CN1029479C - Benzoxazing derivatives and pharmaceutical compositions containing same - Google Patents

Benzoxazing derivatives and pharmaceutical compositions containing same Download PDF

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CN1029479C
CN1029479C CN 90109074 CN90109074A CN1029479C CN 1029479 C CN1029479 C CN 1029479C CN 90109074 CN90109074 CN 90109074 CN 90109074 A CN90109074 A CN 90109074A CN 1029479 C CN1029479 C CN 1029479C
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dimethyl
dihydro
benzoxazine
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group
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CN1051910A (en
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松本祐三
都筑竜二
松久彰
高山和久
内田渡
浅野雅晴
余田撤
柳沢勳
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

The invention relates to a novel benzo and __zine derivate of a molecular formula (I): and the pharmaceutical acceptable salt thereof, which can be used as K+ channel activator, as described in the description.

Description

Benzoxazing derivatives and pharmaceutical compositions containing same
The present invention relates to useful as drug, particularly they and the acceptable salt of pharmacology of the novel benzo-oxazine derivative of potassium-channel activator, the intermediate that contains their pharmaceutical composition and be used to prepare these derivatives and salt.
Benzo-oxazine derivative of the present invention and their salt are the novel compounds of a class, and they can activate K +Passage, thereby demonstrate antitetanic activity, the i.e. activity of smooth muscle loosening.
As smooth muscle relaxant, those (medicines) of acting on contraction process and relaxation are known.The medicine that the front is one type is various irritating chemical transmitter receptor-blocking agent and calcium antagonist, and then one type medicine then is the chemical transmitter receptor agonist and the nitrate of inhibition.
Recently, a kind of by activating K +Passage comes the medicine of relaxing smooth muscle to be reported, and as a kind of new smooth muscle relaxant.
Opposite with common irritated tissue, in coarse motion arteries and veins (particularly coronary artery and arteriae cerebri) and airway unstriated muscle, K +The effect of passage be these are organized can be excited to unnecessary degree (keeping the size of cavity) owing to too early and excessive activation, still, if K +The physiological function of passage is weakened, and electrostimulation produces sharp in common irritated tissue, so that can induce violent local contraction, i.e. spasm.Knew already that the spasm of coronary artery and arteriae cerebri and bronchial smooth muscle can give rise to diseases, for example stenocardia, cerebrovascular disorder and asthma.Therefore, can be sure of K +The passage activator should be useful for preventing and treating these diseases.
Known have an activation K +In the active compound of passage, 4-(2-OXo-1-pyrrolidine base)-2H-benzo [b] pyrans-3-alcohol derivate (discloses 2H-1,4-benzo-oxazine derivative as EP76075.
As furtheing investigate to find effectively to activate K +The result of the compound of passage, present inventor find that the novel benzo-oxazine derivative of the following logical formula I that provides and their salt are effective K +The passage activator, and the compound of logical formula II as follows and (III) can be used as the intermediate of said benzoxazine compound of preparation and their salt.
The invention provides the benzo-oxazine derivative of logical formula I:
Figure 901090743_IMG6
With the acceptable salt of their pharmacology.In above-mentioned molecular formula:
R 1, R 2, R 3And R 4Can be identical or different, they represent hydrogen or halogen atom or low alkyl group separately respectively, the low alkyl group, lower alkoxy, cyano group, nitro, amino, lower alkane acyl amino, low alkyl group sulfuryl amino, low alkyl group alkylsulfonyl or the aryl sulfonyl that are replaced by halogen;
R 5And R 6Can be identical or different, they represent hydrogen atom or low alkyl group separately;
R 7Representation hydroxy-low alkyl group, the carbon ring group that is selectively replaced, the heterocyclic group that is selectively replaced, molecular formula are-A 1-R 8Group (A wherein 1Represent low-grade alkylidene or hydroxyl-low-grade alkylidene, R 8The aryl that representative is selectively replaced, the heterocyclic group that is selectively replaced, or rudimentary alkenyloxy are worked as A 1When representing unsubstituted low-grade alkylidene, R 8Do not represent phenyl), molecular formula is Group (A wherein 2Represent low-grade alkylidene, R 9The heterocyclic group that represent low alkyl group, the aryl that is selectively replaced, is selectively replaced, or hydroxyl, lower alkoxy, amino, one or two elementary alkyl amido, hydroxy lower alkyl amino, aryl alkyl amino or arylamino), molecular formula is
Figure 901090743_IMG8
Figure 901090743_IMG9
Group (A wherein 3Represent singly-bound, the low-grade alkylidene that is selectively replaced, or rudimentary alkylene group, R 10The heterocyclic group that representative is selectively replaced, or carboxyl, lower alkylcarbonyl, formamyl, one or two elementary alkyl amido carbonyl, amino or one or two lower alkyl aminos) or molecular formula be (the A wherein of group 4The low-grade alkylidene that representative is selectively replaced by hydroxyl or low alkyl group, R 11And R 12Can be identical or different, they represent hydrogen atom or low alkyl group separately).
From the viewpoint of chemical structure, compound of the present invention (I) is characterised in that a kind of specific heterocyclic, promptly 3, and 4-dihydro-2H-1,4-benzoxazine ring and a certain location is promptly gone up by one by R for 4 of ring 7The specific substituting group of representative replaces.
This field and known and 3,4-dihydro-2H-1, what the 4-benzo-oxazine derivative was similar is; 4-acyl group-3 for example, 4-dihydro-2H-1,4-benzo-oxazine derivative [people such as C.B.Chapleo; J.Med, Chem., 32(7); 1627-30(1989)] and 4-benzyl-3,4-dihydro-2H-1, the 4-benzo-oxazine derivative [J P1034982(CA111(11): 97257K); people such as C.B.Chapleo, J.Med, Chem.; 32(7), 1627-30(1989)].But, never reported this class compound known and had activation K +The activity of passage.
Useful as intermediates provided by the present invention is the compound of the following logical formula II that provides or (III):
Figure 901090743_IMG11
In formula II, R 5And R 6As defined above, R 1 ', R 2 ', R 3 'And R 4 'Can be identical or different, they represent hydrogen atom, halogen atom, cyano group or nitro separately respectively; R 7aThe carbon ring group that representative is selectively replaced by the oxygen base, or molecular formula is Group (A wherein 2As defined above, R 9aRepresent low alkyl group, aryl unsubstituted or that replaced by halogen or nitro or by at least a nitrogenous heterocyclic group (the N-oxide form that comprises them) that selectively replaces of oxygen base and low alkyl group, hydroxyl, lower alkoxy, amino, one or two elementary alkyl amido, hydroxy lower alkyl amino, aryl alkyl amino or arylamino).
Figure 901090743_IMG13
In formula III, R 1 ', R 2 ', R 3 ', R 4 ', R 5And R 6As defined above, R 13Represent nitroso-group or amino.
Intermediate of the present invention (II) is the novel compound of a class, never puts down in writing in the literature, and can be used for preparing those compounds of logical formula I, comprises their salt, wherein radicals R 7aWith radicals R 7Identical.Intermediate (III) can be used for preparing the nitrogen-atoms by wherein, and nitrogenous heterocyclic group is (as R 7) be connected to those compounds of the logical formula I on 4 nitrogen-atoms of benzo-oxazine derivative.
The purpose of this invention is to provide and can be used as K +Above-claimed cpd of passage activator (I) and the acceptable salt of their pharmacology.
Another object of the present invention provides and comprises any above-claimed cpd (I) and their the acceptable salt of pharmacology and the pharmacology acceptable carrier pharmaceutical composition of fusion mutually.
A further object of the present invention provides the compound (II) and the compound (III) (salt that comprises them) of the intermediate that can be used as preparation above-claimed cpd (I) and their salt.
Compound of the present invention is as described in more detail below.
In the given here definition that relates to the general formula shown in the front and back, except that indicating in addition, term " lower " means comprises the corresponding group of the carbochain of the straight or branched type that contains 1-6 carbon atom.
Therefore, " low alkyl group " comprises, methyl for example, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-first butyl, 2-first butyl, 1, the 2-dimethyl propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl and 1-ethyl-2-methyl-propyl.
" lower alkoxy " comprises, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen, 2-methyl butoxy, 1,2-dimethyl propoxy-, 1-ethyl propoxy-and oxyethyl group.
" rudimentary alkenyloxy " contains 2-6 carbon atom, can be straight chain or side chain, more particularly, they comprise, vinyloxy group for example, allyloxy, the 1-propenyloxy group, different propenyloxy group, 1-butylene oxygen base, 2-butylene oxygen base, the 3-butenyloxy, 2-methyl isophthalic acid-propenyloxy group, the 2-methyl allyloxy, 1-methyl isophthalic acid-propenyloxy group, the 1-methyl allyloxy, 1,1-dimethyl vinyloxy group, 1-amylene oxygen base, 2-amylene oxygen base, 3-amylene oxygen base, 4-amylene oxygen base, 3-methyl-1-butene oxygen base, 1-hexene oxygen base, 2-hexene oxygen base, 3-hexene oxygen base, 4-hexene oxygen base and 5-hexene oxygen base.
" elementary alkoxy carbonyl " is that the ester by carboxyl and straight or branched lower alcohol forms reaction and the group that obtains, it comprises, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, isopentyloxy carbonyl, neopentyl oxygen carbonyl, tert-pentyloxy carbonyl and hexyloxy carbonyl.
" lower alkane acyl group " comprises, formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl and caproyl.
" one or two elementary alkyl amido " means by the deutero-group with one or two hydrogen atom in one or more above-mentioned " low alkyl group " substituted-amino, specifically, it comprises that wherein moieties is an alkylamino of straight or branched low alkyl group, for example methylamino-, ethylamino, third amino, isopropylamino, fourth amino, isobutyl amino, penta amino, isoamylamino and oneself amino; Wherein two moieties are identical, and each symmetrical dialkyl amido of straight or branched low alkyl group naturally, for example dimethylamino, diethylin, dipropyl amino, diisopropylaminoethyl, dibutylamino, diamyl is amino and two oneself is amino; Wherein moieties is different mutually, and each the asymmetric dialkyl amido of straight or branched low alkyl group, for example ethylmethylamino, methyl-propyl amino, ethyl propyl amino, butyl methyl amino, butyl ethyl amino and butyl propyl group amino naturally.
" one or two elementary alkyl amido carbonyl " is attached in above-mentioned " one or two elementary alkyl amido " and the group that obtains by carbonyl, more particularly, it comprises, for example the methylamino carbonyl, the ethylamino carbonyl, the propyl group aminocarboxyl, the sec.-propyl aminocarboxyl, the butyl aminocarboxyl, the isobutylamino carbonyl, the sec-butyl aminocarboxyl, tertiary butyl aminocarboxyl, the amyl group aminocarboxyl, the isopentyl aminocarboxyl, the hexyl aminocarboxyl, the isohexyl aminocarboxyl, the dimethylamino carbonyl, the diethylamino carbonyl, the dipropyl aminocarboxyl, the diisopropylaminoethyl carbonyl, the dibutylamino carbonyl, the diamyl aminocarboxyl, the dihexyl aminocarboxyl, the methylethyl aminocarboxyl, the methyl-propyl aminocarboxyl, the ethyl propyl aminocarboxyl, the methyl butyl aminocarboxyl, ethyl-butyl aminocarboxyl and propyl group butyl aminocarboxyl.
" lower alkane acyl amino " can be straight chain or side chain, it comprises, for example formamido group, kharophen, propionamido, butyrylamino, isobutyryl amino, valeryl amino, isovaleryl amino, pivalyl amino and hexanamido.
" low alkyl group alkylsulfonyl " comprise, for example methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl, butyl alkylsulfonyl, isobutyl-alkylsulfonyl, sec-butyl alkylsulfonyl, tertiary butyl alkylsulfonyl, amyl group alkylsulfonyl, isopentyl alkylsulfonyl, sec.-amyl sec-pentyl secondary amyl alkylsulfonyl, neo-pentyl alkylsulfonyl, tert-pentyl alkylsulfonyl, hexyl alkylsulfonyl and isohexyl alkylsulfonyl.
" low alkyl group sulfonamido " is by a group that hydrogen atom obtains with above-mentioned " low alkyl group alkylsulfonyl " substituted-amino; more particularly; it comprises the low alkyl group sulfonamido of straight or branched, for example sulfonyloxy methyl amino, ethyl sulfonamido, sulfonyl propyl amino, sec.-propyl sulfonamido, butyl sulfonamido, isobutyl-sulfonamido, sec-butyl sulfonamido, tertiary butyl sulfonamido, amyl group sulfonamido and hexyl sulfonamido.
" low-grade alkylidene " is preferably and contains 1-6 carbon atom, it comprises, methylene radical for example, ethylidene, the methyl methylene radical, trimethylene, 2-methyl ethylidene, 1-methyl ethylidene, the dimethylated methylene base, tetramethylene, the 1-methyl trimethylene, the 2-methyl trimethylene, the 3-methyl trimethylene, 1-ethyl ethylidene, 2-ethyl ethylidene, 2,2-dimethyl ethylidene, 1,1-dimethyl ethylidene, the ethyl-methyl methylene radical, pentamethylene, 1-methyl tetramethylene, 2-methyl tetramethylene, 3-methyl tetramethylene, 4-methylene radical tetramethylene, 1,1-dimethyl trimethylene, hexa-methylene, 1-methyl pentamethylene, 4-methyl pentamethylene and 1,1-dimethyl tetramethylene.
" rudimentary alkylene group " is preferably and contains 2-6 carbon atom, it comprises, for example vinylidene, propenylidene, 2-propenylidene, 1-methyl vinylidene, 2-methyl vinylidene, crotonylidene, 2-crotonylidene, 3-crotonylidene, 1-methyl propenylidene, 1-methyl-2-propenylidene, inferior pentenyl and 1-methyl isophthalic acid-crotonylidene.
" halogen atom " is not limited to any special kind, and it comprises fluorine, chlorine, bromine and iodine.
One or more hydrogen atom in above-mentioned " low alkyl group " obtains by replacing with one or more above-mentioned " halogen " atom " low alkyl group that is replaced by halogen ".When halogen atom is fluorine, then such as methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3,3-trifluoro propyl and 2-fluoro-1-methylethyl can be used as typical example.
" hydroxy lower alkyl " means by replace a group that hydrogen atom obtains in above-mentioned " low alkyl group " with hydroxyl, more particularly, it comprises, methylol for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyl-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxyl 2-methyl-propyl, 5-hydroxyl amyl group and 6-hydroxyl hexyl.
" hydroxyl-low-grade alkylidene " comprise, for example hydroxyl methylene radical, 1-hydroxy ethylene, 2-hydroxy ethylene, hydroxymethyl methylene radical, 1-hydroxyl trimethylene, 2-hydroxyl trimethylene, 3-hydroxyl trimethylene, 2-hydroxyl tetramethylene, 2-hydroxyl pentamethylene and 2-hydroxyl hexa-methylene.
" low-grade alkylidene that is selectively replaced by hydroxyl or lower alkoxy " comprises such as those above-mentioned low-grade alkylidenes, those above-mentioned hydroxyl-low-grade alkylidenes and those above-mentioned lower alkoxy-low-grade alkylidenes, when methoxyl group during as the substituent example of lower alkoxy, lower alkoxy-low-grade alkylidene comprises, for example the methoxyl group methylene radical, 1-methoxyl group ethylidene, 2-methoxyl group ethylidene, the methoxy methyl methylene, 1-methoxyl group trimethylene, 2-methoxyl group trimethylene, 3-methoxyl group trimethylene, 1-methoxyl group tetramethylene, 4-methoxyl group tetramethylene, 1-methoxyl group pentamethylene, 5-methoxyl group pentamethylene, 1-methoxyl group hexa-methylene and 6-methoxyl group hexa-methylene.
