated to dried, residue is dissolved in the anhydrous methylene chloride (2mL), after this.Under 0 ℃, the solution that obtains is added in the pyridine (0.8mL) and dichloromethane (3mL) solution of L-methyl lactamine hydrochlorate (1.2mmol).The reaction solution that stirring produces under room temperature 14 hours.Behind evaporation and the chromatography, obtain 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-methoxycarbonyl) ethyl) phosphono acylamino-(phosphon acylamino-)]-furyl } thiazole (6.6), be grease.C
21H
26N
3O
5PS value of calculation: C:54.42; H:5.65; N:9.07.Measured value: C:54.40; H:6.02; N:8.87.
According to said method, the preparation following compounds:
(6.7) 2-amino-5-isobutyl group-4-{2-[5-(O-Phenylphosphine acyl group acylamino-)] furyl } thiazole.Mp205 ℃ (decomposition).C
17H
20N
3O
3PS+0.3H
2O+0.3HCl value of calculation: C:51.86; H:5.35; N:10.67.Measured value: C:51.58; H:4.93; N:11.08.
(6.8) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-ethoxy carbonyl methyl) phosphono acylamino-] furyl } thiazole.C
21H
26N
3O
5PS value of calculation: C:54.42; H:5.65; N:9.07.Measured value: C:54.78; H:5.83; N:8.67.
(6.9) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-isobutyl group) phosphono acylamino-] furyl } thiazole.mp?151-152℃。C
21H
28N
3O
3PS value of calculation: C:58.18; H:6.51; N:9.69.Measured value: C:58.12; H:6.54; N:9.59.
(6.18) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-(1-ethoxy carbonyl-2-phenyl) ethyl) phosphono acylamino-)] furyl } thiazole.C
28H
32N
3O
5PS value of calculation: C:60.75; H:5.83; N:7.59.Measured value: C:60.35; H:5.77; N:7.37.
(6.19) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-(1-ethoxy carbonyl-2-methyl) propyl group) phosphono acylamino-)] furyl } thiazole.C
23H
30N
3O
5PS value of calculation: C:56.20; H:6.15; N:8.55.Measured value: C:55.95; H:5.80; N:8.35.
(6.20) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-(1,3-two (ethoxy carbonyl) propyl group) phosphono acylamino-)] furyl thiazole.C
26H
34N
3O
7PS+0.2CH
2Cl
2Value of calculation: C:54.20; H:5.97; N:7.24.Measured value: C:54.06; H:5.68; N:7.05.
(6.21) furyl 2-amino-5-isobutyl group-4-{2-[5-(O-(3-chlorophenyl)-N-(1-(1-methoxycarbonyl) ethyl) propyl group) phosphono acylamino-)] } thiazole.C
21H
25N
3O
5PSCl value of calculation: C:50.65; H:5.06; N:8.44.Measured value: C:50.56; H:4.78; N:8.56.
(6.22) 2-amino-5-isobutyl group-4-{2-[5-(O-(4-chlorophenyl)-N-(1-(1-methoxycarbonyl) ethyl) phosphono acylamino-)] furyl } thiazole.C
21H
25N
3O
5PSCl+1HCl+0.2H
2O value of calculation: C:46.88; H:4.95; N:7.81.Measured value: C:47.33; H:4.71; N:7.36.
(6.23) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-(1-two (ethoxy carbonyl) methyl) phosphono acylamino-)] furyl } thiazole.C
24H
30N
3O
7PS value of calculation: C:53.83; H:5.65; N:7.85.Measured value: C:53.54 H:5.63; N:7.77
(6.24) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-morpholinyl) phosphono acylamino-)] furyl } thiazole.C
21H
26N
3O
4PS value of calculation: C:56.37; H:5.86; N:9.39.Measured value: C:56.36; H:5.80; N:9.20.
(6.25) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(1-(1-benzyl oxygen base carbonyl) ethyl) phosphono acylamino-)] furyl } thiazole.C
27H
30N
3O
5PS value of calculation: C:60.10; H:5.60; N:7.79.Measured value: C:59.80; H:5.23; N:7.53.
(6.32) furyl 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-benzyl oxygen base carbonyl methyl) phosphono acylamino-)] } thiazole.C
26H
28N
3O
5PS value of calculation: C:59.42; H:5.37; N:8.00.Measured value: C:59.60; H:5.05; N:7.91.
(6.36) 2-amino-5-isobutyl group-4-{2-[5-(O-(4-methoxyphenyl)-N-(1-(1-methoxycarbonyl) ethyl) phosphono acylamino-)] furyl } thiazole.C
22H
28N
3O
6PS+0.1CHCl
3+ 0.1MeCN value of calculation: C:52.56; H:5.62; N:8.52.Measured value: C:52.77; H:5.23:N:8.87.
(6.37) furyl phosphono acylamino-2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-2-methoxycarbonyl) propyl group))] } thiazole.C
22H
28N
3O
5PS+0.6 H
2O value of calculation: C:54.11; H:6.03; N:8.60.Measured value: C:53.86; H:5.97; N:8.61.
(6.38) 2-amino-5-isobutyl group-4-{2-[5-(O-phenyl-N-(2-(1-ethoxy carbonyl) propyl group) phosphono acylamino-)] furyl } thiazole.C
23H
30N
3O
5PS value of calculation: C:56.20; H:6.15; N:8.55.Measured value: C:55.90; H:6.29; N:8.46.
In the presence of suitable alkali (as pyridine, triethylamine), make dichloro-phosphonate ester and 1-amino-3-propanol reaction, also can be used to be prepared as the cyclic amino phosphate ester of phosphonate ester prodrug.In this way, preparation following compounds:
(6.10) 2-methyl-5-isobutyl group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-] furyl } thiazole, less important isomer.C
21H
25N
2O
3PS+0.25H
2O+0.1HCl value of calculation: C:59.40; H:6.08; N:6.60.Measured value: C:59.42; H:5.72; N:6.44.
(6.11) 2-methyl-5-isobutyl group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-]-furyl } thiazole, main isomer.C
21H
25N
2O
3PS+0.25H
2O value of calculation: C:59.91; H:6.11; N:6.65.Measured value: C:60.17; H:5.81; N:6.52.
(6.12) 2-amino-5-isobutyl group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-]-furyl } thiazole, main isomer.C
20H
24N
3O
3PS+0.25H
2O+0.1CH
2C1
2Value of calculation: C:55.27; H:5.72; N:9.57.Measured value: C:55.03; H:5.42; N:9.37.
(6.13) 2-amino-5-isobutyl group-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-]-furyl } thiazole, less important isomer.C
20H
24N
3O
3PS+0.15CH
2Cl
2Value of calculation: C:56.26; H:5.69; N:9.77.Measured value: C:56.36; H:5.46; N:9.59.
(6.14) 2-amino-5-methyl mercapto-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-] furyl } thiazole, the isomer that polarity is less.C
17H
18N
3O
3PS
2+ 0.4HCl value of calculation: C:48.38; H:4.39; N:9.96.Measured value: C:48.47; H:4.21; N:9.96.
(6.15) 2-amino-5-methyl mercapto-4-{2-[5-(1-phenyl-1,3-propyl group) phosphono acylamino-] furyl } thiazole, the isomer that polarity is bigger.C
17H
18N
3O
3PS
2Value of calculation: C:50.11; H:4.45; N:10.31.Measured value: C:49.84; H:4.19; N:10.13.
(6.16) 2-amino-5-methyl mercapto-4-{2-[5-(N-methyl isophthalic acid-phenyl-1,3-propyl group) phosphono acylamino-] furyl } thiazole.C
18H
20N
3O
3PS
2+ 0.25 HCl value of calculation: C:50.21; H:4.74; N:9.76.Measured value: C:50.31; H:4.46; N:9.79.
(6.17) 2-amino-5-methyl mercapto-4-{2-[5-(1-phenyl-1,3-propyl group)-N-acetyl group phosphono acylamino-] furyl } thiazole.C
22H
26N
3O
4PS+1.25H
2O value of calculation: C:54.82; H:5.96; N:8.72.Measured value: C:55.09; H:5.99; N:8.39.
(6.26) 2-amino-5-isobutyl group-4-{2-[5-(1-oxo-1-phospha-2-oxa--7-azepine-3,4-benzocyclohepta-1-yl)] furyl } thiazole, main isomer.Mp233-234℃。C
21H
24N
30O
5PS+0.2CHCl
3Value of calculation: C:52.46; H:5.03; N:8.66.Measured value: C:52.08; H:4.65; N:8.58.
(6.27) 2-amino-5-isobutyl group-4-{2-[5-(1-oxo-1-phospha-2-oxa--7-azepine-3,4-benzocyclohepta-1-yl)] furyl } thiazole, less important isomer.C
21H
24N
3O
5The MS value of calculation of PS+H: 462, measured value: 462.
(6.34) 2-amino-5-isobutyl group-4-{2-[5-(3-(3,5-dichloro-phenyl)-1,3-propyl group) phosphono acylamino-] furyl } thiazole.C
20H
22N
3O
3PSCl
2Value of calculation: C:49.39; H.4.56; N:8.64.Measured value: C:49.04; H:4.51; N:8.37.
(6.35) 2-amino-5-isobutyl group-4-{2-[5-(4,5-phendioxin-oxo-1-phospha-2-oxa--6-azepine) ring heptan-1-yl] furyl } thiazole.C
18H
20N
3O
3PS+0.7H
2O value of calculation: C; 53.78; H:5.37; N:10.45.Measured value: C:53.63; H:5.13; N:10.36.
Part 2
Synthesizing of formula X chemical compound
Embodiment 7
Preparation 2-amino-4-(phosphonomethyl) oxygen base-6-bromo benzothiazole
Steps A. with AlCl
3EtSH (5mmol) (10mL) solution is cooled to 0 ℃, handles with 2-amino-4-methoxyl group benzo thiazole (1mmol).In 0-5 ℃, stirred this mixture 2 hours.After evaporation and the extraction, obtain 2-amino-4-hydroxy benzothiazole, be white solid.
Step B. is in 0 ℃, and DMF (5mL) the mixture stirring 10min with 2-amino-4-hydroxy benzothiazole (1mmol) and NaH (1.3mmol) uses trifluoromethanesulfonic acid diethyl phosphonyl methyl ester (1.2mmol) to handle then.Stirred 8 hours under room temperature, extraction and chromatography reactant obtain 2-amino-4-diethyl phosphonyl methyl oxygen base benzothiazole, are grease.
Step C. is cooled to 10 ℃ with AcOH (6mL) solution of 2-amino-4-(diethyl phosphonyl methyl oxygen base) benzothiazole (1mmol), handles in AcOH (2mL) with bromine (1.5mmol).After 5 minutes, under room temperature, stirred the mixture 2.5 hours.Filter and collect yellow mercury oxide, use washed with dichloromethane, obtain 2-amino-4-diethyl phosphonyl methyl oxygen base-6-bromo benzothiazole.
Step D. handles the CH of 2-amino-4-diethyl phosphonyl methyl oxygen base-6-bromo benzothiazole (1mmol) in 0 ℃ with TMSBr (10mmol)
2Cl
2(4mL) solution.After stirring 8 hours under the room temperature, reactant is evaporated to dried, in the residue water-soluble (5mL).Filtration is collected the precipitation that produces and is washed with water, obtains 2-amino-4-(phosphonomethyl) oxygen base-6-bromo benzothiazole (7.1), is white solid.mp＞220℃(dec.)。C
8H
8N
2O
4PSBr value of calculation: C:28.34; H:2.38; N:8.26.Measured value: C:28.32; H:2.24; N:8.06.
Equally, can prepare following compounds according to said method:
(7.2) 2-amino-4-(phosphonomethyl) oxygen base benzothiazole.mp＞250℃。C
8H
9N
2O
4PS+0.4H
2O value of calculation: C:35.93; H:3.69; N:10.48.Measured value: C:35.90; H:3.37; N:10.37.
Embodiment 8
Preparation 2-amino-4-(phosphonomethyl) oxygen base-6-bromo-7-chloro benzo thiazole
Steps A. chloroform (10mL) solution of 1-(2-methoxyl group-5-chlorophenyl)-2-thiourea (1mmol) is cooled to 10 ℃, with chloroform (10mL) solution-treated of bromine (2.2mmol).Stirred these reactants 20 minutes in 10 ℃, in stirring at room 0.5 hour.Heated this suspension 0.5 hour down in refluxing.Filter collecting precipitation, use washed with dichloromethane, obtain 2-amino-4-methoxyl group-7-chloro benzothiazole, make steps A, B, C and the D of its experience embodiment 34, obtain 2 amino-4-phosphonium mesitoyl methoxy-6-bromo-7-chloro benzo thiazole (8.1).mp＞220℃(dec.)。C
8H
7N
2O
4PSClBr value of calculation: C:25.72; H:1.89; N:7.50.Measured value: C:25.66; H:1.67; N:7.23.
Equally, according to said method, can prepare following compounds:
(8.2) 2-amino-4-phosphonium mesitoyl methoxy-6-bromo-7-methylbenzothiazole.mp＞220℃(dec.)。C
9H
10N
2O
4PSBr value of calculation: C:30.61; H:2.85; N:7.93 measured value: C:30.25; H:2.50; N:7.77.
(8.3) 2-amino-4-phosphonium mesitoyl methoxy-7-methylbenzothiazole.mp＞220℃(dec.)。C
9H
11N
2O
4PS+1.0H
2O value of calculation: C:36.99; H:4.48; N:9.59.Measured value: C:36.73; H:4.23; N:9.38.
(8.4) 2-amino-4-phosphonium mesitoyl methoxy-7-chloro benzo thiazole.mp＞220℃(dec.)。C
8H
8N
2O
4PSCl+0.1H
2O value of calculation: C:32.41; H:2.79; N:9.45.Measured value: C:32.21; H:2.74; N:9.22.
Embodiment 9
Preparation 2-amino-7-ethyl-6-sulfo-cyano group-4-phosphonium mesitoyl methoxy benzothiazole:
Steps A. with 2-diethyl phosphonyl methyl oxygen base-5-bromo nitryl benzene (1mmol; according to embodiment 7 step B preparation) DMF (5mL) solution with tributyl (vinyl) stannum (1.2mmol) and two (triphenyl phasphine) palladium chloride (0.1mmol) processing, in blanket of nitrogen, 60 ℃ of following heating blends 6 hours.Behind evaporation and the chromatography, obtain 2-diethyl phosphonyl methyl oxygen base-5-vinyl Nitrobenzol, be grease.
With SnCl
2Freshly prepd methanol system HCl (10mL) solution (4mmol) adds in MeOH (5mL) solution of cold (0 ℃) 2-diethyl phosphonyl methyl oxygen base-5-vinyl Nitrobenzol (1mmol).Make mixture be warmed to room temperature, stirred 3 hours.Behind evaporation, extraction and the chromatography, obtain 2-diethyl phosphonyl methyl oxygen base-5-vinyl aniline.
Under room temperature, with MeOH (5mL) the solution-treated KSCN (16mmol) and the CuSO of 2-diethyl phosphonyl methyl oxygen base-5-vinyl aniline (1mmol)
4MeOH (7.7mmol) (10mL) solution.In refluxing down, with mixture heated 2 hours.Behind filtration, extraction and the chromatography, obtain product, make its experience embodiment 7 step D, obtain 2-amino-7-ethyl-6-sulfo-cyano group-4-phosphonium mesitoyl methoxy benzothiazole (9.1).mp＞167℃(dec.)。C
11H
12N
3O
4PS
2Value of calculation: C:38.26; H:3.50; N:12.17.Measured value: C:37.87; H:3.47; N:11.93.
Embodiment 10
Prepare various benzothiazole prodrug
Steps A. with 2-amino-4-phosphonium mesitoyl methoxy-5,6,7, DMF (10mL) suspension of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) is used DCC (3mmol) and 3-(3, the 5-dichloro-) phenyl-1 successively, and ammediol (1.1mmol) is handled.In 80 ℃ of reacting by heating mixture 8 hours.Evaporation back chromatography obtains 2-amino-4-{[3-(3,5-dichloro-phenyl) propane-1,3-two bases] phosphonium mesitoyl methoxy }-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole (10.1) is solid.mp＞230℃。C
21H
21N
2O
4PSCl
2Value of calculation: C:50.51; H:4.24; N:5.61.Measured value: C:50.83; H:4.34; N:5.25.
Step B. is with 4-phosphonium mesitoyl methoxy-5; 6,7,8-tetrahydrochysene naphtho-[1; 2-d] thiazole dichloride (deriving from embodiment 6 steps A) dichloromethane solution (5mL) (1mmol) is cooled to 0 ℃, with the dichloromethane (0.5mL) and pyridine (0.3mL) solution-treated of benzylalcohol (0.9mmol).In 0 ℃, the reaction solution that produces was stirred 1 hour, add ammonia (excessive) THF solution then.After stirring 16 hours under the room temperature, the evaporation reaction thing is to doing, and residue obtains 4-phosphono list acylamino-methoxyl group-5,6,7 through chromatography purification, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.
Perhaps, according to the method for following example, prepare other phosphoramidate with diverse ways:
Step C. is with 4-phosphonium mesitoyl methoxy-5,6,7, and 8-tetrahydrochysene naphtho-[1,2-d] thiazole dichloride (deriving from embodiment 6 steps A) dichloromethane solution (5mL) (1mmol) is cooled to 0 ℃, blasts ammonia (excessive) 10min in reactant.After stirring 16 hours under the room temperature, the evaporation reaction thing is to doing, and residue obtains 4-(phosphoro diamido) methoxyl group-5,6,7 through chromatography purification, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.
According to said method, single phenyl-single phosphamide derivant that also can preparation formula X chemical compound:
Step D. is under room temperature, and (1N 1.5mmol) handles 4-diphenyl phosphonium mesitoyl methoxy-5,6,7, the acetonitrile (9mL) of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) and water (4mL) solution 24 hours with Lithium hydrate.Reactant is evaporated to dried, in the residue water-soluble (10mL), is cooled to 0 ℃, the pH of solution is transferred to 4 with 6N HCl.Filter and collect the white solid that produces, obtain 4-phenyl phosphonic ylmethoxy-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole.
Step e. with 4-phenyl phosphonic ylmethoxy-5,6,7, thionyl chloride (3mL) suspension of 8-tetrahydrochysene naphtho-[1,2-d] thiazole (1mmol) is heated to and refluxed 2 hours.Evaporation reaction solution as for, residue is dissolved in the anhydrous methylene chloride (2mL), in 0 ℃ the solution that produces is added in the pyridine (0.8mL) and dichloromethane (3mL) solution of L-alanine ethyl ester hydrochlorate (1.2mmol).The reaction solution that stirring produces under room temperature 14 hours.Evaporation and chromatography obtain 4-[O-phenyl-N-(1-ethoxy carbonyl) ethyl phosphono acylamino-]-methoxyl group-5,6,7,8-tetrahydrochysene naphtho-[1,2-d] thiazole.
