CN1938275A

CN1938275A - Novel thio containing hydroxy-6-phenylphenanthridines and their use as PDE4 inhibitors

Info

Publication number: CN1938275A
Application number: CN 200580006802
Authority: CN
Inventors: B·施密德特; D·弗洛克茨; A·哈策尔曼; C·齐特; J·巴西; D·马克斯; H·-P·克利; U·考茨
Original assignee: AUSTANA PHARMACEUTICAL GmbH
Current assignee: AUSTANA PHARMACEUTICAL GmbH; Takeda GmbH
Priority date: 2004-03-10
Filing date: 2005-03-09
Publication date: 2007-03-28
Also published as: ZA200606671B

Abstract

Compounds of formula (I) in which R1 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 2,2-difluoroethoxy, or completely or predominantly fluorine-substituted 1-4C-alkoxy, or in which R 1 and R2 together are a 1-2C-alkylenedioxy group, R3 is hydrogen or 1-4C-alkyl, R31 is hydrogen or 1-4C-alkyl, either, in a first embodiment (embodiment a) according to the present invention, R4 is -0-R41, in which R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or com pletely or predominantly fluorine-substituted 1-4C-alkyl, and R5 is hydrogen or 1-4C-alkyl, or, in a second embodiment (embodiment b) according to the present invention, R4 is hydrogen or 1-4C-alkyl, and R5 is -O-R51, in which R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-7C-alkylcarbonyl, or com pletely or predominantly fluorine-substituted 1-4C-alkyl, R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R7 is -S(O)2N(R8)R9, -A-N(R10)S(0)2-R11, or -S(O)nR12, A is a bond or 1-4C-alkylene, are novel effective PDE4 inhibitors.

Description

Novel sulfurized hydroxy-6-phenylphenanthridineand and as the purposes of PDE4 inhibitor

Invention field

The present invention relates to novel sulfurized hydroxy-6-phenylphenanthridineand derivative, it is used for pharmaceutical industry with pharmaceutical compositions.

Background technology

At International Patent Application WO 99/57118 and WO02/05616 6-phenylphenanthridineand as the PDE4 inhibitor has been described.

6-alkyl phenanthridines as the replacement of segmental bronchus medicine has been described in International Patent Application WO 99/05112.

The dihydroisoquinoline derivative that is applicable to treatment asthma has been described in European patent application EP 0490823.

In International Patent Application WO 97/35854, the phenanthridines that replaces in the 6-position as the segmental bronchus medicine has been described.

6-phenylphenanthridineand as the segmental bronchus medicine has been described in International Patent Application WO 9905113.

6-phenylphenanthridineand as the segmental bronchus medicine has been described in International Patent Application WO 0042020.

Invention is described

Found the compound that the novel sulfurized 2-that describes in detail below or 3-hydroxy-6-phenylphenanthridineand are different from previously known, it has that do not expected and complicated structural changes and has the wonderful character that has superiority especially.

The present invention relates to formula 1 compound thus:

Wherein

R1 is hydroxyl, 1-4C-alkoxyl group, 3-7C-cycloalkyloxy, 3-7C-cycloalkyl methoxyl group, 2, the complete or most of 1-4C-alkoxyl group that is replaced by fluorine of 2-difluoroethoxy,

R2 is hydroxyl, 1-4C-alkoxyl group, 3-7C-cycloalkyloxy, 3-7C-cycloalkyl methoxyl group, 2, the complete or most of 1-4C-alkoxyl group that is replaced by fluorine of 2-difluoroethoxy,

Or wherein

R1 and R2 are the 1-2C-alkylene dioxo base together,

R3 is hydrogen or 1-4C-alkyl,

R31 is hydrogen or 1-4C-alkyl,

Perhaps, first kind of embodiment according to the present invention (embodiment a) in,

R4 is-O-R41, wherein

R41 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, hydroxyl-2-4C-alkyl, the 1-7C-alkyl-carbonyl is complete or most of 1-4C-alkyl that is replaced by fluorine, and

R5 is hydrogen or 1-4C-alkyl,

Perhaps, in according to second kind of embodiment of the present invention (embodiment b),

R4 is hydrogen or 1-4C-alkyl, and

R5 is-O-R51, wherein

R51 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-1-4C-alkyl, hydroxyl-2-4C-alkyl, the 1-7C-alkyl-carbonyl is complete or most of 1-4C-alkyl that is replaced by fluorine,

R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxyl group,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

Or R8 and R9 are together and comprise that the nitrogen-atoms that they are connected forms heterocycle Het1, wherein

Het1 is optional to be replaced by R81, and is the saturated monocyclic heterocycles group of 3-to 7-unit, and it contains the nitrogen-atoms that links to each other with R9 with R8, and chooses wantonly and contain other heteroatoms that is selected from oxygen, nitrogen and sulphur, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

And the salt of the salt of these compounds, N-oxide compound and N-oxide compound.

The 1-4C-alkyl represent contains the straight or branched alkyl of 1-4 carbon atom.The example that can mention is butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl and preferred ethyl and methyl.

The 2-4C-alkyl represent contains the straight or branched alkyl of 2-4 carbon atom.The example that can mention is butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl and preferred ethyl.

The 1-7C-alkyl represent contains the straight or branched alkyl of 1-7 carbon atom.The example that can mention is heptyl, different heptyl (5-methyl hexyl), hexyl, isohexyl (4-methyl amyl), new hexyl (3, the 3-dimethylbutyl), amyl group, isopentyl (3-methyl butyl), neo-pentyl (2, the 2-dimethyl propyl), butyl, isobutyl-, sec-butyl, the tertiary butyl, propyl group, sec.-propyl, ethyl or methyl.

The 3-7C-cycloalkyl is represented cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, wherein preferred cyclopropyl and cyclopentyl.

The 1-4C-alkylidene group is the straight-chain alkyl-sub-that contains 1-4 carbon atom.The example that can mention is methylene radical (CH in this article ₂-), ethylidene (CH ₂-CH ₂-), trimethylene (CH ₂-CH ₂-CH ₂-) and tetramethylene (CH ₂-CH ₂-CH ₂-CH ₂-).

The representative of 1-4C-alkoxyl group removes the Sauerstoffatom outsourcing and contains straight or branched and group that contain the alkyl of 1-4 carbon atom.The example that can mention is butoxy, isobutoxy, sec-butoxy, tert.-butoxy, propoxy-, isopropoxy and preferred oxyethyl group and methoxyl group.

3-7C-cycloalkyloxy representative ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and ring oxygen in heptan base wherein preferably encircle propoxy-, cyclobutoxy group and cyclopentyloxy.

3-7C-cycloalkyl methoxyl group is represented cyclo propyl methoxy, cyclobutyl methoxy base, cyclopentyl methoxyl group, cyclohexyl methoxyl group and suberyl methoxyl group, wherein preferred cyclo propyl methoxy, cyclobutyl methoxy base and cyclopentyl methoxyl group.

As complete or most of 1-4C-alkoxyl group that is replaced by fluorine, for example can mention 2,2,3,3,3-five fluoro-propoxy-, perfluor oxyethyl group, 1,2,2 trifluoro ethoxies, particularly 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy, trifluoromethoxy and preferred difluoro-methoxy." major part " means in the 1-4C-alkoxyl group hydrogen atom that surpasses half and replaced by fluorine atom in this article.

As fully or most of 1-4C-alkyl that is replaced by fluorine, for example can mention 2,2,3,3,3-five fluoro-propyl group, perfluor ethyl, 1,2,2 trifluoroethyls, particularly 1,1,2,2-tetrafluoro ethyl, 2,2,2-trifluoroethyl, trifluoromethyl and preferred difluoromethyl." major part " means in the 1-4C-alkyl hydrogen atom that surpasses half and replaced by fluorine atom in this article.

The 1-2C-alkylene dioxo base is for example represented methylene radical dioxy base [O-CH ₂-O-] and ethylidene dioxy base [O-CH ₂-CH ₂-O-].

1-4C-alkoxyl group-above-mentioned 1-4C-alkyl of 1-4C-alkyl represent, it is replaced by an above-mentioned 1-4C-alkoxyl group.The example that can mention is methoxymethyl, methoxy ethyl and isopropoxy ethyl, particularly 2-methoxy ethyl and 2-sec.-propyl ethyl.

1-4C-alkoxyl group-2-4C-alkyl represent 2-4C-alkyl, it is replaced by an above-mentioned 1-4C-alkoxyl group.The example that can mention is methoxy ethyl, ethoxyethyl group and isopropoxy ethyl, particularly 2-methoxy ethyl, 2-ethoxyethyl group and 2-isopropoxy ethyl.

The representative of 1-7C-alkyl-carbonyl comprises the group of above-mentioned 1-7C-alkyl except that carbonyl.The example that can mention is ethanoyl, propionyl, butyryl radicals and caproyl.

The 2-4C-alkyl that hydroxyl-2-4C-alkyl represent is replaced by hydroxyl.The example that can mention is 2-hydroxyethyl and 3-hydroxypropyl.

Halogen in implication of the present invention is bromine, chlorine or fluorine.

When A means " key " ,-N (R10) S (O) ₂R11 partly is directly connected in phenyl.

Het1 is optional to be replaced by R81 and is the saturated monocyclic heterocycles group of 3-to 7-unit, contains the nitrogen-atoms that links to each other with R9 with R8 and chooses other heteroatoms that is selected from nitrogen, oxygen and sulphur wantonly.

Het1 can include but not limited to, nitrogen heterocyclic propyl group, azetidinyl, pyrrolidyl, piperidyl, homopiperidinyl, morpholinyl, thio-morpholinyl,  oxazolidinyl, different  oxazolidinyl, thiazolidyl, isothiazole alkyl, pyrazolidyl, imidazolidyl, piperazinyl or high piperazinyl.

Can mention as other example of Het1 of the present invention but be not limited to, the derivative that above-mentioned exemplary Het1 is replaced by R81, in particular, the Het1 group that is for example replaced by R81 on theheterocyclic nitrogen atom is such as 4-N-(R81)-piperazinyl or 4-N-(R81)-Gao piperazinyl.