" hydroxy lower alkyl amino " means by with a group that hydrogen atom obtains in above-mentioned " hydroxy lower alkyl " substituted-amino, more particularly, it comprises, for example methylol amino, 2-hydroxyethylamino, 3-hydroxypropyl amino, 2-hydroxyl-1-methylethyl amino, 4-hydroxyl butyl amino, 5-hydroxyl amyl group amino and 6-hydroxyl hexyl amino.
When " low-grade alkylidene that is selectively replaced " when being substituted, be preferably with amino or one or two lower alkyl aminos as substituting group, mentioned above the exemplary of one or two rudimentary amino.
" carbon ring group " means carbon ring group, cycloalkyl or the cycloalkenyl group of non-aromatics, it itself not aromatic carbocyclic, but preferably, can condense with phenyl ring, more particularly, it comprises, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl and indenyl.
Have one or more substituting group in the carbon ring group, be preferably the substituting group that is selected from aforesaid those low alkyl groups, hydroxyl, oxygen base, aforesaid those elementary alkoxy carbonyls, oxyimino and lower alkoxy imino-(for example methoxyimino, ethoxy imino, propoxy-imino-, isopropoxy imino-, butoxy imino-, pentyloxy imino-and hexyloxy imino-).
" aryl " means aromatic hydrocarbon group, and it comprises as the phenyl of preferable example and naphthyl, aryl can have one or more substituting group, is selected from aforesaid those halogen atoms, nitro etc. separately.
" aralkyl " means by replacing the group that at least one hydrogen atom in above-mentioned " low alkyl group " obtains with above-mentioned " aryl ".More particularly, when with phenyl during as the example of said aryl, said aralkyl comprises, for example benzyl, styroyl, 3-hydrocinnamyl, 2-hydrocinnamyl, 2-phenyl-1-methyl-propyl, 4-phenyl butyl, 3-phenyl butyl, 3-phenyl-2-methyl-propyl, 5-phenylpentyl, 6-phenylpentyl, diphenyl-methyl and trityl.
Can have one or more substituting group in the aralkyl, for example at the aforesaid one or more halogen atoms on the aromatic nucleus and/or an one or more nitro and/or a hydroxyl in alkyl chain.
Aryl moiety in " arylamino " and " aryl sulfonyl " comprises phenyl and the naphthyl as preferred example, as under the situation of above-mentioned " aryl ".Thereby the preferable example of arylamino and aryl sulfonyl is phenyl amino, 1-naphthyl amino, 2-naphthyl amino, phenyl sulfonyl, 1-naphthyl alkylsulfonyl and 2-naphthyl alkylsulfonyl.
" aryl alkyl amino " is by with a group that hydrogen atom obtains in above-mentioned " aralkyl " substituted-amino.When benzyl during as the example of aralkyl, benzylamino can be used as typical example.
" heterocyclic group " comprises, can with the phenyl ring heterocyclic group of condensed 5 or 6 atoms optionally, furyl for example, thienyl, pyrryl, pyrrolidyl, pyranyl, pyridyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, imidazolyl, imidazolinyl, pyrazolyl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, benzofuryl, isobenzofuran-base, benzothienyl, indyl, pseudoindoyl, benzopyranyl, quinolyl, isoquinolyl, 2 base and quinoxalinyl.
Wherein preferably those can be converted into the nitrogenous monocycle of N-oxide form or the heteroaromatic group of dicyclo, for example pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, different azoles quinoline base, 2 base and quinoxalinyl; Those can connect by nitrogen-atoms wherein, and can be by monocycle or the heterocyclic group of dicyclo, for example pyrrolidyl, piperidyl, indyl and the pseudoindoyl of an oxygen base replacement with the nitrogenous non-aromatics of formation lactam nucleus; Such as the nitrogen heterocyclic ring of benzimidazolyl-with such as the oxygen heterocyclic ring of furyl, oxo-cyclopentane base (oxolanyl) and pyranyl.
These heterocyclic groups can have and are selected from halogen atom, low alkyl group, hydroxyl, lower alkoxy, oxygen base, carbamyl, one or the one or more substituting group of two elementary alkyl amido carbonyl etc. separately.Nitrogenous hetero-aromatic ring group also can have the oxygen as the substituent formation N-oxide compound on it.These are described above substituent representative instance.
Especially good in the compound of the present invention (I) is R wherein 2And R 3One of be nitro or cyano group or halogen atom, another is those compounds of hydrogen atom or nitro; R wherein 7Be selectively to be the N-oxide form and/or by the nitrogenous heterogeneous ring compound that one or more low alkyl group replaced, for example R 7The nitrogenous heterocyclic group that replaces for 1-oxygen-2-pyridyl or 6-methyl isophthalic acid-oxygen-2-pyridyl, by oxygen, for example 2-oxygen-1-pyrrolidyl, by the carbon ring group that oxygen replaces, for example 2-oxygen basic ring amyl group or 5-oxygen-1-cyclopentenes-1-base, molecular formula are-A 1-R 8Group (A 1And R 8As defined above), for example (1-oxygen-2-pyridyl) methyl or molecular formula are
Figure 901090743_IMG14
(A 2And R 9Group as defined above), for example acetylmethyl, phenacyl, carboxamide methyl, N-methylamino carbonyl methyl or N, N-dimethylamino carbonyl methyl.
Compound of the present invention (I) in fact can generate salt with acid.According to one or more substituent types, they also can generate salt with alkali.This class salt comprises and mineral acid (hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid and phosphoric acid) acid salt, with with organic acid (formic acid for example, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, oxysuccinic acid, tartrate, methylsulfonic acid and ethyl sulfonic acid) acid generate additive salt, and with the acid salt of acidic amino acid (for example aspartic acid and L-glutamic acid), with mineral alkali (sodium for example, potassium, magnesium, calcium and aluminium) additive salt, with organic bases (methylamine for example, ethamine and thanomin) additive salt, additive salt and ammonium salt with basic aminoacids (for example Methionin and ornithine).
According to one or more substituting groups, compound of the present invention can have two keys and/or one or more unsymmetrical carbon.Therefore, compound of the present invention is included in the various resulting isomer in its scope, geometrical isomer for example, and tautomer and optical isomer, they can be isolating separately isomeric forms or be form of mixtures.
Compound of the present invention (I) can be by utilizing skeleton structure and/or various substituent characteristic, adopts various synthetic methods and must make.Adoptable preparation method's representative instance is following to be provided.
Figure 901090743_IMG15
Method 2
Figure 901090743_IMG16
Method 3
Method 4
Figure 901090743_IMG18
Figure 901090743_IMG19
In following formula, R 1, R 2, R 3, R 4, R 1 ', R 2 ', R 3 ', R 4 ', R 5, R 6, R 7, A 1, R 8, A 2, R 9, A 3, R 10, A 4, R 11And R 12All as mentioned above, other symbol definition is as follows:
R 7CThat representative can be connected by the carbon atom (non-heteroatoms) that forms ring and selectively have one or more substituent heterocyclic groups, molecular formula and be-A 1C-R 8CGroup (A wherein 1CBe low-grade alkylidene, R 8CThe aryl that is selectively replaced, the heterocyclic group that is selectively replaced, or rudimentary alkenyloxy are worked as A 1CWhen representing unsubstituted low-grade alkylidene, R 8Do not represent phenyl), molecular formula is
Figure 901090743_IMG20
Group (A wherein 2And R 9As mentioned above), molecular formula is Group (R wherein 10As defined above, A 3CBe singly-bound or low-grade alkylidene or rudimentary alkylene group) or molecular formula be
Figure 901090743_IMG22
Group (R wherein 14Be hydrogen atom or low alkyl group or elementary alkoxy carbonyl, R 15And R 16Can be identical or different, they are respectively the low-grade alkylidene that low alkyl group or combination representative form ring separately, adjacent phenylene or carbonyl, Z 1Be carbonyl, methylene radical or methanol groups;
Y 1Represent halogen atom or alkyl or aryl sulfonyloxy or ester residue;
R 7a-1Represent molecular formula to be
Figure 901090743_IMG23
(A 2And R 9Group as mentioned above) or molecular formula are
Figure 901090743_IMG24
Group (R 14, R 15And R 16As mentioned above);
R 5Representative is by A 2Or molecular formula is
Figure 901090743_IMG25
Group (R 14And R 15Represented group as defined above);
R 17Be by R 9Or R 16(all as defined above) represented group;
R 18Propyl group that representative is replaced by halogen or the butyl that is replaced by halogen;
A 6Represent trimethylene or tetramethylene;
A 7Represent low-grade alkylidene or molecular formula to be (A 3Group as defined above).
R 19And R 20Can be identical or different, and be respectively hydrogen atom or low alkyl group separately, or combine with contiguous nitrogen-atoms and form and can have one or more substituent heterocyclic groups;
A 8Represent singly-bound, by A 1Or A 2Or molecular formula is (A 3The group that group as defined above) is represented;
The nitrogenous monocycle that representative is selectively replaced or the heterocyclic group of dicyclo;
Y 2Represent halogen atom, or work as and Y 3When combining, represent carbonylic oxygen atom;
Y 3Represent halogen atom, or work as and Y 2When combining, represent carbonylic oxygen atom or work as Y 4When being halogen atom, it is a hydrogen atom; With
Y 4Represent hydrogen atom (to work as Y 2And Y 3Be halogen atom or in conjunction with and when representing carbonylic oxygen atom) or represent halogen atom (to work as Y 2Be halogen atom, Y 3When being hydrogen atom).
By Y 1, Y 2, Y 3Or Y 4Representative or at R 18In halogen atom be preferably iodine, bromine or chlorine atom, and by Y 1The alkyl or aryl sulfonyloxy of representative is preferably mesyloxy, phenylsulfonyloxy or tosyloxy (particularly tolysulfonyl oxygen base).By Y 1The ester residue of representative is, lower alkoxy (for example methoxy or ethoxy) for example, or have active ester residue of N-hydroxybenzotriazole, N-hydroxy-succinamide etc.
Below, with the method above describing in further detail.
Method 1
In the compound of the present invention; the compound of general formula (I c) can synthesize by described N-alkylating or the effect of N-acylations, and it comprises having the benzo-oxazine derivative of molecule formula IV of nomadic nitrogen atom and the ester reaction of halogenide, sulfonate or molecular formula (V).
This reaction is carried out in to the organic solvent of reactionlessness usually, for example, carry out in dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, ether, diox, tetrahydrofuran (THF), methylene dichloride, ethylene dichloride, chloroform, benzene, toluene or the dimethylbenzene at N.Also can carry out although be reflected at when lacking solvent.
When reacting, be to use alkali preferably, for example Trimethylamine 99, triethylamine, sodium hydride, potassium hydride KH, alkali metal alcoholates (for example uncle's fourth oxygen potassium) or salt of wormwood, or copper catalyst, for example copper, cupric iodide or copper sulfate.
Temperature of reaction is not crucial, but can select suitably according to reactant.Thereby this reaction can at room temperature or under heating be carried out under cooling.
Method 2
Those benzo-oxazine derivatives with molecular formula (I d) of hydroxyalkyl can prepare by described N-alkylating or the effect of N-acylations; it comprises that (resulting molecular formula (II is reduced in the ester reaction of V-a) then for benzo-oxazine derivative and halogenide, sulfonate or molecular formula with the 3-oxygen of molecule formula VI a-1) the substituted carbonylic alkyl benzo-oxazine derivative of 3-oxo-4-.
(I a) prepares to have the compound that those compounds of the molecular formula (I e) of carbonyl can obtain with aforesaid method by oxidation.
N-alkylation in the first step or N-acylations can be carried out with the method identical with method 1.
The second step reduction is preferably by being added to reductive agent with compound (II a-1) or the reaction mixture that obtains from the first step, as borane, be preferably in borane-tetrahydrofuran (THF) mixture (it can have been bought), heating or heat under refluxing reaches then.
The 3rd step oxidation preferably adopts Swern oxidation or Jones method for oxidation to carry out, and also can adopt although methanol-based can be oxidized to any other method of carbonyl.As under the situation of Swern oxidation, be reflected at carrying out in the organic solvent of reactionlessness, for example in methylene dichloride, carry out, be preferably under atmosphere of inert gases, carry out under the condition of companion's cooling (-60 ℃ approximately).Under this condition, earlier it makes from oxalyl chloride and dimethyl sulfoxide (DMSO) with active DMSO(), and then handle intermediate (I d) with triethylamine.
Method 3
In the compound of the present invention, those compounds with nitrogen-atoms and molecular formula (I f) of 4 lactan ring keies that combine of benzoxazine ring by lactam nucleus can prepare by corresponding halo butyrylamino or halo pentanamide based compound (X) are carried out cyclisation.
Cyclisation (ring form) be reflected at method 1 in carry out under the essentially identical condition of the alkylating condition of N-that adopted, adopt acyl halide.Alkali metal alcoholates preferably uses as alkali as uncle's fourth oxygen potassium.
Intermediate (X) can be by with compound (IV) nitrosification, reduces resulting nitroso compound (VII) and the carboxylic acid of resulting aminocompound (VIII) and molecular formula (IX) or its activity derivatives reaction prepared.
In order to carry out nitrosylation, with compound (IV) and nitrosation agent, Sodium Nitrite for example, nitrous acid or nitrous acid ester reaction are reflected at inert solvent, for example among alcohol (as methyl alcohol, ethanol, Virahol) or the acetate-water, under acidic conditions, companion's cooling is not higher than 20 ℃ with holding temperature, is preferably not to be higher than in 10 ℃ to carry out, after the heat that produces goes down, at room temperature carry out then.
Reduction is usually in the organic solvent to reactionlessness, for example in alcohols (as methyl alcohol, ethanol or Virahol), in the presence of alkali (for example sodium hydroxide), under cooling or room temperature, carry out, reaction will be adopted appropriate reductant, for example formamidine sulfinic acid or hydroborates (as two boranes) or sodium borohydride.In some cases, reduction can be carried out in the mode of catalytic hydrogenation, adopts Raney nickel, palladium-carbon, platinum black or platinum as catalyzer, or carries out in the mode of chemical reduction, adopts iron, tin or zinc and acid, and for example hydrochloric acid, sulfuric acid or acetic acid combine and carries out.
Amidation is carried out with customary way.As the reactive derivative of compound (IX), can be ester (for example methyl esters or ethyl ester), acylations thing (for example chloride of acid, acid bromide, acid azide), active ester (for example N-hydroxybenzotriazole ester or N-hydroxy-succinamide ester), symmetric anhydride and here by the mixed acid anhydride of alkyl carbonic acid, tosic acid, diphenyl phosphoryl chloride etc.When compound (IX) carries out amidation with free form, adopt a kind of condensing agent, dicyclohexyl carbodiimide for example, 1,1 '-carbonyl dimidazoles, diphenylphosphine acylazide or diethyl phosphinylidyne cyanogen.Be reflected in the organic solvent to reactionlessness, for example at alcohol (methyl alcohol, ethanol, Virahol), N, dinethylformamide, pyridine, tetrahydrofuran (THF) diox, ether, benzene, toluene, dimethylbenzene, methylene dichloride, ethylene dichloride, chloroform, in ethyl acetate or the acetonitrile, usually in room temperature or heat down (and for the certain activity derivative, reaction is then under cooling conditions), in alkali, for example organic bases is (as pyridine, picoline, lutidine, xylidine or N-methylmorpholine), mineral alkali is (as salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide or potassium hydroxide) exist down, adopt with compound (VIII) compound equimolar amount or excessive (IX) or its reactive derivative and carry out.
Method 4
In the compound of the present invention, the compound of molecular formula (I h) can be by preparing the carboxylic acid of molecular formula (I g) or the amine or its reactant salt (amidation) of its reactive derivative and molecular formula (IX).
Amidate action can with aforesaid method 3 in prepare under the identical condition of the amidated reaction conditions of intermediate (X), carry out in an identical manner.
When obtaining, this ester cpds can be hydrolyzed, and resulting compound (I g) is carried out above-mentioned amidation with the corresponding ester cpds of compound (I g).Hydrolysis preferably in the presence of acid (for example trifluoroacetic acid) or alkali (for example sodium hydroxide or potassium hydroxide), is carried out with method commonly used.