Step F. with 4-phosphonium mesitoyl methoxy-5; 6,7,8-tetrahydrochysene naphtho-[1; 2-d] the DMF solution N of thiazole (1mmol); N '-dicyclohexyl-4-morpholine carbonamidine (5mmol) and ethyl propyl oxygen base ketonic oxygen ylmethyl iodine (5mmol) are handled, and according to the method for bibliographical information, prepare ethyl propyl oxygen base ketonic oxygen ylmethyl iodine (Nishimura etc. with chloro-methyl-chloroformate; J Antibiotics; 1987,40,81).In 25 ℃ of stirred reaction mixtures 24 hours.Behind evaporation and the chromatography, obtain two (ethoxy carbonyl oxygen the ylmethyl)-phosphonium mesitoyl methoxies-5,6,7 of 4-, 8-tetrahydrochysene naphtho-[1,2-d] thiazole.
Also can prepare 4-(two oxy acid methyl neopentyls) phosphonium mesitoyl methoxy-5,6,7, two (the isobutyl acyl-oxygen ylmethyl) phosphonium mesitoyl methoxies-5,6,7 of 8-tetrahydrochysene naphtho-[1,2-d] thiazole and 4-, 8-tetrahydrochysene naphtho-[1,2-d] thiazole with similar method.
Embodiment 11
The general preparation method of two-phosphamide prodrug
The formation of dichloride
In phosphonic 5mL dichloromethane suspension, add 0.1mmol pyridine (or DMF of 0.1mmol) and 6mmol thionyl chloride successively, be heated to and refluxed 2.5 hours.Solvent and excessive thionyl chloride are removed in decompression, obtain described dichloride after the drying.
Coupling reaction:
Method A: the crude product dichloride is dissolved in the anhydrous CH of 5mL
2Cl
2In, add the 8mmol amino-acid ester in 0 ℃.Make the mixture of generation be warmed to room temperature, under this temperature, stirred 16 hours.Reactant mixture is carried out water treatment and chromatography.
Method B: the crude product dichloride is dissolved in the anhydrous CH of 5mL
2Cl
2In, in 0 ℃ of mixture that adds 4mmol amino-acid ester and 4mmol N-Methylimidazole..Make the mixture of generation be warmed to room temperature, under this temperature, stirred 16 hours.Reactant mixture is carried out water treatment and chromatography.
According to this method, the preparation following compounds:
(11.1) 2-amino-5-isobutyl group-4-[2-(5-N, N '-two (L-glutamate diethyl ester) phosphono acylamino-) furyl] thiazole.C
29H
45N
4O
10PS assay value: C:51.78; H:6.74; N:8.33.Measured value: C:51.70; H:6.64; N:8.15.
(11.2) 2-amino-5-isobutyl group-4-[2-(5-N, N '-two (L-alanine dibenzyl ester) phosphono acylamino-) furyl] thiazole.Assay value C
31H
37N
4O
6PS:C:59.60; H:5.97; N:8.97.Measured value: C:59.27; H:5.63; N:8.74.
(11.3) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two (benzyl oxygen base carbonyl methyl) phosphono diamido] furyl thiazole.C
19H
25N
4O
6PS+0.3CH
2Cl
2Assay value: C:46.93; H:5.22; N:11.34.Measured value: C:46.92; H:5.00; N:11.22.
(11.4) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two (benzyl oxygen base carbonyl methyl) phosphono diamido] furyl thiazole.C
29H
33N
4O
6PS assay value: C:58.38; H:5.57; N:9.39.Measured value: C:58.20; H:5.26; N:9.25.
(11.5) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((R)-1-methoxycarbonyl) ethyl) phosphono acylamino-] furyl } thiazole.Assay value C
19H
29N
4O
6PS+0.6CH
2Cl
2: C:44.97; H:5.82; N:10.70.Measured value: C:44.79; H:5.46; N:10.48.
(11.6) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-ethoxy carbonyl) ethyl) phosphono acylamino-] furyl } thiazole.Mp.164-165 ℃: C
21H
33N
4O
6PS+0.61CH
2Cl
2Assay value: C:46.99; H:6.24; N:10.14.Measured value: C:47.35; H:5.85; N:9.85.
(11.7) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((t-butoxy carbonyl) methyl) phosphono acylamino-] furyl thiazole.C
23H
37N
4O
6PS+0.15CH
2Cl
2Assay value: C:51.36; H:6.94; N:10.35.Measured value: C:51.34; H:6.96; N:10.06.
(11.8) furyl 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two (ethoxy carbonyl) methyl) phosphono acylamino-)] } thiazole.C
19H
29N
4O
6PS+0.1EtOAc+0.47CH
2Cl
2Assay value: C:45.79; H:5.94; N:10.75.Measured value: C:46.00; H:5.96; N:10.46.
(11.9) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two (1-methyl isophthalic acid-ethoxy carbonyl) ethyl) phosphono acylamino-] furyl } thiazole.Mp.142-145 ℃; C
23H
37N
4O
6PS assay value: C:52.26; 7.06; 10.60.Measured value: C:52.21; 6.93; 10.62.
(11.10) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two (ethoxy carbonyl methyl)-N, N '-dimethyl phosphine acyl group acylamino-)] furyl } thiazole.C
21H
33N
4O
6PS assay value: C:50.39; H:6.65; N:11.19.Measured value: C:50.57; H:6.56; N:11.06.
(11.11) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-benzyl oxygen base carbonyl-2-methyl) propyl group) phosphono acylamino-] furyl } thiazole.C
35H
45N
4O
6PS+0.5H
2O assay value: C:60.94; H:6.72; N:8.12.Measured value: C:61.01:H:6.48; N:7.82.
(11.12) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-methoxycarbonyl-3-methyl) butyl) phosphono acylamino-] furyl } thiazole.C
25H
41N
4O
6PS assay value: C:53.94; H:7.42; N:10.06.Measured value: C:54.12; H:7.62; N:9.82.
(11.13) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((R)-1-ethoxy carbonyl-2-(S-benzyl)) ethyl) phosphono acylamino-] furyl } thiazole.C
35H
45N
4O
6PS
3+ 0.4 toluene assay value: C:58.07; H:6.21; N:7.17.Measured value: C:57.87; H:6.14; N:6.81.
(11.14) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-ethoxy carbonyl-3-(S-methyl)) butyl) phosphono acylamino-] furyl } thiazole.C
23H
37N
4O
6PS
3Assay value: C:46.61; H:6.92; N:9.45.Measured value: C:46.26; H:6.55; N:9.06.
(11.15) 2-amino-5-propyl dithiocarbamate-4-{2-[5-(N, N '-(1-(S) ethoxy carbonyl) ethyl) phosphono acylamino-] furyl } thiazole.C
20H
31N
4O
6PS
2Assay value: C:46.32; H:6.03; N:10.80.Measured value: C:46.52; H:6.18; H:10.44.
(11.16) 2-amino-5-isobutyl group-4-2-[5-(N, N '-two ((S)-1-benzyl oxygen base carbonyl-2-methyl) isobutyl group) phosphono acylamino-] furyl } thiazole.C
37H
49N
4O
6PS assay value: C:62.69; H:6.97; H:7.90.Measured value: C:62.85; H7.06,7.81.
(11.17) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-ethoxy carbonyl-3-methyl) butyl) phosphono acylamino-] furyl } thiazole.C
27H
45N
4O
6PS assay value: C:55.46; H:7.76; N:9.58.Measured value: C:55.35; H:7.94; N:9.41.
(11.18) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-ethoxy carbonyl-2-methyl) propyl group) phosphono acylamino-] furyl } thiazole.Assay value C
25H
41N
4O
6PS:C:53.94; H:7.42; N:10.06.Measured value: C:54.01; H:7.58; N:9.94.
(11.19) 2-amino-5-isobutyl group-4-{2-[5-(N, N '-two ((S)-1-ethoxy carbonyl-2-phenyl) ethyl) phosphono acylamino-] furyl } thiazole.C
33H
41N
4O
6PS+0.15CH
2Cl
2Assay value: C:59.83; H:6.26; H:8.42.Measured value: C:59.88; H:6.28; H:8.32.
(11.20) 2-amino-5-propyl dithiocarbamate-4-{2-[5-(N, N '-(1-methyl isophthalic acid ethoxy carbonyl) ethyl) phosphono acylamino-] furyl } thiazole.Mp.110-115 ℃: C
22H
35N
4O
6PS
2+ 0.4HCl+0.5Et
2O assay value: C:48.18; H:6.81; N:9.36.Measured value: C:48.38; H:6.60; H:8.98.
(11.21) 2-amino-5-methyl mercapto-4-{2-[5-(N, N '-two (1-methyl isophthalic acid-ethoxy carbonyl) ethyl) phosphono acylamino-] furyl } thiazole.C
20H
31N
4O
6PS
2+ 0.5H
2O assay value: C:45.53; H:6.11; N:10.62.Measured value: C:45.28; H:5.85; N:10.56.
In addition, can adopt improved method to prepare chemical compound 11.6.The dry toluene slurry of chemical compound 3.1 (1mmol), oxalyl chloride (3.2mmol) and DMF (1.1mmol) is heated to backflow 1 hour.The solution that concentrating under reduced pressure produces is cooled to 0 ℃ to 80% of original volume, adds triethylamine (3mmol) and L-alanine ethyl ester (2.2mmol).Stirred this mixture 2 hours in 0 ℃ then, in stirring at room 6 hours.In reactant mixture, add acetic acid (9.5mmol) and ethanol (21mmol), with the mixture heated that produces to refluxing 16 hours.After extraction and the crystallization, obtain chemical compound 11.6 into pale solid.
Embodiment 12
The general preparation method of mixing bis-amino phosphate ester prodrug
In 0 ℃, successively to the crude product dichloride anhydrous CH of 5mL of (1mmol prepares according to embodiment 40)
2Cl
2Add amine (1mmol) and 4-dimethylaminopyridine (3mmol) in the solution.Make the mixture of generation be warmed to room temperature and stirred 1 hour.Again reactant is cooled to 0 ℃ and stablizes, add amino-acid ester (2mmol) then, under room temperature, placed 16 hours.Reactant mixture mixes bis-amino phosphate ester prodrug and handles through column chromatography through water treatment.
With similar method, the preparation following compounds.
(12.1) 2-amino-5-isobutyl group-4-{2-[5-(N-morpholino-N '-(1-methyl isophthalic acid-ethoxy carbonyl) ethyl)-phosphono acylamino-] furyl } thiazole.Mp.182-183 ℃: C
21H
33N
4O
5PS assay value: C:52.05; H:6.86; N:11.56.Measured value: C:51.66; H:6.68; N:11.31.
(12.2) 2-amino-5-isobutyl group-4-{2-[5-(N-pyrrolidinyl-N '-(1-base-1-ethoxy carbonyl) ethyl)-phosphono acylamino-] furyl } thiazole.Mp.189-190 ℃: C
21H
33N
4O
4PS assay value: C:53.83; H:7.10; N:11.96.Measured value: C:54.15; H:7.48; N:12.04.
Synthesizing of formula VII chemical compound
Embodiment 13
Preparation 5-(3, the 5-dinitrophenyl)-2-furan phosphonic acids (compound N o.13.01).
1) in-78 ℃, use N, N, N ' N '-tetramethylethylenediamine (TMEDA) (1mmol) and nBuLi (1.1mmol) handle the 1mL diethyl ether solution 0.5 hour of furan (1mmol).In-60 ℃, the solution that produces is added in the 1mL diethyl ether solution of chloro diethyl phosphate (1.33mmol) by conduit, make reactant mixture be warmed to room temperature, restir 16 hours.Extraction and distillation under 75 ℃/0.2mm obtain 2-furan diethyl phosphonate, are clarification grease.
2) the 2mL THF solution with 2-furan diethyl phosphonate (1mmol) is cooled to-78 ℃, and it is added in diisopropyl lithamide (LDA) the 5mL THF solution (1mmol) with 20 minutes in-78 ℃.In-78 ℃ of mixture that stir to produce 20 minutes, in-78 ℃ with the 1mL THF solution that it was added in 20 minutes tributyltin chloride (1mmol) in.Stirred these mixture 15 minutes in-78 ℃ then, stirred 1 hour in 25 ℃.Behind extraction and the chromatography, obtain 5-tributyl tin alkyl-2-furan diethyl phosphonate into colorless oil.
3) in 80 ℃, heating 5-tributyl tin alkyl-2-furan diethyl phosphonate (1mmol), 1-iodo-2,4-dinitro benzene (1mmol) and four (triphenyl phasphine)-palladiums (O) 6mL dioxane mixture (0.05mmol) 16 hours.Evaporating solvent and chromatography obtain 5-(3, the 5-the dinitrophenyl)-2-furan diethyl phosphonate into solid foam shape thing.
4) under room temperature, with the 10mL CH of 5-(3, the 5-dinitrophenyl)-2-furan diethyl phosphonate (1mmol) and TMSBr (6mmol)
2Cl
2Mixture stirred 16 hours, then evaporation.Residue is dissolved in 85/15 CH
3In the CN/ water, evaporation then.Again residue is suspended in the dichloromethane, is collected as the target compound (No.13.01) of light yellow solid: HPLC R
t=5.30min; Negative ion electrospray spraying MSM-1 measured value: 313.
Adopt embodiment 13 step C and the described method of step D, make following reagent and 5-tributyl tin alkyl-2-furan diethyl phosphonate coupling, and be converted into the chemical compound (in bracket, indicating) of embodiment: 2-bromo-4,6-dinitroaniline (for 13.02); Chloro-2-iodobenzene methyl ether (for 13.03); 2,5-dichloro--1-iodobenzene (for 13.04); N
1-methyl-2-iodo-4-(trifluoromethyl) benzene-1-sulfonamides (for 13.05); N
1-methyl-4-chloro-2-iodobenzene-1-sulfonamides (for 13.06); N
1-methyl-2-iodobenzene-1-sulfonamides (for 13.07); N
1-propyl group-4-chloro-2-iodobenzene-1-sulfonamides (for 13.08); 2-iodo phenol (for 13.09); 5-iodo-m-dimethylbenzene (for 13.10); 1-bromo-3-iodobenzene (for 13.11); 4-iodo aniline (for 13.12); 2,5-dimethoxy-4 '-iodo chlorobenzene (for 13.13); N
1-(4-chloro benzyl)-2-iodobenzene Methanamide (for 13.14); N
1-(4-chlorobenzene ethyl)-2-iodobenzene Methanamide (for 13.15); N
1-benzyl-2-iodobenzene-1-sulfonamides (for 13.16); 2-iodobenzene sulfonamides (for 13.17); 1-iodo-2,3,4,5,6-pentamethylbenzene (for 13.18); 3-iodobenzene dioctyl phthalate (iodic ether and the diisopropylamine that comprise step C are for 13.19); 4-iodo-2-methyl N-acetanilide (for 13.20); 3,5-dichloro--2-iodo toluene (for 13.21); 5-hydroxyl-2-iodobenzoic acid methyl ester (for 13.22); 2-iodo-5-methyl benzamide (for 13.23); 5-hydroxyl-2-iodobenzoic acid (iodic ether and the diisopropylamine that comprise step C are for 13.24); 1-iodo-4-Nitrobenzol (for 13.25); N
1-(2,4-difluoro-benzene base)-2-iodobenzene Methanamide (for 1 3.26); 3,5-dichloro--1-iodobenzene (13.27); 3-iodo phenol (for 13.28); 3-bromo-5-iodobenzoic acid (for 13.29); 3-bromo-4,5-dimethoxy benzaldehyde (for 13.30); 1-iodo-2-Nitrobenzol (for 13.31); 2-iodo biphenyl (for 13.32); 2-iodobenzoic acid (iodic ether and the diisopropylamine that comprise step C are for 13.33); 1-bromo-4-iodobenzene (for 13.34); 3 '-bromo Propiophenone (for 13.35); 3-bromo-4-HOMOVERATRONITRILE (for 13.36); 1-ethyl-2-iodobenzene (for 13.37); 2-bromo-3-Methylnitrobenzene (for 13.38); 4-iodo monoacetylaniline (for 13.39); 2,3,4,5-tetramethyl iodobenzene (for 13.40); 3-bromo biphenyl (for 13.41); 4-chloro-2-iodobenzene sulfonamides (for 13.42); N1-(4-iodine substituted phenyl)-2-tetrahydro-1 H-pyrrolo-1-yl acetamide (for 13.43); 3,4-dimethyl iodobenzene (for 13.44); 2,4-dinitro iodobenzene (for 13.45); 3-benzyl iodide amine (for 1 3.46); 2-fluoro-4-iodo aniline (for 13.47); 3-benzyl iodide alcohol (for 13.48); 2-bromo-1-iodobenzene (for 13.49); 2-bromobenzene ethyl alcohol (for 13.50); 4-iodobenzene Methanamide (for 13.51); 4-bromo benzonitrile (for 13.52); 3 bromo benzonitriles (for 13.53); 2-bromo benzonitrile (for 13.54); 4-bromo-2-nitroaniline (for 13.55); 2-iodo cumene (for 13.56); 6-amino-2-chloro-3-pyridine bromide (under room temperature, make 6-amino-2-chlorobenzene (1mmol) and bromine (1mmol) in acetic acid (4mL), react 2 hours, then evaporate also chromatography, obtain 6-amino-2-chloro-3-pyridine bromide) (for 13.57); 3-bromo-4-methylthiophene (for 13.58); 2-bromo-4-chloro aminobenzen (for 13.59); 1-bromo-3-chloro-5-fluoro aniline (for 13.60); 2-bromo-4-cyano group methyl phenyl ethers anisole (for 13.61); 2-bromo-4-Methylnitrobenzene (for 13.62); 3-nitro-5-fluoro-1-iodobenzene (for 13.63); 2-iodo-4-methoxyl group (carbomethoxy) aniline (for 13.64); 2-bromo-4-Nitroanisole (for 13.65); 2-chloro-1-iodo-5-trifluoromethylbenzene (for 13.66) and 1-bromo-2,5-pair-(trifluoromethyl) benzene (for 13.67).
Embodiment 14
Preparation 5-(4-fluoro phenyl)-2-furan phosphonic acids (compound N o.14.01).