Say it for example, exemplary suitable Het1 group can be mentioned but be not limited to tetramethyleneimine-1-base, morpholine-4-base or 4-N-(R81)-piperazine-1-base, or piperidines-1-base.

As known in the art, the compound that contains nitrogen-atoms can form the N-oxide compound.Especially, the imines nitrogen of imines nitrogen, especially heterocycle or assorted virtue, or pyridine type nitrogen (=N-) atom can be oxidized to by N-and contain=N ⁺(O ^-)-the N-oxide compound.Thus, contain imine nitrogen atom and optional (depending on substituent implication) at 5 places of phenylphenanthridineand skeleton and one or morely be suitable for existing N-oxidation state (=N according to of the present invention ⁺(O ^-The compound of other nitrogen-atoms of)-) can form (depending on the number of nitrogen atoms that is suitable for forming stable N-oxide compound) list-N-oxide compound, two-N-oxide compound or many-N-oxide compound, or its mixing.

Be used for term N-oxide compound of the present invention and comprise all possible particularly all stable N-oxide forms thus, such as list-N-oxide compound, two-N-oxide compound or many-N-oxide compound, or it is with the mixture of any blending ratio.

Depend on the replacement situation, the possible salt of formula I compound is all acid salt or all base addition salt.Specifically can mention the salt of inorganic and organic bronsted lowry acids and bases bronsted lowry of pharmaceutically tolerable commonly used in the pharmacy.On the one hand; suitable is and the water-insoluble of following acid and particularly water-soluble acid salt; such as hydrochloric acid; Hydrogen bromide; phosphoric acid; nitric acid; sulfuric acid; acetate; citric acid; the D-glyconic acid; phenylformic acid; 2-(4-hydroxy benzoyl) phenylformic acid; thiosalicylic acid; toxilic acid; lauric acid; oxysuccinic acid; fumaric acid; succsinic acid; oxalic acid; tartrate; pamoic acid; stearic acid; toluenesulphonic acids; methylsulfonic acid or 3-hydroxyl-2-naphthoic acid, depend on whether considered single-or polyprotonic acid and depend on required salt with wait mole quantitatively than or different ratios and in the preparation of salt use sour.

On the other hand, the salt with alkali formation also suits.The salt that forms with alkali that can mention for example is basic metal (lithium, sodium, potassium) or calcium, aluminium, magnesium, titanium, quaternary ammonium, meglumine or guanidinesalt, wherein in the preparation of salt also with wait mole quantitative than or different ratios use these alkali.

The salt that can not tolerate on the originally obtainable pharmacology for example is that technical scale prepares the process product in the The compounds of this invention, can transform the salt that can tolerate on the pharmacology by method known to those skilled in the art.

It is known to those skilled in the art that The compounds of this invention and salt thereof, when for example separating them, may comprise various amounts of solvent with crystallized form.The present invention also comprises all solvates of formula I compound and particularly all hydrates thus, also comprises all solvates and particularly all hydrates of the salt of formula I compound.

The R6 of formula I compound and R7 substituting group can be connected in the neighbour, or contraposition, with reference to 6-phenyl ring key be connected in the phenanthridines ring system binding site, thus preferably in a position or contraposition connect.In one embodiment, R6 is hydrogen or methyl, is connected in the position of phenanthridines ring system with reference to the 6-benzyl ring, position or contraposition between the R7 group is connected in.In one embodiment, R6 is a hydrogen, between the R7 group is connected in or contraposition.

More noteworthy formula I compound is a following compounds, wherein

R1 is 1-2C-alkoxyl group, 3-5C-cycloalkyloxy, 3-5C-cycloalkyl methoxyl group, 2, the complete or most of 1-2C-alkoxyl group that is replaced by fluorine of 2-difluoroethoxy,

R2 is 1-2C-alkoxyl group, 3-5C-cycloalkyloxy, 3-5C-cycloalkyl methoxyl group, 2, the complete or most of 1-2C-alkoxyl group that is replaced by fluorine of 2-difluoroethoxy,

R3 is a hydrogen,

R31 is a hydrogen,

Perhaps, first kind of embodiment according to the present invention (embodiment a) in

R4 is-O-R41, wherein

R41 is hydrogen or 1-7C-alkyl-carbonyl, and

R5 is a hydrogen,

Perhaps, in according to second kind of embodiment of the present invention (embodiment b)

R4 is a hydrogen, and

R5 is-O-R51, wherein

R51 is hydrogen or 1-7C-alkyl-carbonyl,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

Het1 is optional to be replaced by R81, and is the saturated monocyclic heterocycles group of 3-to 7-unit, and it contains the nitrogen-atoms that links to each other with R9 with R8, and chooses wantonly and contain other heteroatoms that is selected from oxygen, nitrogen and sulphur,

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

Noteworthy especially formula I compound is a following compounds, wherein

R3 is a hydrogen,

R31 is a hydrogen,

Perhaps, first embodiment of the present invention (embodiment a) in

R4 is-O-R41, wherein

R41 is hydrogen or 1-7C-alkyl-carbonyl,

R5 is a hydrogen,

Perhaps, in second embodiment of the present invention (embodiment b)

R4 be hydrogen and

R5 is-O-R51, wherein

R51 is hydrogen or 1-7C-alkyl-carbonyl,

R6 is hydrogen or 1-4C-alkyl,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

Het1 is the saturated monocyclic heterocycles group of 3-to 7-unit, and it contains the nitrogen-atoms that links to each other with R9 with R8, and chooses wantonly and contain other heteroatoms that is selected from oxygen, nitrogen, N (R81) and sulphur, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

Noteworthy more especially formula I compound is a following compounds, wherein

R1 is a 1-2C-alkoxyl group, 2, the 2-difluoroethoxy, and complete or most of 1-2C-alkoxyl group that is replaced by fluorine,

R2 is a 1-2C-alkoxyl group, 2, the 2-difluoroethoxy, and complete or most of 1-2C-alkoxyl group that is replaced by fluorine,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is the 1-4C-alkyl-carbonyl, or especially, is hydrogen in indivedual embodiments of the present invention,

R5 is a hydrogen,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

Het1 is morpholinyl, thio-morpholinyl, pyrrolidyl, 4-N-(R81)-piperazinyl, 4-N-(R81)-Gao piperazinyl, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0 or 2,

R12 is the 1-4C-alkyl,

The formula I compound that also is worth more mentioning especially is a following compounds, wherein

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R5 is a hydrogen,

R6 is hydrogen or methyl,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

Het1 is morpholinyl, thio-morpholinyl, pyrrolidyl, piperidyl, 4-N-(R81)-piperazinyl, 4-N-(R81)-Gao piperazinyl, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

The formula I compound that is worth more again mentioning especially is a following compounds, wherein

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-ethyl or 3-5C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl or 4-N-(R81)-piperazinyl, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-2C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is fluorine or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0 or 2,

R12 is the 1-4C-alkyl,

The formula I compound that further is worth more mentioning especially is a following compounds, wherein

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is ethanoyl or particularly hydrogen,

R5 is a hydrogen,

R6 is hydrogen or methyl,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-ethyl or 3-5C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl, piperidyl or 4-N-(R81)-piperazinyl, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-2C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is fluorine, chlorine or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

The formula I compound that more further is worth mentioning especially is a following compounds, wherein

R1 is a methoxy or ethoxy,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is methyl, ethyl, propyl group, 2-methoxyl group-ethyl or cyclopropyl,

R9 is hydrogen, methyl, ethyl, propyl group or 2-methoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl, piperidyl or 4-N-(R81)-piperazinyl, wherein

R81 is a methyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or methylene radical,

R10 is hydrogen or methyl,

The phenyl that R11 is replaced by R111, wherein

R111 is fluorine, chlorine or methyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl, such as methyl,

The formula I compound that more further is worth again mentioning especially comprises following formula I compound, wherein

R1 is a methoxyl group,

R2 is an oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-OR41,

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is methyl, ethyl, propyl group, 2-methoxyl group-ethyl or cyclopropyl,

R9 is hydrogen, methyl, ethyl, propyl group or 2-methoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl, piperidyl or 4-N-(R81)-piperazinyl, wherein

R81 is a methyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or methylene radical,

R10 is hydrogen or methyl,

The phenyl that R11 is replaced by R111, wherein

R111 is fluorine, chlorine or methyl,

Such as 4-(R111)-phenyl, as 4-aminomethyl phenyl or 4-fluorophenyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl, such as methyl,

The formula I compound that also further is worth more mentioning especially is a following compounds, wherein

R1 is a methoxy or ethoxy,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

R7 is-S (O) _nR12, wherein

N is 0 or 1,

R12 is a methyl,

The formula I compound that further is worth more again mentioning especially is a following compounds, wherein

R1 is a methoxyl group,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

R7 is connected in the position of phenanthridines ring system with reference to the 6-benzyl ring, position or contraposition between it is connected in, and be-S (O) _nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl, such as methyl,

Further the concrete scheme of the worth more formula I compound of mentioning especially comprises following formula I compound again, wherein

R1 is a methoxyl group,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

The position that R7,6-benzyl ring are connected in the phenanthridines ring system is reference, and it is connected in contraposition, and is-S (O) _nR12, wherein

N is 0,

R12 is a methyl,

Further the more specifically scheme of the worth more formula I compound of mentioning especially comprises following formula I compound again, wherein

R1 is a methoxyl group,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

R7, the position that is connected in the phenanthridines ring system with the 6-benzyl ring is reference, it is connected in contraposition, and is-S (O) _nR12, wherein

N is 1,

R12 is a methyl,

Further the further concrete scheme of the worth more formula I compound of mentioning especially comprises following formula I compound again, wherein

R1 is a methoxyl group,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

N is 2,

R12 is a methyl,

Significant especially The compounds of this invention relate to be included among the meaning of the present invention following one or may the time the included compound of a plurality of embodiments:

Significant especially The compounds of this invention comprises that wherein R1 and R2 independently are the 1-2C-alkoxyl groups, 2, and 2-difluoroethoxy, the formula I compound of complete or most of 1-2C-alkoxyl group that is replaced by fluorine.