Method 5
The N-oxide compound of the compound of molecular formula (I j) can make by the corresponding nitrogen-containing heterocycle compound of oxidation (I i).
Oxidation can be in the organic solvent to reactionlessness, for example at methylene dichloride, chloroform, tetracol phenixin, alcohol (as methyl alcohol), or in the ether, carry out in room temperature or under heating, adopt oxygenant, for example hydrogen peroxide, inorganic peracid (as perphosphoric acid, chromium trioxide, persulfuric acid or Potassium Persulphate), or organic peracid (for example peroxybenzoic acid, metachloroperbenzoic acid, peroxyformic acid, trifluoroperacetic acid, cross phthalic acid, cross toxilic acid or peracetic acid).
Method 6
In the compound of the present invention, the compound of molecular formula (I k) can be by preparing dihalide or two reactive ketones of compound (IV) with molecular formula (VIII).
Dihalide compound can be by will having active hydrogen corresponding carbonyl compound on the α position of carbonyl with halogenating agent, halogen gas for example, N-bromosuccinimide, SULPHURYL CHLORIDE or cupric chloride react and prepare, be reflected at inert organic solvents, methylene dichloride for example, ethylene dichloride, chloroform, tetracol phenixin, N, dinethylformamide, ether diox, in benzene or the acetate, at acid catalyst or group initiator, as benzoyl peroxide, azo isobutyl acyl cyanide or hydrogen halide exist down, carry out in room temperature or heating condition, cited in the reaction formula as shown below.
(in the superincumbent reaction formula, R 14, R 15And R 16As defined above, Y 5Represent halogen atom).
The reaction of compound (VI) and dihalide or diketone is preferably in the organic solvent to reactionlessness, as at methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, ether diox, tetrahydrofuran (THF), benzene, in toluene or the dimethylbenzene, at acid catalyst, for example organic acid (as tosic acid or methylsulfonic acid) or Louis (Lewis) acid (as titanium tetrachloride) is carried out under existing, when compound (IV) and two reactive ketones, can be at alkali, Trimethylamine 99 for example, triethylamine, pyridine, picoline, lutidine, N, accelerine or N-methylmorpholine carry out under existing, when reactant (VI) reacts with dihalide, the heating of accompanying, be preferably heating under refluxing, adopt and compound (IV) compound equimolar amount or excessive (VII).
Intermediate (II), it is different with compound of the present invention, on 3 of the skeleton of benzoxazine, have an oxygen base, can by with essentially identical method preparation of producing compound of the present invention above-mentioned, unless carbonyl is with reducing described in the method 2.
Thereby, for instance, R wherein 7aAt least one these compound that selectively replace the nitrogenous heterocyclic group in ground and be the molecule formula II of N-oxide form by in oxygen base or the low alkyl group can prepare by adopting aforesaid method 1,3 or 5.R wherein 7aThe compound of the molecule formula II of the carboxyl that is selectively replaced by the oxygen base can prepare by employing method 6.Have by molecular formula-A 1-R 8aThe compound of the molecule formula II of the group of representative can prepare by method 1 or 5, has molecular formula
Figure 901090743_IMG30
Group the molecule formula II that compound can by method 1 or 4 the preparation.
In order to provide final product, compound promptly of the present invention (I) is gone through method 2 with intermediate (II), and at this moment, their 4 bit substituents contain in the presence of such as the reductive agent of borane reductive carbonyl rapidly.When 4 bit substituents were irreducible group, intermediate (II) can adopt borane directly to reduce and provide corresponding compounds (I).
Intermediate (III) can prepare by the method (step 1 and step 2) that is adopted in the employing method 3, compound of the present invention then can by in the employing method 3 subsequently the successive step derive.
Should determine suitably according to various reaction conditionss the reaction time that in each step of above-mentioned method, is adopted.
The given product of each reaction can easily separate and purifying.
For instance, after reaction finishes, reaction mixture can be poured onto in the excessive water or frozen water, use appropriate organic solvent, for example methylene dichloride, chloroform, benzene, diethyl ether or ethyl acetate extracting organism, dry then extracting layer, solvent evaporated, resistates carries out purification by silica gel column chromatography by recrystallization or on silica gel, and provides needed intermediate or the product that is purified form.The solvent of recrystallization and/or column chromatography can be selected from hexane, benzene, methylene dichloride, chloroform, ethyl acetate, acetone, ethanol, methyl alcohol etc. and their mixture suitably.
In some cases, reaction product can be precipitated out with crystallized form along with the carrying out of reaction process.In this case, product can more easily separate and purifying with recrystallization from appropriate organic solvent by filtering collection crystalline deposit thing.
Add the above, compound of the present invention can comprise various types of steric isomers.The different body of geometrical isomer and change can be separated into independently isomer, and each isomer can utilize such as one or more differences of the physicals between the isomer and purifying.
Optical isomer can be by adopting suitable initial compounds to prepare or by being generally used for the optical resolution technology of racemic mixture, for example comprising the isomer that above-mentioned purpose optical resolution technology obtains to be respective pure form that is generally used for that adopts optically active acid (particularly tartrate) to form diastereomeric salt.
Compound provided by the present invention has activation K +The activity of passage, and can be used for prevention and treatment cardiac ischemia disease (for example stenocardia and formation myocardial infarction) and cardiovascular disorder (for example hypertension) and diseases associated (arteriosclerosis, obesity, hyperlipidemia etc.), congestive heart failure, irregular pulse and peripheral blood vessel disorder (alopecia etc.) etc.
In addition, compound of the present invention can be used as the therapeutical agent of the various diseases relevant with smooth muscle contraction, for example as cerebrovascular disorder (cerebral vasospasm, migraine, dizziness etc.), respiratory disorder (reversibility obstruction of the air passage, the supersensitivity obstruction of the air passage, asthma etc.), gastrointestinal dysfunction (ulcer, the nervosa gastrointestinal disorder, irritable colon syndrome, diverticulosis, bile duct obstruction etc.), vision and auditory disorder are (disorderly in the ear, auditory organ's disorder, glaucoma, visual disorder, intraocular pressure is high excessively), urethra disorder (renal failure, with urinary stone disease passage diseases associated, pollakiuria, odynuria, the urinary incontinence etc.), genital organ disease (premature labor, dysmenorrhoea etc.), or the like therapeutical agent.In addition, compound conduct of the present invention also is effective by abnormal blood sugar concentration (hypoglycemia, diabetes etc.) and the caused treatment of diseases agent of heart conduction system undesired (irregular pulse etc.).
These pharmacological actions of compound of the present invention can confirm by test method as described below.Thereby, the activation K of compound +The effect of passage can be to have 10 in isolating tissue -9-10 -4Concentration in the scope of M and showing.When giving compound with intravenous injection, with 1-1, the dosage of 000 μ g/kg, compound can bring high blood pressure down and increase volume of blood flow coronarius, when to the coronary artery administration, can make coronary artery expansion with the dosage of 0.3-100 μ g.In addition, also observing compounds more of the present invention hypotensive is effective with making the activity of coronary artery diastole in a long time cycle.
The following test method that will describe in order to the pharmacological effect of several exemplary compounds of proving compound of the present invention.
Test method:
(1) for by 3, the effect that the rhythm and pace of moving things that the 4-diamino-pyridine brings out shrinks
Adopt the method (Myakkangaku, 24,133-143,1984) of Uchida and Sugimoto.With the Mongrel dog of any sex of Sodital (30mg/kgi.v.) anesthesia, and bloodletting then, cuts out heart to dog death from each animal body.In Krebs-Henseleit solution, the ring that thick about 2mm was separated and be cut into to the crown crooked offshoot or the preceding descending offshoot in left side.The ring plate section is fixed on the stainless steel hook, and hangs in the Krebs-Henseleit bath (37 ℃), feeding tension loading is the 95%O of 1.0g 2-5%CO 2Gas mixture, write down isometric contraction.
After sample is stablized 30 minutes, add 3,4-diamino-pyridine (10mm) shrinks to bring out the rhythm and pace of moving things.When amplitude of shrinking when the rhythm and pace of moving things and frequency become basicly stable, begin test compound is added in the organ bath.Set up the amplitude of contraction and the concentration-response curve of frequency, and estimate effect.
Be shown in for the retarding effect of contraction frequency in the hurdle (1) of table 1.
(2) effect of for cardiovascular systems
With the Mongrel dog of any sex of Sodital (30mg/kg i.v.) anesthesia, behind the airway intubation, test is carried out under the artificial respiration condition.After the thoracotomy operation, measure dL VP/dt, Ppa pulmonary artery pressure, central vein pressure, heart output volume of blood flow and the coronary artery blood flow of rhythm of the heart blood pressure, left ventricular pressure, maximum.Be administered in femoral vein by interpolation pipe test compound and estimate effect.
Table 1 intermediate hurdles (2) have shown mean blood pressure (MBP)-reduction effect, reduce (△ %) expression with percentage.
(3) coronary artery diastole effect
With the Mongrel dog of any sex of Sodital (30mg/kg i.v.) anesthesia, and under artificial respiration, test by airway intubation.After the thoracotomy, go in the crown crooked offshoot in left side with constant pressure infusing by the blood of stopping certainly that extracorporeal circuit will obtain from common carotid artery.With the Electromagnetic Flow probe measurement coronary artery blood flow that is installed in the extracorporeal circuit.Test compound by extracorporeal circuit directly to crown animals administer and estimate crown animal arteries and veins vasodilator effect.
As the result of the coronary artery diastole effect of test compound, the percentage ratio of response adopts determining for the medicine of 300 μ g Papaverines as 100% response to coronary artery, and calculate be enough to make volume of blood flow increase 100%(ED100pap) dosage.
Test-results:
Table 1
（1） （2）
Example IC 50MBP
No. （μM） [μg/kg i.v.（△%）]
1 0.01 3（-16）
2 0.24 10（-20）
38 0.05 10（-23）
41（4） 0.07 3（-20）
56 0.02 3（-11）
70 0.01 10（-9）
Cromakalim 0.39 10（-28）
Then, relevant with example 1 and 2, pressure reduction effect that reaches by oral test compound in sentient spontaneous hypertension rat (SHR) and the intravenously acute toxicity in mouse are determined.
Test method:
(1) pressure reduction effect
Spontaneous hypertension rat (SHR) with Sodital (60mg/kg, abdominal injection) anesthesia Okamoto-Aoki kind.Then, an end that will be used for the pipe of blood pressure measurement is inserted into common carotid artery, and the other end of pipe is then stayed the collare outside.Behind 4-5 after the operation days stabilization period, after narcotic effect is calmed down, measure blood pressure and heart rate.Test compound is suspended in 0.5% the methocel solution, suspension is estimated effect with the volume oral administration of 5ml/kg.
Table 2 has shown the reduction effect that mean blood pressure (MBP) is represented with △ %.
(2) acute poisoning effect
Deliver medicine to the acute toxicity dosage (LD of the test compound of caudal artery 50) by the method that dosage changes up and down, in male mouse, measure.
Table 3 has shown acute toxicity dosage (LD 50).
Test-results
Table 2
Example dosage
No. （μg/kg p.o.） MBP（△%）
1 30 -25
2 300 -40
Cromakalim 300 -35
Table 3
Example No. LD 50(mg.kg i.v.)
1 50.4
2 ＞60
Cormakalim 49.7
Compound of the present invention (I) or their salt can be used as the potassium-channel activator, activator can be comprise as active ingredient one or more said compound or their salt, and common carrier, vehicle and/or other additive, being suitable for the common pharmaceutical dosage forms of oral or oral administration, for example can be tablet, lozenge, pulvis, fine particle, particle, capsule, pill, the liquid preparation (comprising syrup) that is used for oral administration, injection, inhalation, suppository, the liquid preparation that is used for percutaneous dosing, ointment, through the intracutaneous therapy system with through phlegmatic temperament therapy system (for example taking in the mouth), be used for liquid preparation forms such as (for example nasal formulations of liquid) through the mucus administration.
The carrier and the vehicle that are used for said various preparations are acceptable and avirulent solid of pharmacology or liquid substance, for example other material in the pure and mild common medicinal application of lactose, Magnesium Stearate, starch, talcum, gelatin, agar, pectin, gum arabic, sweet oil, sesame oil, theobroma oil, ethylene.
The clinical dosage of compound of the present invention should be determined suitably according to the disease that will treat, symptom, patient body weight, age and sex, route of administration and other factors.But the dosage to adult every day is usually: be under case of oral administration in each adult's of 0.1-300mg/ scope, and next in each adult's of 0.60-100mg/ scope in the situation of intravenous administration.Such dosage can or be divided into the separate doses administration of 2-4 with disposable dosed administration.
Following example and dosage form example have further been enumerated the present invention.Precursor compound comprises the compound that some are novel.The typical method for preparing the novel compound of this class from compound known has been described following reference example.Except that indicating in addition, after this ratio that is adopted is a volume ratio.
Reference example 1
Figure 901090743_IMG31
With 480mg6-bromo-3,4-dihydro-2,2-dimethyl-2H-,-benzoxazines, 206mg cuprous cyanide and 5ml N, the mixture of N-dimethylformamide dimethyl acid amides stirred 4 hours down at 130 ℃, and then stirred 5 hours down at 150 ℃.Use 0.5ml, 2-quadrol and 10ml water dilute this reaction mixture and use the benzene extracting.Wash organic phase with water and pass through anhydrous magnesium sulfate drying, the solvent distillation is removed.Resistates carries out silica gel column chromatography and adopts ethyl acetate-hexane (10: 1) to carry out wash-out.The coarse crystal that obtains from eluate provides 160mg6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine with the also dry of hexane wash.This compound has following physico-chemical property.
ⅰ) fusing point: 102-103.5 ℃
ⅱ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），1.5-2.5（1H，s），
3.12（2H，s）6.77（1H，d），6.86（1H，d），
6.97（1H，dd）.
Reference example 2.
Figure 901090743_IMG32
11.05g2-nitro-4-phenyl sulphonyl phenol is suspended in the 120ml dehydrated alcohol, and interior (Raney) nickel of Ruan that adds catalytic amount then is to reduce, and reduction is carried out under hydrogen stream and envrionment temperature and environmental stress.After reduction reaction was finished, solvent was removed in elimination catalyzer and distillation.Resistates drying under reduced pressure and provide the thick 2-amino of 9.73g-4-phenyl sulfonyl phenol.This product is dissolved in 19mlN, in the dinethylformamide, and solution dropwise joined contains 5.89g Potassium monofluoride, 7.61g2-isobutyl ethyl bromide and 11mlN, in the mixture of dinethylformamide.Then mixture is stirred down at 60 ℃ and spend the night.Reaction mixture is poured in the frozen water and use the ethyl acetate extracting, wash organic phase with water and, distillation removal solvent by anhydrous magnesium sulfate drying.Resistates carries out silica gel column chromatography, and with hexane-ethyl acetate (2: 1) wash-out.With deriving from coarse crystal recrystallization from 15ml ethanol of eluate, be recovered to 3,4-dihydro-2,2-dimethyl-3-oxygen-6-phenyl sulfonyl-2H-1,4-benzoxazine.
This compound has following physico-chemical property
ⅰ) fusing point: 153-157 ℃
ⅱ) ultimate analysis is (to C 16H 15NO 4S)
C（%） H（%） N（%） S（%）
Calculated value: 60.55 4.76 4.41 10.10
Actual value: 60.62 4.79 4.25 10.13
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.52（6H，s），6.99（1H，d），7.3-7.6（5H，m），
7.8-8.0（2H，m），9.27（1H，s）.
Reference example 3
Following compounds is synthetic with the method identical with reference example 2 usually.
3,4-dihydro-2,2-dimethyl-6-methyl sulphonyl-3-oxygen-2H-1,4-benzoxazine physico-chemical property:
ⅰ) fusing point: 241-243 ℃
ⅱ) ultimate analysis: (to C 11H 13NO 4S)
C（%） H（%） N（%） S（%）
Calculated value: 51.75 5.13 5.49 12.56
Actual value: 51.74 5.13 5.43 12.56
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.43（6H，s），3.15（3H，s），7.15（1H，d），
7.3-7.6（2H，m），10.54（1H，s）.