1) 2-furan diethyl phosphonate (according to embodiment 13 steps A preparations) 2mL THF solution (1mmol) is cooled to-78 ℃, with 20 minutes, under-78 ℃, it is added in isopropylcyclohexyl-lithamide (LICA) the 2mL THF solution (1mmol).To obtain mixture in-78 ℃ and stir 20 minutes, then with 20 minutes, under-78 ℃, it is added in the 1mL THF solution of iodine (1mmol).Stirred this mixture 20 minutes in-78 ℃ then.Behind extraction and the chromatography, obtain 5-iodo-2-furan diethyl phosphonate into yellow oil.
2) in 75 ℃, (4mmol) and two (acetonitrile) palladium chloride (II) 6mL DMF mixture heated (0.05mmol) 16 hours with 5-iodo-2-furan diethyl phosphonate (1mmol), 4-fluorobenzene ylboronic acid (2mmol), diisopropyl ethyl amine (DIEA).Behind extraction and the chromatography, obtain 5-(4-fluoro phenyl)-2-furan diethyl phosphonate into grease.
Make the reaction of this material experience embodiment 13 step D, obtain target compound (No.14.01) into white solid.HPLC R
t=5.09min; Negative ion electrospray spraying MS M-1 measured value: 241.
In the method, adopt 2, o.14.02 4-dichlorobenzene ylboronic acid obtains compound N as raw material.In the method, adopt 3-amino-5-methoxybenzene ylboronic acid, obtain compound N o.14.03.
Embodiment 15
Preparation 5-(4-bromo-3-aminophenyl)-2-furan phosphonic acids (compound N o.15.01).
According to embodiment 14 step B, make 3-aminophenyl borate hydrochlorate and 5-iodo-2-furan diethyl phosphonate reaction, obtain 5-(3-aminophenyl)-2-furan diethyl phosphonate into grease.
Under room temperature, with the 30mL CCl of 5-(3-aminophenyl)-2-furan diethyl phosphonate (1mmol), NBS (0.9mmol) and AIBN (0.1mmol)
4Mixture stirred 2 hours.Behind extraction and the chromatography, obtain 5-(4-bromo-3-aminophenyl)-2-furan diethyl phosphonate into grease.
This material is carried out the reaction of embodiment 13 step D, obtain target compound No.15.01) into white solid.HPLC R
t=4.72min; Negative ion electrospray spraying MS M-1 measured value: 316/318.
Bioassay embodiment
The following examples are used for the following character of authenticating compound: 1) suppress FBP enzyme and gluconeogenesis at cell and diabetes animal model; Or 2) improve cell culture and diabetes animal model sensitivity to insulin; Or 3), unite and give the FBP enzyme inhibitor or insulin secretagogue has better pharmacologically active with respect to independent employing FBP enzyme inhibitor or insulin secretagogue.
Following compounds A-K is used for following part biological embodiment:
The compd A compd B
The Compound C Compound D
The compd E compound F 17-hydroxy-corticosterone
Chemical compound G
The compound H Compound I
Chemical compound J compound K
Compound F 17-hydroxy-corticosterone is to prepare in embodiment 5.6, chemical compound G prepares in embodiment 3.26, compound H is to prepare in embodiment 3.69, Compound I is preparation in embodiment 3.58, chemical compound J be in embodiment 11.6 preparation with compound K in embodiment 11.2, preparing.
Embodiment A: to the inhibitory action of people liver FBP enzyme
Use the E.coli strain BL21 of the plasmid conversion of coding people liver FBP enzyme by the Dr.M.R.El-Maghrabi place acquisition of the State University of New York that is positioned at Stony Brook.Usually according to M.GidhJain etc. at J.Biol.Chem.269, the method described in the 27732-27738 (1994) is by purification hlFBP enzyme in 10 liters of E.coli cultures.By following reaction, adopt the spectrophotometry enzymatic activity: adopt phosphogvlucoisomerase and glucose 6-phosphate dehydrogenase as the coupling enzyme, make the product (fructose 6-phosphoric acid) of formation and product coupling through NADP and azophenlyene methosulfate (PMS) reduction dimethylthiazole diphenyl bromination tetrazole (MTT).Preparation feedback mixture on 96 hole microtitration plates (200 μ L), comprising 50mMTris-HCl, pH7.4,100mM KCl, 5mM EGTA, 2mM MgCl
2, 0.2mMNADP, 1mg/ml BSA, 1mM MTT, 0.6mM PMS, 1 unit/mL phosphogvlucoisomerase, 2 units/mL glucose 6-phosphate dehydrogenase and 0.150mM substrate (fructose 1,6-diphosphonic acid).The concentration of inhibitor is 0.01 μ M-10 μ M.The pure hlFBP enzyme that adds 0.002 unit starts reaction, and 590nm place monitoring reaction is 7 minutes under Molecular Devices Plate Reader (37 ℃).
The chemical compound of selecting is listed in the following table the effectiveness of people liver FBP enzyme:
Table 1
Compound I C
50, μ M
AMP??????????1.3
E????????????0.055
D????????????1.0
B????????????5.0
C????????????30
F????????????0.12
G????????????0.015
H????????????0.025
I????????????0.018
Embodiment B: to the inhibitory action of rats'liver and Mouse Liver FBP enzyme
Use the E.coli strain BL21 of the plasmid conversion of coding rats'liver FBP enzyme by the Dr.M.R.El-Maghrabi place acquisition of the State University of New York that is positioned at Stony Brook, and according to El-Maghrabi, M.R and Pilkis, S.J. (1991) carries out purification in the method described in the Biochem.Biophys.Res.Commun.176:137:144.At 100mM Tris-HCl buffer, the Mouse Liver of homogenize fresh separated is to obtain Mouse Liver FBP enzyme among the pH7.4 (containing 1mM EGTA and 10% glycerol).Centrifugal clarification homogenize thing separates 45-75% ammonium sulfate component.This component is dissolved in the homogenize buffer again, and, uses the homogenize buffer solution elution in PD-10 solvent resistant column (Biorad) desalination.The component of this purification is used for enzymatic determination.According to the method for the mensuration people liver FBP enzyme described in the embodiment A, measure rats'liver and Mouse Liver FBP enzyme.As a rule, as higher IC
50Be worth representedly, with respect to people's liver enzyme, rat and mouse liver enzyme are insensitive by the inhibition of test-compound.
Provide the IC of the several compounds for preparing among the embodiment in the following table
50Value.
Table 2
| Chemical compound | IC 50Rats'liver (μ M) | IC 50Mouse Liver (μ M) |
| ??AMP | 25 | ?15 |
| ??B | 140 | ?33 |
| ??D | 1.25 | ?55 |
| ??C | ＞100 | ?＞100 |
| ??E | 0.4 | ?1.1 |
| ??F | 2.0 | |
| ??G | 0.25 | |
| ??H | 0.175 | |
| ??I | 0.05 |
Embodiment C: the FBP enzyme inhibitor is to the inhibitory action of rat hepatocytes gluconeogenesis
According to Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J.M., 1982, Eur.J.Bio.Chem.122 is 87-93) to Berry and Friend (Berry, M.N., Friend, D.S., 1969, J.Cell.Biol.43,506-520) improving one's methods of described method is by Sprague-Dawley rat (250-300g) the preparation hepatocyte of raising.(75mg weight in wet base/mL) cultivate in 1mL Krebs-bicarbonate buffer contains 10mM lactate, 1mM pyruvate, 1mg/mLBSA and test-compound in the described buffer, the concentration of test-compound is 0-500 μ M with hepatocyte.In 95% oxygen, 5%-carbon dioxide environment, cultivate in the Falcon of airtight 50ml pipe, described sealed tube immerses in the water-bath (37 ℃) of shaking fast.After 1 hour, get a duplicate samples (0.25mL), be transferred in the Eppendorf pipe also centrifugal.According to manufacturer's explanation, adopt the content of glucose in the Sigma glucoseoxidase kit measurement 50 μ l supernatant then.
Provide the IC of the several compounds for preparing among the embodiment in the following table
50Value.
Table 3
| Chemical compound | ?IC 50(μM) |
| Compd A | ?50 |
| Compound D | ?4.5 |
| Compd E | ?2.5 |
| Compound C | ?＞100 |
| Compound F 17-hydroxy-corticosterone | ?15 |
| Chemical compound G | ?10 |
| Compound H | ?2.5 |
| Compound I | ?2.0 |
| Chemical compound J | ?2.0 |
| Compound K | ?2.1 |
Rats'liver FBP enzyme is poor than people liver FBP enzyme to the sensitivity of AMP.So, the IC of rat hepatocytes
50Value is than the IC of human liver cell
50Value is high.
Because formula I chemical compound can and become the FBP enzyme inhibitor thus by the hepatocyte phosphorylation, thus can screen these chemical compounds to hepatocellular effect by them, as described in Embodiment C and D.
Embodiment D: with inhibition and the fructose-1 that glucose in the rat hepatocytes of FBP enzyme inhibitor processing produces, the raising of 6-bisphosphate level
State method according to the C of embodiment institute, separate rat hepatocytes and cultivation.In addition, according to glucose content and fructose 1 in the described methods analyst cell extract of Embodiment C, 6-bisphosphate content.By making enzymatic preparation glyceraldehyde-3 phosphate ester and the coupling of NADH oxidation product, adopt spectrophotometry fructose 1,6-bisphosphate content is monitored in the 340nm place.Reactant mixture (1mL) contains 200mM Tris HCl, pH7.4,0.3mM NADH, 2 units/mL glyceraldehyde-3 phosphate ester dehydrogenase, 2 units/ml triose-phosphate isomerase and 50-100 μ L cell extract.After 30 minutes, add 1 unit/ml aldolase in 37 ℃ of cultivations, observe being changed to of absorption value and observe stable value.In this reaction, the fructose 1 in every mole of cell extract, the 6-bisphosphate makes 2 moles of NADH oxidized.
Compd A and compd E suppress glucose in dosage dependence mode and produce its IC
50Value is respectively 50 and 2.5 μ M.Be suppressed with the FBP enzyme and conform to, all observe fructose 1 in the cell for two kinds of chemical compounds, the dose dependent of 6-bisphosphate raises.
Embodiment E: per os is analyzed liver and drug plasma metabolite level, blood-glucose regulating liver-QI fructose 1,6-diphosphonic acid level after giving normal rat compd A on an empty stomach.
Sprague Dawley rat (250-300g) compd A that oral gavage freers and takes food.Be suspension liquid of carboxyl methyl cellulose with described compound and give with the dosage of 250mg/kg.After administration, in 24 hours, rat is put to death mensuration hepatic metabolism thing successively.With liver is freezing clamps (freeze-clamped), homogenize in perchloric acid, neutralization, then by anion exchange HPLC analysis of compounds B.
Before oral administration, insert carotid duct to rat and be beneficial to the analysed for plasma metabolite.After administration, in 8 hours, pass through the conduit blood sampling at reasonable time point.Centrifugal in blood sample separated plasma, add methanol to 60% precipitation plasma protein.Undertaken quantitatively by the metabolite of reversed-phase HPLC the compd A in the Deproteinated plasma sample.(1.4cm * 250mm), carry out gradient elution with this buffer to acetonitrile detects in the 254nm place with 10mM sodium phosphate buffer (pH5.5) balance C18 post.
Measure the blood sample glucose regulating liver-QI fructose 1 of compd A, the influence of 6-bisphosphate level to the Sprague-Dawley rat (250-300g) of fasting in 18 hours.Carry out animals administer as mentioned above.The reasonable time point is used the alkyl halide anesthetized rat after administration, takes out hepatic tissue (about 1g), and by posterior vena cava blood sampling (2mL).Syringe and syringe needle with heparinization are collected blood.Immediately with liver sample homogenize, centrifugal in ice-cold 10% perchloric acid (3mL), with the 3M KOH/3M KH of 1/3rd volume
2CO
3In and supernatant.Centrifugal and filter after, the method described in separating according to the Embodiment C hepatocyte is analyzed the fructose 1 in the neutral extract, the backflow of 6-bisphosphate.Employing Hemocue analyser (Hemocue Inc, Mission viejo,
CA) measure blood-glucose content.
The result that the hepatic metabolism thing is analyzed shows that compd A is converted into compd B effectively, and the level of compd B in liver reached 3 μ mol/g tissue in 1 hour.Although its level slowly descends in time, when finishing in 24 hours, still can detect compd B.In blood plasma, detect 5-bromo-1 β D-ribofuranosyl (ribofuranosyl)-imidazoles-Methanamide and do not detect compd A and show, at all three position compd As all by deacetylated fast.
It is about 8 hours that the disposable 250mg/kg of giving compd A can significantly reduce blood glucose levels, at this moment between in the scope, the glucose level of the animal of treatment group slowly rebounds to the level of solvent matched group.Drug treating makes liver fructose 1, and 6-bisphosphate level raises.The time course that time course that the intermediate of this gluconeogenesis raises and glucose reduce has dependency preferably.Near maximum glucose reduction level the time, observe peak value, and along with the bounce-back of blood glucose levels, fructose-1,6-bisphosphate level slowly returns to normally.This observed result with at fructose-1, compd A conforms to the inhibition of gluconeogenesis under the 6-bisphosphate level.
Embodiment F: after intraperitoneal gives normal rat Compound D, E, F and G on an empty stomach, to the analysis of liver and drug plasma level.
With Sprague-Dawley rat (250-300g) fasting 18 hours, intraperitoneal gave normal saline or FBP enzyme inhibitor then.The solvent that is used for administration is the 10mM bicarbonate.Injected back 1 hour, and used the alkyl halide anesthetized rat, take out liver and blood sample and handle according to embodiment E is described.Analyze FBP enzyme inhibitor in the neutral liver extract by HPLC.(250 * 4.6cm), usefulness 10mM sodium phosphate (pH5.5) is measured absorption value to 75% acetonitrile gradient eluting in the 310nm place to adopt anti-phase YMC ODS AQ post.According to the described method of Embodiment C, measure glucose level in the blood sample.Centrifugal preparation blood plasma also adds methanol to 60% (v/v) extraction.The centrifugal clarification methanolic extract filters, and analyzes through HPLC according to said method then.
To provide in the measurement result table below of chemical compound to preparation in an embodiment:
Table 4
| Chemical compound | Glucose reduces, % | Plasma concentration (μ M) | Liver concentration (nmol/g) |
| ??D | ??31 | ?8.8 | 27.2 |
| ??E | ??44.4 | ?79.2 | 38.4 |
| ??F | ??51 | ?18 | 35 |
| ??G | ??73 | ?56.1 |
Embodiment G: the oral effect that glucose is reduced of the mensuration of the oral administration biaavailability of chemical compound G, H, I and J and chemical compound G and J
Adopt rat homaluria method, measure the oral administration biaavailability of prodrug and parent compound.Prodrug is dissolved in 10% ethanol/90% Polyethylene Glycol (MW400), gives the solution of the described prodrug of Sprague Dawley rat (220-240g) of fasting in 6 hours with the dosage oral gavage of 10-40mg/kg parent compound homologue.Usually parent compound is dissolved in the deionized water,, gives with the dosage per os of 10-40mg/kg then or give through vein with the dosage of about 10mg/kg with sodium hydroxide neutralization.
Subsequently rat is placed metabolic cage, collected urine 24 hours.According to the described method of embodiment F, the amount of excretory parent compound in HPLC assay determination urine.Method according to embodiment F is analyzed.For prodrug, give the amount of the parent compound that in urine, reclaims after the prodrug by per os relatively and the amount of the parent compound that gives at vein to reclaim behind the corresponding parent compound is estimated the percentage ratio of oral administration biaavailability in urine.For parent compound, then the amount of the parent compound that reclaims in urine behind amount by the parent compound that reclaims in urine in the orally give parent compound relatively and the intravenously administrable is calculated the percentage ratio of oral administration biaavailability.
During the percentage ratio of the part prodrug of estimation and the oral administration biaavailability of parent compound is listed in the table below.
Table 5A
| Chemical compound | Oral administration biaavailability % |
| ??G | ??18 |
| ??H | ??4 |
| ??I | ??5 |
| ??J | ??21 |
The oral usefulness that the Sprague Dawley rat of employing overnight fasting comes assessing compound J.Chemical compound G or J are prepared as 0.1% suspension liquid of carboxyl methyl cellulose, and with 0,10 or the dosage oral gavage administration of 30mg/kg.1.5 or 4 hours the time, collect blood sample after the administration, adopt automatic glucose analyser (HemoCue, HemoCue Inc, MissionViejo, CA) analyzing blood glucose by the tail vein.The results are shown in following table:
Table 5B:
| Glucose reduces, % | ||
| Dosage, mg/kg | Chemical compound G (4h) | Chemical compound J (1.5h) |
| ??0 | ?0 | ??0 |
| ??10 | ?48 | ??66％ |
| ??30 | ?＞70 | ??85％ |
Embodiment H: islets of langerhans uelralante (insulin secretagogue)
Separate normal or diabetes rat or normal or diabetic mice islets of langerhans by collagenolysis.These islets of langerhans can directly use after preparation, perhaps cultivate the back and use in RPMI 1640 culture medium of improvement, and described culture medium contains 5.5mM glucose and 10% Ox blood serum.Add test-compound in cell culture medium, concentration is 0-100 μ M.Adopt slight irrigation injection system [(Bergsten P and Hellman B Diabetes 42:670-674 (1993)] to measure the insulin of fresh single islet secretion, perhaps measure the insulin of the islet secretion of cultivating according to the described method of J.Biol.Chem.270:7882-7889 such as Frodin (1995).By adopting as Amerlex magnetism separate method (magnetic separation procedure) (Amersham LifeScience) through the radioimmunoassay method insulin, when suitable with rat or mouse islets element as standard substance.Be used for preferred insulin secretagogue of the present invention in the presence of the glucose of physiological level, be lower than 10 micromoles, can making insulin secretion increase at least 20% when preferably being lower than 1 micromole, preferably be higher than 100%,
Example I: reduce rat glucose (insulin secretagogue) on an empty stomach
With the rat foodstuff of standard grow up Sprague-Dawley or Wistar rat (200-220g) are carried out freely feeding, and be placed in the chamber of 12/12h light/secretly circulate at 7 (in the morning at 7 in afternoon be between the light time).Do not provide food in preceding 24 hours beginning one's study, research is usually in 8 beginnings in the morning.Chemical compound is suspended in methylcellulose or other solvents, and oral gavage gives.When administration, reach and after this per hour pass through the tail vein by clear-headed animal blood sampling.The manual method of employing standard or automated process analyzing blood glucose.The largest percentage that observed blood-glucose reduces in 4 hours is for measuring the activity index that chemical compound reduces blood-glucose.The ED of chemistry chemical compound
50Be worth, and it is defined as the dosage of chemical compound half maximum effect.Adopt " student " t-test evaluation significance,statistical.The ED of the preferred insulin secretagogue that adopts among the present invention
50Value＜30mg/kg (preferred＜5mg/kg), at ED
50The time blood-glucose 10% can be reduced more than.