Another significant especially The compounds of this invention comprises that wherein R1 and R2 independently are 1-2C-alkoxyl groups, 2, the 2-difluoroethoxy, and complete or most of 1-2C-alkoxyl group that is replaced by fluorine, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 and R2 independently are 1-2C-alkoxyl groups, 2, the 2-difluoroethoxy, and complete or most of 1-2C-alkoxyl group that is replaced by fluorine, and R3, R31 and R6 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein one of R1 and R2 are methoxyl groups, and another is methoxyl group, oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is oxyethyl group or particularly methoxyl group, and R2 is methoxyl group or particularly oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is a methoxyl group, and R2 is methoxyl group, oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is a methoxyl group, and R2 is oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein one of R1 and R2 are 2,2-difluoroethoxy, and another is not 2, and the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is oxyethyl group or particularly methoxyl group, and R2 is 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is a methoxyl group, and R2 is 2, the 2-difluoroethoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is a methoxyl group, and R2 is an oxyethyl group, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprises that wherein R1 is a methoxyl group, and R2 is a difluoro-methoxy, and R3 and R31 all are formula I compounds of hydrogen.

The special embodiment of another of The compounds of this invention comprise wherein R5 or especially R4 be (1-4C-alkyl-carbonyl)-O-group such as acetoxyl group or hydroxyl, and the formula I compound of the definition in any as mentioned above compound of all other substituting groups.

The special embodiment of another of The compounds of this invention comprise wherein R5 or especially R4 be the formula I compound of hydroxyl.

The special embodiment of another of The compounds of this invention comprises that wherein R6 is the formula I compound of hydrogen or methyl.

The special embodiment of another of The compounds of this invention comprises the formula I compound according to aspect 1.

The special embodiment of another of The compounds of this invention comprises the formula I compound according to aspect 2.

The special embodiment of another of The compounds of this invention comprises the formula I compound according to aspect 3.

The special embodiment of another of The compounds of this invention comprises the formula I compound of the aspect 3 according to the present invention, and wherein R7 is-S (O) n-R12, wherein

R12 is the 1-4C-alkyl, such as methyl, and

N is 0 or 1.

R12 is the 1-4C-alkyl, such as methyl, and

N is 1.

The preferred embodiments of the invention are embodiment a.

Other preferred embodiment of The compounds of this invention comprises the compound according to embodiment a, wherein R5 and R41 all are hydrogen, and wherein R1 and R2 independently are 1-2C-alkoxyl groups, 2, the complete or most of 1-2C-alkoxyl group that is replaced by fluorine of 2-difluoroethoxy, and R3, R31 and R6 all are hydrogen.

Other more preferred of The compounds of this invention comprise the compound according to embodiment a, and wherein R5 is a hydrogen, and wherein R1 is a methoxyl group, and R2 is oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are hydrogen.

The further preferred embodiment of other of The compounds of this invention comprises the compound according to embodiment a, and wherein R5 and R41 all are hydrogen, and wherein R1 is a methoxyl group, and R2 is oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy, and R3 and R31 all are hydrogen.

Noteworthy more suitable compound of the present invention comprise wherein R5 or, R4 is the formula I compound of hydroxyl especially.

Exemplary compound of the present invention includes but not limited to be selected from those compounds of the final compound of mentioning among the following embodiment of conduct, particularly according to the formula I compound of those embodiment of embodiment a, wherein R3, R31, R41 and R5 all are hydrogen, the salt of the enantiomorph of these compounds and these compounds and enantiomorph, N-oxide compound and N-oxide salt.

Preferably, the significant especially aspect of the present invention should be mentioned in that at the listed The compounds of this invention of additional " biological study " Table A, and its enantiomorph particularly, particularly has formula Ia ^{* * * *}Those and these compound and the salt of enantiomorph.

Formula I compound is a chipal compounds, and the implication that in 4a and 10b position chiral centre is arranged at least and depend on R3, R31, R4 and R5 is at 1,2,3 and 4 chiral centre that other is arranged.

Numbering

The present invention includes the steric isomer of all surmisable pure forms and any blending ratio.The hydrogen atom of preferred wherein 4a and 10b position is mutually at the formula I of cis-position compound.More preferably pure in this article cis enantiomorph and with any ratio they mixture and comprise racemic modification.

Particularly preferred formula 1 compound of this paper, its 4a and 10b position have suc as formula (I ^*) shown in configuration:

For example, if at formula I ^*R3, R31 and R5 are that hydrogen and R4 are-OR41 in the compound, and so according to Cahn, the configuration of Ingold and Prelog rule 4a position is that the configuration of R and 10b position is R.

According to the preferred formula I compound of embodiment a be 2,4a and 10b position configuration such as cotype Ia ^*And Ia ^{* *}And Ia ^{* * *}Those shown compounds:

For example, if at formula Ia ^*In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 2 is that S, 4a position are that R and 10b position are R.

For example, if at formula Ia ^{* *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 2 is that R, 4a position are that S and 10b position are S.

For example, if at formula Ia ^{* * *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 2 is that S, 4a position are that S and 10b position are S.

According to the preferred formula I compound of embodiment a be 2,4a and 10b position configuration such as cotype Ia ^{* * * *}Those shown compounds:

For example, if at formula Ia ^{* * * *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 2 is that R, 4a position are that R and 10b position are R.

According to the preferred formula I compound of embodiment b be 3,4a and 10b position configuration such as cotype Ib ^*And Ib ^{* *}And Ib ^{* * *}Those shown compounds:

For example, if at formula Ib ^*In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 3 is that R, 4a position are that R and 10b position are R.

For example, if at formula Ib ^{* *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 3 is that S, 4a position are that S and 10b position are S.

For example, if at formula Ib ^{* * *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 3 is that R, 4a position are that S and 10b position are S.

According to the preferred formula I compound of embodiment b be 3,4a and 10b position configuration such as cotype Ib ^{* * * *}Those shown compounds:

For example, if at formula Ib ^{* * * *}In the compound, R3, R31 and R5 are hydrogen, and so according to Cahn, the configuration that Ingold and Prelog rule is 3 is that S, 4a position are that R and 10b position are R.

In according to embodiment of the present invention a and b, lay special stress on formula Ia ^{* * * *}Compound.

Can the known mode enantiomer separation of use itself (for example, by preparing and separate suitable diastereomeric compound).Preferably, can carry out Chiral Separation in the initial compounds stage of containing free amine group, such as the initial compounds of formula IVa, wherein R1, R2, R3, R31, R41 and R5 define as above, or VIIb as described below.

For example, during the enantiomer separation body, can make formula IVa or VIIb racemic compound and optical activity acid optimization acid form salt, split this salt subsequently and from salt, discharge required compound.The optically active carboxylic acid that can mention for example is amygdalic acid, tartrate, the O of enantiomeric form in this article, O '-dibenzoyl tartaric acid, dextrocamphoric acid, quinic acid, L-glutamic acid, Pyrrolidonecarboxylic acid, oxysuccinic acid, camphorsulfonic acid, 3-bromo-camphor sulfonic acid, α-anisole guanidine-acetic acid, α-methoxyl group-α-trifluoromethyl phenylacetic acid and 2-phenylpropionic acid.The initial compounds that alternatively, can prepare these formulas of enantiomer-pure via asymmetric synthesis.Also can obtain the initial compounds of enantiomer-pure and the formula I compound of enantiomer-pure: the chromatographic separation on chiral chromatographic column by following method; By deriving, separate diastereomer subsequently and remove chiral auxiliary group with chiral auxiliary(reagent); Or (segmentation) crystallization from suitable solvent.

Can be during the preparation The compounds of this invention according to following reaction process and according to following concrete reactions steps, or especially, exemplary described mode among the embodiment below adopting, perhaps well known by persons skilled in the art be similar to or similar in appearance to its preparation method or synthesis strategy.

According to the formula I compound of embodiment a or b (that is, being respectively formula Ia or Ib), wherein R1, R2, R3, R31, R4, R5, R6 and R7 have above-mentioned definition, can followingly obtain.

Formula Ia compound according to embodiment a can prepare shown in the following surface current journey 1.

In the reaction of the first step of the synthetic route shown in the flow process 1, formula Va compound, wherein as above embodiment a definition but R41 is not a hydrogen of R1, R2, R3, R31, R41 and R5 is not that the R41 group of hydrogen prepares by corresponding formula VIa compound by introducing.This introducing reaction with etherificate commonly used itself or esterification mode or as following embodiment in the mode of exemplary description carry out.

Reaction process 1:

In next reactions steps of synthetic route shown in the reaction process 1, the nitro of formula Va compound, wherein as above definition but R41 is not a hydrogen among the embodiment a of R1, R2, R3, R31, R41 and R5 is reduced to the amino of formula IVa respective compound.Described reduction is J.Org.Chem.1962 for example in the manner known to persons skilled in the art, described in 27,4426 or as following embodiment in the mode of exemplary description carry out.More specifically, this reduction reaction can be finished by for example catalytic hydrogenation, as Raney's nickel or at the noble metal catalyst on the gac such as in the presence of the palladium, under room temperature and normal pressure or high pressure, carry out in such as methyl alcohol or ethanol in suitable solvent.Randomly, can in solvent, add the acid of catalytic amount such as spirit of salt.But preferably, this reduction reaction uses the mixture that produces hydrogen to finish, for example metallic zinc or zinc-copper conjugates or iron and organic acid such as acetate or ore deposit acid such as hydrochloric acid.More preferably, use zinc-copper conjugates to have this reaction when finishing at organic acid or mineral acid.Such zinc-copper conjugates can obtain by the known mode of those of ordinary skills.

Formula IVa compound, wherein R1, R2, R3, R31, R41 and R5 as above among the embodiment a definition but R41 be not that hydrogen and these groups are for the catalytic hydrogenation sensitivity, can prepare by mode selective reduction nitro well known by persons skilled in the art by corresponding formula Va compound, for example in the presence of metal catalyst such as palladium or preferred Raney's nickel, for example in lower alcohol solvent, use ammonium formiate or preferably hydrazine hydrate carry out hydrogen transfer reactions as hydrogen donor.