Reference example 4
Figure 901090743_IMG33
Toward 40g Potassium monofluoride, 40ml2-isobutyl ethyl bromide and 200ml N, add 49.1g2-amino-4-chloro-5-nitrophenols in the mixture of dinethylformamide, whole mixture was stirred 4 days down at 60 ℃.Then reaction mixture is poured onto in the frozen water, with resulting solid recrystallization and provide 37.03g6-3,4-dihydro-2,2-dimethyl-7-nitro-3-oxygen-2H-1,4-benzoxazine from the 800ml Virahol.With the 0.51g of the said products part recrystallization and provide the sample that 0.31g is used for ultimate analysis from 14ml ethanol.
This compound has following physico-chemical property.
ⅰ) fusing point: 243-245 ℃
ⅱ) ultimate analysis is (to C 10H 9ClN 2O 4)
C（%） H（%） N（%） S（%）
Calculated value: 46.80 3.53 10.92 13.81
Actual value: 46.84 3.46 10.90 13.91
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.43（6H，s），7.04（1H，s），7.68（1H，s），
11.23（1H，s）.
Reference example 5
Under the ice bath cooling, past 35ml contains the middle 4.625g 3 of adding of tetrahydrofuran solution (1M) of borane-tetrahydrofuran (THF) mixture, 4-dihydro-2; 2-dimethyl-3-oxygen-6-phenyl sulfonyl-2H-1; the 4-benzoxazine refluxes this mixture companion's constant agitation 2 hours under heating.Dilute this reaction mixture and further the backflow 45 minutes with 4.3ml methyl alcohol, add the 3.6ml concentrated hydrochloric acid then, and mixture was refluxed 45 minutes again.Concentrated reaction mixture then, resulting solid pulverize and filtering in ether.The powder of wearing into is suspended in rare aqueous sodium hydroxide solution and uses the ethyl acetate extracting.Wash organic phase with water and pass through anhydrous magnesium sulfate drying.Distillation removes and desolvates.Resistates recrystallization from 15ml ethanol is recovered to 3.76g 3,4-dihydro-2,2-dimethyl-6-phenyl sulfonyl-2H-1,4-benzoxazine.
This compound has following physico-chemical property.
ⅰ) fusing point: 138-140.5 ℃
ⅱ) ultimate analysis is (to C 16H 17NO 3S)
C（%） H（%） N（%） S（%）
Calculated value: 63.34 5.65 4.62 10.57
Actual value: 63.36 5.65 4.54 10.65
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.28（6H，s），3.04（3H，s），3.2-4.2（1H），
6.76（1H，dd），7.1-7.3（2H，m），
7.3-7.6（3H，m），7.8-8.0（2H，m）.
Reference example 6-8
Following compounds is synthetic with the method identical with reference example 5.
Reference example 6
3,4-dihydro-2,2-dimethyl-6-methyl sulphonyl-2H-1,4-benzoxazine physico-chemical property:
ⅰ) fusing point: 137-142 ℃
ⅱ) ultimate analysis is (to C 11H 15NO 3S)
C（%） H（%） N（%） S（%）
Calculated value: 54.75 6.27 5.80 13.29
Actual value: 54.86 6.29 5.78 13.30
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（6H，s），3.50（3H，s），3.09（2H，d），
4.33（1H，s），6.80（1H，dd），7.1-7.2（2H，m）
Reference example 7
6-chloro-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine physico-chemical property:
ⅰ) fusing point: 139-140.5 ℃
ⅱ) ultimate analysis is (to C 10H 11ClN 2O 3)
C（%） H（%） N（%） Cl（%）
Calculated value: 49.50 4.57 11.54 14.61
Actual value: 49.45 4.53 11.52 14.57
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（6H，s），3.18（2H，d），4.72（1H，s），
6.57（1H，s），7.54（1H，s）
Reference example 8
3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 151-153 ℃
ⅱ) ultimate analysis is (to C 10H 12N 2O 3)
C（%） H（%） N（%）
Calculated value: 57.69 5.81 13.45
Actual value: 57.59 5.88 13.48
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），3.15（2H，d），6.78（1H，d），
7.50（1H，d），7.59（1H，dd）
Reference example 9
Figure 901090743_IMG35
(1) toward 10g 2-nitro-4-trifloro methyl phenol, 8.0g Carbon Dioxide calcium and 30mlN, dropwise add the 23mlN that contains 8.8g 2-bromine isobutyric aldehyde in the mixture of dinethylformamide, the solution of dinethylformamide at room temperature stirred mixture 4 days.Then reaction mixture is poured into and also use the toluene extracting in the frozen water.Use 0.5N aqueous sodium hydroxide solution and water washing organic phase successively, and by anhydrous magnesium sulfate drying it, solvent is distilled removal.Resistates carries out silica gel column chromatography and carries out wash-out with hexane-ethyl acetate (3: 1).With the crystal that derives from eluate from the 15ml hexane twice in recrystallization and provide 4.428g 2-(2-nitro-4-4-trifluoromethylphenopendant) isobutyric aldehyde.
(2) the above-mentioned aldehyde of 4.408g is dissolved in the 40ml ethanol, behind the Raney nickel of adding catalytic amount, in hydrogen stream, under envrionment temperature and normal pressure, reduces.Filter then and remove catalyzer and distillation removal solvent.Resistates carries out silica gel column chromatography, and carries out wash-out with hexane-benzene (3: 2), and is recovered to 2.294g 3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-2H-1,4-benzoxazine.With the part of the 1g of this product recrystallization and provide the sample that 908mg is used to carry out ultimate analysis from the 2ml hexane.
This compound has following physico-chemical property
ⅰ) fusing point: 81-82 ℃
ⅱ) ultimate analysis is (to C 11H 12F 3NO)
C（%） H（%） N（%） F（%）
Calculated value: 57.14 5.23 6.06 24.65
Actual value: 57.10 5.31 6.00 24.62
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.10（2H，s），
3.3-4.4（1H，broad s），6.7-7.1（3H，m）
Example 1
With 2.66g 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, the 4-benzoxazine is dissolved in 10mlN, in the dinethylformamide, add 1.02g sodium hydride (60%, in oil) then, mixture was at room temperature stirred 30 minutes, then, under ice-cooled, add 2.77g 2-bromopyridine N-oxide salt acidulants, after hot driving stops, mixture was at room temperature stirred 2 hours.Then reaction mixture is toppled over and also use the ethyl acetate extracting in the entry.Isolate organic phase and pass through anhydrous magnesium sulfate drying and filtration.Filtrate decompression concentrates, and resistates carries out silica gel column chromatography, adopts chloroform as eluent, and provides thick 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) pyridine N-oxides.
Recrystallization provides 2.0g purpose compound from chloroform-ethanol.
Physico-chemical property:
ⅰ) fusing point: 224-226 ℃
ⅱ) ultimate analysis is (to C 15H 15N 3O 4)
C（%） H（%） N（%）
Calculated value: 59.80 5.02 13.95
Actual value: 59.73 5.20 13.80
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.42（6H，s），3.69（2H，s），6.94（1H，d），
7.05-7.41（3H，m），7.49（1H，d），7.77（1H，dd），
8.31（1H，ddd）
Example 2
With 1.5g 6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1, the 4-benzoxazine is dissolved in 10mlN, in the dinethylformamide, then, adds 0.96g sodium hydride (60%, in oil) gradually.After 10 minutes, divide several parts to add 3.36g 2-bromopyridine N-oxide salt acidulants, heat at room temperature stirred mixture 3 hours after stopping to discharge.The dilute with water reaction mixture, and with the ethyl acetate extracting it.Separate organic phase, by anhydrous magnesium sulfate drying and filtration.Filtrate decompression concentrates, and resistates carries out silica gel column chromatography, adopts ethyl acetate-methyl alcohol (5: 1) to provide thick 2-(6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl as eluent) pyridine N-oxides.Crystallization provides the 0.78g coarse crystal from ethyl acetate.At last, with crystal recrystallization and be recovered to 0.6g purpose compound from ethanol.
This compound has following physico-chemical property
ⅰ) fusing point: 175-177 ℃
ⅱ) ultimate analysis is (to C 16H 15N 3O 2)
C（%） H（%） N（%）
Calculated value: 68.31 5.37 14.94
Actual value: 68.20 5.38 14.88
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.40（6H，s），3.67（2H，s），
6.86-7.33（6H，m），8.26-8.33（1H，m）
Example 3-32
Compound listed in the following table is synthetic by the method in the example 1 and 21.Should see that at room temperature reaction can not be carried out well here, reaction will be carried out under the temperature that improves.As alkali, not only sodium hydride, and triethylamine or salt of wormwood also can adopt.Promptly in example 13-27 and 32, be reflected under 100 ℃-120 ℃ and carry out, or heating under refluxing.As alkali, in example 13,14,17-21 and 28-31, adopt triethylamine, and in example 15,16 and 22, adopt Anhydrous potassium carbonate.
Figure 901090743_IMG38
Figure 901090743_IMG40
Figure 901090743_IMG41
Figure 901090743_IMG42
Figure 901090743_IMG43
The physico-chemical property of these compounds is as follows.
Example 3
2-(3,4-dihydro-2,2-dimethyl-6-phenyl sulfonyl-2H-1,4-benzoxazine-4-yl) pyridine N-oxides
Physico-chemical property:
ⅰ) fusing point: 123-124 ℃
ⅱ) ultimate analysis is (to C 21H 20N 2O 4S)
C（%） H（%） N（%） S（%）
Calculated value: 63.62 5.08 7.07 8.09
Actual value: 63.42 5.09 7.05 8.09
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.69（2H，t），
6.9-7.6（9H，m），7.8-7.9（2H，m），
8.2-8.4（1H，m）
Example 4
2-(3,4-dihydro-6-nitro-2H-1,4-benzoxazine-4-yl) pyridine N-oxides
Physico-chemical property:
ⅰ) fusing point: 139-141 ℃
ⅱ) ultimate analysis is (to C 13H 11N 3O 40.1H 2O)
C（%） H（%） N（%）
Calculated value: 56.77 4.10 15.28
Actual value: 56.74 4.10 15.17
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：3.96（2H，t），4.44（2H，t），7.02（1H，d），
7.2-7.4（3H，m），7.52（1H，d），
7.78（1H，dd），8.36（1H，d）
Example 5
2-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) pyridine N-oxides
Physico-chemical property:
ⅰ) fusing point: 149-151 ℃
ⅱ) ultimate analysis is (to C 15H 15N 2O 2Br)
C（%） H（%） N（%） Br（%）
Calculated value: 53.75 4.51 8.36 23.84
Actual value: 53.74 4.49 8.39 23.83
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.34（6H，s），3.65（2H，s），
6.68-7.40（6H，m），8.19-8.28（1H，m）
Example 6
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-the 6-PICOLINE N-OXIDES
Physico-chemical property:
ⅰ) fusing point: 161-163 ℃
ⅱ) ultimate analysis is (to C 16H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 60.94 5.43 13.33
Actual value: 60.97 5.48 13.21
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.43（6H，s），2.57（3H，s），3.65（2H，s），
6.89（1H，d），7.13-7.28（3H，m），
7.40（1H，d），7.70（1H，dd）
Example 7
2-(3,4-dihydro-2,2-dimethyl-6-methyl sulphonyl-2H-1,4-benzoxazine-4-yl) pyridine N-oxides
Physico-chemical property:
ⅰ) fusing point: 220-222 ℃
ⅱ) ultimate analysis is (to C 16H 18N 2O 4S)
C（%） H（%） N（%） S（%）
Calculated value: 57.47 5.43 8.38 9.59
Actual value: 57.51 5.49 8.30 9.59
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（6H，s），2.86（3H，s），3.65（2H，s），
6.9-7.5（6H，m），8.2-8.3（1H，m）
Example 8
2-(6-chloro-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine-4-yl) pyridine N-oxides
Physico-chemical property:
ⅰ) fusing point: 179-180.5 ℃
ⅱ) ultimate analysis is (to C 15H 14N 3O 4Cl)
C（%） H（%） N（%） Cl（%）
Calculated value: 53.66 4.20 12.52 10.56
Actual value: 53.58 4.25 12.39 10.61
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ (ppm): 1.40(6H, s), 3.60(2H, wide s),
6.46（1H，s），7.1-7.5（3H，m），
7.60（1H，s），8.2-8.4（1H，m）
Example 9
2-(3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-2H-1,4-benzoxazine-4-yl) the pyridine N-oxides hydrochloride
Physico-chemical property:
ⅰ) fusing point: 144-166 ℃
ⅱ) ultimate analysis is (to C 16H 15N 2O 2F 3HCl)
C（%） H（%） N（%） Cl（%） F（%）
Calculated value: 53.27 4.47 7.77 9.83 15.80
Actual value: 53.08 4.38 7.68 9.86 15.67
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），3.97（2H，s），7.03（1H，d），
7.2-7.5（3H，m），7.64（1H，dd），
7.8-8.1（1H，m），8.76（1H，dd），
11.85(1H, wide s)
Example 10
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) quinoline 1-oxide compound
Physico-chemical property:
ⅰ) fusing point: 183-184 ℃
ⅱ) ultimate analysis is (to C 19H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 64.95 4.88 11.96
Actual value: 64.92 4.90 11.92
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.43（6H，s），3.84（2H，s），6.94（1H，d），
7.24-7.90（7H，m），8.71（1H，d of t）
Example 11
3-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-N, N-dimethylpyrazine-2-azanol
Physico-chemical property:
ⅰ) fusing point: 134-135 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 17H 19N 5O 4)
C（%） H（%） N（%）
Calculated value: 57.14 5.36 19.60
Actual value: 57.19 5.47 19.52
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.48（6H，s），2.82（3H，s），3.19（3H，s），
3.80（2H，s），6.95（1H，d），7.66（1H，d），
7.84（1H，dd），8.26（1H，d），8.37（1H，d）
Example 12
3,4-dihydro-2,2-dimethyl-6-nitro-4-(3,4,5,6-tetrachloro-2-pyridyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 117-119 ℃
ⅱ) ultimate analysis is (to C 15H 11N 3O 3Cl 4)
C（%） H（%） N（%） Cl（%）
Calculated value: 42.58 2.62 9.93 33.52
Actual value: 42.14 2.56 9.76 33.40
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.51（6H，s），3.49（2H，s），
6.92-7.04（2H，m），7.77（1H，dd）
Example 13
3-(6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) picoline
Physico-chemical property:
ⅰ) fusing point: 107-108 ℃ (ethanol-hexane)
ⅱ) ultimate analysis is (to C 17H 17NO 3O)
C（%） H（%） N（%）
Calculated value: 73.10 6.13 15.04
Actual value: 73.01 6.19 15.02
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.07（2H，s），4.46（2H，s），
6.74-7.04（3H，m），7.20-7.33（1H，m）
7.51-7.65（1H，m），8.50-8.58（2H，m）
Example 14
3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-picolyl)-2H-1,4-benzoxazine hydrochloride
ⅰ) fusing point: 174-178 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 16H 17N 3O 3HCl)
C（%） H（%） N（%） Cl（%）
Calculated value: 57.23 5.40 12.51 10.56
Actual value: 57.36 5.39 12.59 10.77
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.34（6H，s），3.37（2H，s），5.04（2H，s），
6.84-6.96（1H，m），7.48-7.61（2H，m），
7.72-7.91（2H，m），8.37（1H，d of t），
8.80-8.90（1H，m）
Example 15
The 4-(3-luorobenzyl)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzo
Oxazine
Physico-chemical property:
ⅰ) fusing point: 68-69 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 17H 17N 2O 3F)
C（%） H（%） N（%） F（%）
Calculated value: 64.55 5.42 8.86 6.01
Actual value: 64.68 5.43 8.78 6.08
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（6H，s），3.11（2H，s），4.52（2H，s），
6.7-7.7（7H，m）
Example 16
4-(2-benzoglyoxaline ylmethyl)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 213-214 ℃