Measurement result in following table, provide (J.Med.Chem.41:5219-5246 (1998) of Grell W etc.:
Table 6:
| Dosage | Glucose reduces, % | ?ED 50，mg/kg | |
| ?Glibenclamide | ?0.3 | ?-25 | ?0.255(2h) |
| Glimepiride | ?0.1 | ?-18 | ?0.182(2h) |
| Repaglinide | ?0.01 | ?-21 | ?0.01(2h) |
Embodiment J: the toleration (insulin secretagogue) of fasting rat vein glucose
With the rat foodstuff of standard grow up Sprague-Dawley or Wistar rat (200-220g) are carried out freely feeding, and be placed in the chamber of 12/12h light/secretly circulate at 7 (in the morning at 7 in afternoon be between the light time).Do not provide food in preceding 24 hours beginning one's study, research is usually in 8 beginnings in the morning.Intraperitoneal gives pentobarbital sodium (60mg/kg) anesthetized rat, gives medicine (15mg/kg) when needing again and keeps anesthesia.Jugular vein inserts conduit to give medicine to the right, and left neck artery inserts conduit and is used for blood sample collection.Vein single dose (bolus) gives rat glucose (the 20%w/v solution of 0.5g/kg), gives test-compound (0-100mg/kg) simultaneously or does not give test-compound.Blood sample collection when before giving glucose/chemical compound, reaching after this 2,5,10,20,30,40 and 60 minutes at once.The manual method of employing standard or automated process analyzing blood glucose.The preferred insulin secretagogue that adopts among the present invention can be with blood-glucose and the AUC minimizing down of change curve in time more than 5%.
The toleration (insulin secretagogue) of embodiment K:Zucker diabetes obese rat (Zucker Diabetic Fatty rat) oral glucose
With Zucker diabetes obese rat (9.5 age in week) fasting 6 hours, begin test at 8 in the morning then, oral gavage gives glucose (1g/kg) and test-compound (0.01-100mg/kg) simultaneously.Control animal only gives glucose.Before giving glucose/test-compound, reach after this 6 hours per hour by tail vein blood sample collection.The manual method of employing standard or automated process analyzing blood glucose.By separated plasma in the blood sample and mensuration insulin wherein.By adopting the radioimmunoassay method insulin content, use rat insulin as standard substance as Amerlex magnetism separate method (Amersham Life Science).Reactive compound can reduce glucose AUC under the change curve and of short duration rising plasma insulin level in time.The preferred insulin secretagogue that adopts among the present invention can be reduced by at least the AUC of glucose and time (preferred more than 10%) more than 5%, and improves insulin level more than 20% (preferred more than 50%).
Embodiment L: secretion of insulin in the rat (insulin secretagogue)
With the rat foodstuff of standard grow up Sprague-Dawley or Wistar rat (200-220g) are carried out freely feeding, and be placed in the chamber of 12/12h light/secretly circulate at 7 (in the morning at 7 in afternoon be between the light time).Do not provide food in preceding 24 hours beginning one's study, usually in 8 beginnings in the morning.Intraperitoneal gives pentobarbital sodium (60mg/kg) anesthetized rat, gives medicine (15mg/kg) when needing again and keeps anesthesia.Jugular vein inserts conduit to give medicine to the right, and left neck artery inserts conduit and is used for blood sample collection.Adopting syringe pump venoclysis 10% (w/v) glucose solution to keep the arterial blood concentration of glucose is 6mM.Give medicine (0-100mg/kg) or solvent immediately, blood sample collection in the time of after this 2,5,10,20,30,40 and 60 minutes after blood glucose concentration is stable.By adopt radioimmunoassay method plasma insulin content as Amerlex magnetism separate method (Amersham Life Science), use rat insulin as standard substance.By calculating the cumulative area (0-60 was total for phase I, 10-60 are second stage in 0-10 minute) that tremulous pulse blood plasma insulin concentration is higher than baseline, calculate insulin response.The preferred insulin secretagogue that adopts among the present invention can increase the insulin concentration in phase I or second stage or total stage more than 10%, preferred more than 50.
Embodiment M: to the inhibition (insulin secretagogue) of mice pancreatic beta cell KATP passage
Cultivate by collagenase digesting separation mice beta cell and in improvement RPMI 1640 culture medium, described culture medium contains 5.5mM glucose and 10% hyclone.According to [Br.J.Pharmacol.113:903-911 (1999) such as Schwanstecher] described method, adopt the diaphragm that turns up (inside-outpatche) of miniflow system (microflow system) preparation cell, and carry out the evaluation of Patch-clamp electrophysiology.Transmembrane potential is-50mV to measure and pass through the interior to membrane current of KATP passage.Determine zero-current level by perfusion 1mM ATP.In each research, (there is ADP in the KATP channel activity to the contrast stage before administration, do not have medicine) and administration (0-100 μ M) after channel activity carry out normalization, the preferred insulin secretagogue of Cai Yonging can suppress activity of potassium channels in the present invention, its IC
50＜10 μ M, preferred＜100nM.
Embodiment N: sulphur urea receptors bind (insulin secretagogue)
In method described in the Science 268:423-426 (1995), clone sulphur urea receptor SURl also is transfected into the Cos-7 cell according to Aguilar-Bryan etc.After transfection 60-72 hour, by the cell separation cell membrane.In the presence of the test-compound of [3H] of fixed concentration glibenclamide (or other standard substance) and various concentration, cultivate the film of resuspending.Adopt the unlabelled standard substance of 100nM to measure non-specific binding.Under room temperature, cultivated 1 hour, filter each duplicate samples cessation reaction fast by adopting Whatman GF/B filter.Washing nozzle is with liquid flashing counting measuring 3H content.Reduce expression, i.e. the displacement number of the standard substance of labelling with the binding capacity of receptor by counting.The Kd of the preferred insulin secretagogue that adopts in the invention (dissociation constant)＜10 μ M, preferred＜100nM.
Embodiment O: to the inhibition (DPP-IV inhibitor) of dipeptidase IV
This is measured according to Deacon CF, Hughes TE, and the described method of Holst JJ Diabetes 47:764-769 (1998) is carried out, and wherein adopts H-glycine-proline-7-amino-4-methylcoumarin as synthetic substrate, adopts human plasma as the enzyme source.Preferred DPP-IV inhibitor can suppress described enzyme, its IC
50＜10 μ M, preferred＜500nM.
Embodiment P: alpha-Glucosidase is measured
Small intestinal brush shape limitans (brush bordermembranes) by the Sprague Dawley rat that grows up separates saccharase and maltase, and measures this two kinds of enzymes by measuring sucrose and maltose generation glucose respectively.Referring to Samulitis BK, Goda T, Lee SM, Koldovsky O, Drugs Exp Clin Res 13:517-24 (1987).Adopt the commercial reagents box that the glucose that produces is carried out quantitatively (glucose oxidase method, Sigma Chemical Co.).Preferred Alpha-glucosidase inhibitor can suppress the activity of described enzyme, its IC
50Be 1nM-10 μ M.Preferred its IC
50Be 1nM-1 μ M.
Embodiment Q: glycogen phosphorylase is measured
Separate glycogen phosphorylase by people's liver, in buffered reaction mixture, measure this enzyme by the release of measuring the synthetic middle glucose 1-phosphate ester of glycogen, described buffer contains 0.5mM glucose 1-phosphate ester and 1mg/mL glycogen.Add the salt acidity test phosphate ester that contains ammonium molybdate and peacock green.Measure absorption value in the 620nm place.The DMSO solution that adds test-compound.Referring to Martin WH, Hoover DJ, PNAS 95:1776-1781 (1998) such as Armento SJ.The IC of preferred glycogen phosphorylase inhibitors
50Be 1nM-10 μ M.Preferred IC
50Be 1nM-1 μ M.
Embodiment R: the mensuration of glucose 6-inhibitors of phosphatases
Discharge the activity that phosphate ester is measured glucose 6-phosphatase by monitoring glucose 6-phosphate ester.Under room temperature, in the buffer that contains 1mM glucose 6-phosphate ester, hatch microsome by the preparation of empty stomach rat.The phosphate ester that adds the salt acidity test release that contains ammonium molybdate and peacock green.Measure the absorption value of the solution that obtains in the 620nm place.Add the DMSO solution of test-compound, add enzyme then.Referring to Parker JC, van Volkenburg A, Levy CB etc., Diabetes 47:1630-1636 (1998).The IC of preferred glucose 6-phosphatase inhibitors
50Be 0.1nM-10 μ M.Preferred IC
50Be 0.1nM-300nM.
Embodiment S: glucagon antagonist is measured
Measure the activity of glucagon antagonist by the displacement of iodate glucagon in the baby hamster kidney cell membrane plasmapheresis prepared product of people's receptor of expression cloning by mensuration.Referring to MadsenP, Knudsen LB, Wiberg FC, Carr RD, J.Med.Chem.41:5150-5157 (1998).These are determined on the filter-type microtitration plate and carry out.In each hole, add the test-compound of various concentration, the glucagon tracer and the buffer of fixed amount.In the presence of a large amount of unlabelled parts, measure non-specific binding.Isolated by vacuum filtration combination and unconjugated tracer.The washing titer plate is counted filter membrane on gamma counter.From above-mentioned counting, deduct non-specific binding.The employing standard method obtains the Scatchard saturation curve and it is analyzed, to measure binding constant.According to the ability of the glucagon tracer of labelling in the described chemical compound displacement filter membrane, measure antagonism.The IC of preferred antagonist
50Be 0.1nM-100 μ M.Preferred chemical compound suppresses bonded IC
50Be 0.1nM-1 μ M.
Embodiment T: the mensuration of dextrin agonist
By rat nuclear accumbens and forebrain substrate peripheral region diffusion barrier.The displacement of the iodate people dextrin of film preparation thing is measured the activity of dextrin agonist by mensuration.These are determined on the filter-type microtitration plate and carry out.In each hole, add the test-compound of various concentration, the dextrin tracer and the buffer of fixed amount.In the presence of a large amount of unlabelled parts, measure non-specific binding.Isolated by vacuum filtration combination and unconjugated tracer.The washing titer plate is counted filter membrane on gamma counter.From above-mentioned counting, deduct non-specific binding.The employing standard method obtains the Scatchard saturation curve and it is analyzed, to measure binding constant.The Ki of preferred agonist is 0.001nM-1 μ M.It is 0.001nM-10nM that preferred chemical compound suppresses bonded Ki.
Embodiment U: fatty acid oxidation inhibitors is measured
By Berry and the described collagenase digestion of Friend by empty stomach rat isolating hepatocytes.In the inhibitor existence of a series of concentration ranges or not, cell is cultivated in the Krebs bicarbonate buffer.Add
14The C-labelling startup with cetylate albumin bound (0.05Ci/mol, 0.5mM final concentration) reacts.Cultivate after 10 minutes, add the perchloric acid cessation reaction, extract oxidation product.Referring to Guzman M, Geelen MJH, BiochemJ, 287,487-492 (1992).Total oxidation product is represented with the solubility in acid product (ketoboidies) and the carbon dioxide sum that discharge.The IC of preferred fatty acid oxidation inhibitors blocking-up fatty acid oxidation
50Be 10nM-300 μ M.More preferably IC
50Be 10nM-30 μ M.
EXAMPLE V: to the reduction effect (FBP enzyme inhibitor) of db/db mice glucose
(Bar Harbor Maine) buys the male db/db mice in 8 ages in week, and this kind mice is widely used as the NIDDM model by Jackson Labs.These mices are placed (25 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and powdery Purina5008 foodstuff and water freely are provided.In 10 weeks during ages, with blood-glucose＞400mg/dl and＜animal of 900mg/dl is divided into two treatment groups (n=5-6/ group).Treat after 18 days, adopt HemoCue glucose analyser (HemoCue Inc., Mission Viejo, CA) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.Difference by two groups of " student " t-test evaluations.P＜0.05 is for having significant difference.
As shown in following table, in the last day (the 18th day) of treatment, the blood glucose levels of chemical compound G treatment group significantly is lower than matched group:
Table 7
| Blood-glucose, mg/dl | ||
| Treatment | The 0th day | The 18th day |
| Contrast | ?707±65 | ?870±32 |
| Chemical compound G | ?708±55 | ?646±37 |
* p＜0.05 is compared with matched group
Embodiment W: to the reduction effect (chemical compound G and J) of ZDF rat glucose
Zucker diabetes obesity (ZDF) rat is widely used as people NIDDM model, because these rodentine pathogenic processes are with similar to what describe in 1983 human patientses.Sophisticated ZDF rat not only has obesity, hyperglycemia, insulin resistance and hepatic glucose and produces symptoms such as increase, but also has some common trunk and microvascular complication relevant with NIDDM.Referring to Clark JB, Palmer CJ (1982) Diabetes 30:126A Terrettaz J, Jeanrenaud B (1983) Endocrinology 112:1346-1351.
(a) to the research approach of chemical compound G: (Indianapolis Indiana) buys the male ZDF rat in 8 ages in week by Genetics Models Inc..These rats are placed (25 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and powdery Purina 5008 foodstuffs and water freely are provided.When 11 ages in week, select the animal of blood-glucose＞500mg/dl and they are divided into two processed group (n=8/ group).Processed group comprises matched group and chemical compound G group (form with 0.2% foodstuff mixture gives 14 days).Adopt HemoCue glucose analyser (HemoCue Inc., Mission Viejo, CA) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.Difference by two groups of " student " t-test evaluations.P＜0.05 is for having significant difference.
(b) research approach of chemical compound J: carry out this test according to the described method of above-claimed cpd G part, but improve wherein two places: treatment time changes 21 days into, and the dosage of chemical compound J is 0.4%.
(c) result:
Show research in 8.14-days, chemical compound G (0.2% foodstuff mixture)
| Blood-glucose, mg/dl | ||
| Treatment | The 0th day | The 14th day |
| Contrast | ?655±39 | ?762±31 |
| Chemical compound G | ?653±55 | ?530±48 * |
*P＜0.05, compared with the control
Show research in 9.21-days, chemical compound J (0.4% foodstuff mixture)
| Blood-glucose, mg/dl | ||
| Treatment | The 0th day | The 21st day |
| Contrast | ?678±19 | ?815±34 |
| Chemical compound J | ?674±20 | ?452±40 * |
*P＜0.05, compared with the control
Chemical compound G and J all can significantly improve the control to the ZDF rat blood sugar.These results show that the FBP enzyme inhibitor can be used for the treatment of NIDDM clinically.
Embodiment X: insulin secretagogue and FBP enzyme inhibitor (chemical compound J) are united the ZDF rat are carried out acute treatment
Testing program: since at 8 in the morning, with Zucker diabetes obese rat (9.5 age in week) fasting 5 hours.Then animal is divided into similar statistically 4 groups of blood glucose levels baseline.Oral gavage gives test-compound.Processing method is as follows:
Table 10
| Group | Processing method | Dosage |
| 1 | Normal saline | ?n/a |
| 2 | Glibenclamide | ?100mg/kg |
| 3 | Chemical compound J | ?300mg/kg |
| 4 | Glibenclamide+chemical compound J | ?100+300mg/kg |
Give normal saline or medicine after 1 hour, give all animal glucoses (1g/kg) with the form per os heavy dose of simulating foodstuff.And then periodic monitoring blood-glucose 3 hours.Test-compound is prepared 0.1% suspension liquid of carboxyl methyl cellulose.Through tail vein otch blood sample collection.(HemoCue Inc., Mission Viejo CA), adopt the HemoCue glucose analyser to measure blood-glucose according to manufacturer's explanation.The result represents with the standard error of the meansigma methods ± meansigma methods of all numerical value.
The result: in sample research, analyze, glibenclamide and chemical compound J respectively 100 and the dosage of 300mg/kg under have maximum efficiency.In this research, glibenclamide and chemical compound J can suppress the rising that per os gives the blood-glucose of glucose induction, and chemical compound J can be reduced to blood-glucose (referring to following Fig. 1) below the baseline values.As showing, with respect to any single medicine treatment, therapeutic alliance better effects if in the increase that area (AUC) reduces under the change curve in time of initial 4 hours inner blood glucoses after the administration.
Table 11:
| Treatment | The AUC glucose, mg/dL*h |
| Contrast | ?1463±99 |
| Glibenclamide | ?1324±132 |
| Chemical compound J | ?1121±82 |
| Therapeutic alliance | ?895±74 |
Therapeutic alliance can also weaken in adopting the treatment of chemical compound J single medicine, observe blood lactate increase (p=0.01 during at 0 time point, Fig. 2).
This studies show that, with respect to the single therapy method that adopts any medicine, adopts insulin secretagogue and FBP enzyme inhibitor to significantly improve Blood glucose control.The raising of glycemic control will make the sickness rate of the complication relevant with NIDDM reduce.In addition, in this acute therapeutic alliance, the side effect-blood lactate that has weakened the FBP ihibitors for treatment increases.In long-term treatment, this kind abated effect is more remarkable.
Fig. 1: the OGTT in the ZDF rat
*Compare with all groups, p＜0.05:ANOVA adopts Dunnet ' s post hoc test
+ comparing with the solvent group, p＜0.05:ANOVA adopts Dunnet ' s post hoc test, Fig. 2: the OGTT in the ZDF rat
Embodiment Y: adopt insulin secretagogue and FBP enzyme inhibitor that the ZDF rat is carried out long-term therapeutic alliance
(Indianapolis Indiana) buys the male ZDF rat in 7 ages in week by Genetics Models Inc..These rats are placed (25 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and powdery Purina 5008 foodstuffs and water freely are provided.When 8 ages in week, animal is divided into four processed group (n=8/ group).Processed group comprises that matched group, chemical compound J group, glibenclamide group and chemical compound J and glibenclamide unite group.Give 2-12 week with the form of drinking water or with the form of foodstuff mixture with maximal dose with chemical compound J and glibenclamide oral gavage.Adopt HemoCue glucose analyser (HemoCue Inc., MissionViejo, CA) glucose in the mensuration tail vein sample.Other parameters that adopt the standard test method to measure comprise lactate, glycerol, alanine, triglyceride, free fatty, ketoboidies, liver and muscle glycogen, cholesterol, VLDL, HDL, hemoglobin A lc, body weight, foodstuff and water intake amount, and carbohydrate, lipid and proteometabolic other measurement indexes.Its value is all represented with the standard error of meansigma methods ± meansigma methods.Adopt suitable post hoc testANOVA to estimate the respectively difference between group.P＜0.05 is for having significant difference.