Formula IIa compound, wherein as above definition but R41 is not a hydrogen among the embodiment a of R1, R2, R3, R31, R41, R5, R6 and R7, can obtain with corresponding formula III compound reaction by corresponding formula IVa, wherein the suitable preferred chlorine atom of leavings group of X representative.

Alternatively, formula IIa compound also can be connected reagent react with amido linkage well known by persons skilled in the art by the formula III compound that corresponding formula IVa and corresponding wherein X are hydroxyls and prepare.Exemplary amido linkage well known by persons skilled in the art connect reagent for example can mention carbodiimide (as, dicyclohexylcarbodiimide, or preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride), the azodicarboxy acid derivative (as, the diethylazodicarboxylate), uronium salt [as, O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea positively charged ion a tetrafluoro borate or O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea positively charged ion hexafluorophosphate] and N, N '-carbonyl dimidazoles.Within the scope of the present invention, it is uronium salt and preferred especially carbodiimide that preferred amido linkage connects reagent, preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride.

The formula III compound is known or can prepares in a known way.

Formula Ia compound, wherein as above definition but R41 is not a hydrogen among the embodiment a of R1, R2, R3, R31, R41, R5, R6 and R7 can prepare by the ring-closing condensation reaction of corresponding formula IIa compound.

Described also condensation reaction is finished as the mode of exemplary description among mode well known by persons skilled in the art or the following embodiment with this, according to Bischler-Napieralski (as, be described in J.Chem.Soc., 1956, among the 4280-4282) at suitable condensing agent such as polyphosphoric acid, phosphorus pentachloride, Vanadium Pentoxide in FLAKES or Phosphorus Oxychloride exist down, suitable inert solvent such as hydrochloric ether such as chloroform in, or cyclic hydrocarbon such as toluene or dimethylbenzene or other inert solvent such as isopropyl acetate or acetonitrile in, or use excessive condensing agent and do not use other solvent, under the boiling temperature of low temperature or room temperature or high temperature or solvent for use or condensing agent, carry out.In case of necessity, described ring-closing condensation reaction can be at one or more suitable lewis' acids such as suitable metal halide (as muriate) or sulfonate (as fluoroform sulphonate), comprise under the rare earth metal salt existence and finishing, such as aluminum trichloride (anhydrous), alchlor, zinc chloride, boron fluoride etherate (ethereate), titanium tetrachloride or particularly tin tetrachloride, or the like.

Following reaction process 2 has represented that wherein R1, R2, R3, R31 and R5 as above define among the embodiment a by the method for corresponding formula VIIa compound via the reduction reaction synthesis type VIa compound of carbonyl.The suitable reductive agent that is used for above-mentioned reduction reaction for example can comprise that metal hydride is such as di-isopropyl aluminum hydride, borine, sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, zinc borohydride, three-sec-butyl POTASSIUM BOROHYDRIDE, three-sec-butyl sodium borohydride, three-sec-butyl lithium borohydride, assorted dicyclo [3.3.1] nonane of β-isopinocampheol base-9-boron etc.Preferred described reductive agent for example is assorted dicyclo [3.3.1] nonane of sodium cyanoborohydride, β-isopinocampheol base-9-boron and three-sec-butyl POTASSIUM BOROHYDRIDE.Above-mentioned most preferred reductive agent for example is assorted dicyclo [3.3.1] nonane of β-isopinocampheol base-9-boron and three-sec-butyl POTASSIUM BOROHYDRIDE, and the two all can be used for Stereoselective preparation formula VIa compound." stereoselectivity " herein mean preferred acquisition wherein 1 and 3 hydrogen atom be positioned at cyclohexane ring the formula VIa compound of definite planar opposite side.

Reaction process 2:

Formula VIIa compound, wherein R1, R2, R3, R31 and R5 as above define among the embodiment a, be known maybe can by wherein R1 and R2 as defined above the formula VIIIa compound reaction that as above defines among the embodiment a of formula IXa compound and wherein R3, R31 and R5 obtain.This cycloaddition reaction is carried out according to the known mode of Diels-Alder with those skilled in the art, for example is described in J.Amer.Chem.Soc.1957, in 79,6559 or J.Org.Chem.1952,17,581 or be described in mode in the following examples.

Formula VIa or Va compound, wherein phenyl ring and nitro are trans each other, can be converted into corresponding cis-compound in the manner known to persons skilled in the art, as be described in J.Amer.Chem.Soc.1957, in 79,6559 or be described in mode in the following examples.

Formula VIIIa and IXa compound are known or can prepare in known manner.Formula IXa compound for example can for example be described in J.Chem.Soc.1951 with manner known in the art by corresponding formula Xa compound, in 2524 or J.Org.Chem.1944,9,170 or be described in mode in the following examples.

Formula Xa compound, wherein R1 and R2 as above define among the embodiment a, are known or can prepare in the manner known to persons skilled in the art, for example are described in Ber.Dtsch.Chem.Ges.1925, the mode in 58,203.

According to the formula Ib compound of embodiment b, wherein as above definition but R51 is not a hydrogen among the embodiment b of R1, R2, R3, R31, R4 and R51, can according to described in the following reaction process 3 and shown in the method preparation.

In the first step reaction of reaction process 3, the nitro of formula VIIIb compound, wherein R1, R2, R3, R31 and R4 as above define among the embodiment b, obtain corresponding formula VIIb compound through reduction.Described reduction reaction is carried out in the manner known to persons skilled in the art, for example is described in J.Org.Chem.1962, in 27,4426 or be described in mode in the following examples.More specifically, when carrying out this reaction, for example compound VIII b and the mixture that produces hydrogen contact in such as acetate at the media of moderate acid such as preferred metallicity zinc, lower alcohol such as methyl alcohol or ethanol in, under room temperature or high temperature or preferred boiling temperature, carry out at solvent mixture.Alternatively, finish this reaction by the selective reduction nitro in the manner known to persons skilled in the art, for example in the presence of metal catalyst such as palladium or the preferred Raney's nickel, in The suitable solvent, preferred lower alcohol, for example use ammonium formiate or preferably hydrazine hydrate carry out hydrogen transfer reactions as hydrogen donor.

Reaction process 3:

The formula VIIb compound that is obtained can react with the formula III compound, and for example as exemplary description among the following embodiment, wherein R6 and R7 as above define and the suitable leavings group of X representative, and preferred chlorine atom is to generate corresponding formula VIb compound.

Alternatively, formula VIb compound, wherein R1, R2, R3, R31, R4, R6 and R7 as above define among the embodiment b, also can by for example corresponding formula VIIb compound and accordingly wherein X be that the formula III compound of hydroxyl is connected reagent react with amido linkage well known by persons skilled in the art and prepares.Exemplary amido linkage well known by persons skilled in the art connect reagent for example can mention carbodiimide (as, dicyclohexylcarbodiimide, or preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride), the azodicarboxy acid derivative (as, the diethylazodicarboxylate), uronium salt [as, O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea positively charged ion a tetrafluoro borate or O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea positively charged ion hexafluorophosphate] and N, N '-carbonyl dimidazoles.Within the scope of the present invention, it is uronium salt and preferred especially carbodiimide that preferred amido linkage connects reagent, preferred 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride.

In next step, formula VIb compound is converted into corresponding formula Vb compound through epoxidation reaction, it can be finished as the description among the following embodiment or in the known mode of those of ordinary skills, for example adopt suitable epoxidizing method or suitable epoxidizing agent such as peracid (as, between-chloroperoxybenzoic acid) or the organic or inorganic superoxide (as, dimethyl dioxirane, hydrogen peroxide or persulphate).

The formula Vb compound that is obtained can be reduced to corresponding formula IVb compound by methods known in the art.More specifically, described reduction reaction can adopt the sodium borohydride of exemplary description among for example following embodiment to carry out as reactant.Alternatively, described reduction reaction for example also can be used lithium aluminum hydride or contain precious metal and finish such as the original mixture of going back of dioxy platinum or palladium and suitable hydrogen donor.Described method of reducing auxiliary down, formula Vb compound can with marking area-and cis-selectivity be converted into formula IVb compound, wherein 1 hydroxyl and 3 s' amido is positioned at by the definite planar homonymy of cyclohexane ring.

Those of ordinary skills are also known, the absolute configuration of chiral carbon atom, and preferably it has connected hydroxyl and hydrogen atom, can transform.Thus, the configuration of 1 of formula IVb compound carbon atom can be chosen conversion wantonly.Can realize the configuration conversion of 1 carbon atom of described formula IVb compound in the manner known to persons skilled in the art, for example deriving mutually subsequently with suitable leavings group by 1 replaces described leavings group with the nucleophilic substitution reaction of suitable nucleophilic reagent by SN2 mechanism.Alternatively, can be as the configuration conversion of description exemplary among the following embodiment according to 1 carbon atom of formula IVb compound as described in specifically described two-step reaction is realized in the later reaction flow process 4.More specifically, in the first step of method shown in the described reaction process 4, formula IVb ^*Exemplary compound, wherein R1, R2, R6 and R7 as above among the embodiment b definition and R3, R31 and R4 be that hydrogen and 1 are the R configurations, be converted into corresponding formula IXb compound through oxidizing reaction.Described oxidizing reaction is finished under conventional condition own equally, for example uses tetrachlorobenzoquinone, oxygen atmosphere, Manganse Dioxide or preferred chromic oxide as oxygenant.Then second the step in, by ketone group reduction reaction known in the art, preferably use metal hydride or more specifically metal borohydride such as sodium borohydride formula IXb compound is converted into corresponding formula IVb ^*Compound, wherein 1 is the S configuration, described thus formula IVb ^*The configuration of 1 carbon atom of compound has been realized reversing.

Reaction process 4:

In the last subsequent reactions step of showing the synthetic route shown in the reaction process 3, not the R51 base of hydrogen and formula IVb compound is converted into corresponding formula IIb compound by introducing.This introduce reaction with mode commonly used itself (as, via alkylation or acylation reaction) or as following embodiment in the mode of exemplary description carry out.