ⅱ) ultimate analysis is (to C 18H 18N 4O 3)
C（%） H（%） N（%）
Calculated value: 63.89 5.36 16.56
Actual value: 63.87 5.39 16.55
ⅲ) mass spectrum (EI): m/z 338(M +)
Example 17
3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-nitrobenzyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 116-118 ℃
ⅱ) ultimate analysis is (to C 17H 17N 3O 5)
C（%） H（%） N（%）
Calculated value: 59.47 4.99 12.24
Actual value: 59.31 4.98 12.26
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.39（6H，s），3.18（2H，s），4.93（2H，s），
6.90（1H，d），7.4-7.7（5H，m），
8.1-8.2（1H，m）
Example 18
3,4-dihydro-2,2-dimethyl-6-nitro-4-(3-nitrobenzyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 125-127 ℃
ⅱ) ultimate analysis is (to C 17H 17N 3O 50.1H 2O)
C（%） H（%） N（%）
Calculated value: 59.16 5.02 12.17
Actual value: 59.04 4.93 12.10
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.20（6H，s），3.12（2H，s），4.60（2H，s），
6.81（1H，d），7.4-7.7（4H，m），
8.0-8.2（2H，m）
Example 19
3-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) the picoline hydrochloride
ⅰ) fusing point: 186-189 ℃
ⅱ) ultimate analysis is (to C 16H 18N 3O 3Cl)
C（%） H（%） N（%） Cl（%）
Calculated value: 57.23 5.40 12.51 10.56
Actual value: 57.21 5.26 12.70 10.78
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.33（6H，s），3.29（2H，s），4.84（2H，s），
6.84-6.93（1H，m），7.48-7.59（2H，m），
7.91-8.06（1H，m），8.36-8.50（1H，m），
8.77-8.89（2H，m）
Example 20
4-benzyl-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 92-93 ℃
ⅱ) ultimate analysis is (to C 17H 18N 2O 3)
C（%） H（%） N（%）
Calculated value: 68.44 6.08 9.39
Actual value: 68.57 6.13 9.30
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.36（6H，s），3.06（2H，s），4.28（2H，s），
6.78（1H，d），7.2-7.4（5H，m），
7.5-7.7（2H，m）
Example 21
3,4-dihydro-2,2-dimethyl-6-nitro-4-(4-nitrobenzyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 118-119 ℃
ⅱ) ultimate analysis is (to C 17H 17N 3O 5)
C（%） H（%） N（%）
Calculated value: 59.47 4.99 12.24
Actual value: 59.47 4.90 12.32
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.39（6H，s），3.13（2H，s），4.61（2H，s），
6.82（1H，d），7.40-7.67（4H，m），
8.13-8.28（2H，m）
Example 22
The 4-(2-luorobenzyl)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: oily matter
ⅱ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（6H，s），3.11（2H，s），4.54（2H，s），
6.77（1H，dd），6.9-7.4（4H，m），
7.5-7.7（2H，m）
ⅲ) mass spectrum (FAB): m/z
316（M +）
Example 23
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(phthalimidomethyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 147-148 ℃
ⅱ) ultimate analysis is (to C 20H 17N 3O 3)
C（%） H（%） N（%）
Calculated value: 69.15 4.93 12.10
Actual value: 69.21 4.96 12.06
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（6H，s），3.44（2H，s），5.23（2H，s），
6.76（1H，d），7.01（1H，dd），
7.67-7.96（5H，m）
Example 24
(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) ethyl acetate
Physico-chemical property:
ⅰ) fusing point: 95-96 ℃ (ethyl acetate-normal hexane)
ⅱ) ultimate analysis is (to C 14H 18N 2O 5)
C（%） H（%） N（%）
Calculated value: 57.14 6.16 9.52
Actual value: 57.16 6.15 9.43
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.27（3H，t），1.36（6H，s），3.21（2H，s），
4.10（2H，s），4.20（2H，q），6.77（1H，d），
7.37（1H，d），7.59（1H，dd）
Example 25
(6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) ethyl acetate
Physico-chemical property:
ⅰ) fusing point: 52-53 ℃
ⅱ) ultimate analysis is (to C 15H 18N 2O 3)
C（%） H（%） N（%）
Calculated value: 65.68 6.61 10.21
Actual value: 65.81 6.65 10.20
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.28（3H，t），1.36（6H，s），3.20（2H，s），
4.01（2H，s），4.20（2H，q），6.67（1H，d），
6.75（1H，d），6.95（1H，dd）
Example 26
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) ethyl propionate
Physico-chemical property:
ⅰ) fusing point: 77-78 ℃
ⅱ) ultimate analysis is (to C 15H 20N 2O 5)
C（%） H（%） N（%）
Calculated value: 58.43 6.54 9.09
Actual value: 58.41 6.47 9.13
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.15-1.75（12H，m），3.15（2H，s），
4.20（2H，q），4.57（1H，q），6.80（1H，dd），
7.50-7.75（2H，m）
Example 27
3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-ethylene oxy ethyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 56-56.5 ℃
ⅱ) ultimate analysis is (to C 14H 18N 2O 4)
C（%） H（%） N（%）
Calculated value: 60.42 6.52 10.07
Actual value: 60.37 6.44 10.00
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.23（2H，s），3.68（2H，t），
3.93（2H，s），4.05（1H，dd），4.21（1H，dd），
6.47（1H，dd），6.90（1H，d），
7.47-7.84（2H，m）
Example 28
3,4-dihydro-2,2-dimethyl-4-nicotinoyl-6-nitro-2H-1,4-benzoxazine hydrochloride
Physico-chemical property:
ⅰ) fusing point: 158-199 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 16H 15N 3O 4HCl)
C（%） H（%） N（%） Cl（%）
Calculated value: 54.95 4.61 12.01 10.14
Actual value: 55.01 4.64 12.04 10.16
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.28（6H，s），3.75（2H，s），7.13（1H，d），
7.8-8.1（2H，m），8.4-8.8（2H，m），
8.9-9.2（2H，m），11.1（1H，broad s）
Example 29
The 4-(2-furancarbonyl)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 112-116.5 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 15H 14N 2O 5)
C（%） H（%） N（%）
Calculated value: 59.60 4.67 9.27
Actual value: 59.56 4.62 9.31
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：2.42（6H，s），3.84（2H，s），
6.53（1H，dd），6.94（1H，d），7.16（1H，dd），
7.45（1H，dd），7.91（1H，dd），8.13（1H，d）
Example 30
Trans-4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-4-oxygen-2-butylene acetoacetic ester
Physico-chemical property:
ⅰ) fusing point: 93-95 ℃
ⅱ) ultimate analysis is (to C 16H 18N 2O 6)
C（%） H（%） N（%）
Calculated value: 57.48 5.43 8.38
Actual value: 57.30 5.41 8.19
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.24（3H，t），1.32（6H，s），3.86（2H，s），
4.21（2H，q），6.74（1H，d），7.08（1H，d），
7.56（1H，d），7.97（1H，dd）
8.5-8.9(1H, wide s)
Example 31
3,4-dihydro-2,2-dimethyl-6-nitro-4-ethyl oxalyl group-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 80-81 ℃
ⅱ) ultimate analysis is (to C 14H 16N 2O 6)
C（%） H（%） N（%）
Calculated value: 54.54 5.23 9.09
Actual value: 54.51 5.19 9.05
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37-1.41（3H，m），1.42（3H，s），
1.45（3H，s），3.57（2H x 2/5，s），
3.83（2H x 3/5，s），4.36-4.46（2H，m），
6.99（1H，d），8.02（1H，m），
9.11(1H, wide s)
Example 32
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(2-oxo-3-tetrahydrofuran base (oxolanyl)-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 144-146 ℃ (ethanol)
ⅱ) ultimate analysis is (to C 15H 16N 2O 3)
C（%） H（%） N（%）
Calculated value: 66.16 5.92 10.29
Actual value: 66.03 5.93 10.21
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（3H，s），1.41（3H，s），
2.2-2.7（2H，m），2.99（2H，d），
4.2-4.8（3H，m），6.82（1H，d），
6.89（1H，d），7.05（1H，dd）
Example 33
In argon gas stream, under 0-10 ℃, with 1.5g 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-4-phenacyl-2H-1, the 4-benzoxazine adds in the 1.0M borane solution of 30ml in tetrahydrofuran (THF).
Above-mentioned solution was stirred 1 hour at 70 ℃, add 5.6ml methyl alcohol then gradually.Stirring is after 15 minutes down at 70 ℃, and adding 5.6ml concentrated hydrochloric acid, mixture continue to stir 1 hour under 70 ℃.Solvent is removed in distillation then, with 30ml water dilution resistates, makes it to be alkalescence with salt of wormwood, and with the ethyl acetate extracting it.Extract is removed solvent by anhydrous magnesium sulfate drying and distillation.Resistates provides 1.67g 3 by purification by silica gel column chromatography, 4-dihydro-4-(2-hydroxyl-2-styroyl)-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine (being oily).Mass spectrum (EI): m/z 328(M +)
Example 34
In argon gas stream, be precooled to-50--60 ℃ under, the dimethyl sulfoxide (DMSO) that 0.7ml is done is added in the dichloromethane solution that the 10ml that contains the 0.41ml oxalyl chloride does gradually, and mixture was stirred 2 minutes under identical temperature.
Then, to contain 1.5g 3,4-dihydro-4-(2-hydroxyl-2-styroyl)-2,2-dimethyl-6-nitro-2H-1, the dichloromethane solution that the 20ml of 4-benzoxazine does added in 5 minutes time, and mixture stirred 15 minutes under temperature same as described above.
At room temperature, add the 1.3ml triethylamine in this reaction mixture, dilute this mixture with 30ml water, and with the methylene dichloride extracting it.Extract is by anhydrous magnesium sulfate drying, and solvent is distilled removal.Resistates recrystallization and provide 1.31g 3,4-dihydro-2,2-dimethyl-6-nitro-4-phenacyl-2H-1,4-benzoxazine, fusing point: 125-128 ℃ from ether.
Physico-chemical property:
Ultimate analysis is (to C 18H 18N 2O 4)
C（%） H（%） N（%）
Calculated value: 66.25 5.56 8.58
Actual value: 66.16 5.62 8.47
Mass spectrum (EI): m/z 326(M +)
Example 35-40
The compound of listing in the following table be by with the identical method synthetic of method 2 in example 33 and 34.
Figure 901090743_IMG46
Figure 901090743_IMG47
These compounds have following physico-chemical property
Example 35
3,4-dihydro-4-[2-hydroxyl-2-(2-pyridyl) ethyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Mass spectrum (EI): m/z 329(M +)
Example 36
3,4-dihydro-4-(2-hydroxypropyl)-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Mass spectrum (EI): m/z 266(M +)
Example 37
3,4-dihydro-2,2-dimethyl-6-nitro-4-[(2-pyridyl carbonyl) methyl]-2H-1, the 4-benzoxazine
Fusing point: 106-107 ℃
Ultimate analysis is (to C 17H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 63.38 5.23 12,84
Actual value: 62.38 5.23 12,76
Mass spectrum (GC-MS): m/z 327(M +)
Example 38
A-acetonyl-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Fusing point: 98-99 ℃
Ultimate analysis is (to C 13H 16N 2O 4)
C（%） H（%） N（%）
Calculated value: 59.08 6.10 10.60
Actual value: 58.92 6.21 10.52
Mass spectrum (GC-MS): m/z 264(M +)
Example 39
3,4-dihydro-2,2-dimethyl-4-(2-hydroxycyclopent base)-6-nitro-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) ultimate analysis is (to C 15H 20N 2O 4)
C（%） H（%） N（%）
Calculated value: 61.63 6.90 9.58
Actual value: 61.60 7.00 9.53
ⅱ) fusing point: 87-88 ℃ (normal hexane)
ⅲ) mass spectrum (m/z): 292(M +) (EI)
ⅳ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（3H，s），1.39（3H，s），1.58-2.22
（6H，m），3.26（2H，s），3.80（1H，m），
4.50-4.68（1H，m），6.79（1H，d），
7.59（1H，d），7.60（1H，dd）
Example 40
3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-oxocyclopentyl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) ultimate analysis is (to C 15H 18N 2O 4)
C（%） H（%） N（%）
Calculated value: 62.06 6.25 9.65
Actual value: 61.84 6.38 9.52
ⅱ) fusing point: 118-119 ℃ (ether-normal hexane)
ⅲ) mass spectrum (m/z): 299(M +) (EI)
ⅳ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.34（3H，s），1.41（3H，s），
1.75-2.60（6H，m），2.83（1H，d），
2.99（1H，d），4.22-4.44（1H，m），
6.79（1H，d），7.51（1H，d），7.61（1H，dd）
Example 41
(1) with 3g 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine are dissolved in the mixture of 34ml methyl alcohol and 2.07ml acetate.Then, dropwise add the 6.6ml aqueous solution that contains the 2.0g Sodium Nitrite, mixture is at room temperature stirred spend the night.With aqueous sodium hydroxide solution neutralization reaction mixture, under reduced pressure concentrate and use the chloroform extracting.Wash organic phase with saturated sodium-chloride water solution, by anhydrous magnesium sulfate drying and filtration.Filtrate under reduced pressure concentrates and provides 3.2g 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-group-2H-1,4-benzoxazine.
This compound has following physico-chemical property:
ⅰ) fusing point: 104-105 ℃
ⅱ) ultimate analysis is (to C 10H 11N 3O 4)
C（%） H（%） N（%）
Calculated value: 50.63 4.67 17.71
Actual value: 50.36 4.63 17.71
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），3.87（2H，s），7.06（1H，d），
8.08（1H，dd），8.90（1H，d）
（2）
Figure 901090743_IMG49
(2) with 2.29g 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-group-2H-1, the 4-benzoxazine is dissolved in the 69ml methyl alcohol, and this solution is carried out the ice bath cooling.Add in the above-mentioned solution contain the 8.1ml aqueous solution of 1.16g sodium hydroxide after, add 3.13g formamidino-sulfinic acid gradually.Mixture at room temperature stirs and spends the night, and concentrates then.Enriched material carries out column chromatography (eluent: hexane-ethyl acetate=9: 1) provide 0.4g 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
Recrystallization provides 0.28g purpose compound from ether-hexane.
This compound has following physico-chemical property:
ⅰ) fusing point: 83-85 ℃
ⅱ) ultimate analysis is (to C 10H 13N 3O 3)
C（%） H（%） N（%）
Calculated value: 53.81 5.87 18.82
Actual value: 53.75 5.80 18.93
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.41（6H，s），3.18（2H，s），6.77（1H，d），
7.66（1H，dd），8.06（1H，d）
（3）
(3) with 0.35g 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine are dissolved in the 4ml methylene dichloride, and solution carries out the ice bath cooling.In this solution, add the 0.16g triethylamine, dropwise add the 1.4ml dichloromethane solution that contains 0.18ml 4-chlorobutanoylchloride then.After 30 minutes, the dilute with water reaction mixture is also used the chloroform extracting.Organic phase is by anhydrous magnesium sulfate drying and under reduced pressure concentrated.Enriched material from ether crystallization and provide 0.43g 4-chloro-N-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) coarse crystal of butyramide.This coarse crystal does not need purifying promptly to can be used for next step reaction.
(4) the above-mentioned acid amides of 0.41g is dissolved in 8ml N, in the dinethylformamide, the cooling of solution ice bath.Then, add uncle's 0.14g fourth oxygen potassium gradually.Down mixture was stirred 1 hour ice-cooled, then dilute with water and wash organic phase with saturated sodium-chloride water solution again with ethyl acetate extraction, by anhydrous magnesium sulfate drying and filter.Filtrate under reduced pressure concentrates and crystallization from ether.Coarse crystal recrystallization from ethanol provides 0.16g 3,4-dihydro-2,2-dimethyl-4-(2-oxygen-1-pyrrolidyl)-6-nitro-2H-1, the 4-benzoxazine.