Along with the carrying out of this research, control animals blood glucose raises gradually, and obviously controlled when beginning at all three medication therapy groups blood glucose.With respect to chemical compound J or glibenclamide single medicine treatment group, the therapeutic alliance group has significant more glucose reduction effect.Because the deterioration of pancreas beta cell situation and the insulin secretion that causes are impaired thereupon, so the effect of employing glibenclamide treatment worse and worse, animal blood glucose significantly raises, and promptly produces the Secondary cases failure.Because pancreatic function descends, so it is better than glibenclamide to adopt chemical compound J to carry out therapeutic effect.But in whole research process, therapeutic alliance is all very remarkable to the effect of glycemic control.
Embodiment Z: adopt insulin and FBP enzyme inhibitor (chemical compound G) to unite the db/db mice is carried out acute treatment
By Clea Japan, (Tokyo Japan) buys the male C57BL/KsJdb/db mice in 5 ages in week to Inc..These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 20 ages in week, animal is divided into four processed group (n=6/ group).Processed group comprises matched group, chemical compound G group, insulin and chemical compound G and insulin combination group.Dosage per os with 200mg/kg gives chemical compound G.With the dosage subcutaneous injection of 1.5U/kg give insulin (biosynthetic human insulin, PenfillN300, Novo Nordisk, Denmark).Foodstuff no longer is provided after the processing.Adopt Glucoloader-F automatic glucose analyser (A ﹠amp; T Co., Ltd., Tokyo, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
Provide the plasma glucose levels value before and after handling in the table below:
Plasma glucose levels before and after table 12. is handled
Handle plasma glucose (mg/dl)
Front and back
(0 hour) 1 hour 2.5 hours 4 hours
Handle 761.5+/-41.9 667.7+/-50.1 549.5+/-47.5 609.3+/-52.6
(100.0+/-0.0)????(87.2+/-2.9)?????(71.6+/-3.5)?????(79.3+/-3.7)
Chemical compound G 774.0+/-18.3 650.8+/-14.8 459.7+/-11.5 373.7+/-24.7
(100.0+/-0.0)????(84.2+/-1.9)?????(59.6+/-23)??????(48.6+/-4.0)
Insulin 756.2+/-15.2 410.8+/-34.4 463.2+/-40.2 540.3+/-35.9
(100.0+/-0.0)????(54.2+/-4.1)?????(61.1+/-4.9)?????(71.4+/-4.1)
Associating 728.0+/-29.8 378.0+/-43.8 243.0+/-60.5 130.8+/-53.9
(100.0+/-0.0)????(51.9+/-5.5)?????(33.7+/-8.5)?????(18.3+/-7.5)
Meansigma methods % before () expression is handled
Because the fasting effect is so the plasma glucose of control animals improves to a certain extent.Give behind the insulin 2.5 hours, hyperglycemia is improved.But in the time of 4 hours, matched group and insulin processed group plasma glucose levels do not have difference.Chemical compound G reduces plasma glucose levels gradually, in the time of 4 hours, shows the glucose reduction effect higher than insulin.With respect to chemical compound G or insulin single therapy, the therapeutic alliance group shows higher glucose reduction effect.
Embodiment A A: insulin and FBP enzyme inhibitor (chemical compound G) associating long-term treatment is to the beneficial effect of db/db mice
By Clea Japan, (Tokyo Japan) buys the male C57BL/KsJdb/db mice in 5 ages in week to Inc..These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 16 ages in week, animal is divided into 2 processed group (n=5 or 9-10/ group).(Denmark), administration every day is 250-300mg/dL to regulate plasma glucose levels to two groups of equal subcutaneous injection administration of human Recombulins for Penfill N300, Novo Nordisk.Group gives chemical compound G with the form of foodstuff mixture, contains 0.2% chemical compound G in the described mixture.Adopt Glu-test-ace automatic glucose analyser (Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
As shown in following table, the plasma glucose levels value of two groups all maintains 250-300mg/dL.
Plasma glucose levels before and after table 13. is handled
Handle plasma glucose (mg/dl)
Front and back
2 all 3 weeks of (0 week) 1 week
Adopt insulin 736.5+/-17.0 297.1+/-46.0 375.6+/-53.5 282.4+/-43.1 separately
Associating 693.8+/-44.7 290.8+/-64.1 274.6+/-50.3 273.8+/-55.9
Provide the body weight change value in the table below:
Body weight change before and after table 14. is handled
Handle body weight (g)
Front and back
2 all 3 weeks of (0 week) 1 week
Adopt insulin 43.4+/-2.2 50.7+/-1.5 54.3+/-1.2 57.4+/-1.6 separately
Associating 42.7+/-1.8 48.1+/-1.3 51.1+/-0.8 53.8+/-0.6
Although insulinize treated animal body weight significantly increases, the increment rate of body weight and degree but significantly reduce in the therapeutic alliance group.
The plasma glucose levels value that has provided the animal that makes each group in the table below maintains the dosage of the required insulin of 250-300mg/dL.
Table 15
Handle insulin dose (U/kg)
Front and back
2 all 3 weeks of (0 week) 1 week
Adopt insulin 548+/-18 753+/-72 492+/-68 306+/-67 separately
Associating 501+/-47 494+/-108 252+/-78 114+/-37
In the therapeutic alliance group, give chemical compound G simultaneously and can significantly make plasma glucose reduce to the dosage of the required insulin of target zone.
Embodiment B B: insulin and FBP enzyme inhibitor (chemical compound J) associating long-term treatment is to the beneficial effect of db/db mice
By Clea Japan, (Tokyo Japan) buys the male C57BL/KsJdb/db mice in 5 ages in week to Inc..These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 19 ages in week, animal is divided into 2 processed group (n=6/ group).(Denmark), administration every day is 300mg/dL to regulate plasma glucose levels to two groups of equal subcutaneous injection administration of human Recombulins for Penfill N300, Novo Nordisk.Group gives chemical compound J with the form of foodstuff mixture, contains 0.2% chemical compound G in the described mixture.Adopt Glucoloader-F automatic glucose analyser (A ﹠amp; T Co., Ltd., Tokyo, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
Plasma glucose levels value shown in the table below.
Plasma glucose levels before and after table 16. is handled
Handle plasma glucose (mg/dl)
Front and back
3 all 4 weeks of 2 weeks in (0 week) 1 week
Adopt insulin 617.2+/-28.1 408.8+/-15.3 447.7+/-17.6 396.3+/-39.3 316.7+/-17.2 separately
Associating 611.8+/-30.9 360.8+/-37.3 335.2+/-31.5 266.0+/-18.5 281.6+/-24.9
During the treatment of 4 weeks, two groups plasma glucose levels all maintains near the 300mg/dl.
Provide each processed group body weight change in the following table.
Body weight change before and after table 17. is handled
Handle body weight (g)
Front and back
3 all 4 weeks of 2 weeks in (0 week) 1 week
Adopt insulin 54.9+/-1.4 57.9+/-1.3 59.7+/-1.3 61.4+/-1.2 64.2+/-1.0 separately
Associating 55.5+/-1.7 56.4+/-0.9 58.3+/-1.0 60.0+/-1.2 61.8+/-1.1
Although insulinize treated animal body weight significantly increases, during 4 weeks handled, the increase of body weight significantly reduced in insulin and the chemical compound J therapeutic alliance group.
As shown in following table, in the Combined Treatment group, the dosage that chemical compound J will make the plasma glucose levels value of animal maintain the required insulin of target level reduces about 40%.
Table 18. makes the plasma glucose levels value maintain the dosage of the required insulin of target level
Handle insulin dose (U/kg)
Front and back
3 all 4 weeks of 2 weeks in (0 week) 1 week
Adopt insulin 0+/-0 495+/-32 699+/-63 760+/-95 802+/-129 separately
Associating 0+/-0 303+/-31 411+/-62 440+/-80 491+/-112
Embodiment C C: insulin and FBP enzyme inhibitor carry out acute therapeutic alliance to the Goto-Kakizaki rat
By Charles River Japan, (Tokyo Japan) buys male Goto-Kakizaki (GK) rat in 9 ages in week to Inc..These rats are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 48 ages in week,, be divided into 4 processed group (n=6/ group) with the animal overnight fasting.Processed group is matched group, chemical compound J group, insulin group and chemical compound J and insulin combination group.Dosage per os with 50mg/kg gives chemical compound J.(Denmark), dosage is 1.5U/kg to subcutaneous injection administration of human Recombulin for Penfill N300, Novo Nordisk.Adopt Glucoloader-F automatic glucose analyser (A﹠amp; T Co., Ltd., Tokyo, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
Plasma glucose levels value before and after each processed group administration shown in the table below.
Plasma glucose levels before and after table 19. is handled, mg/dL or (% baseline)
Handle plasma glucose (mg/dl)
Front and back
(0 hour) 2 hours 4 hours 6 hours
Matched group 160.5+/-16.3 189.5+/--15.8 187.5+/-20.4 186.0+/-16.3
(100.0+/-0.0)?????(119.1+/-2.9)?????(116.6+/-4.3)????(116.8+/-3.6)
Chemical compound J organizes 161.8+/-6.6 106.3+/-11.0 79.6+/-4.9 35.4+/-10.8
(100.0+/-0.0)?????(65.6+/-6.6)??????(51.0+/-2.7)?????(22.6+/-6.7)
Insulin group 163.7+/-5.8 88.8+/-16.8 71.3+/-20.9 90.7+/-19.7
(100.0+/-0.0)?????(55.0+/-11.0)?????(43.9+/-13.3)????(55.4+/-12.4)
Unite group 151.3+/-4.4 47.5+/-4.0 1.8+/-1.0 (ND)
(100.0+/-0.0)?????(31.6+/-3.0)??????(1.3+/-0.7)??????(ND)
(): % before handling.ND: undetermined.
During this research, the plasma glucose levels of control animals does not change.In 2 hours, chemical compound J or insulin processed group plasma glucose reduce after administration.In the time of 2 or 4 hours, the plasma glucose levels of chemical compound J and insulin processed group does not have difference.And chemical compound J increases gradually to the reduction effect of plasma glucose, shows the glucose reduction effect stronger than insulin in the time of 6 hours.Since 2 hours,, unite and adopt the group of uniting of chemical compound J and insulin to show stronger insulin reduction effect with respect to independent employing chemical compound J or insulin processed group.The intensity of this effect shows that the dosage of the insulin of employing can significantly reduce.So when using with insulin combination, chemical compound J can reduce the consumption of insulin.And the sickness rate and the intensity of the side effect (as weight increase) that insulin dosage minimizing can reduction insulin monotherapy is produced.
Embodiment DD: biguanides and FBP enzyme carry out acute therapeutic alliance to the db/db mice
By Clea Japan, (Tokyo Japan) buys the male C57BL/KsJdb/db mice in 5 ages in week to Inc..These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 10 ages in week, animal is divided into 4 processed group (n=6/ group).Processed group is that matched group, chemical compound J group, metformin group and chemical compound J and metformin are united group.Dosage per os with 150mg/kg gives chemical compound J and/or metformin (Sigma).Food no longer is provided after the administration.Adopt Glucoloader-F automatic glucose analyser (A ﹠amp; T Co., Ltd., Tokyo, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
As shown in following table, in the fasting stage, the control animals plasma glucose levels reduces gradually.With respect to matched group, metformin and the independent treatment of chemical compound J can significantly reduce blood-glucose.But, in the Combined Treatment group, observe blood-glucose and reduce very big.Surprisingly, although metformin has identical mechanism of action (inhibition gluconeogenesis) with the FBP enzyme inhibitor, treat with respect to a kind of medicine of independent employing, their therapeutic alliance but significantly improves Blood glucose control.
Table 20.
Handle plasma glucose (mg/dl)
Front and back
(0 hour) 2 hours 4 hours 6 hours 8 hours
Matched group 541.3+/-10.0 465.5+/-23.2 468.8+/-21.6 460.5+/-29.3 495.8+/-28.1
000.0+/-0.0) (85.0-5.0) (91.5+/-4.6) chemical compound J group 514.3+/-23.0 448.6+/-42.5 376.7+/-39.9 357.7+/-40.4 386.5+/-43.1, (85.8+/-3.2) (86.5+/-3.3)
(100.0+/-0.0)????(70.2+/-14.6)???(72.4+/-5.0)????(68.7+/-5.5)????(74.2+/-5.8)
Metformin 515.7+/-37.0 347.0+/-21.2 346.5+/-34.6 348.3+/-30.7 407.8+/-40.0
(100.0+/-0.0)????(67.7+/-1.9)????(66.4+/-3.1)????(67.7+/-4.1)????(79.1+/-5.6)
Unite group 538.4+/-20.2 317.2+/-21.0 265.4+/-31.0 253.4+/-32.7 289.2+/-49.3
(100.0+/-0.0)????(59.9+/-2.1)????(49.3+/-3.3)????(45.9+/-3.6)????(53.4+/-5.5)
(): meansigma methods % before handling.
Embodiment E E: Alpha-glucosidase inhibitor and FBP enzyme inhibitor carry out acute therapeutic alliance to the Goto-Kakizaki rat
By Charles River Japan, (Tokyo Japan) buys the Goto-Kakizaki rat in 5 ages in week to Inc., and this rat is a fragile type NIDDM animal model.These rats are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.When 18 ages in week, animal is divided into 4 processed group (n=5/ group).Processed group is matched group, chemical compound J group, (Bayer, Japan) group and chemical compound J and acarbose are united group to acarbose.The equal oral gavage of all animals gives 1g/kg corn starch.Giving starch preceding 1 hour, and giving chemical compound J with the dosage per os of 10mg/kg.Dosage and starch while per os with 1mg/kg give acarbose.Adopt Glucoloader-F automatic glucose analyser (A﹠amp; T Co, Ltd., Tokyo, Japan) glucose in the mensuration tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
Plasma glucose levels value before and after each processed group administration shown in the table below.
Plasma glucose levels value before and after table 21. is handled
Processing gives the time behind the starch
-60min??????????0min????????????30min???????????60min????????????120min??????????240min
Plasma glucose (mg/dl) or relative value (%)
Matched group 148.6+/-8.1 211.4+/-9.6 291.0+/-10.4 342.4+/-4.0 248.6+/-9.8 16.5.4+/-9.5
(100.0+/-0.0)???(142.6+/-2.2)???(197.0+/-7.4)???(233.7+/-15.1)???(168.9+/-9.8)???(111.9+-5.8)
Chemical compound J organizes 179.8+/-15.2 218.4+/-19.9 245.2+/-29.9 251.0+/-28.6 182.8+/-18.0 144.6+/-9.8
(100.0+/-0.0)???(121.8+/-8.0)???(135.2+/-9.2)???(138.5+/-6.2)????(101.8+/-7.2)???(81.7+/-6.7)
Acarbose 175.4+/-5.9 226.4+/-5.3 243.8+/-8.5 247.2+/-8.2 209.4+/-5.9 164.2+/-10.7
(100.0+/-0.0)???(129.4+/-2.8)???(139.5+/-6.0)???(1413+/-4.9)?????(119.9+/-4.9)???(93.5+/-4.7)
Unite group 164.4+/-3.6 198.2+/-9.7 150.0+/-11.2 129.4+/-9.6 103.0+/9.1 111.2+/-12.1
(100.0+/-0.0)???(120.4+/-4.4)???(91.1+/-6.0)????(78.6+/-5.3)?????(62.7+/-5.5)????(67.8+/-7.7)
(): meansigma methods % before handling.
In control animals, give starch after, plasma glucose levels increases by 1.6 times.In chemical compound J and acarbose processed group, give starch after the plasma glucose increase weaken.And in chemical compound J and acarbose Combined Treatment group, handle with respect to the single medicine of chemical compound J or acarbose, glucose reduction degree significantly improves.So employing FBP enzyme inhibitor and Alpha-glucosidase inhibitor Combined Treatment can significantly improve the control action to post-prandial glycemia.As if the absorption of gluconeogenesis and carbohydrate all are key factors of decision blood glucose levels behind the food digestion.
Embodiment F F: glycogen phosphorylase inhibitors and FBP enzyme inhibitor carry out acute therapeutic alliance to db/db or ob/ob mice
(Bar Harbor Maine) buys the db/db or the ob/ob mice in 5 ages in week by Jackson Laboratories.These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.Greater than 10 ages in week the time, animal is divided into 4 processed group (n=5-7/ group).Processed group is that matched group, chemical compound J group, CP-91149 (Pfizer) group and chemical compound J and CP-91149 unite group.After fasting 0-48 hour, give chemical compound J and/or CP-91149 with the dosage per os of 0.5-300mg/kg.Begin to provide food after the administration.The manual method of employing standard or automated process are measured the glucose in the tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
With respect to matched group, chemical compound J and CP-91149 single therapy group all significantly reduce blood-glucose.With respect to the single therapy of any medicine, therapeutic alliance group glucose reduces more remarkable.
Embodiment GG: G-6-Pase inhibitor and FBP enzyme inhibitor carry out acute therapeutic alliance to db/db or ob/ob mice
(Bar Harbor Maine) buys the db/db or the ob/ob mice in 5 ages in week by Jackson Laboratories.These mices are placed (24-26 ℃, dark circulation in 12-hour bright/12-hour) under the zoo condition of standard, and standard foodstuff and water freely are provided.Greater than 10 ages in week the time, animal is divided into 4 processed group (n=5-7/ group).Processed group is that matched group, chemical compound J group, G-6-Pase inhibitor group and chemical compound J and G-6-Pase inhibitor are united group.After fasting 0-48 hour, give chemical compound J and/or G-6-Pase inhibitor with the dosage per os of 0.5-300mg/kg.Can not begin to provide food also can provide food after the administration.The manual method of employing standard or automated process are measured the glucose in the tail vein sample.Its value is represented with the standard error of meansigma methods ± meansigma methods.
With respect to matched group, chemical compound J and G-6-Pase inhibitor single therapy group all significantly reduce blood-glucose.With respect to the single therapy of any medicine, therapeutic alliance group glucose reduces more remarkable.
Embodiment HH:FBP enzyme inhibitor and dextrin agonist carry out acute therapeutic alliance
Intravenous injection streptozotocin 65mg/kg induces 2-3 week behind the Sprague Dawley rat diabetes, and with described rat overnight fasting, water-soluble element of intravenous injection normal saline or starch (10 μ g) or oral gavage give chemical compound J (300mg/kg) then.Gavage gives animal 1mL 50% glucose then, ad lib.Giving glucose in the time of 0,30,60,120,180 and 240 minutes, collecting blood sample through the tail vein and measure blood-glucose.Water-soluble element of starch and chemical compound J all can weaken GLPP and raise.With respect to the single therapy of any medicine, the therapeutic alliance group is more remarkable to the control action of post-prandial glycemia.