For example can as description exemplary among the following embodiment or to its similar or similar mode, perhaps as above-mentioned mode to embodiment a compound finish cyclization with growth formula Ib compound, wherein as above embodiment b definition but R51 is not a hydrogen of R1, R2, R3, R31, R4, R51, R6 and R7.

Formula VIIIb compound, wherein as above embodiment b definition of R1, R2, R3, R31 and R4, be known or can be for example shown in reaction process 5, obtain, even R1 and R2 formula IXa compound and the wherein as above formula Xb compound reaction of embodiment b definition of R3, R31 and R4 as defined above wherein.

Reaction process 5:

The cycloaddition reaction of this moment is finished according to the known mode of Diels-Alder with those skilled in the art, for example as J.Amer.Chem.Soc.1957, and 79,6559 or J.Org.Chem.1952, described in 17,581 or as described in the following examples.

Formula VIIIb compound, wherein phenyl ring and nitro are trans each other, can be converted into corresponding cis-compound as is known to persons skilled in the art like that, as J.Amer.Chem.Soc.1957, described in 79,6559 or as described in the following examples.

Formula Xb compound is known or can prepares in known manner.

Alternatively, formula IIb compound, wherein R1, R2, R3, R31, R4, R51, R6 and R7 as above among the embodiment b definition but R5 be not hydrogen (formula IIb compound particularly, wherein as above definition but R5 is not a hydrogen among the embodiment b of R1, R2, R51, R6 and R7, and R3, R31 and R4 all are hydrogen) also can be shown in reaction process 6 or as following embodiment in exemplary description obtain.

In the first step reaction of route shown in the reaction process 6, the amino of formula VIIb compound is protected through protecting group PG1 known in the art, such as tert-butoxycarbonyl.Protected compound obtains formula XIb compound through hydroboration through two-step reaction.When carrying out described hydroboration such as described in the following embodiment, use suitable hydroborating agents, such as 9-BBN, isopinocampheol base borine etc., or borine-tetrahydrofuran (THF) (H particularly ₃B-THF), at room temperature carry out with having superiority.Not the R51 base of hydrogen and the gained compound is converted into formula XIb compound to be similar to that aforesaid way introduces then.

In the next step of synthetic route shown in the reaction process 6, by removing the PG1 protecting group and using the amidation of formula III compound and formula XIb compound is converted into corresponding formula IIb compound.Described reaction is finished with mode or the mode described in specification sheets of the present invention or following embodiment itself used always.

In case of necessity, the derivative that the product that obtains via hydroboration or its suitable R51-replace is removed gained solid-and/or regional isomer by product by the method known to those skilled in the art purifying, for example passes through chromatographic separation technology.

Reaction process 6:

Alternatively, formula I compound (the following formula I ' compound of using is represented) according to aspect 2, wherein A is a key, can obtain by the method shown in the reaction process 1 ', this method is as described below: with formula III, compound is as initiator, wherein R1, R2, R3, R31, R4, R5 and R6 as above definition and R4 and R5 be not hydroxyl, the reduction formula III ' nitro of compound generates corresponding formula II ' compound.Described reduction reaction can be carried out in the manner known to persons skilled in the art or as the mode of exemplary description among the following embodiment, for example in the presence of suitable metal catalyst, carry out hydrogenation, perhaps use suitable reductive agent especially such as tin protochloride.

Formula II ' compound and preparation thereof also are described among WO2004/019944 or the WO2004/019945, and these documents are incorporated herein.

In next step, formula II ' compound and formula R11-S (O) ₂The reaction of the sulfonic acid of-X, wherein X is a for example chlorine atom of the leavings group that suits, to generate corresponding sulfonamide compounds.Randomly, described sulfonamide compounds can carry out the N-alkylation, uses suitable alkali and suitable alkylating reagent R10-Y, and wherein Y is the leavings group that suits, one pot or successive reaction (reaction that at first removes deprotonation adds R10-Y then)

Reaction process 1 ':

As described in reaction process 1-5 and top the specifying or with the similar or similar mode of following embodiment, can obtain formula III I ' compound.

Randomly, also formula I compound can be converted into other formula I compound by the known method of those of ordinary skills.More specifically, for example, by formula I compound, wherein

A) R41 or R51 are hydrogen, can obtain corresponding ester cpds by esterification;

B) R41 or R51 are hydrogen, can obtain corresponding ether compound by etherification reaction;

C) R41 or R51 are acyl groups, such as ethanoyl, can obtain corresponding oxy-compound by de-esterification (as saponification reaction);

D) R10 is a hydrogen, can obtain corresponding N-ether compound by etherification reaction;

E) R7 is-SR12, the list by sulphur atom-or two-oxidation can obtain corresponding sulfoxide or sulphones;

A), d c b))) and method e) can carry out easily according to being similar to method exemplary among method known to those skilled in the art or the following embodiment.

Randomly, formula I compound can be converted into their salt, or randomly, the salt of formula I compound can be converted into free cpds.

In addition, formula I compound can be chosen the N-oxide compound that is converted into them wantonly, for example and hydrogen peroxide in methyl alcohol or and-chloroperoxybenzoic acid reacts in methylene dichloride.Those skilled in the art know well concrete required reaction conditions when carrying out the N-oxidation based on its expertise.

Those skilled in the art are also known, if having a plurality of reactive centers in initiator or the midbody compound, just may need to hinder one or more reactive centers by protecting group and carry out specifically so that be reflected at required reactive center.The application of the protecting group that has been proved in a large number is described in detail in for example T.Greene and P.Wuts, " Protective Groups in OrganicSynthesis " (John Wiley ﹠amp; Sons, Inc.1999,3rd Ed.) or among the P.Kocienski, " Protecting Groups (Thieme Foundations Organic Chemistry Series NGroup " (Thieme Medical Publishers, 2000).

According to material of the present invention separation and purification in a manner known way, for example remove solvent under reduced pressure and from suitable solvent recrystallization gained residue, or make this material stand conventional purification process such as the column chromatography on the appropriate carrier material.

During preparation salt, with free cpds be dissolved in suitable solvent (as, ketone is such as acetone, methyl ethyl ketone or methyl iso-butyl ketone (MIBK), ether is such as ether, tetrahydrofuran (THF) or dioxane, hydrochloric ether is such as methylene dichloride or chloroform, or low-molecular-weight Fatty Alcohol(C12-C14 and C12-C18) is such as ethanol or Virahol) in, required acid or alkali comprised in these solvents, or the dissolving back is to wherein adding required acid or alkali.By filtration, redeposition, obtain salt with the non-solvent precipitation of additive salt or by evaporating solvent.The salt of gained can be converted into free cpds by alkalization or acidifying, and it also can be converted into salt.In this way, pharmaceutically unacceptable salt can be converted into pharmacy acceptable salt.

Aptly, mentioned conversion can be by being similar to or finishing similar in appearance to the method that itself is well known to those skilled in the art among the present invention.

Those skilled in the art are based on its knowledge and based on synthetic route, and it all is illustrated description in specification sheets of the present invention, can know route how to find other possible synthesis type 1 compound.All these other possible synthetic routes also are parts of the present invention.

The present invention is described in detail, and scope of the present invention is not limited only to specifically described feature or embodiment.Those skilled in the art obviously as seen, based on knowledge known in the art and/or particularly can modify the present invention, simulate, change, derive based on open (for example clear and definite, that infer or inherent) of the present invention, homology changes and change and do not depart from the spirit and scope of the present invention that claims limited as appendix.

The following examples are in order to explain the present invention but not limitation ot it.Equally, other formula I compound, its preparation is clearly described, and also can prepare with similar or similar mode or the mode that is well known to those skilled in the art with itself Technology by routine.

The salt of any or all compound of the final compound of mentioning among the following embodiment of conduct and salt thereof, N-oxide compound and N-oxide compound is preferred for this invention.

In an embodiment, m.p. represents fusing point, h representative hour, min representative minute, the retention factors of Rf representative in tlc, s.p. represents sintering point, and EF represents empirical formula, MW represents molecular weight, MS represents mass spectrum, and M represents molion, and fnd. represents measured value, calc. represent calculated value, other abbreviation has the implication that itself is well known to those skilled in the art.

According to the conventional practice in the stereochemistry, use RS and SR symbol to indicate the concrete configuration of each chiral centre of racemic modification.More specifically, for example racemic modification (racemic mixture) represented in term " (2RS, 4aRS, 10bRS) ", comprises a kind ofly to have that (2R, 4aR, 10bR) enantiomorph of configuration and another kind have (2S, 4aS, 10bS) enantiomorph of configuration.

Embodiment

Final compound

Begin by suitable ester cpds, it clearly is mentioned or describes (compound 13-22) below, or it can be in the manner known to persons skilled in the art or be similar to or prepare similar in appearance to the mode of embodiment described herein, obtains compound 1-10 according to the method among the embodiment 11.