This compound has following physico-chemical property:
ⅰ) fusing point: 141-143 ℃
ⅱ) ultimate analysis is (to C 14H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 57.72 5.88 14.42
Actual value: 57.61 5.89 14.40
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.41（3H，s），1.42（3H，s），2.1-2.7（4H，m），
3.15（1H，d），3.4-3.8（3H，m），6.84（1H，d），
7.46（1H，d），7.70（1H，dd）
Example 42-44
Following compounds and example 41 methods 3 are synthetic in the same manner.
Figure 901090743_IMG51
Figure 901090743_IMG52
These compounds have following physico-chemical property.
Example 42
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(2-oxygen-1-pyrrolidyl)-2H-1, the 4-benzoxazine
ⅰ) fusing point: 149-150 ℃
ⅱ) ultimate analysis is (to C 15H 17N 3O 2)
C（%） H（%） N（%）
Calculated value: 66.40 6.32 15.49
Actual value: 66.29 6.08 15.51
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（3H，s），1.45（3H，s），2.1-2.6（4H，m），
3.11（1H，d），3.4-3.7（3H，m），
6.74-6.84（2H，m），7.04（1H，dd）
Example 43
N-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) ethanamide
ⅰ) fusing point: 167-168 ℃
ⅱ) ultimate analysis is (to C 12H 15N 2O 2Br)
C（%） H（%） N（%） Br（%）
Calculated value: 48.18 5.05 9.36 26.71
Actual value: 48.14 5.01 9.29 26.51
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.36-1.45（6H，m），2.06，2.12（3H，s x 2），
3.16，3.30（2H，s x 2），6.56-6.97（3H，m）
Example 44
3,4-dihydro-2,2-dimethyl-4-(2-oxygen-1-pyrrolidyl)-2H-1, the 4-benzoxazine
ⅰ) fusing point: 139-141 ℃
ⅱ) ultimate analysis is (to C 14H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 68.27 7.37 11.37
Actual value: 67.75 7.44 11.26
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（3H，s），1.46（3H，s），
2.04-2.58（4H，m），3.0-3.6（4H，m），
6.51-6.84（4H，m）
Example 45
Figure 901090743_IMG53
At room temperature, toward containing 3.01g 2-(3,4-dihydro-2,2-dimethyl-6-nitro-1,4-benzoxazine-4-yl) add the aqueous solution (50ml) that contains 10.9g ammonium chloride in the 50ml methanol solution of pyridine N-oxides.Then, add the 13.1g zinc powder down, mixture was stirred 15 hours down at 3 ℃ ice-cooled.Remove by filter insoluble material, filtrate concentrates, and dilute with water is also used the chloroform extracting.Solvent is removed in dry organic phase and distillation.Resistates carries out silica gel column chromatography, carries out wash-out with chloroform-methanol (50: 1).Wash-out obtains 1.86g 2-(6-amino)-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) pyridine N-oxides.This compound has following physico-chemical property.
ⅰ) fusing point: 200-202 ℃
ⅱ) ultimate analysis is (to C 15H 17N 3O 20.1H 2O)
C（%） H（%） N（%）
Calculated value: 65.97 6.35 15.39
Actual value: 65.94 6.35 15.39
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ (ppm): 1.30(6H, s), 3.28(2H, wide s), 3.69(2H, s),
6.19-7.49（6H，m），8.23（1H，m）
Example 46
Figure 901090743_IMG54
Toward containing 0.474g 2-(6-amino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) add 3 pyridines in the 5ml solution of acetic anhydride of pyridine N-oxides, mixture was at room temperature stirred 63 hours.After concentrating, resistates is dissolved in the chloroform, washs it with saturated sodium bicarbonate aqueous solution, dry and concentrated.Resistates recrystallization from chloroform-ether provides 0.285g 2-(6-acetylaminohydroxyphenylarsonic acid 3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) pyridine N-oxides.
This compound has following physico-chemical property:
ⅰ) fusing point: 290-295 ℃ (decomposition)
ⅱ) ultimate analysis is (to C 17H 19N 3O 30.1H 2O)
C（%） H（%） N（%）
Calculated value: 64.79 6.14 13.33
Actual value: 64.74 6.18 13.20
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.30（6H，s），2.04（3H，s），3.65（2H，s），
6.68-7.64（6H，m），8.18（1H，m）
Example 47
Figure 901090743_IMG55
Following compound is with synthetic with example 46 essentially identical methods.
2-(3,4-dihydro-2,2-dimethyl-6-methylsulfinyl amino-2H-1,4-benzoxazine=4=yl) pyridine N=oxide compound
ⅱ) ultimate analysis is (to C 16H 19N 3O 40.5H 2O)
C（%） H（%） N（%） S（%）
Calculated value: 53.62 5.62 11.72 8.95
Actual value: 53.74 5.33 11.68 9.21
ⅱ) NMR collection of illustrative plates (CDCl 3+ DMSO-d 6)
δ（ppm）：1.28（6H，s），2.84（3H，s），3.51（2H，s），
6.24-8.40(7H, m), 9.12(1H, wide s)
ⅲ) mass spectrum (m/z): 349(M +)
Example 48
With 0.5g trans-4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-4-oxygen-2-butylene acetoacetic ester is dissolved in the 2ml ethanol, add 1.5ml then and contain the aqueous solution of 0.06g NaOH, mixture was at room temperature stirred 2 hours.Ethanol is removed in distillation under reduced pressure, with 1N hydrochloric acid resistates is adjusted to pH4.The resulting throw out of filtered and recycled, water and washing with alcohol and provide 0.31g trans-4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-4-oxygen-2-butylene acid.
This compound has following physico-chemical property:
ⅰ) fusing point: 222-226 ℃
ⅱ) ultimate analysis is (to C 14H 14N 2O 6)
C（%） H（%） N（%）
Calculated value: 54.90 4.61 9.15
Actual value: 54.90 4.70 9.08
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.32（6H，s），3.86（2H，s），6.70（1H，d），
7.08（1H，d），7.48（1H，d），7.96（1H，dd），
8.4-8.8(1H, wide s)
Example 49
Figure 901090743_IMG57
Following compounds is with synthetic with example 48 essentially identical methods.
(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) acetate
Physico-chemical property:
ⅰ) fusing point: 162-164 ℃ of (decomposition) (hexane-ethyl acetate)
ⅱ) ultimate analysis is (to C 12H 14N 2O 5)
C（%） H（%） N（%）
Calculated value: 54.13 5.30 10.52
Actual value: 53.95 5.22 10.58
ⅲ) NMR collection of illustrative plates (DMRO-d 6)
δ（ppm）：1.29（6H，s），3.24（2H，s），4.22（2H，s），
6.83（1H，d），7.34（1H，d），7.50（1H，dd），
12.84(1H, wide s).
ⅳ) mass spectrum (m/z): 267(M ++ 1) .Fab(pos.)
Example 50
Figure 901090743_IMG58
5ml methylamine (40%, in methyl alcohol) is joined 1.00g(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) in the ethyl acetate, mixture was stirred 1 hour down at 100 ℃.Then, under reduced pressure concentrate this reaction mixture and provide thick 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-the N-methylacetamide.Wash this product and obtain the 950g coarse crystal with normal hexane-ethyl acetate.Recrystallization provides 866mg purpose compound from ethyl acetate-normal hexane.
This compound has following physico-chemical property:
ⅰ) fusing point: 127-128 ℃
ⅱ) ultimate analysis is (to C 13H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 55.91 6.14 15.05
Actual value: 55.93 6.11 15.16
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.40（6H，s），2.86（3H，d），3.18（2H，s），
3.93(2H, s), 6.18(1H, wide s),
6.82（1H，d），7.42（1H，d），7.66（1H，dd）
Example 51-55
Adopt by method 4 synthetic esters, following compounds obtains with the method identical with example 50.
Figure 901090743_IMG59
Example
No. R 2R 5R 6R 7Initial compounds
51 CN CH 3CH 3-CH 2CONHCH 3
Figure 901090743_IMG60
Figure 901090743_IMG61
Example 51
2-(6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl)-the N-methylacetamide
Physico-chemical property:
ⅰ) fusing point: 150-151 ℃
ⅱ) ultimate analysis is (to C 14H 17N 3O 2)
C（%） H（%） N（%）
Calculated value: 64.85 6.61 16.20
Actual value: 64.85 6.59 16.29
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.39（6H，s），2.87（3H，d），3.17（2H，s），
3.85（2H，s），6.75-6.86（2H，m），
7.05（1H，dd）
Example 52
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-the N-ethyl acetamide
Physico-chemical property:
ⅰ) fusing point: 115-116 ℃
ⅱ) ultimate analysis is (to C 14H 19N 3O 4)
C（%） H（%） N（%）
Calculated value: 57.33 6.53 14.33
Actual value: 57.24 6.57 14.34
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.12（3H，t），1.40（6H，s），3.19（2H，s），
3.34（2H，m），3.91（2H，s），
6.17(1H, wide s), 6.82(1H, d),
7.44（1H，d），7.66（1H，dd）
Example 53
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-the N-(2-hydroxyethyl) ethanamide
Physico-chemical property:
ⅰ) fusing point: 146-147 ℃
ⅱ) ultimate analysis is (to C 14H 19N 3O 5)
C（%） H（%） N（%）
Calculated value: 54.36 6.19 13.58
Actual value: 54.29 6.21 13.49
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ (ppm): 1.40(6H, s), 1.64(1H, wide s),
3.19（2H，s），3.34-3.82（4H，m），
3.93(2H, s), 6.72(1H, wide s),
6.81（1H，d），7.43（1H，d），7.64（1H，dd）
Example 54
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-the N-methyl propanamide
Physico-chemical property:
ⅰ) fusing point: 181-182 ℃
ⅱ) ultimate analysis is (to C 14H 19N 3O 4)
C（%） H（%） N（%）
Calculated value: 57.33 6.53 14.33
Actual value: 57.27 6.54 14.34
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（6H，s），1.45（3H，d），2.86（3H，d），
3.05（2H，s），4.43（1H，q），
6.14(1H, wide s), 6.83(1H, dd),
7.50-7.75（2H，m）
Example 55
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-N-methyl-2-acetamide oxide
Physico-chemical property:
ⅰ) fusing point: 129-130 ℃
ⅱ) ultimate analysis is (to C 13H 15N 3O 5)
C（%） H（%） N（%）
Calculated value: 53.24 5.16 14.33
Actual value: 53.04 5.05 14.25
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.39（6H，s），2.95（3H，d），
4.28(1H, wide s), 6.93(1H, d),
7.99(1H, dd), 9.87(1H, wide s)
Example 56
Figure 901090743_IMG62
With 1.0g(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) acetate and 1.34g sulfur oxychloride be dissolved in the 6ml chloroform, adds 2 pyridines then.Mixture refluxed 5 hours, when 5 hours finish, under reduced pressure concentrated and provided chloride of acid as thick product.
Above-mentioned thick chloride of acid is dissolved in the 5ml chloroform, this solution dropwise is added in the mixing solutions of the 20ml chloroform that contains 0.93g Dimethylammonium chloride and 1.15g triethylamine, the companion's is ice-cooled.Then, mixture is at room temperature stirred 4 hours and concentrate.Resistates is carried out silica gel column chromatography, adopt hexane-ethyl acetate (3: 1-1: 3) provide 0.46g 2-(3 as eluent, 4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-N, the N-N,N-DIMETHYLACETAMIDE is then with its recrystallization from ethyl acetate-hexane.This compound has following physico-chemical property.
ⅰ) fusing point: 179-180 ℃
ⅱ) ultimate analysis is (to C 14H 19N 3O 4)
C（%） H（%） N（%）
Calculated value: 57.33 6.53 14.33
Actual value: 57.26 6.48 14.23
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（6H，s），2.99（3H，s），3.12（3H，s），
3.23（2H，s），4.18（2H，s），6.79（1H，d），
7.31（1H，d），7.60（1H，dd）
ⅳ) mass spectrum (m/z): 293(M +)
Example 57-58
Following compounds is with synthetic with example 56 essentially identical modes.
Example 57
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) ethanamide
Physico-chemical property:
ⅰ) fusing point: 183-184 ℃
ⅱ) ultimate analysis is (to C 12H 15N 3O 4)
C（%） H（%） N（%）
Calculated value: 54.33 5.70 15.84
Actual value: 54.34 5.68 15.84
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.40（6H，s），3.20（2H，s），3.93（2H，s），
6.07(2H, wide d), 6.81(1H, d),
7.44（1H，d），7.64（1H，dd）
Example 58
Figure 901090743_IMG64
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-phenyl acetanilide,Phenacetylaniline
Physico-chemical property:
ⅰ) fusing point: 185-187 ℃
ⅱ) ultimate analysis is (to C 18H 19N 3O 4)
C（%） H（%） N（%）
Calculated value: 63.33 5.61 12.31
Actual value: 63.15 5.70 12.15
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.46（6H，s），3.24（2H，s），4.03（2H，s），
6.81-7.80(8H, m), 9.10(1H, wide s)
Example 59
Figure 901090743_IMG65
With 0.4g 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-4-oxygen-2-butylene acid, 0.3g dicyclohexyl carbodiimide and 0.26g I-hydroxybenzotriazole be dissolved in the 10ml tetrahydrofuran (THF).Ice-cooled down, adding 2ml contains 0.1g Dimethylammonium chloride and the mixing solutions of 0.13g triethylamine in the 2ml tetrahydrofuran (THF) in this solution.Mixture was at room temperature stirred 3 days, then, filter out throw out, and distillation under reduced pressure is except that desolvating.Resistates is dissolved in the ethyl acetate, with wet chemical and this solution of water washing and pass through anhydrous magnesium sulfate drying.Then, distillation under reduced pressure removes desolvates, and resistates passes through silica gel column chromatography and purifying.Provide 0.26g 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl with the resulting coarse crystal of ethyl acetate-hexane wash)-N, N-dimethyl-4-oxygen-2-butylene acid amides.
This compound has following physico-chemical property
ⅰ) fusing point: 179-182 ℃
ⅱ) ultimate analysis is (to C 16H 19N 3O 5)
C（%） H（%） N（%）
Calculated value: 57.65 5.75 12.61
Actual value: 57.55 5.96 12.21
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.36（6H，s），3.04（3H，s），3.20（3H，s）
3.80（2H，s），6.94（1H，d），7.36（1H，d）
7.60（1H，d），7.98（1H，dd）
Example 60-62
Following compounds is with synthetic with example 59 essentially identical methods.
Example 60
Figure 901090743_IMG66
2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-N-sec.-propyl ethanamide
Physico-chemical property:
ⅰ) fusing point: 156-156.5 ℃
ⅱ) ultimate analysis is (to C 14H 17N 3O 2)
C（%） H（%） N（%）
Calculated value: 58.62 6.89 13.67
Actual value: 58.58 6.96 13.63
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.13（6H，d），1.40（6H，s），3.17（2H，s）
3.86（2H，s），4.09（1H，m），6.81（1H，d）
7.43（1H，d），7.65（1H，dd）
Mass spectrum (m/z): 293(M +)
Example 61
Figure 901090743_IMG67
3,4-dihydro-2,2-dimethyl-6-nitro-4-[(1-pyrrolidyl carbonyl) methyl]-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 165-166 ℃
ⅱ) ultimate analysis is (to C 16H 21N 3O 4)
C（%） H（%） N（%）
Calculated value: 60.18 6.63 13.16
Actual value: 60.17 6.68 13.10
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.38（6H，s），1.70-2.24（4H，m），3.27（2H，s），
3.34-3.66（4H，m），4.08（2H，s），6.79（1H，d），
7.33（1H，d），7.59（1H，dd）
Example 62
Figure 901090743_IMG68
N-benzyl-2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) ethanamide
Physico-chemical property:
ⅰ) fusing point: 133-135 ℃
ⅱ) ultimate analysis is (to C 19H 21N 3O 4)
C（%） H（%） N（%）
Calculated value: 64.21 5.96 11.82
Actual value: 64.17 6.08 11.88
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.19（2H，s），3.98（2H，s），
4.50(2H, d), 6.55(1H, wide t), 6.81(1H, d),
7.26（5H，s），7.48（1H，d），7.66（1H，dd），
Example 63
Figure 901090743_IMG69
With 0.33g 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridylmethyl)-2H-1, the 4-benzoxazine is dissolved in the 4ml methylene dichloride, adds the 0.26g metachloroperbenzoic acid then, mixture is at room temperature stirred spend the night.With sodium bicarbonate aqueous solution dilute this reaction mixture and with the methylene dichloride extracting it.Organic phase is by anhydrous magnesium sulfate drying and filtration.Filtrate under reduced pressure concentrates and provides 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) PICOLINE N-OXIDES.Recrystallization provides 0.2g purpose compound from ethanol.This compound is found has following physico-chemical property.