Embodiment JJ: fatty acid oxidation inhibitors and FBP enzyme inhibitor carry out long-term treatment to the inductive diabetes rat of streptozotocin
In this when beginning research, the Sprague-Dawley male rat (Charles Rivers Laboratories) of the about 120g of body weight is placed the chamber under the condition of standard zoo, and feed with standard foodstuff (Purina 5001).Streptozotocin (STZ) is dissolved in the citrate buffer (pH4.7), induces rat diabetes with the injection of 55mg/kg body weight.After 3 days, measure the blood glucose levels of non-fasting state, glucose level is divided into 4 groups greater than the rat of 250mg/dL: matched group, rely on not department+chemical compound J of department, chemical compound J, support.The disposable not department (3300mg/kg) that relies on of subcutaneous injection every day.Give chemical compound J (0.2%w/w) with the foodstuff form of mixtures.Drug treating continues 2-6 week.During handling, the periodic monitoring blood-glucose.When research finished, anesthetized rat also inserted jugular vein and carotid duct.Continuous infusion (
3H)-generation of 6-glucose assays hepatic glucose.Blood sample collection after 2 hours is by the specific activity of gas phase-mass spectrograph mensuration glucose.Adopt standard method to calculate the hepatic glucose generation rate.
In whole research process, control animals blood glucose raises gradually.And relying on not department and all significantly reductions of chemical compound J treatment group separately blood-glucose.But with respect to relying on the not independent treatment of department and any medicine of chemical compound J, their therapeutic alliance is more remarkable to the Blood glucose control effect.With respect to the single medicine treatment, therapeutic alliance group hepatic glucose produces speed significantly to be reduced.
All lists of references of quoting in this article all should be as prior art, and the full content of all these documents is all incorporated herein by reference.Except that the specific embodiments of the present invention of foregoing description, also be conspicuous to those skilled in the art for various modifications and other embodiments of these embodiments, be also included within the scope of the present invention.
Although according to height of the present invention, various embodiments and reaction condition are illustrated in this article, scope of the present invention is not subjected to the restriction of these explanations.Is conspicuous for improvement of the present invention and modification for those skilled in the art, does not depart from scope of the present invention and aim.So, be appreciated that scope of the present invention is defined by the appended claims, rather than limit by the specific embodiment that provides as example.
Claims (114)
1. Pharmaceutical composition, said composition comprises at least a insulin secretagogue of medicinal effective dose and at least a FBP enzyme inhibitor of medicinal effective dose.
2. the Pharmaceutical composition of claim 1, wherein said insulin secretagogue is a sulphur urea antidiabetic drug.
3. the Pharmaceutical composition of claim 2, wherein said sulphur urea antidiabetic drug is the chemical compound of formula XV:
Wherein:
A is selected from hydrogen, halo, alkyl, alkanoyl, aryl, aralkyl, heteroaryl and cycloalkyl; With
B is selected from alkyl, cycloalkyl and Heterocyclylalkyl.
4. the Pharmaceutical composition of claim 2, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
5. the Pharmaceutical composition of claim 1, wherein said insulin secretagogue is non-sulphur urea.
6. the Pharmaceutical composition of claim 5, wherein said non-sulphur urea is selected from mitiglinide, BTS-67582, repaglinide and Nateglinide.
7. the Pharmaceutical composition of claim 1, wherein said insulin secretagogue is dipeptidyl peptidase-IV (DPP-IV) inhibitor.
8. the Pharmaceutical composition of claim 7, wherein said dipeptidyl peptidase-IV (DPP-IV) inhibitor is selected from NVP-DPP728 and P32/98.
9. the Pharmaceutical composition of claim 1, wherein said insulin secretagogue is glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
10. the Pharmaceutical composition of claim 9, wherein said glucagon-like-peptide-1 (GLP-1) receptor stimulating agent is NN-2211, exendin or exendin agonist.
11. the Pharmaceutical composition of claim 1, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, its Chinese style I and IA are as follows:
With
Its Chinese style I and IA chemical compound are in vivo or the external M-PO that is converted into
3 2-, they are the FBP enzyme inhibitor, in the formula:
Y independently is selected from-O-and-NR
6, prerequisite is as Y during for-O-, is connected in so-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate (carbonate) or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6-, so with-NR
6The R of-connection
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H; With
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkylidene ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 atom, optional contain a hetero atom that is selected from O, N and S and connect together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl and aralkyl, perhaps R
12And R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
Each R
12With each R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl, all these groups are optional to be substituted, perhaps R
12And R
13Link to each other by 2-6 carbon atom and to form optional 1 the heteroatomic cyclic group that is selected from O, N and S that comprises together;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
12. the Pharmaceutical composition of claim 11, wherein M is:
Wherein:
U
6And V
6Independently be selected from hydrogen, hydroxyl and acyloxy, perhaps U
6And V
6Form the rudimentary ring that contains at least one oxygen together;
W
6Be selected from amino and lower alkyl amino; With
Z
6Be selected from alkyl and halogen.
13. the Pharmaceutical composition of claim 11, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
14. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A
2Be selected from-NR
8 2,-NHSO
2R
3,-OR
25,-SR
25, halogen, low alkyl group ,-CON (R
4)
2, guanidine, amidine ,-H and whole haloalkyl;
E
2Be selected from-H, halogen, lower alkylthio, rudimentary whole haloalkyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy ,-CN and-NR
7 2
X
3Be selected from-alkyl (hydroxyl)-;-alkyl-;-alkynyl-;-aryl-;-carbonyl-alkyl-;-1,1-dihalo alkyl-;-alkoxyalkyl-;-alkyl oxy-;-alkylthio alkyl-;-alkylthio group-;-alkyl amino-carbonyl-;-alkyl-carbonyl-amino-; Alcyl-;-aralkyl-;-alkylaryl-;-alkoxy carbonyl-;-ketonic oxygen base alkyl-;-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted, and prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, outside the dehydrogenation, all groups all can be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps two R
4Form cyclic alkyl;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
Each R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
Each R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps two R
8Form two coordination alkyl;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
15. the Pharmaceutical composition of claim 14, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
16. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A, E and L independently are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl, perhaps J and Y form and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-;-alkyl-;-alkynyl-;-aryl-;-carbonyl-alkyl-;-1,1-dihalo alkyl-;-alkoxyalkyl-;-alkyl oxy-;-alkylthio alkyl-;-alkylthio group-;-alkyl amino-carbonyl-;-alkyl-carbonyl-amino-;-alcyl-;-aralkyl-;-alkylaryl-;-alkoxy carbonyl-;-ketonic oxygen base alkyl-;-alkoxycarbonyl amino-; With-alkyl amino-carbonyl amino-, all these groups all can be substituted, and prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps two R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl; Each R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10Each R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps two R
8Form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl; With
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
17. the Pharmaceutical composition of claim 16, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
18. the Pharmaceutical composition of claim 17, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
19. the Pharmaceutical composition of claim 16, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
20. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
B
5Be selected from-NH-,-N=and-CH=;
D
5Be selected from
Q
5Be selected from-C=and-N-;
Prerequisite is: work as B
5During for-NH-, Q
5For-C=and D
5For
Work as B
5During for-CH=, Q
5For-N-and D
5For
Work as B
5During for-N=, D
5For
And Q
5For-C=;
A, E and L independently are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cycloalkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-, alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-, alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
3
21. the Pharmaceutical composition of claim 20, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
22. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is-X-R
5, R
5Be selected from following formula:
With
Wherein:
Each G independently is selected from C, N, O, S and Se, and wherein to be no more than a G be O, S or Se and to be no more than a G be N;
Each G ' independently is selected from C and N, and wherein being no more than two G ' is N;
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, every other group is all optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X passes through 2-4 atom with R for the optional linking group that replaces, this group
5Be connected with phosphorus atoms, comprise 0-1 hetero atom that is selected from N, O and S, except that following situation: if X is urea or carbamic acid root, have 2 hetero atoms so, the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein: X is selected from furan-2,5-two bases ,-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl or heterocyclic radical together, wherein said hetero atom is selected from O, S and N;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2With
Prerequisite is:
1) when G ' is N, A, B, D or E are respectively zero;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not any two atoms linking group, the optional replacement-alkyl oxy-or optional replacement the-alkylthio group-;
4) when G is N, A or B are not respectively halogen or the direct group that is connected with G by hetero atom;
5) as X be not-aryl-time, so R
5Do not replaced: two or more aryl by following groups.
23. the Pharmaceutical composition of claim 22, wherein: R
5Be selected from pyrrole radicals; Imidazole radicals; Oxazolyl; Thiazolyl; Isothiazolyl; 1,2, the 4-thiadiazolyl group; Pyrazolyl; Isoxazolyl; 1,2,3-oxadiazole base; 1,2,4-oxadiazole base; 1,2,5-oxadiazole base; 1,3,4-oxadiazole base; 1,2, the 4-thiadiazolyl group; 1,3, the 4-thiadiazolyl group; Pyridine radicals; Pyrimidine radicals; Pyrazinyl; Pyridazinyl; The 1,3,5-triazines base; 1,2,4-triazine radical and 1,3-selenazoles base, all these substituent groups all contain at least one substituent group.
24. the Pharmaceutical composition of claim 22, wherein R
5Not 2-thiazolyl or 2-oxazolyl.
25. the Pharmaceutical composition of claim 22, wherein R
5Be selected from:
Wherein:
A " be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Whole haloalkyl, C
1-C
6Haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2With-NHAc;
B " and D " independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
92 ,-OR
3,-SR
3, whole haloalkyl and halo, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
E " be selected from-H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
4-C
6Alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-OR
3,-SR
3, C
1-C
6Whole haloalkyl and halo, except that H ,-CN, whole haloalkyl and halo, all groups are all optional to be substituted; With
Each R
3Independently be selected from C
1-C
6Alkyl, C
6Aryl, C
3-C
6Heteroaryl, C
3-C
8Alcyl, C
2-C
7Heterolipid cyclic group, C
7-C
10Aralkyl and C
4-C
9Heteroarylalkyl;
Each R
4And R
9Independently be selected from-H and C
1-C
2Alkyl;
X is selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-and-alkoxy carbonyl-;
Each R
11Be selected from-NR
4 2,-OH ,-OR
3, C
1-C
6Alkyl, C
6Aryl and C
3-C
6Heteroaryl.
26. the Pharmaceutical composition of claim 25, wherein X be selected from-heteroaryl-and-alkoxy carbonyl-.
27. the Pharmaceutical composition of claim 25, wherein said chemical compound are the chemical compound of formula XII, XIII or XIV:
28. the Pharmaceutical composition of claim 25, wherein:
A " be selected from-NH
2,-Cl ,-Br and-CH
3
Each B " be selected from-H ,-C (O) OR
3,-C (O) SR
3, C
1-C
6Alkyl, alcyl, halo, heteroaryl and-SR
3
D " be selected from-H ,-C (O) OR
3, low alkyl group, alcyl and halo; With
E " be selected from-H ,-Br and-Cl.
29. the Pharmaceutical composition of claim 27, wherein: R
18Be selected from-H, methyl and ethyl;
Each R
12And R
13Independently be selected from-H, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl ,-CH
2CH
2-SCH
3, phenyl and benzyl, perhaps R
12And R
13By the continuous cyclic alkyl that forms together of 2-5 carbon atom chain;
N is 1 or 2;
Each R
14Independently be selected from-OR
17, wherein: R
17Be selected from methyl, ethyl, propyl group and benzyl; With
R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16Link to each other by 2-6 atomic link, optionally comprise 1 hetero atom that is selected from O, N and S.
30. the Pharmaceutical composition of claim 27, wherein R
16For-(CR
12R
13)
n-C (O)-R
14
31. the Pharmaceutical composition of claim 27, wherein:
R
18Be selected from-H, methyl and ethyl;
R
12And R
13Independently be selected from-H, methyl, i-propyl group, i-butyl and benzyl, perhaps linking to each other by 2-5 carbon atom chain forms cyclic alkyl together;
R
14For-OR
17
R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; With
R
15And R
16Independently be selected from low alkyl group and rudimentary aralkyl, perhaps R
15And R
16It is continuous to pass through 2-6 atomic link together, chooses wantonly to comprise 1 hetero atom that is selected from O, N and S.
32. the Pharmaceutical composition of claim 22, wherein said FBP enzyme inhibitor are the chemical compound of following formula:
Wherein: X is selected from furan-2,5-two bases;-alkoxy carbonyl-and-alkyl amino-carbonyl-.
33. the Pharmaceutical composition of claim 32, wherein:
N is 1;
R
12And R
13Independently be selected from-H, methyl, i-propyl group, i-butyl and benzyl, perhaps R
12And R
13Form cyclic alkyl together by the chain of 2-5 carbon atom is continuous, and work as R
12And R
13When inequality, H
2N-CR
12R
13-C (O)-R
14Be naturally occurring amino acid whose ester or monothioester;
R
14Be selected from-OR
17With-SR
17
R
17Be selected from methyl, ethyl, propyl group, t-butyl and benzyl; With
R
18Be selected from-H, methyl and ethyl.
34. the Pharmaceutical composition of claim 25, wherein R
5For:
A " be selected from-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H;
B " be selected from-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3, OR
3With-NR
9 2With
X is selected from-heteroaryl-,-alkoxy carbonyl-and-alkyl amino-carbonyl-, all these groups are optional to be substituted.
35. the Pharmaceutical composition of claim 34, wherein said FBP enzyme inhibitor are the chemical compound of formula 1A, wherein:
Be selected from
With
Wherein:
C
*Has S type three-dimensional chemical configuration;
R
18And R
15Independently be selected from H and methyl;
Each R
12And R
13Independently be selected from-H, methyl, i-propyl group, i-butyl and benzyl, perhaps R
12And R
13By the continuous cyclic alkyl that forms together of the chain of 2-5 carbon atom;
N is 1;
R
14For-OR
17
R
16For-(CR
12R
13)
n-C (O)-R
14With
R
17Be selected from methyl, ethyl, propyl group, phenyl and benzyl.
36. the Pharmaceutical composition of claim 34, wherein A " be-NH
2, X is a furan-2,5-two bases and B " be-S (CH
2)
2CH
3
37. the Pharmaceutical composition of claim 34, wherein A " be-NH
2, X is a furan-2,5-two bases and B " be-CH
2-CH (CH
3)
2
38. the Pharmaceutical composition of claim 37, wherein said FBP enzyme inhibitor are the chemical compound of formula IA, wherein:
For
39. the Pharmaceutical composition of claim 37, wherein said FBP enzyme inhibitor are the chemical compound of formula IA, wherein:
For
Wherein: C
*Has S type three-dimensional chemical configuration.
40. the Pharmaceutical composition of claim 22, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
41. the Pharmaceutical composition of claim 40, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
42. the Pharmaceutical composition of claim 22, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
43. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
G " be selected from-O-and-S-;
A
2, L
2, E
2And J
2Be selected from-NR
4 2,-NO
2,-H ,-OR
2,-SR
2,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO
2R
9,-SO
2NR
4 2,-CN ,-S (O) R
3, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps L
2And E
2Or E
2And J
2Form the cyclic group of ring formation together;
X
2Be selected from-CR
2 2-,-CF
2-,-CR
2 2-O-,-CR
2 2-S-,-C (O)-O-,-C (O)-S-,-C (S)-O-and-CR
2 2-NR
19-, and the atom that wherein links to each other with phosphorus is a carbon atom; Prerequisite is X
2Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
19Be selected from low alkyl group ,-H and-COR
2
44. the Pharmaceutical composition of claim 43, wherein G " be-S-.
45. the Pharmaceutical composition of claim 43, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
46. the method for treatment mammal diabetes, this method comprises the component that comprises at least a FBP enzyme inhibitor (b) that gives comprising of the medicinal effective dose of described mammal of at least a insulin secretagogue component (a) and medicinal effective dose.
47. the method for claim 46, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
48. the method for claim 47, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
49. the method for claim 46, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
50. the method for claim 46, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt:
With
Wherein: formula I and IA chemical compound are in vivo or the external M-PO that is converted into
3 2-, they can suppress the FBP enzyme, wherein:
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, with-R that O-is connected
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate (carbonate) or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6-time, with-NR
6The R of-connection
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, should-O-is not that another Y is-N (R when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Or
Or
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement;
Perhaps V links to each other by an other 3-5 atom with Z and forms cyclic group together, optionally contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H, alkylidene ,-alkylidene aryl and aryl, perhaps R
4And R
4By 2-6 the atom optional hetero atom that is selected from O, N and S that contains that connects together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl and aralkyl, perhaps R
12And R
18By the continuous cyclic group that forms together of 1-4 carbon atom;
Each R
12With each R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl, all these groups are optional to be substituted, perhaps R
12And R
13Linking to each other by 2-6 carbon atom forms cyclic group together, optionally comprises 1 hetero atom that is selected from O, N and S;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17,-SR
17With-NR
2R
20
R
15Be selected from-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14,-H, low alkyl group, lower aryl and rudimentary aralkyl, perhaps R
15And R
16By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps work as R
14For-N (R
17)
2The time, two R
17By the continuous cyclic group that forms together of 2-6 atom, wherein said cyclic group is chosen wantonly and is comprised a hetero atom that is selected from O, N and S;
R
20Be selected from-H, rudimentary R
3With-C (O)-rudimentary R
3
51. the method for claim 50, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A
2Be selected from-NR
8 2, NHSO
2R
3,-OR
25,-SR
25, halogen, low alkyl group ,-CON (R
4)
2, guanidine, amidine ,-H and whole haloalkyl;
E
2Be selected from-H, halogen, lower alkylthio, rudimentary whole haloalkyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy ,-CN and-NR
7 2
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
52. the method for claim 51, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
53. the method for claim 52, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
54. the method for claim 51, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
55. the method for claim 50, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group or E and J together and form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
56. the method for claim 55, wherein said sercretogogue are sulphur urea antidiabetic drug.
57. the method for claim 56, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
58. the method for claim 55, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
59. the method for claim 50, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
B
5Be selected from-NH-,-N=and-CH=;
D
5Be selected from
With
Q
5Be selected from-C=and-N-;
Prerequisite is:
Work as B
5During for-NH-, Q so
5For-C=and D
5For
Work as B
5During for-CH=, Q so
5For-N-and D
5For
With
And work as B
5During for-N=, D
5For
And Q
5For-C=;
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
60. the method for claim 59, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
61. the method for claim 60, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
62. the method for claim 59, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
63. the method for claim 50, wherein M is-X-R
5, at this R
5Be selected from:
With
Wherein:
Each G independently is selected from C, N, O, S and Se, and wherein being no more than a G is O, S or Se, and to be no more than a G be N;
Each G ' independently is selected from C and N, and wherein to be no more than two G ' be N;
A is selected from-H ,-NR
4 2,-ONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, all substituent groups are all optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X passes through 2-4 atom with R for the optional linking group that replaces, this group
5Be connected with phosphorus atoms, comprise 0-1 hetero atom that is selected from N, O and S, if but X is urea or carbamic acid root, there are 2 hetero atoms so, and the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein: X is selected from-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2With
Prerequisite is:
1) when G ' is N, A, B, D or E are zero respectively so;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not the linking group of two atoms, optional replacements-alkyl oxy-or choose wantonly replacement-alkylthio group-;
4) when G is N, A or B are not halogen or pass through the group that hetero atom directly links to each other with G;
5) as X be not-aryl-time, so R
5Do not replaced: two or more aryl by following groups.