1, N-[4-((2RS, 4aRS, 10bRS)-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-4, N-dimethyl-benzsulfamide

EF：C ₂₉H ₃₂N ₂O ₅S MW：520，65 MS：521，2(MH ⁺)

2,4-fluoro-N-[4-((2RS, 4aRS, 10bRS}-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-benzsulfamide

EF：C ₂₇H ₂₇FN ₂O ₅S MW：510，59 MS：511，2(MH ⁺)

3, N-[4-((2RS, 4aRS, 10bRS)-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-2-methyl-phenyl]-4-methyl-benzsulfamide

EF：C ₂₉H ₃₂N ₂O ₅S MW：520，65 MS：521，3(MH ⁺)

4, N-[4-((2RS, 4aRS, 10bRS)-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-benzyl]-4-methyl-benzsulfamide

EF：C ₂₉H ₃₂N ₂O ₅S MW：520，65 MS：521，3(MH ⁺)

5, N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-Toluidrin

6, N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-4-methyl-benzsulfamide

EF：C ₂₈H ₂₈F ₂N ₂O ₅S MW：542，61 MS：543，3(MH ⁺)

7, N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-4-fluoro-benzsulfamide

EF：C ₂₇H ₂₅F ₃N ₂O ₅S MW：546，57 MS：547，2(MH ⁺)

8, N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzyl-4-methyl-benzsulfamide

EF：C ₂₉H ₃₀F ₂N ₂O ₅S MW：556，63 MS：557，4(MH ⁺)

9, N-(4-[(2RS, 4aRS, 10bRS)-9-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl-4-methyl-benzsulfamide

EF：C ₂₈H ₂₈F ₂N ₂O ₅S MW：542，61 MS：543，3(MH ⁺)

10, N-{4-[(2RS, 4aRS, 10bRS)-and 9-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzyl }-4-methyl-benzsulfamide

EF：C ₂₉H ₃₀F ₂N _2O5S MW：556，63 MS：557，4(MH ⁺)

11, N-[4-((2RS, 4aRS, 10bRS)-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-4-methyl-benzsulfamide

With 440mg acetate (2RS, 4aRS, 10bRS)-8,9-dimethoxy-6-[4-toluene-4-sulfonamido)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester (compound 12) and 136mg cesium carbonate be dissolved in the 2ml methylene dichloride with 14ml methyl alcohol in.Stirred solution 16h.Add the 136mg cesium carbonate then and the 24h that stirs the mixture once more.Removing then desolvates and pass through the purified by flash chromatography residue generates the 204mg title compound.

Begin by suitable initial compounds, it clearly is mentioned below or describes, or it can be in the manner known to persons skilled in the art or be similar to or prepare similar in appearance to the mode of embodiment described herein, obtains to be similar to embodiment 11, that other is relevant, the clear similar compound of describing according to the method among the embodiment 11.

12, acetate (2RS, 4aRS, 10bRS)-8,9-dimethoxy-6-[4-(toluene-4-sulfonamido)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

The 1.417g phosphorus pentachloride is suspended in the 50ml methylene dichloride.Add the 963mg A1 and the 10ml isopropyl acetate that are dissolved in the 30ml methylene dichloride.In 50 ℃ of stirred reaction mixture 6h, then stirring at room 16 hours.And the mixture of adding 25ml methylene dichloride and 25ml triethylamine, the careful 25ml water that adds under the vigorous stirring then.After using methylene dichloride to extract, organic layer generates the 670mg title compound through dried over mgso and through the purified by flash chromatography crude product again.

EF：C ₃₀H ₃₂N ₂O ₆S MW：548，66 MS：549，3(MH ⁺)

Begun by suitable initial compounds, it can be in the manner known to persons skilled in the art or is similar to or prepares the compound below obtaining according to method similar or in embodiment 12 similar in appearance to the mode of embodiment described herein.In case of necessity, the lewis' acid at catalytic amount carries out cyclization such as in the presence of the tin tetrachloride.

13, acetate (2RS, 4aRS, 10bRS)-8,9-dimethoxy-6-{4-[methyl-(toluene-4-alkylsulfonyl)-amino]-phenyl-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₁H ₃₄N ₂O ₆S MW：562，69 MS：563，3(MH ⁺)

14, acetate (2RS, 4aRS, 10bRS)-6-[4-(4-fluoro-phenylsulfonamido)-phenyl]-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₂₉H ₂₉FN ₂O ₆S MW：552，63 MS：553，3(MH ⁺)

15, acetate (2RS, 4aRS, 10bRS)-8,9-dimethoxy-6-[3-methyl-4-(toluene-4-sulfonamido)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₁H ₃₄N ₂O ₅S MW：562，69 MS：563，4(MH ⁺)

16, acetate (2RS, 4aRS, 10bRS)-8,9-dimethoxy-6-{4-[(toluene-4-sulfonamido)-methyl]-phenyl }-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₁H ₃₄N ₂O ₆S MW：562，69 MS：563，4(MH ⁺)

17, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-6-(4-methanesulfonamido-phenyl)-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₂₄H ₂₆F ₂N ₂O ₆S MW：508，55 MS：509，3(MH ⁺)

18, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(toluene-4-sulfonamido)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₀H ₃₀F ₂N ₂O ₆S MW：584，64 MS：585，3(MH ⁺)

19, acetate (2RS, 4aRS, 10bRS) 8-(1,1-two fluoro-methoxyl groups)-6-[4-(4-fluoro-phenylsulfonamido)-phenyl]-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₂₉H ₂₇F ₃N ₂O ₆S MW：588，61 MS：589，3(MH ⁺)

20, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-{4-[(toluene-4-sulfonamido)-methyl]-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₁H ₃₂F ₂N ₂O ₆S MW：598，67 MS：599，3(MH ⁺)

21, acetate (2RS, 4aRS, 10bRS)-9-(1,1-two fluoro-methoxyl groups)-8-methoxyl group-6-[4-(toluene-4-sulfonamido)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₀H ₃₀F ₂N ₂O ₆S MW：584，64 MS：585，3(MH ⁺)

22, acetate (2RS, 4aRS, 10bRS)-9-(1,1-two fluoro-methoxyl groups)-8-methoxyl group-6-{4-[(toluene-4-sulfonamido)-methyl]-phenyl-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

EF：C ₃₁H ₃₂F ₂N ₂O ₆S MW：598，67 MS：599，3(MH ⁺)

Begin by suitable ester initial compounds, it clearly is mentioned or describes (compound 43-62) below, or it can be in the manner known to persons skilled in the art or be similar to or prepare similar in appearance to the mode of embodiment described herein, obtains compound 23-42 according to the method among the embodiment 11.

23,4-((2RS, 4aRS, 10bRS)-2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N, N-dipropyl-benzsulfamide

C ₂₇H ₃₆N ₂O ₅S MW：500，66 MS：501，4(MH ⁺)

24,4-((2RS, 4aRS, 10bRS)-9-oxyethyl group-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N, N-dipropyl-benzsulfamide

C ₂₈H ₃₈N ₂O ₅S MW：514，69 MS：515，4(MH ⁺)

25,4-((2RS, 4aRS, 10bRS)-9-oxyethyl group-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl) N-(2-methoxyl group-ethyl)-N-methyl-benzsulfamide

C ₂₅H ₃₄N ₂O ₅S MW：502，63 MS：503，3(MH ⁺)

26, (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl }-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₅H ₂₈F ₂N ₂O ₅S MW：506，57 MS：507，3(MH ⁺)

27, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(piperidines-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₆H ₃₀F ₂N ₂O ₆S MW：520，6 MS：521，4(MH ⁺)

28, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₅H ₂₈F ₂N ₂O ₅S MW：506，57 MS：507，4(MH ⁺)

29,4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-N, N-dipropyl-benzsulfamide

C ₂₇H ₃₄F ₂N ₂O ₅S MW：536，64 MS：537，4(MH ⁺)

30, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₅H ₂₈F ₂N ₂O ₆S MW：522，57 MS：523，3(MH ⁺)

31, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₅H ₂₈F ₂N ₂O ₆S MW：522，57 MS：523，4(MH ⁺)

32, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(piperidines-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₆H ₃₀F ₂N ₂O ₅S MW：520，6 MS：521，3(MH ⁺)

33,3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-N, N-dimethyl-benzsulfamide

C ₂₃H ₂₆F ₂N ₂O ₅S MW：480，53 MS：481，3(MH ⁺)

34, N-cyclopropyl-3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzsulfamide

C ₂₄H ₂₆F ₂N ₂O ₅S MW：492，55 MS：493，3(MH ⁺)

35,3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-N, N-two-(2-methoxyl group-ethyl)-benzsulfamide

C ₂₇H ₃₄F ₂N ₂O ₇S MW：568，64 MS：569，3(MH ⁺)

36, (2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₅H ₃₁F ₂N ₃O ₅S MW：535，61 MS：536，3(MH ⁺)

37, (2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₇H ₃₃F ₂N ₃O ₅S MW：549，64 MS：550，3(MH ⁺)

38, (2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₆H ₃₀F ₂N ₂O ₅S MW：520，6 MS：521，3(MH ⁺)

39, (2RS, 4aRS, 10bRS)-and 6-(3-methylsulfonyl-phenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₂H ₂₅NO ₅S MW：415，51 MS：416，3(MH ⁺)

40, (2RS, 4aRS, 10bRS)-and 9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₃H ₂₇NO ₃S MW：397，54 MS：398，2(MH ⁺)

41, (2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₃H ₂₇NO ₃S MW：397，54 MS：398，3(MH ⁺)

42, (2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

C ₂₃H ₂₅F ₂NO ₃S MW：433，52 MS：434，2(MH ⁺)

Begin by being similar to the suitable initial compounds that following method obtains, can obtain following or other relevant ester according to the similar or similar cyclization of describing among the embodiment 12.In case of necessity, the lewis' acid at catalytic amount carries out cyclization such as in the presence of the tin tetrachloride.