ⅰ) fusing point: 139-140 ℃
ⅱ) ultimate analysis is (to C 16H 17N 3O 4)
C（%） H（%） N（%）
Calculated value: 60.94 5.43 13.33
Actual value: 60.69 5.47 13.18
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.41（6H，s），3.27（2H，s），4.78（2H，s）
6.83（1H，d），7.12-7.34（4H，m），7.61（1H，dd）
8.24-8.42（1H，m），
Example 64
Following compounds is with synthetic with example 63 essentially identical methods.
Figure 901090743_IMG70
3-(6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-yl) PICOLINE N-OXIDES
Physico-chemical property:
ⅰ) fusing point: 144-147 ℃
ⅱ) ultimate analysis is (to C 17H 17N 3O 2)
C（%） H（%） N（%）
Calculated value: 69.14 5.80 14.23
Actual value: 69.33 5.82 14.23
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），3.11（2H，s），4.42（2H，s）
6.70-7.36（5H，m），8.08-8.18（2H，m），
Example 65
Figure 901090743_IMG71
With 3.33g 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, the 4-benzoxazine is dissolved in 40ml N, in the dinethylformamide, adds the 0.77g sodium hydride then.Mixture was at room temperature stirred 30 minutes and carry out ice-cooled.Then, be no more than under 5 ℃ the temperature, 6ml is contained the N of 2.76g 2-chloropyrazine-3-carboxylate methyl ester, dinethylformamide dropwise adds.Reaction mixture was at room temperature stirred 3.5 hours, when this time finishes, be poured into and also use the ethyl acetate extracting in the frozen water.Wash extract with water and pass through anhydrous magnesium sulfate drying.Then, solvent is removed in distillation under reduced pressure, and resistates passes through silica gel column chromatography and purifying.Resulting coarse crystal from ethanol recrystallization and provide 1.27g 3,4-dihydro-2,2-dimethyl-4-(2-methoxyl group-3-pyrazinyl) carbonyl-6-nitro-2H-1, the 4-benzoxazine.This compound has following physico-chemical property.
ⅰ) fusing point: 183-186 ℃
ⅱ) ultimate analysis is (to C 16H 16N 4O 5)
C（%） H（%） N（%）
Calculated value: 55.81 4.68 16.27
Actual value: 55.96 4.55 16.09
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ (ppm): 1.4-1.6(9H, wide s), 3.90(2H, s),
6.90(1H, d), 7.80-8.0(1H, wide s),
8.1-8.2（2H，m）
Example 66
Figure 901090743_IMG72
(1) by the process identical, obtain 3,4-dihydro-4-[(2-methoxypyridine-3-yl with example 65) carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
This compound has following physico-chemical property:
ⅰ) fusing point: 179-182 ℃
ⅱ) ultimate analysis is (to C 17H 17N 3O 5)
C（%） H（%） N（%）
Calculated value: 59.47 4.99 12.24
Actual value: 59.50 5.08 12.01
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.45（6H，s），3.1-4.0（5H，m），
6.90-7.26（3H，m），7.85-7.98（2H，m），
8.29（1H，dd）
(2) with 0.4g 3,4-dihydro-4-[(2-methoxypyridine-3-yl) carbonyl]-2,2-methyl-6-nitro-2H-1,4-benzoxazine are dissolved in the 6ml tetrahydro-carbon, dropwise add 0.26g trimethylammonium iodine silicomethane then.Mixture 50 ℃ of heating 2 hours, is cooled off then.The dilute with water reaction mixture is also used the chloroform extracting.Organic phase is by anhydrous magnesium sulfate drying and filtration, and filtrate under reduced pressure concentrates, and methyl alcohol is added in the enriched material with crystallization.Recrystallization from ethyl acetate and provide 0.31g 3,4-dihydro-4-[(2-pyridone-3-yl) carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
This compound has following physico-chemical property:
ⅰ) fusing point: 183-184 ℃
ⅱ) ultimate analysis is (to C 16H 15N 3O 50.8CH 3COOC 2H 5)
C（%） H（%） N（%）
Calculated value: 57.68 5.40 10.51
Actual value: 57.66 5.40 10.56
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ (ppm): 1.41(6H, s), 3.70(2H is wide, s), 6.34(1H, m)
6.94（1H，d），7.40-7.96（3H，m），8.61（1H，m）
Example 67
Figure 901090743_IMG73
Add the 20ml tetracol phenixin in the 2.53g cyclopentanone, the dibenzoyl peroxide of inferior acid amides of 5.34gN-bromo amber and catalytic amount refluxes mixture 3 hours under heating.After the cooling, filter reaction mixture, filtrate under reduced pressure concentrates.Enriched material and 2.43g triethylamine joined contain 0.38g 6-cyano group-3,4-dihydro-2,3-dimethyl-2H-1 in the solution of the 5ml tetrahydrofuran (THF) of 4-benzoxazine, at room temperature stirs mixture and to spend the night.Then, concentrated reaction mixture under reduced pressure, dilute with water and use the ethyl acetate extracting.Isolate organic phase, by anhydrous magnesium sulfate drying and under reduced pressure concentrated.Resistates carries out silica gel column chromatography (eluent: hexane-ethyl acetate=10: 1-4: 1) provide the thick 6-cyano group-3 of 0.3g, 4-dihydro-2,2-dimethyl-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1,4-benzoxazine.Recrystallization from ethanol-hexane and provide the pure product of 0.16g, this compound has following physico-chemical property.
ⅰ) fusing point: 124-126 ℃
ⅱ) ultimate analysis is (to C 16H 16N 2O 2)
C（%） H（%） N（%）
Calculated value: 71.62 6.01 10.44
Actual value: 71.52 5.99 10.30
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.33（6H，s），2.50-2.77（4H，m），3.42（3H，s）
6.84（1H，d），7.01-7.14（2H，m），7.21（1H，t）
Example 68-72
Following compounds is synthetic with the method identical with example 67.
Example 68
Figure 901090743_IMG74
6-bromine 3,4-dihydro-2,2-dimethyl-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 110-115 ℃
C（%） H（%） Br（%） N（%）
Calculated value: 55.92 5.01 24.80 4.35
Actual value: 55.61 5.06 24.49 4.28
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.26（6H，s），2.4-2.8（4H，m），3.36（2H，s）
6.59（1H，d），6.74（1H，d），6.87（1H，dd）
7.11（1H，t）
Example 69
3,4-dihydro-6-methoxyl group-2,2-dimethyl-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 95-97 ℃
ⅱ) ultimate analysis is (to C 16H 19NO 3)
C（%） H（%） N（%）
Calculated value: 70.31 7.01 5.12
Actual value: 70.17 6.90 4.92
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.28（6H，s），2.44-2.70（4H，m），3.43（2H，s）
3.69（3H，s），6.36（1H，dd），6.47（1H，d）
6.72（1H，d），7.17（1H，t）
Example 70
Figure 901090743_IMG76
3,4-dihydro-2,2-dimethyl-6-nitro-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 96-98 ℃
ⅱ) ultimate analysis is (to C 15H 16N 2O 40.1H 2O)
C（%） H（%） N（%）
Calculated value: 62.10 5.63 9.66
Actual value: 62.11 5.64 9.43
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：2.33（6H，s），2.51-2.59（2H，m），
2.64-2.75（2H，m），3.44（2H，s）
6.83（1H，dd），7.24（1H，t），
7.61-7.22（2H，m）
Example 71
Figure 901090743_IMG77
6-ethyl-3,4-dihydro-2,2-dimethyl-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 68-70 ℃
ⅱ) ultimate analysis is (to C 17H 21NO 2)
C（%） H（%） N（%）
Calculated value: 75.25 7.80 5.16
Actual value: 75.30 7.95 5.17
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.11（3H，t），1.27（6H，s），
2.54-2.72（6H，m），3.44（2H，s），
6.55-6.82（3H，m），7.06-7.17（1H，t）
Example 72
3,4-dihydro-2,2-dimethyl-7-nitro-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
ⅰ) fusing point: 88-89 ℃
ⅱ) ultimate analysis is (to C 15H 16N 2O 4)
C（%） H（%） N（%）
Calculated value: 62.49 5.59 9.72
Actual value: 62.21 5.61 9.60
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），2.50-2.64（2H，m），
2.68-2.79（2H，m），3.41（2H，s），
6.68（1H，s），7.35（1H，t）
7.60-7.74（2H，m）
Example 73
Figure 901090743_IMG79
With 0.5g 6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1, the 4-benzoxazine, 0.33g hexanaphthene-1, the tosic acid of 2-diketone and catalytic amount are dissolved in the 15ml toluene, adopt dean stark trap, and solution was refluxed 4 hours under heating.After the cooling, with saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution washing reaction mixture, and by anhydrous magnesium sulfate drying, solvent is removed in distillation under reduced pressure.Resistates provides 0.5g 6-cyano group-3,4-dihydro-2,2-dimethyl-4-(6-oxygen-1-cyclopentenes-1-yl by purification by silica gel column chromatography with the resulting coarse crystal of washing with alcohol)-2H-1, the 4-benzoxazine
This compound has following physico-chemical property:
ⅰ) fusing point: 166-170 ℃
ⅱ) ultimate analysis is (to C 17H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 72.32 6.43 9.92
Actual value: 72.36 6.38 9.83
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.34（6H，s），2.0-2.2（2H，m），
2.5-2.7（4H，m），2.20（2H，s），
6.60（1H，d），6.76（1H，d），6.8-7.0（2H，m）
Example 74-76
Following compounds is with synthetic with example 73 essentially identical methods.
Example 74
Figure 901090743_IMG80
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(4-methyl-5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 106-108 ℃
ⅱ) ultimate analysis is (to C 17H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 72.32 6.43 9.92
Actual value: 72.49 6.50 9.88
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.26（3H，d），1.34（6H，s），2.1-3.1（3H，m）
3.43（2H，s），6.84（1H，d），7.0-7.2（3H，m）
Example 75
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(3-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 180-184 ℃
ⅱ) ultimate analysis is (to C 16H 16N 2O 20.1H 2O)
C（%） H（%） N（%）
Calculated value: 71.15 6.05 10.37
Actual value: 71.23 6.10 10.10
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.39（6H，s），2.4-2.6（2H，m），
2.7-2.9（2H，m），3.55（2H，s），5.73（1H，s）
6.96（1H，d），7.34（1H，dd），7.68（1H，d）
Example 76
6-cyano group-3,4-dihydro-2,2-dimethyl-4-(3-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 147-150 ℃
ⅱ) ultimate analysis is (to C 17H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 72.32 6.43 9.92
Actual value: 72.40 6.48 9.91
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），2.12（2H，m），2.44（2H，t）
2.64（2H，t），3.48（2H，s），5.75（1H，s）
6.93（1H，d），7.23（1H，d），7.36（1H，dd）
Example 77
Figure 901090743_IMG83
With 0.5g 6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1, the 4-benzoxazine, 1.2ml 2, and the toluenesulphonic acids of crossing of 3-dimethyl diketone and catalytic amount is dissolved in the 2ml toluene, and mixture was stirred 2 days down at 100 ℃.Under reduced pressure solvent is removed in distillation then, and resistates is dissolved in the toluene again, washs it with saturated sodium bicarbonate aqueous solution, passes through anhydrous magnesium sulfate drying.Solvent is removed in distillation then, and resistates provides 0.15g 6-cyano group-3 by purification by silica gel column chromatography, 4-dihydro-2,2-dimethyl-4-(2,5-dimethyl-3-furyl)-2H-1, the 4-benzoxazine.
Physico-chemical property:
ⅰ) fusing point: 130-132 ℃
ⅱ) ultimate analysis is (to C 17H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 72.32 6.43 9.92
Actual value: 72.35 6.49 9.93
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.36（6H，s），2.12（3H，s），2.24（3H，s）
3.20（2H，s），5.80（1H，s），6.70（1H，d）
6.76（1H，d），6.94（1H，dd）
Example 78-79
Following compound is with synthetic with example 73 essentially identical methods.
Example 78
Figure 901090743_IMG84
3,4-dihydro-2,2-dimethyl-6-nitro-4-(1-oxo indenes-2-yl)-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 161-165 ℃
ⅱ) ultimate analysis is (to C 19H 16N 2O 4)
C（%） H（%） N（%）
Calculated value: 67.85 4.79 8.33
Actual value: 67.89 4.90 8.22
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.37（6H，s），3.66（2H，s），
6.8-7.4（6H，m），7.76（1H，dd），
8.04（1H，d），
Example 79
Figure 901090743_IMG85
4-(2-ethoxycarbonyl cyclopentenes-1-yl)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 157-158 ℃
ⅱ) ultimate analysis is (to C 18H 22N 2O 50.5H 2O)
C（%） H（%） N（%）
Calculated value: 60.83 6.52 7.88
Actual value: 61.03 6.26 7.71
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.20（3H，t），1.35（6H，s），
1.76-2.09（2H，m），2.64-2.84（4H，m）
3.41（2H，s），4.11（2H，q），6.83（1H，d），
7.59-7.77（2H，m）
Example 80
Figure 901090743_IMG86
With 0.3g 6-cyano group-3,4-dihydro-2,2-dimethyl-4-(5-oxygen-1-cyclopentenes-1-yl)-2H-1, the 4-benzoxazine is dissolved in the 3ml pyridine, adds the 0.26g methoxy-amine hydrochloride then.Mixture at room temperature stirred spend the night, under reduced pressure solvent is removed in distillation then.Resistates is toppled in the entry, with the ethyl acetate extracting it.Wash with water extract and by anhydrous magnesium sulfate drying it, solvent is removed in distillation under reduced pressure.At last, with ethanol, ether debris and provide 0.26g 6-cyano group-3,4-dihydro-4-(5 methoxyimino-1-cyclopentenes-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine
This compound has following physico-chemical property:
ⅰ) fusing point: 138-141 ℃
ⅱ) ultimate analysis is (to C 17H 19N 3O 2)
C（%） H（%） N（%）
Calculated value: 68.67 6.44 14.13
Actual value: 68.40 6.60 13.95
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（6H，s），2.4-2.8（4H，m），
3.38（2H，s），3.84（3H，s），6.26（1H，t），
6.78（1H，d），6.98（1H，dd），7.14（1H，d）
Example 81
Figure 901090743_IMG87
With 1.0g 6-cyano group-3,4-dihydro-2,2-dimethyl-2H-1, the 4-benzoxazine is dissolved in 20ml N, in the dinethylformamide, adds the 0.24g sodium hydride then.Mixture was stirred 1 hour down at 70 ℃, be cooled to room temperature after, add the 0.5ml cyclopentene oxide.Mixture was stirred 3 hours down at 70 ℃ again.With the reaction mixture cooling, dilute with water is also used the ethyl acetate extracting then.Extract water and sodium chloride aqueous solution washing, and by anhydrous magnesium sulfate drying, solvent under reduced pressure distills removal.Resistates is by silica gel column chromatography and purifying, recrystallization from ethyl acetate-hexane and provide 0.53g 6-cyano group-3,4-dihydro-4-(2-hydroxycyclopent-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine.