64. the method for claim 63, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
65. the method for claim 64, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
66. the method for claim 63, wherein said sercretogogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, DPP IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
67. the method for claim 50, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
G " be selected from-O-and-S-;
A
2, L
2, E
2And J
2Be selected from-NR
4 2,-NO
2,-H ,-OR
2,-SR
2,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO
2R
9,-SO
2NR
4 2,-CN ,-S (O) R
3, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps L
2And E
2Or E
2And J
2Be formed with the cyclic group of ring together;
X
2Be selected from-CR
2 2-,-CF
2-,-CR
2 2-O-,-CR
2 2-S-,-C (O)-O-,-C (O)-S-,-C (S)-O-and-CR
2 2-NR
19-, and the atom that wherein links to each other with phosphorus is a carbon atom; Prerequisite is X
2Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
19Be selected from low alkyl group ,-H and-COR
2
68. the method for claim 67, wherein said insulin secretagogue are sulphur urea antidiabetic drug.
69. the method for claim 68, wherein said sulphur urea antidiabetic drug is selected from glibenclamide, azoles sulphur _ urea, acetohexamide, chlorpropamide, glibornuride, tolbutamide, first sulphur nitrogen _ urea, glipizide, gliclazide, gliquidone, subose, Phenbutamide, metahexamide and glimepiride.
70. the method for claim 67, wherein said insulin secretagogue are selected from mitiglinide, BTS-67582, repaglinide, Nateglinide, dipeptidyl peptidase-IV (DPP-IV) inhibitor and glucagon-like-peptide-1 (GLP-1) receptor stimulating agent.
71. the method for claim 46, the wherein said associating is oral administration.
72. the method for claim 46, wherein said disease be characterized as hyperglycemia.
73. the method for claim 46, wherein said disease are obesity.
74. the method for claim 46 is wherein will about 100mg-about 2, the described sulphur urea antidiabetic drug of the described FBP enzyme inhibitor of 000mg and the about 250mg of about 3mg-gives described mammal.
75. Pharmaceutical composition, said composition comprise the insulin of medicinal effective dose or the FBP enzyme inhibitor of insulin analog and medicinal effective dose.
76. the Pharmaceutical composition of claim 75, wherein said insulin or insulin analog are selected from insulin, insulin lispro, insulin aspart and insulin gargline.
77. Pharmaceutical composition, said composition comprise the biguanide of medicinal effective dose and the FBP enzyme inhibitor of medicinal effective dose.
78. the Pharmaceutical composition of claim 77, wherein said biguanide is selected from metformin, phenformin and buformin.
79. Pharmaceutical composition, said composition comprise the Alpha-glucosidase inhibitor of medicinal effective dose and the FBP enzyme inhibitor of medicinal effective dose.
80. the Pharmaceutical composition of claim 79, wherein said Alpha-glucosidase inhibitor is selected from acarbose, miglitol and voglibose.
81. Pharmaceutical composition, said composition comprise that the FBP enzyme inhibitor of medicinal effective dose and the hepatic glucose output inhibitor of medicinal effective dose are selected from glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, glucide agonist and fatty acid oxidation inhibitors.
82. the Pharmaceutical composition of claim 81, wherein said glucide agonist is pramlintide.
83. claim 75,77 or 79 Pharmaceutical composition, wherein said FBP enzyme inhibitor is chemical compound and pharmaceutically acceptable prodrug and the salt that is selected from formula I and IA:
Its Chinese style I and IA chemical compound are in vivo or the external M-PO that is converted into
3 2-, they suppress the FBP enzyme, wherein:
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps with R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
Each R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl, all these groups are optional to be substituted, perhaps R
12And R
13By the continuous cyclic group that forms together of 2-6 carbon atom;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17With-SR
17
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps with R
16By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14, low alkyl group, lower aryl, rudimentary aralkyl, perhaps with R
15By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps the R on the N
17And R
17By 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other.
84. comprising, the Pharmaceutical composition of claim 83, wherein said compositions be selected from following insulin or insulin analog: insulin, insulin lispro, insulin aspart and insulin gargline.
85. comprising, the Pharmaceutical composition of claim 83, wherein said compositions be selected from following biguanide: metformin, phenformin and buformin.
86. comprising, the Pharmaceutical composition of claim 83, wherein said compositions be selected from following Alpha-glucosidase inhibitor: acarbose, miglitol and voglibose.
87. the Pharmaceutical composition of claim 83, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
Z
6Be selected from alkyl and halogen;
U
6And V
6Independently be selected from hydrogen, hydroxyl and acyloxy, perhaps form the rudimentary ring that contains at least one oxygen together;
W
6Be selected from amino and lower alkyl amino.
88. the Pharmaceutical composition of claim 83, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A
2Be selected from-NR
8 2, NHSO
2R
3,-OR
25,-SR
25, halogen, low alkyl group ,-CON (R
4)
2, guanidine, amidine ,-H and whole haloalkyl;
E
2Be selected from-H, halogen, lower alkylthio, rudimentary whole haloalkyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy ,-CN and-NR
7 2
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl; With
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
89. the Pharmaceutical composition of claim 83, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-, alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
90. the Pharmaceutical composition of claim 87, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
B
5Be selected from-NH-,-N=and-CH=;
D
5Be selected from
Q
5Be selected from-C=and-N-;
Prerequisite is:
Work as B
5During for-NH-, Q so
5For-C=and D
5For
Work as B
5During for-CH=, Q so
5For-N-and D
5For
With
Work as B
5During for-N=, D so
5For
And Q
5For-C=;
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cycloalkanes shape base and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
3
91. the Pharmaceutical composition of claim 83, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is-X-R
5, at this R
5Be selected from following formula:
Wherein:
Each G independently is selected from C, N, O, S and Se, and wherein having only a G is O, S or Se, and a G is arranged at most is N;
Each G ' independently is selected from C and N, and wherein being no more than two G ' is N;
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, all groups are optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X passes through 2-4 atom with R for the optional linking group that replaces, this group
5Be connected with phosphorus atoms, comprise 0-1 hetero atom that is selected from N, O and S, if but X is urea or carbamic acid root, there are 2 hetero atoms so, and the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein X be selected from-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2With
Prerequisite is:
1) when G ' is N, A, B, D or E are respectively zero so;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not the linking group of two atoms, optional replacements-alkyl oxy-or choose wantonly replacement-alkylthio group-;
4) when G is N, A or B are not halogen or pass through the group that hetero atom directly links to each other with G;
5) as X be not-aryl-time, so R
5Do not replaced: two or more aryl by following groups.
92. the Pharmaceutical composition of claim 91, wherein R
5Be selected from pyrrole radicals; Imidazole radicals, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl group, pyrazolyl, isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, 1,3,5-triazine radical, 1,2,4-triazine radical and 1,3-selenazoles base, all these groups contain at least one substituent group.
93. the Pharmaceutical composition of claim 92, wherein R
5Be selected from:
With
Wherein:
A " be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Whole haloalkyl, C
1-C
6Haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2With-NHAc;
B " and D " independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl and halo, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
E " be selected from-H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
4-C
6Alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-OR
3,-SR
3, C
1-C
6Whole haloalkyl and halo, except that H ,-CN, whole haloalkyl and halo, all groups are all optional to be substituted; With
Each R
3Independently be selected from C
1-C
6Alkyl, C
6Aryl, C
3-C
6Heteroaryl, C
3-C
8Alcyl, C
2-C
7Heterolipid cyclic group, C
7-C
10Aralkyl and C
4-C
9Heteroarylalkyl;
Each R
4And R
9Independently be selected from-H and C
1-C
2Alkyl;
X is selected from-heteroaryl-,-alkyl-carbonyl-amino-,-alkyl amino-carbonyl-and-alkoxy carbonyl-;
Each R
11Be selected from-NR
4 2,-OH ,-OR
3, C
1-C
6Alkyl, C
6Aryl and C
3-C
6Heteroaryl.
94. the Pharmaceutical composition of claim 93, wherein said FBP enzyme inhibitor are the chemical compound of formula IA, wherein R
5For:
A " be selected from-NH
2,-CONH
2, halo ,-CH
3,-CF
3,-CH
2-halo ,-CN ,-OCH
3,-SCH
3With-H;
B " be selected from-H ,-C (O) R
11,-C (O) SR
3, alkyl, aryl, alcyl, halo ,-CN ,-SR
3, OR
3With-NR
9 2
X is selected from-heteroaryl-,-alkoxy carbonyl-and-alkyl amino-carbonyl-, all these groups all can be substituted; With
Wherein
Be selected from
With
Wherein:
C
*Has S type three-dimensional chemical configuration;
R
18And R
15Independently be selected from H and methyl respectively;
Each R
12And R
13Independently be selected from-H, methyl, i-propyl group, i-butyl and benzyl, perhaps R
12And R
13By the continuous cyclic alkyl that forms together of 2-5 carbon atom;
N is 1;
R
14For-OR
17
R
16For-(CR
12R
13)
n-C (O)-R
14With
R
17Be selected from methyl, ethyl, propyl group, phenyl and benzyl.
95. comprising, the Pharmaceutical composition of claim 94, wherein said compositions be selected from following insulin or insulin analog: insulin, insulin lispro, insulin aspart and insulin gargline.
96. comprising, the Pharmaceutical composition of claim 94, wherein said compositions be selected from following biguanide: metformin, phenformin and buformin.
97. comprising, the Pharmaceutical composition of claim 94, wherein said compositions be selected from following Alpha-glucosidase inhibitor: acarbose, miglitol and voglibose.
98. the Pharmaceutical composition of claim 83, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is a following formula:
Wherein:
G " be selected from-O-and-S-;
A
2, L
2, E
2And J
2Be selected from-NR
4 2,-NO
2,-H ,-OR
2,-SR
2,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine radicals, amidino groups, aryl, aralkyl, alkoxyalkyl ,-SCN ,-NHSO
2R
9,-SO
2NR
4 2,-CN ,-S (O) R
3, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps L
2And E
2Or E
2And J
2Be formed with the cyclic group of ring together;
X
2Be selected from-CR
2 2-,-CF
2-,-CR
2 2-O-,-CR
2 2-S-,-C (O)-O-,-C (O)-S-,-C (S)-O-and-CR
2 2-NR
19-, and the atom that wherein links to each other with phosphorus is a carbon atom; Prerequisite is X
2Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
19Be selected from low alkyl group ,-H and-COR
2
99. the method for treatment mammal diabetes, this method comprises the component (a) that comprises at least a insulin, insulin analog, biguanide, hepatic glucose output inhibitor or Alpha-glucosidase inhibitor that gives the medicinal effective dose of described mammal; With
The component that comprises at least a FBP enzyme inhibitor (b) of medicinal effective dose.
100. the method for claim 99, wherein said insulin or insulin analog are selected from insulin, insulin lispro, insulin aspart and insulin gargline.
101. the method for claim 99, wherein said biguanide is selected from metformin, phenformin and buformin.
102. the method for claim 99, wherein said hepatic glucose output inhibitor is selected from glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist, glucide agonist and fatty acid oxidation inhibitors.
103. the method for claim 102, wherein said glucide agonist is pramlintide.
104. the method for claim 99, wherein said alpha-Glucosidase is selected from acarbose, miglitol and voglibose.
105. the method for claim 99, wherein said FBP enzyme inhibitor is selected from formula I and IA chemical compound:
With
Its Chinese style I and IA chemical compound are in vivo or the external M-PO that is converted into
3 2-, they suppress the FBP enzyme, wherein:
Y independently is selected from-O-and-NR
6, prerequisite is:
When Y be-during O-, be connected in-R on the O-
1Independently be selected from-H, alkyl, the optional aryl that replaces, the optional alcyl that replaces, wherein said annulus contains carbonate or thio-carbonate, optional replace-aralkyl ,-C (R
2)
2OC (O) NR
2 2,-NR
2-C (O)-R
3,-C (R
2)
2-OC (O) R
3,-C (R
2)
2-O-C (O) OR
3,-C (R
2)
2OC (O) SR
3,-alkyl-S-C (O) R
3,-alkyl-S-S-alkyl hydroxy and-alkyl-S-S-S-alkyl hydroxy;
When Y is-NR
6In-time, be connected in so-NR
6-on R
1Independently be selected from-H ,-[C (R
2)
2]
q-COOR
3,-C (R
4)
2COOR
3,-[C (R
2)
2]
q-C (O) SR and-cycloalkylidene-COOR
3, wherein q is 1 or 2;
When having only a Y to be-O-, wherein-O-is not that another Y is-N (R so when containing cyclic group a part of of another Y
18)-(CR
12R
13)-C (O)-R
14With
When Y independently be selected from-O-and-NR
6The time, R
1And R
1Be alkyl-S-S-alkyl-and form cyclic group, perhaps R together
1And R
1Form together:
Wherein:
A) V is selected from aryl, the heteroaryl of aryl, replacement, heteroaryl, 1-alkynyl and the 1-alkenyl of replacement; Perhaps
V links to each other by an other 3-5 atom with Z and forms cyclic group together, optional contains 1 hetero atom, described cyclic group on the β of the Y adjacent and γ position with V with aryl-condensed; Perhaps
Z is selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OC (S) OR
3,-CHR
2OC (O) SR
3,-CHR
2OCO
2R
3,-OR
2,-SR
2,-CHR
2N
3,-CH
2Aryl ,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-R
2,-NR
2 2,-OCOR
3,-OCO
2R
3,-SCOR
3,-SCO
2R
3,-NHCOR
2,-NHCO
2R
3,-CH
2The NH aryl ,-(CH
2)
p-OR
2With-(CH
2)
p-SR
2, wherein p is 2 or 3 integer; Perhaps
Z links to each other by an other 3-5 atom with W and forms cyclic group together, choose wantonly to contain a hetero atom, and V must be the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; Perhaps
W and W ' independently be selected from-heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of H, alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement; Perhaps
W and W ' form cyclic group together by an other 2-5 atom, choose wantonly to contain 0-2 hetero atom, and V must be the heteroaryls of aryl, heteroaryl or the replacement of aryl, replacement;
B) V
2, W
2And W " independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Z
2Be selected from-CHR
2OH ,-CHR
2OC (O) R
3,-CHR
2OC (S) R
3,-CHR
2OCO
2R
3,-CHR
2OC (O) SR
3,-CHR
2OC (S) OR
3,-CH (aryl) OH ,-CH (CH=CR
2 2) OH ,-CH (C ≡ CR
2) OH ,-SR
2,-CH
2The NH aryl ,-CH
2Aryl; Perhaps
V
2With Z
2By the continuous cyclic group that contains 5-7 annular atoms that forms together of an other 3-5 atom, choose wantonly and contain 1 hetero atom, and replaced by following groups: hydroxyl, acyloxy, alkoxy-carbonyl oxy or aryloxycarbonyl oxygen base, described substituent group are connected in distance and are connected on the carbon atom of three atoms of Y of phosphorus;
C) Z ' be selected from-OH ,-OC (O) R
3,-OCO
2R
3With-OC (O) SR
3
D ' is-H;
D " be selected from-H, alkyl ,-OR
2,-OH and-OC (O) R
3
Each W
3Independently be selected from-H, heteroaryl, 1-alkenyl and the 1-alkynyl of the aryl of alkyl, aralkyl, alcyl, aryl, replacement, heteroaryl, replacement;
Prerequisite is:
A) V, Z, W, W ' are not-H entirely, and V
2, Z
2, W
2, W " be not entirely-H;
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
6Be selected from-H, low alkyl group, acyloxy alkyl, alkoxy-carbonyl oxy alkyl and lower acyl;
N is the integer of 1-3;
R
18Independently be selected from H, low alkyl group, aryl, aralkyl, perhaps with R
12By the continuous cyclic group that forms together of 1-4 carbon atom;
Each R
12And R
13Independently be selected from H, low alkyl group, lower aryl, rudimentary aralkyl, all these groups are optional to be substituted, perhaps R
12And R
13By the continuous cyclic group that forms together of 2-6 carbon atom;
Each R
14Independently be selected from-OR
17,-N (R
17)
2,-NHR
17With-SR
17
R
15Be selected from-H, low alkyl group, lower aryl, rudimentary aralkyl, perhaps with R
16Together by 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
R
16Be selected from-(CR
12R
13)
n-C (O)-R
14, low alkyl group, lower aryl, rudimentary aralkyl, perhaps with R
15Together by 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
Each R
17Independently be selected from low alkyl group, lower aryl and rudimentary aralkyl, perhaps the R on the N
17And R
17Together by 2-6 atom, optional comprise that 1 hetero atom that is selected from O, N and S links to each other;
M comprises:
Wherein:
A, E and L are selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-COR
11,-SO
2R
3, guanidine, amidine ,-NHSO
2R
25,-SO
2NR
4 2,-CN, sulfoxide, perhalogeno acyl group, whole haloalkyl, perhalogeno alkoxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynyl and rudimentary alcyl, perhaps A and L form cyclic group together, and perhaps L and E form cyclic group together, and perhaps E and J form cyclic group together, and described cyclic group is selected from aryl, cyclic alkyl and heterocyclic radical;
J is selected from-NR
8 2,-NO
2,-H ,-OR
7,-SR
7,-C (O) NR
4 2, halo ,-C (O) R
11,-CN, sulfonyl, sulfoxide, whole haloalkyl, hydroxy alkyl, perhalogeno alkoxyl, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alcyl, aryl and aralkyl perhaps form with Y and are selected from following cyclic group: aryl, cyclic alkyl and Heterocyclylalkyl;
X
3Be selected from-alkyl (hydroxyl)-,-alkyl-,-alkynyl-,-aryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alcyl-,-aralkyl-,-alkylaryl-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is X
3Do not replaced :-COOR by following groups
2,-SO
3H or-PO
3R
2 2
Y
3Be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, aromatic yloxy yl alkyl, alkoxyalkyl ,-C (O) R
3,-S (O)
2R
3,-C (O)-R
11,-CONHR
3,-NR
2 2With-OR
3, except that H, all groups are optional to be substituted;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
R
25Be selected from low alkyl group, lower aryl, rudimentary aralkyl and rudimentary alcyl;
R
7Independently be selected from-H, low alkyl group, rudimentary alcyl, rudimentary aralkyl, lower aryl and-C (O) R
10
R
8Independently be selected from-H, low alkyl group, rudimentary aralkyl, lower aryl, rudimentary alcyl ,-C (O) R
10, perhaps they form two coordination alkyl together;
R
10Be selected from-H, low alkyl group ,-NH
2, lower aryl and rudimentary whole haloalkyl;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2And
M is-X-
R5, at this R
5Be selected from:
Wherein:
Each G independently is selected from C, N, O, S and Se, and wherein having only a G is O, S or Se, and a G is arranged at most is N;
Each G ' independently is selected from C and N, and wherein being no more than two G ' is N;
A is selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, whole haloalkyl, haloalkyl, aryl ,-CH
2OH ,-CH
2NR
4 2,-CH
2CN ,-CN ,-C (S) NH
2,-OR
3,-SR
3,-N
3,-NHC (S) NR
4 2,-NHAc and zero;
Each B and D independently be selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, aralkyl, alkoxyalkyl ,-C (O) R
11,-C (O) SR
3,-SO
2R
11,-S (O) R
3,-CN ,-NR
9 2,-OR
3,-SR
3, whole haloalkyl, halo ,-NO
2With zero, remove-H ,-CN, whole haloalkyl ,-NO
2Outside halo, all groups are optional to be substituted;
E is selected from-H, alkyl, alkenyl, alkynyl, aryl, alcyl, alkoxyalkyl ,-C (O) OR
3,-CONR
4 2,-CN ,-NR
9 2,-NO
2,-OR
3,-SR
3, whole haloalkyl, halo and zero, except that-H ,-CN, whole haloalkyl and halo, every other group is all optional to be substituted;
J is selected from-H and zero;
X passes through 2-4 atom with R for the optional linking group that replaces, this group
5Be connected with phosphorus atoms, comprise 0-1 hetero atom that is selected from N, O and S, if but X is urea or carbamic acid root, there are 2 hetero atoms so, and the number of described atom is by R
5And short distance between the phosphorus atoms is directly determined, the wherein said atom that is connected with phosphorus atoms is a carbon atom, and wherein X be selected from-alkyl (hydroxyl)-,-alkynyl-,-heteroaryl-,-carbonylic alkyl-,-1,1-dihalo alkyl-,-alkoxyalkyl-,-alkyl oxy-,-alkylthio alkyl-,-alkylthio group-,-alkyl amino-carbonyl-,-alkyl-carbonyl-amino-,-alkoxy carbonyl-,-ketonic oxygen base alkyl-,-alkoxycarbonyl amino-and-alkyl amino-carbonyl amino-, all these groups all can be substituted; Prerequisite is that X is not replaced by following groups :-COOR
2,-SO
3H or-PO
3R
2 2
R
2Be selected from R
3With-H;
R
3Be selected from alkyl, aryl, alcyl and aralkyl;
Each R
4Independently be selected from-H and alkyl, perhaps R
4And R
4Form cyclic alkyl together;
Each R
9Independently be selected from-H, alkyl, aralkyl and alcyl, perhaps R
9And R
9Form cyclic alkyl together;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
With prerequisite be:
1) when G ' is N, A, B, D or E are respectively zero so;
2) at least one is not to be selected from-H or zero among A and B or A, B, D and the E;
3) work as R
5Be 6 yuan of whens ring, so X be not the linking group of two atoms, optional replacements-alkyl oxy-or choose wantonly replacement-alkylthio group-;
4) when G is N, A or B are not halogen or pass through the group that hetero atom directly links to each other with G;
5) as X be not-aryl-time, so R
5Do not replaced: two or more aryl by following groups.