43, acetate (2RS, 4aRS, 10bRS)-6-(4-dipropyl sulphonamide-phenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₉H ₃₈N ₂O ₆S MW：542，7 MS：543，4(MH ⁺)

44, acetate (2RS, 4aRS, 10bRS)-6-(4-dipropyl sulphonamide-phenyl)-9-oxyethyl group-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₃₀H ₄₀N ₂O ₆S MW：556，73 MS：557，4(MH ⁺)

45. acetate (2RS, 4aRS, 10bRS)-9-oxyethyl group-8-methoxyl group-6-{4-[(2-methoxyl group-ethyl)-methyl-sulphonamide]-phenyl }-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₈H ₃₆N ₂O ₇S MW：544，67 MS：545，3(MH ⁺)

46, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₇H ₃₀F ₂N ₂O ₆S MW：548，61 MS：549，3(MH ⁺)

47, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(piperidines-1-alkylsulfonyl) phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

48, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(tetramethyleneimine-1-alkylsulfonyl) phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₇H ₃₀F ₂N ₂O ₆S MW：548，61 M8：549，3(MH ⁺)

49, acetate (2RS, 4aRS, 10bRS)-8-(two fluoro-methoxyl groups)-6-(4-dipropyl sulphonamide-phenyl)-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₉H ₃₆F ₂N ₂O ₆S MW：578，68 MS：579，3(MH ⁺)

50, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

51, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₇H ₃₀F ₂N ₂O ₇S MW：564，61 MS：565，3(MH ⁺)

52, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(piperidines-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

53, acetate (2RS, 4aRS, 10bRS)-8-(two fluoro-methoxyl groups)-6-(3-dimethylamino sulphonyl-phenyl)-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₅H ₂₈F ₂N ₂O ₈S MW：522，57 MS：523，3(MH ⁺)

54, acetate (2RS, 4aRS, 10bRS)-6-(3-cyclopropyl sulphonamide-phenyl)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₆H ₂₈F ₂N ₂O ₆S MW：534，58 MS：535，5(MH ⁺)

55, acetate (2RS, 4aRS, 10bRS)-6-{3-[two-(2-methoxyl group-ethyl)-sulphonamide]-phenyl-8-(two fluoro-methoxyl groups)-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₉H ₃₆F ₂N ₂O ₈S MW：610，68 MS：611，3(MH ⁺)

56, acetate (2RS, 4aRS, 10bRS)-8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₈H ₃₃F ₂N ₃O ₆S MW：577，65 MS：578，3(MH ⁺)

57, acetate (2RS, 4aRS, 10bRS)-9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

58, acetate (2RS, 4aRS, 10bRS)-9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

59, acetate (2RS, 4aRS, 10bRS)-6-(3-methylsulfonyl-phenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₄H ₂₇NO ₆S MW：457，55 MS：458，2(MH ⁺)

60, acetate (2RS, 4aRS, 10bRS)-9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C ₂₅H ₂₉NO ₄S MW：439，58 MS：440，2(MH ⁺)

61, acetate (2R, 4aR, 10bR)-9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

C25H29NO4S MW：439，58 MS：440，3(MH ⁺)

62, acetate (2RS, 4aRS, 10bRS)-9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-(4-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-base ester

63, (2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(3-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

Via being similar to or obtaining title compound similar in appearance to embodiment 41 described synthetic routes.

In the proper time of synthetic route, obtain following compounds to be similar to mode as herein described via list known in the art-S-oxidizing reaction.

64, (2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfinyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

65, (2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(3-methyl sulfinyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

Initial compounds

A1. acetate (1RS, 3RS, 4RS)-4-{[1-(4-(toluene-4-sulfonamido) phenyl) formyl radical] amino-3-(3, the 4-Dimethoxyphenyl) cyclohexyl

Under the nitrogen atmosphere, 874mg 4-(toluene-4-sulfonamido)-phenylformic acid, 575mg N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) and 2mg 4-dimethylaminopyridine are placed flask.Add the 734mg acetate be dissolved in the 2.5ml methylene dichloride (1RS, 3RS, 4RS)-4-amino-3-(3, the 4-Dimethoxyphenyl) cyclohexyl (compound B-11) and stir this solution 3h.React with the quencher of 3ml water.Separate each mutually after, organic layer is through saturated NaHCO ₃Solution washing and with methylene dichloride aqueous layer extracted again.Organic layer is after dried over mgso, and residue generates the 1.198g title compound through chromatography purification.

Initial by suitable amino initial compounds and suitable benzoic acid derivative known in the art, aminocompound such as following or obtain wherein to be similar to following method, according to embodiment A 1 similarly or similar methods can obtain other relevant initial compounds.

B1, acetate (1RS, 3RS, 4RS)-4-amino-3-(3, the 4-Dimethoxyphenyl) cyclohexyl

With 10.37g acetate (1RS, 3RS, 4RS)-3-(3,4 Dimethoxyphenyls)-the 240ml ethanolic soln of 4-nitrocyclohex ester (Compound C 1) adds in zinc-copper conjugates, this conjugates is prepared in acetate by 16.8g zinc powder and 920mg venus crystals (II) monohydrate, and backflow gained suspension also uses 26ml acetate, 3.2ml water and 26ml Ethanol Treatment.Further backflow gained mixture 15min.Suction filtration is removed precipitation, and removes and desolvate.At the enterprising circumstances in which people get things ready for a trip of silica gel spectrum purifying, usage ratio is that the mixture of petrol ether/ethyl acetate/triethylamine of 2/7/1 and concentrate eluant stream section obtain 5.13g (theoretical value 55%) title compound, is light brown oily thing.

Rf=0.35 (petrol ether/ethyl acetate/triethylamine=2/7/1)

By those skilled in the art according to being similar to suitable initial compounds that exemplary initial compounds can get and, as described in embodiment B1, can obtaining compd B 2-B5 according to the open synthetic route of describing in the present embodiment.

B2, acetate (1RS, 3RS, 4RS)-4-amino-3-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl

Begin by following C2 compound, according to the method acquisition title compound of Embodiment B 1.

B2a, acetate (1R, 3R, 4R)-4-amino-3-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl

EF：C ₁₇H ₂₅NO ₄；MW：307.39

MS：308.0(MH ⁺)

The pyroglutamate (compd B 2b) of 24.0g (55.0mmol) title compound is suspended in the 150ml water, adds the 100ml methylene dichloride and add KHCO then ₃-saturated solution is until there not being gas to emerge.Separate each mutually after, aqueous layer extracted and the organic layer that merges with dried over sodium sulfate again, removing desolvates generates the salt-free title compound of 16.9g.

Analytical column chromatography (CHIRALPAK AD-H 250 * 4.6mm 5 μ No.ADHOCE-DB030, eluent: normal hexane/iPrOH=80/20 (v/v)+0.1% diethylamine): retention time: 6.54min.

B2b, acetate (1R, 3R, 4R)-and 4-amino-3-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl, the L-pyroglutamate

Solution A: with the racemic acetate of 55.2g (180mmol) (1RS, 3RS, 4RS)-4-amino-3-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl (compd B 2) is dissolved in the 540ml isopropyl acetate.

Solution B: heating is dissolved in 18.6g (144mmol) L-Pyrrolidonecarboxylic acid in the 260ml Virahol down, carefully adds the 290ml isopropyl acetate then.

Add solution B in the solution A and left standstill 48 hours.Filter to such an extent that solid also washs with the small amount of acetic acid isopropyl ester, obtain the 32.48g colourless crystallization after the drying, the ratio of enantiomorph is 97: 3, helps title compound.

M.p.：165-167℃

B3, acetate (RS, 3RS, 4RS)-4-amino-3-[4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-phenyl]-cyclohexyl

By following Compound C 3 beginnings, obtain title compound according to the method that is similar to Embodiment B 1.

EF：C ₁₆H ₂₁F ₂NO ₄；MW：329.35

MS：330.0(MH ⁺)

B4, acetate (1RS, 3RS, 4RS)-4-amino-3-[3-(1,1-two fluoro-methoxyl groups)-4-methoxyl group-phenyl]-cyclohexyl

By following Compound C 4 beginnings, obtain title compound according to the method that is similar to Embodiment B 1.

EF：C ₁₆H ₂₁F ₂NO ₄；MW：329.35

MS：330.0(MH ⁺)

B5, acetate (1RS, 3RS, 4RS)-4-amino-3-[3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-cyclohexyl

By following Compound C 5 beginnings, obtain title compound according to the method that is similar to Embodiment B 1.

B5a, acetate (1R, 3R, 4R)-4-amino-3-[3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-cyclohexyl

According to being similar to the described method of compd B 2a, using sodium hydrogen carbonate solution, obtaining title compound by its pyroglutamate (compd B 5b).

B5b, acetate (1R, 3R, 4R)-4-amino-3-[3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-cyclohexyl, the L-pyroglutamate

With 343mg (1.00mmol) acetate (1RS, 3RS, 4RS)-4-amino-3-[3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-cyclohexyl (compd B 5) is dissolved in the 3ml Virahol.The 2ml aqueous isopropanol that adds 103mg (0.80mmol) L-Pyrrolidonecarboxylic acid.Filter after drying, separate obtaining the 162mg pyroglutamate, enantiomeric ratio is 97: 3, helps title compound.

B6, acetate (1SR, 3RS, 4RS)-3-amino-4-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl

With 3.0g (7.36mmol) acetate (1SR, 3RS, 4RS)-uncle 3--butoxy carbonyl amino-4-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl (Compound C 6) is dissolved in the dioxane solution of 6ml 4 M HCl and stirs 30min.Except that after desolvating, be dissolved in residue in the methylene dichloride and the saturated NaHCO of the careful 25ml of adding ₃Solution.Separate each mutually after, aqueous layer extracted and the dry organic layer (Na that merges again ₂SO ₄), removing desolvates generates the 2.25g title compound.

EF：C17H25NO4；MW：307.39

MS：308.1(MH ⁺)

B7, acetate (1SR, 3RS, 4RS)-3-amino-4 (3,4-dimethoxy-phenyl)-cyclohexyl

Be similar to compound B-26 describedly, can obtain title compound by Compound C 7.

C1, acetate (1RS, 3RS, 4RS)-3-(3, the 4-Dimethoxyphenyl)-4-nitrocyclohex ester

With 10.18g (1RS, 3RS, 4RS)-3-(3, the 4-Dimethoxyphenyl)-4-nitrocyclohex alcohol (Compound D 1) is dissolved in the 100ml diacetyl oxide and in 100 ℃ of heated solution 1-2h.Remove desolvate after, residue on silica gel is 2/1 petrol ether/ethyl acetate chromatography through ratio.

Concentrate corresponding eluent stream section and obtain 10.37g (theoretic 89%) title compound, be oily matter.

Rf=0.32 (petrol ether/ethyl acetate=2/1)

C2, acetate (1RS, 3RS, 4RS)-3-(3-oxyethyl group-4-methoxyl group-phenyl)-4-nitrocyclohex ester

By following Compound D 2 beginnings, according to the method acquisition title compound of Embodiment C 1.