Physico-chemical property:
ⅰ) fusing point: 95-97 ℃
ⅱ) ultimate analysis is (to C 16H 20N 2O 2)
C（%） H（%） N（%）
Calculated value: 70.56 7.40 10.29
Actual value: 70.40 7.46 10.23
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.30（6H，s），1.4-2.2（6H，m），2.94（2H，s）
3.8-4.3（2H，m），6.72（1H，d，J＝8.5Hz），
6.92（1H，dd，J＝2.5，8.5Hz），
7.06（1H，dd，J＝2.5，8.5Hz）
Example 82
At-50 ℃--under 60 ℃ the steady temperature, the 0.2ml oxalyl chloride is dissolved in the 5ml methylene dichloride, will dropwise adds by the solution that the 0.34ml dmso solution is made in the 1ml methylene dichloride.Mixture stirred 2 minutes, then, dropwise added and contained 0.54g 6-cyano group-3,4-dihydro-2,2-dimethyl-4-(2-hydroxycyclopent-1-yl)-2H-1, the 2ml dichloromethane solution of 4-benzoxazine.Mixture was further stirred 15 minutes, add the 0.7ml triethylamine.With mixture restir 5 minutes, make it to be returned to room temperature then.With 10ml water diluted reaction mixture, and use the methylene dichloride extracting.With NaCl solution washing extract and by anhydrous magnesium sulfate drying, solvent under reduced pressure distills removal.The filtered and recycled resistates, with washing with alcohol and from ethyl acetate recrystallization and provide 0.28g 6-cyano group-3,4-dihydro-2,2-dimethyl-4-(2-oxygen cyclopentyl)-2H-1, the 4-benzoxazine.
Physico-chemical property:
ⅰ) fusing point: 172-175 ℃
ⅱ) ultimate analysis is (to C 16H 18N 2O 2)
C（%） H（%） N（%）
Calculated value: 71.09 6.71 10.36
Actual value: 71.01 6.82 10.29
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（3H，s），1.36（3H，s），1.7-2.6（6H，m）
2.86（2H，dd，J＝3.5，11.5Hz），
4.0-4.3(1H, wide s),
6.74（1H，d，J＝8.5Hz），
6.80（1H，d，J＝2.5Hz），
6.94（1H，dd，J＝2.5，8.5Hz）
Example 83
Figure 901090743_IMG89
In the tetrahydrofuran solution (1M) of 9ml borane-tetrahydrofuran (THF) mixture, add 1.30g 4-(2-furoyl base)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, the 4-benzoxazine, the companion's is ice-cooled.Then mixture is refluxed under heating and stirred 2.5 hours.Add 1.1ml methyl alcohol in this mixture, after refluxing again 1 hour, pour into reaction mixture in the frozen water and use the ethyl acetate extracting.Wash organic phase with water, and by anhydrous magnesium sulfate drying, solvent is removed in distillation.Resistates carries out silica gel column chromatography and uses hexane-toluene (2: 1) wash-out.To derive from coarse crystallization recrystallization from 2ml ethanol of eluate, and provide 546mg 4-furfuryl group-3,4-dihydro-2,2-methyl-6-nitro-2H-1,4-benzoxazine.
This compound has following physico-chemical property:
ⅰ) fusing point: 94-97 ℃
ⅱ) ultimate analysis is (to C 15H 16N 2O 4)
C（%） H（%） N（%）
Calculated value: 62.49 5.59 9.72
Actual value: 62.44 5.51 9.76
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.35（6H，s），3.13（2H，s），4.50（2H，s），
6.3-6.4（2H，m），6.77（1H，d），3.36（1H，t），
7.58（1H，dd），7.71（1H，d）
Example 84
Under 140 ℃, with 2.08g 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1, the 4-benzoxazine, the mixture of 2.96g ethyl orthoformate and 2.40g diethyl malonate stirred 12 hours in the test tube of a sealing.After the cooling, solvent is removed in distillation, resistates provides 0.33g 2-[1-(3 by purification by silica gel column chromatography, 4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) ethoxyl methyl] diethyl malonate (compd A) and 0.31g2-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl) methylene radical diethyl malonate (compd B)
Compd A
ⅰ) fusing point: 71-74 ℃
ⅱ) ultimate analysis is (to C 20H 28N 2O 8)
C（%） H（%） N（%）
Calculated value: 56.60 6.65 6.60
Actual value: 56.46 6.61 6.46
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.1-1.5（15H，m），3.29（2H，s），
3.72（2H，q），4.28（4H，q），6.95（1H，d），
7.9-8.1（3H，m），
Compd B
ⅰ) fusing point: 89-91 ℃
ⅱ) ultimate analysis is (to C 18H 22N 2O 7)
C（%） H（%） N（%）
Calculated value: 57.14 5.86 7.40
Actual value: 56.93 5.80 7.27
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.2-1.6（12H，m），3.36（2H，s），
4.28（4H，q），6.95（1H，d），7.9-8.0（3H，m）
Example 85
Figure 901090743_IMG91
With 0.5g 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl)-4-oxygen-2-butylene acetoacetic ester, add 0.116g40% methylamine (in methyl alcohol) then.Mixture was at room temperature stirred 4 days, and under reduced pressure solvent is removed in distillation then.Resistates provides 0.2g 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-yl by purification by silica gel column chromatography with the resulting coarse crystal of ethanol-hexane wash)-3-methylamino-4-oxy butyrate ethyl ester.
This compound has following character:
ⅰ) fusing point: 75-77 ℃
ⅱ) ultimate analysis is (to C 17H 23N 3O 6)
C（%） H（%） N（%）
Calculated value: 55.88 6.34 11.50
Actual value: 55.68 6.30 11.47
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.28（3H，t），1.36（6H，s），2.42（3H，s），
3.02（2H，d），3.6-3.8（3H，m），
4.20（2H，q），6.90（1H，d），7.94（1H，dd），
8.3-8.5(1H, wide s)
Example 86
Figure 901090743_IMG92
With 0.35g 3,4-dihydro-2,2-dimethyl-4-(2-oxygen-1-pyrrolidyl)-2H-1, the 4-benzoxazine is dissolved in the 5.2ml acetonitrile, progressively adds the 0.22g nitronium tetrafluoroborate then.Mixture was stirred 30 minutes, pour into then and also use the ethyl acetate extracting in the frozen water.Dry organic phase also under reduced pressure concentrates, and resistates carries out silica gel column chromatography.With the coarse crystal that derives from eluate from chloroform-ether recrystallization and provide 0.07g 3,4-dihydro-2,2-dimethyl-5,7-dinitrobenzene-4-(2-oxygen-1-pyrrolidyl)-2H-1, the 4-benzoxazine.
This compound has following physico-chemical property:
ⅰ) fusing point: 189-191 ℃
ⅱ) ultimate analysis is (to C 14H 16N 4O 6)
C（%） H（%） N（%）
Calculated value: 50.00 4.80 16.66
Actual value: 49.40 4.76 16.07
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.44（3H，s），1.46（3H，s），
1.92-2.44（4H，m），3.18-3.61（4H，m），
7.76（1H，d），7.90（1H，d）
Following compound is with synthetic with example 41 essentially identical methods.
Example 87
Figure 901090743_IMG93
3,4-dihydro-2,2-dimethyl-4-(2-oxygen-1-piperazine alkyl)-6-nitro-2H-1, the 4-benzoxazine
ⅰ) fusing point: 166-168 ℃
ⅱ) ultimate analysis is (to C 15H 19N 3O 4)
C（%） H（%） N（%）
Calculated value: 59.01 6.27 13.76
Actual value: 58.89 6.32 13.73
ⅲ) NMR collection of illustrative plates (DMSO-d 6)
δ（ppm）：1.33（3H，s），1.40（3H，s），1.7-2.1（2H，m），
2.4-2.6（4H，m），3.3-3.7（4H，m），
6.92（1H，d），7.28（1H，d），7.59（1H，dd）
Example A
Figure 901090743_IMG94
With 6.66g 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-2H-1, the 4-benzoxazine, the 5.51g bromoethyl acetate, the mixture of 4.56g salt of wormwood and 20ml acetonitrile refluxed 2.5 hours under heating.Then, add 10ml N, dinethylformamide stirs mixture 2 hours down at 80 ℃.In this mixture, add the 2.80g bromoethyl acetate.Stirring is after 1 hour down at 80 ℃, and adding 2.28g salt of wormwood, mixture continue to stir 1 hour under 80 ℃.Then, under reduced pressure concentrate this reaction mixture, resistates carries out silica gel column chromatography, adopts hexane-ethyl acetate (10: 1) to carry out wash-out.With the crystal that derives from eluate from ethyl acetate-hexane recrystallization and provide 7.4g(3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-2H-1,4-benzoxazine-4-yl) ethyl acetate.This compound has following physico-chemical property:
ⅰ) fusing point: 67-68 ℃
ⅱ) ultimate analysis is (to C 14H 16N 2O 6)
C（%） H（%） N（%）
Calculated value: 54.54 5.23 9.09
Actual value: 54.49 5.24 9.06
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（3H，t），1.59（6H，s），4.28（2H，q），
4.69（2H，s），7.08（1H，d），7.62（1H，d），
7.97（1H，dd），
Example B
Obtain following compounds by the process identical with example A:
Figure 901090743_IMG95
(3,4-dihydro-6-nitro-3-oxygen-2H-1,4-benzoxazine-4-yl) ethyl acetate
Physico-chemical property
ⅰ) fusing point: 102-103 ℃
ⅱ) ultimate analysis is (to C 12H 12N 2O 6)
C（%） H（%） N（%）
Calculated value: 51.43 4.32 10.00
Actual value: 51.52 4.28 10.07
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.32（3H，t），4.28（2H，q），
4.68（2H，s），4.78（2H，s），7.08（1H，d），
7.62（1H，d），7.94（1H，dd）
Example C
Figure 901090743_IMG96
In argon gas stream, with 2.0g 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-2H-1,4-benzoxazine are added to the dried N of 40ml that contains 0.4g 60% sodium hydride (in oil) gradually, in the dinethylformamide.Mixture was at room temperature stirred 1 hour, add the 2.68g phenacyl bromide.Mixture was at room temperature stirred 1 hour, and under reduced pressure solvent is removed in distillation then.With 50ml water dilution resistates, and use the ethyl acetate extracting.Extract is by anhydrous magnesium sulfate drying and under reduced pressure concentrated.Resistates carries out silica gel column chromatography and carries out wash-out with methylene dichloride-ethyl acetate.Recrystallization from ethyl acetate-ether and provide 2.04g 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-4-phenacyl-2H-1,4-benzoxazine.
Physico-chemical property:
ⅰ) ultimate analysis (C 18H 16N 2O 5)
C（%） H（%） N（%）
Calculated value: 63.53 4.74 8.23
Actual value: 63.61 4.72 8.05
ⅱ) mass spectrum (EI): m/z 340(M +)
Example D-F
Obtain following compounds by the process identical with example C.
Example D
Figure 901090743_IMG97
3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-4-[(2-pyridyl carbonyl) methyl]-2H-1, the 4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 177-178 ℃
ⅱ) ultimate analysis (C 17H 15N 3O 5)
C（%） H（%） N（%）
Calculated value: 59.82 4.43 12.31
Actual value: 59.87 4.45 12.21
ⅲ) mass spectrum (EI): m/z 341(M +)
Example E
Figure 901090743_IMG98
4-acetonyl-3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-2H-1,4-benzoxazine
Physico-chemical property:
ⅰ) fusing point: 136-137 ℃
ⅱ) ultimate analysis (C 13H 14N 2O 5)
C（%） H（%） N（%）
Calculated value: 56.11 5.07 10.07
Actual value: 56.11 5.03 10.04
ⅲ) mass spectrum (EI): m/z 278(M +)
Example F
Figure 901090743_IMG99
3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-oxygen basic ring amyl group)-2H-1,4-benzoxazine-3-ketone
Physico-chemical property:
ⅰ) fusing point: 141-142 ℃
ⅱ) mass spectrum (EI): m/z 304(M +)
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.47（3H，s），1.59（3H，s），
1.80-2.96（6H，m），4.26（1H，t），
7.08（1H，d），7.79（1H，d），7.96（1H，dd）
Example G
Figure 901090743_IMG100
With 0.5g(3,4-dihydro-6-nitro-3-oxygen-2H-1,4-benzoxazine-4-yl) methylamine-dissolve with methanol of ethyl acetate and 0.16g 40% in the 1.5ml methylene dichloride, mixture was at room temperature left standstill 3 days.Solvent is removed in distillation then, resistates from methylene dichloride-hexane recrystallization and provide 0.2g 2-(3,4-dihydro-6-nitro-3-oxygen-2H-1,4-benzoxazine-4-yl)-N-first and second acid amides.This compound has following physico-chemical property:
ⅰ) fusing point: 180-185 ℃
ⅱ) ultimate analysis (C 11H 11N 3O 50.1H 2O)
C（%） H（%） N（%）
Calculated value: 49.48 4.23 15.74
Actual value: 49.32 4.25 15.73
ⅲ) NMR spectrum (CDCl 3)
δ（ppm）：2.82（3H，d），4.56（2H，s），4.78（2H，s），
5.9-6.1(1H, wide s), 7.06(1H, d),
7.94（1H，dd），7.98（1H，d）
Example H
Obtain following compounds by the identical process of example G.
Figure 901090743_IMG101
2-(3,4-dihydro-2,2-dimethyl-6-nitro-3-oxygen-2H-1,4-benzoxazine-4-yl)-N-first and second acid amides
Physico-chemical property:
ⅰ) fusing point: 212-214 ℃
ⅱ) ultimate analysis (C 13H 15N 3O 5)
C（%） H（%） N（%）
Calculated value: 53.24 5.16 14.33
Actual value: 53.06 5.10 14.35
ⅲ) NMR collection of illustrative plates (CDCl 3)
δ（ppm）：1.56（6H，s），2.86（3H，d），4.54（2H，s），
5.86(1H, wide s), 7.06(1H, d),
7.86-7.98（2H，m）
Preparation example 1
The compound 0.1mg of example 1
Lactose 63mg
W-Gum 16mg
Magnesium Stearate 0.9mg
80mg
Compound, lactose and the W-Gum of example 1 are mixed equably, and adopt W-Gum as caking agent and wet method is made particle.Then, add Magnesium Stearate, the composition extrusion forming is obtained tablet.
Preparation example 2
Following component is inserted ampoule, after melting sealed, sterilized 30 minutes down at 115 ℃.
Form (every milliliter)
The compound 50 μ g of example 1
Sodium-chlor 9mg
The distilled water of injection is added to 1ml
Although the present invention at length and with reference to special case has described, for the person skilled in art, in aim of the present invention and scope, can make various variations and modification is tangible.

Claims (1)

1, a kind of preparation molecular formula (Ij) by the benzo-oxazine derivative that heterocycle replaced of N-oxide form or the method for its salt
Wherein
R 1, R 2, R 3And R 4Can be identical or different; they represent hydrogen or halogen atom or low alkyl group separately respectively; the low alkyl group, lower alkoxy, cyano group, nitro, amino, lower alkane amido, low alkyl group sulfonamido, low alkyl group alkylsulfonyl or the aryl sulfonyl that are replaced by halogen
R 5And R 6Can be identical or different, they represent hydrogen atom or low alkyl group separately;
A 8Represent singly-bound, low-grade alkylidene or rudimentary alkylene group; With
Figure 901090743_IMG3
Representative contains the monocyclic heterocycles aryl of 1-2 nitrogen-atoms, and base is characterised in that it comprises the compound of oxidation molecular formula (Ii)
Figure 901090743_IMG4
(Ij) R wherein 1, R 2, R 3, R 4, R 5, R 6, A 8With
Figure 901090743_IMG5
Define as above, and can at random change corresponding salt into.
CN 90109074 1989-11-08 1990-11-08 Benzoxazing derivatives and pharmaceutical compositions containing same Expired - Fee Related CN1029479C (en)

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