106. the Pharmaceutical composition of claim 11, wherein said FBP enzyme inhibitor are selected from formula I and IA chemical compound and pharmaceutically acceptable prodrug and salt, wherein M is-X
4-R
55, at this R
55Be selected from:
With
Wherein:
G
2Be selected from C, O and S;
G
3And G
4Independently be selected from C, N, O and S;
Wherein: a) G
2, G
3And G
4In be no more than one for O or S;
B) work as G
2During for O or S, G
3And G
4In be no more than one for N;
C) G
2, G
3And G
4In at least one is C; With
D) G
2, G
3And G
4Not C entirely;
G
5, G
6And G
7Independently be selected from C and N, wherein G
5, G
6And G
7In be no more than two for N;
J
3, J
4, J
5, J
6And J
7Independently be selected from-H ,-NR
4 2,-CONR
4 2,-CO
2R
3, halo ,-S (O)
2NR
4 2,-S (O) R
3,-SO
2R
3, alkyl, alkenyl, alkynyl, alkylidene aryl, whole haloalkyl, haloalkyl, aryl, heteroaryl, alkylidene-OH ,-C (O) R
11,-OR
11,-alkylidene-NR
4 2,-alkylidene-CN ,-CN ,-C (S) NR
4 2,-OR
2,-SR
2,-N
3,-NO
2,-NHC (S) NR
4 2With-NR
21COR
2
X
4Be selected from:
I) has the linking group of 2-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-furyl-,-thienyl-,-pyridine radicals-,-oxazolyls-,-imidazole radicals-,-phenyl-,-pyrimidine radicals-,-pyrazinyl-and-alkynyl-, all these groups are optional to be substituted; With
The linking group that ii) has 3-4 atom, measure by the minimum atomic number that connects between aromatic ring carbon and the phosphorus atoms, be selected from-the alkylidene carbonylamino-,-the alkylene amino carbonyl-,-alkylidene oxygen base carbonyl-,-alkylidene oxygen base-and-alkylidene oxygen base alkylidene-, all these groups are optional to be substituted;
R
11Be selected from alkyl, aryl ,-NR
2 2With-OR
2
R
20Be selected from-H, rudimentary R
3With-C (O)-(rudimentary R
3);
R
21Be selected from-H and rudimentary R
3
Prerequisite is:
1) works as G
5, G
6Or G
7During for N, J
4, J
5Or J
6Be respectively zero;
2) work as X
4During for the furyl that replaces, J so
3, J
4, J
5And J
6In at least one is not-H or zero;
3) work as X
4When not being the furyl that replaces, the J among the formula VII-5 so
3, J
4, J
5And J
6Or the J among the formula VII-6
3, J
4, J
5, J
6And J
7In at least two be not-H or zero;
4) work as G
2, G
3Or G
4During for O or S, J
3, J
4Or J
5Be respectively zero;
5) work as G
3Or G
4During for N, J so
4Or J
5It respectively is not halogen or by hetero atom and G
3Or G
4The direct group of Xiang Lianing;
6) if two Y are-NR
6-, and R
1And R
1Do not link to each other and form cyclic amino phosphate ester, at least one R so
1For-(CR
12R
13)
n-C (O)-R
14
7) work as X
4For-alkylidene carbonylamino-or-alkylene amino carbonyl-time, G so
5, G
6And G
7Not C entirely;
8) work as X
4For-alkyleneoxyalkylene group-, and G
5, G
6And G
7When being C, J
4And J
6All do not replaced by the amine of acidylate;
9) work as R
55During for the phenyl that replaces, J
4, J
5And J
6Be not purine radicals, purine radicals alkylidene, assorted (the deaza)-purine radicals of denitrification or the assorted purine radicals alkylidene of denitrification;
10) have only as another YR
1For-NR
18-C (R
12R
13)
n-C (O)-R
14The time, R
1Just be selected from low alkyl group;
11) work as R
55Be the phenyl that replaces, and X
4During for ethynylene, J
4Or J
6It is not heterocyclic radical;
12) work as X
4During for ethynylene, G so
5Or G
7Can not be N.
107. the Pharmaceutical composition of claim 40, wherein said FBP enzyme inhibitor is
Chemical compound J.
108. the method for claim 46 or 99 wherein gives in the space described component (a) and described component (b) in about 1 hour.
109. the method for claim 108 wherein gives in the space described component (a) and described component (b) in about 10 minutes.
110. the method for claim 46 or 99 wherein at first gives a kind of in described component (a) and the described component (b), gives the another kind in described component (a) and the described component (b) then after 1-12 hour.
111. the method for claim 46 or 99, wherein said mammal are the fragile type diabetics.
112. the method for claim 46 or 99, wherein said mammal has NIDDM.
113. the method for claim 46 or 99, wherein said mammal has IDDM.
114. the Pharmaceutical composition of claim 9, wherein said glucagon-like-peptide-1 (GLP-1) receptor stimulating agent is NN-2211 or exendin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21653100P | 2000-07-06 | 2000-07-06 | |
| US60/216,531 | 2000-07-06 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200810098112XA Division CN101301294A (en) | 2000-07-06 | 2001-07-05 | Combinated inhibitors of FBP-ase and antidiabetic agents for diabetes treatment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1599612A true CN1599612A (en) | 2005-03-23 |
| CN100396283C CN100396283C (en) | 2008-06-25 |
Family
ID=22807416
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200810098112XA Pending CN101301294A (en) | 2000-07-06 | 2001-07-05 | Combinated inhibitors of FBP-ase and antidiabetic agents for diabetes treatment |
| CNB018149243A Expired - Fee Related CN100396283C (en) | 2000-07-06 | 2001-07-05 | Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200810098112XA Pending CN101301294A (en) | 2000-07-06 | 2001-07-05 | Combinated inhibitors of FBP-ase and antidiabetic agents for diabetes treatment |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1372660A2 (en) |
| JP (1) | JP2004508297A (en) |
| KR (1) | KR100854851B1 (en) |
| CN (2) | CN101301294A (en) |
| AU (2) | AU2001273271B2 (en) |
| BR (1) | BR0112212A (en) |
| CA (1) | CA2412142A1 (en) |
| CZ (1) | CZ20035A3 (en) |
| HU (1) | HUP0301830A3 (en) |
| IL (2) | IL153513A0 (en) |
| MX (1) | MXPA02012713A (en) |
| NO (1) | NO20030034L (en) |
| NZ (1) | NZ523227A (en) |
| PL (1) | PL365779A1 (en) |
| RU (1) | RU2328308C2 (en) |
| SK (1) | SK62003A3 (en) |
| WO (1) | WO2002003978A2 (en) |
| ZA (1) | ZA200300044B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114907285A (en) * | 2021-02-10 | 2022-08-16 | 华中师范大学 | Acylated saccharin compound, preparation method and application thereof, and hypoglycemic drug |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039344A1 (en) | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
| AU761267C (en) | 1998-09-09 | 2007-08-09 | Metabasis Therapeutics, Inc. | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase |
| ATE350385T1 (en) | 2000-03-08 | 2007-01-15 | Metabasis Therapeutics Inc | NEW ARYL FRUCTOSE-1,6-BISPHOSPHATASE INHIBITORS |
| DE60230818D1 (en) | 2001-09-24 | 2009-02-26 | Imp Innovations Ltd | PYY3-36 FOR REDUCING OR PREVENTING GREASE LUBRICITY |
| EP2329839B1 (en) | 2002-01-10 | 2015-09-16 | Imperial Innovations Limited | Modification of feeding behavior by GLP-1 and PYY |
| GB0300571D0 (en) | 2003-01-10 | 2003-02-12 | Imp College Innovations Ltd | Modification of feeding behaviour |
| PT1700856E (en) | 2003-12-26 | 2016-02-19 | Kyowa Hakko Kirin Co Ltd | Thiazole derivative |
| US20070225259A1 (en) * | 2004-08-18 | 2007-09-27 | Qun Dang | Novel Thiazole Inhibitors of Fructose 1,6-Bishosphatase |
| EP1857118A1 (en) * | 2004-12-13 | 2007-11-21 | Daiichi Sankyo Company, Limited | Medicinal composition for treating diabetes |
| TW200738245A (en) * | 2005-08-22 | 2007-10-16 | Sankyo Co | Pharmaceutical composition containing FBPase inhibitor |
| WO2007129522A1 (en) * | 2006-04-10 | 2007-11-15 | Daiichi Sankyo Company, Limited | Preparation produced by dry process |
| US20100222304A1 (en) | 2006-11-02 | 2010-09-02 | Lillian W Chiang | Methods of Treating Neuropathic Pain by Modulation of Glycogenolysis or Glycolysis |
| TWI428346B (en) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | Novel compounds and their effects on feeding behaviour |
| CN103665043B (en) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | A kind of tenofovir prodrug and its application in medicine |
| UY35065A (en) * | 2012-10-08 | 2014-05-30 | Lg Life Sciences Ltd | COMBINED DRUG THAT INCLUDES GEMIGLIPTINE AND METFORMIN AND METHOD FOR PREPARATION |
| CN104788350A (en) * | 2014-01-22 | 2015-07-22 | 天津大学 | Method for acquiring medicinally-advantageous crystal form of tolbutamide through rapid cooling and crystallization |
| CN106831437B (en) * | 2016-02-03 | 2019-06-21 | 华中师范大学 | Ester type compound and its preparation method and application containing nitroethenyl group |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2008325A1 (en) * | 1989-01-24 | 1990-07-24 | Harry E. Gruber | Method and compounds for aica riboside delivery and for lowering blood glucose |
| WO1998039344A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
| US6110903A (en) * | 1997-03-07 | 2000-08-29 | Sankyo Company Ltd. | Benzimidazole inhibitors of fructose 1,6-bisphosphatase |
| AU6691798A (en) * | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
| AU3087099A (en) * | 1998-03-16 | 1999-10-11 | Ontogen Corporation | Piperazines as inhibitors of fructose-1,6-bisphosphatase (FBPase) |
| AU761267C (en) * | 1998-09-09 | 2007-08-09 | Metabasis Therapeutics, Inc. | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase |
| DE69926400T2 (en) * | 1998-12-24 | 2006-05-24 | Metabasis Therapeutics Inc., San Diego | COMPOSITION CONTAINING INSULIN-SENSITIVE ACTIVE SUBSTANCES AND INHIBITORS OF FRUKTOSE-1,6-BISPHOSPHATASE (FBPASE) FOR THE TREATMENT OF DIABETES |
| DK1248604T4 (en) * | 2000-01-21 | 2012-05-21 | Novartis Ag | Combinations containing dipeptidyl peptidase IV inhibitors and antidiabetic agents |
| GB0015627D0 (en) * | 2000-06-26 | 2000-08-16 | Rademacher Group Limited | Phosphoglycan messengers and their medical uses |
-
2001
- 2001-07-05 CN CNA200810098112XA patent/CN101301294A/en active Pending
- 2001-07-05 AU AU2001273271A patent/AU2001273271B2/en not_active Ceased
- 2001-07-05 NZ NZ523227A patent/NZ523227A/en not_active IP Right Cessation
- 2001-07-05 AU AU7327101A patent/AU7327101A/en active Pending
- 2001-07-05 CN CNB018149243A patent/CN100396283C/en not_active Expired - Fee Related
- 2001-07-05 IL IL15351301A patent/IL153513A0/en unknown
- 2001-07-05 RU RU2003103436/15A patent/RU2328308C2/en not_active IP Right Cessation
- 2001-07-05 WO PCT/US2001/021557 patent/WO2002003978A2/en active IP Right Grant
- 2001-07-05 HU HU0301830A patent/HUP0301830A3/en unknown
- 2001-07-05 MX MXPA02012713A patent/MXPA02012713A/en not_active Application Discontinuation
- 2001-07-05 EP EP01952530A patent/EP1372660A2/en not_active Withdrawn
- 2001-07-05 SK SK6-2003A patent/SK62003A3/en unknown
- 2001-07-05 JP JP2002508433A patent/JP2004508297A/en active Pending
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- 2001-07-05 CZ CZ20035A patent/CZ20035A3/en unknown
- 2001-07-05 CA CA002412142A patent/CA2412142A1/en not_active Abandoned
-
2002
- 2002-12-18 IL IL153513A patent/IL153513A/en not_active IP Right Cessation
-
2003
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114907285A (en) * | 2021-02-10 | 2022-08-16 | 华中师范大学 | Acylated saccharin compound, preparation method and application thereof, and hypoglycemic drug |
| CN114907285B (en) * | 2021-02-10 | 2023-09-22 | 华中师范大学 | Acylated saccharin compound, preparation method and application thereof, and hypoglycemic drug |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2328308C2 (en) | 2008-07-10 |
| SK62003A3 (en) | 2003-09-11 |
| KR20030031952A (en) | 2003-04-23 |
| EP1372660A2 (en) | 2004-01-02 |
| NO20030034D0 (en) | 2003-01-03 |
| IL153513A0 (en) | 2003-07-06 |
| MXPA02012713A (en) | 2004-09-10 |
| WO2002003978A3 (en) | 2003-10-16 |
| AU2001273271B2 (en) | 2006-01-05 |
| WO2002003978A2 (en) | 2002-01-17 |
| BR0112212A (en) | 2003-12-30 |
| AU7327101A (en) | 2002-01-21 |
| CN100396283C (en) | 2008-06-25 |
| KR100854851B1 (en) | 2008-08-27 |
| CZ20035A3 (en) | 2003-05-14 |
| CN101301294A (en) | 2008-11-12 |
| IL153513A (en) | 2014-07-31 |
| HUP0301830A3 (en) | 2007-10-29 |
| HUP0301830A2 (en) | 2003-11-28 |
| CA2412142A1 (en) | 2002-01-17 |
| JP2004508297A (en) | 2004-03-18 |
| ZA200300044B (en) | 2004-05-06 |
| NO20030034L (en) | 2003-03-05 |
| NZ523227A (en) | 2005-04-29 |
| PL365779A1 (en) | 2005-01-10 |
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Owner name: METABASIS THERAPEUTICS INC. Free format text: FORMER OWNER: METABASIS THERAPEUTICS INC.; FIRST SANKYO CO., LTD. Effective date: 20080704 Owner name: METABASIS THERAPEUTICS INC.; FIRST SANKYO CO., LT Free format text: FORMER OWNER: METABASIS THERAPEUTICS INC.; SANKYO CO., LTD. Effective date: 20080704 |
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Effective date of registration: 20080704 Address after: California, USA Patentee after: METABASIS THERAPEUTICS, Inc. Address before: California, USA Co-patentee before: DAIICHI SANKYO Co.,Ltd. Patentee before: METABASIS THERAPEUTICS, Inc. Effective date of registration: 20080704 Address after: California, USA Co-patentee after: DAIICHI SANKYO Co.,Ltd. Patentee after: METABASIS THERAPEUTICS, Inc. Address before: California, USA Co-patentee before: Sankyo Co.,Ltd. Patentee before: METABASIS THERAPEUTICS, Inc. |
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