Begin by following initial compounds, obtain following compounds according to the method for Embodiment C 1:

C3, acetate (1RS, 3RS, 4RS)-3-[4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-phenyl]-4-nitrocyclohex ester

C4, acetate (1RS, 3RS, 4RS)-3-[3-(1,1-two fluoro-methoxyl groups)-4-methoxyl group-phenyl]-4-nitrocyclohex ester

C5, acetate (1RS, 3RS, 4RS)-3-(3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-4-nitrocyclohex ester

C6, acetate (1SR, 3RS, 4RS)-uncle 3--butoxy carbonyl amino-4-(3-oxyethyl group-4-methoxyl group-phenyl)-cyclohexyl

With 22.64g (65mmol) [(1RS, 6RS)-6-(3-oxyethyl group-4-methoxyl group-phenyl)-hexamethylene-3-thiazolinyl]-t-butyl carbamate (Compound D 6) is dissolved in 180ml THF and dropwise adds (30min) 50ml BH ₃(the THF solution of 1M).After stirring 2h, use the ice bath cooling mixture, add 30ml H ₂O ₂(30%) and the mixture of 60ml NaOH (3M) aqueous solution.Stirring at room mixture 30min.Add 400ml water and 200ml methylene dichloride.Separate each mutually after, aqueous layer extracted and the dry organic layer (Na that merges again ₂SO ₄), remove and desolvate, need not to be further purified direct use crude product (23.42g, about 2: 1 mixture of two kinds of described regional isomers helps title compound).

Then with above-mentioned thick substance dissolves in the 50ml pyridine.Add 50mg 4-dimethylaminopyridine and 60ml diacetyl oxide and in 100 ℃ of 90min that stir the mixture.Remove and desolvate and diacetyl oxide (saturated NaHCO ₃Solution).Obtain the 9.4g title compound through chromatography purification, be the colourless foam thing.

EF：C22H33NO6；MW：407.51

MS：308.1(MH ⁺-Boc)，407.8(MH ⁺)，430.1(MNa ⁺)

C7, acetate (1SR, 3RS, 4RS)-uncle 3--butoxy carbonyl amino-4-(3,4-dimethoxy-phenyl)-cyclohexyl

Can obtain title compound to Compound C 6 described methods by Compound D 7 according to being similar to.

D1, (1RS, 3RS, 4RS)-3-(3,4 Dimethoxyphenyl)-4-nitrocyclohex alcohol

With 10g (1RS, 3RS, 4SR)-that 3-(3, the 4-Dimethoxyphenyl)-4-nitrocyclohex alcohol (compd E 1) is dissolved in 170ml is absolute 1, in the 2-glycol dimethyl ether.The methanol solution that dropwise adds 14.3ml 30% sodium methylate.Add finish after, continue to stir 10min, add and contain 85% phosphoric acid and methanol mixture to pH1.By adding in the saturated potassium hydrogen carbonate solution and gained suspension.Mixture separates organic layer and uses dichloromethane extraction through water and methylene dichloride dilution.Removal of solvent under reduced pressure obtains title compound, is yellow oil, its crystallization.Title compound need not to be further purified and is used for following step.

M.p.:126-127 ℃ of Rf=0.29 (petrol ether/ethyl acetate=1/1)

D2, (1RS, 3RS, 4RS)-3-(3-oxyethyl group-4-methoxyl group-phenyl)-4-nitrocyclohex alcohol

Begin by the suitable E2 compound of mentioning below, according to the method acquisition title compound of embodiment D1.

Begin by the suitable initial compounds of mentioning below, obtain following compounds according to the method for embodiment D1:

D3, (1RS, 3RS, 4RS) 3-[4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-phenyl]-4-nitrocyclohex alcohol

D4, (1RS, 3RS, 4RS)-3-[3-(1,1-two fluoro-methoxyl groups)-4-methoxyl group-phenyl]-4-nitrocyclohex alcohol

D5, (1RS, 3RS, 4RS)-3-(3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl)-4-nitrocyclohex alcohol

D6, [(1RS, 6RS)-6-(3-oxyethyl group 4-methoxyl group-phenyl)-hexamethylene-3-thiazolinyl]-t-butyl carbamate

By (1RS, 6RS)-6-(3-oxyethyl group-4-methoxyl group-phenyl)-hexamethylene-3-enamine (compd E 6) beginning, according to being similar to Compound D 7 described methods are obtained title compound.

EF：C20H29NO4；MW：347.46，

MS：370.1(MNa ⁺)

D7, [(1RS, 6RS)-6-(3,4-dimethoxy-phenyl)-hexamethylene-3-thiazolinyl]-t-butyl carbamate

In methylene dichloride, stir 15.18g (65.06mmol) (±)-cis-6-(3, the 4-Dimethoxyphenyl)-hexamethylene-3-enamine (compd E 7) and 14.21g (65.11mmol) Boc ₂O 2.5h removes then and desolvates and crystalline residue generation 19.1g title compound from ethyl acetate/normal hexane.

EF：C19H27NO4；MW：333.43，

MS：334.2(MH ⁺)

E1, (1RS, 3RS, 4SR)-3-(3,4 Dimethoxyphenyl)-4-nitrocyclohex alcohol

In the nitrogen atmosphere, with 16.76g (3RS, 4SR)-3-(3, the 4-Dimethoxyphenyl)-4-nitrocyclohexanone (compound F 17-hydroxy-corticosterone 1) is dissolved in the 300ml tetrahydrofuran (THF), solution is chilled to-78 ℃, dropwise adds the tetrahydrofuran solution of 75ml 1M three-sec-butyl POTASSIUM BOROHYDRIDE.After continuing to stir 1h, add the mixture that contains 30% superoxol and phosphoric acid buffer.

Continue to stir 10min, reaction mixture is through the dilution of 400ml ethyl acetate and use the ethyl acetate extraction water layer, the organic phase that merges generates the foam thing through concentrating, and its usage ratio on silica gel is that 1/1 petrol ether/ethyl acetate is carried out chromatography purification and obtained 10.18g (theoretic 60%) title compound.

EF：C ₁₄H ₁₉NO ₅；MW：281.31

MS：299.1(MNH ₄ ⁺)

Rf=0.29 (petrol ether/ethyl acetate=1/1)

M.p.：139-141℃

E2, (1RS, 3RS, 4SR)-3-(3-oxyethyl group-4-methoxyl group-phenyl)-4-nitrocyclohex alcohol

By following suitable compound F 17-hydroxy-corticosterone 2 beginnings, according to the method acquisition title compound of embodiment E 1.

Begin by following suitable initial compounds, obtain following compound according to the method for embodiment E 1:

E3, (1RS, 3RS, 4SR)-3-[4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-phenyl]-4-nitrocyclohex alcohol

E4, (1RS, 3RS, 4RS)-3-[3-(1,1-two fluoro-methoxyl groups)-4-methoxyl group-phenyl]-4-nitrocyclohex alcohol

E5, (1RS, 3RS, 4SR)-3-(3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl)-4-nitrocyclohex alcohol

E6, (1RS, 6RS)-6-(3-oxyethyl group-4-methoxyl group-phenyl)-hexamethylene-3-enamine

(beginning of (1RS, 6RS)-6-nitro-hexamethylene-3-thiazolinyl)-benzene (compound F 17-hydroxy-corticosterone 6) obtains title compounds according to being similar to compd E 7 described methods by 2-oxyethyl group-1-methoxyl group-4-.

E7, (±)-suitable-6-(3, the 4-Dimethoxyphenyl)-hexamethylene-3-enamine

With 40g (±)-cis-1,2-dimethoxy-4 '-(2-nitrocyclohex-4-thiazolinyl) benzene (compound F 17-hydroxy-corticosterone 7) is dissolved in the 400ml ethanol and adds the 40g zinc powder.Be heated to boil after, dropwise add the 65ml glacial acetic acid.After this, filter reaction mixture and concentrated.Residue is dissolved in the hydrochloric acid of dilution again and uses the toluene extraction.Water layer is with the alkalization of 6N sodium hydroxide solution and use toluene extraction several times.Through the organic phase of the merging of alkali extraction through dried over sodium sulfate and concentrate.Residue chromatography on silica gel obtains the 11.5g title compound.

F1, (3RS, 4SR)-3-(3, the 4-Dimethoxyphenyl)-4-nitrocyclohexanone

With 90.0g 3,4-dimethoxy-ω-nitrostyrolene (compound G1), 90ml 2-trimethylsiloxy-1,3-butadiene and 180ml absolute toluene place autoclave, stir cooling then 2 days in 140 ℃ therein.After adding the 1000ml ethyl acetate, under agitation dropwise add 300ml 2N hydrochloric acid soln.Separate each phase and use the dichloromethane extraction water three times.The organic extract that merges washs through saturated sodium bicarbonate solution, dried over mgso, and removal of solvent under reduced pressure generates the thick title compound of 150g.Usage ratio is that 1/1 petrol ether/ethyl acetate is further purified by chromatography as eluent on silica gel, generates the pure title compound of 81.5g (theoretic 67%).

EF：C ₁₄H ₁₇NO ₅；MW：279.30

MS：279(M ⁺)，297.1(MNH ₄ ⁺)

M.p.:147-148 ℃ of Rf=0.47 (petrol ether/ethyl acetate=1/1)

F2, (3RS, 4SR)-3-(3-oxyethyl group-4-methoxyl group-phenyl)-4-nitrocyclohexanone

Begin by following compound G2, obtain title compound according to the method in the embodiment F 1.

Begin by following suitable initial compounds, obtain following compound according to the method in the embodiment F 1:

F3, (3RS, 4SR)-3-[4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-phenyl]-the 4-nitrocyclohexanone

F4, (3RS, 4SR)-3-[3-(1,1-two fluoro-methoxyl groups) 4-methoxyl group-phenyl]-the 4-nitrocyclohexanone

F5, (3RS, 4SR)-3-(3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl]-the 4-nitrocyclohexanone

F6,2-oxyethyl group-1-methoxyl group-4-((1RS, 6RS)-6-nitro-hexamethylene-3-thiazolinyl)-benzene

(beginning of (1RS, 6SR)-6-nitro-hexamethylene-3-thiazolinyl)-benzene (compound G6) obtains title compounds according to being similar to compound F 17-hydroxy-corticosterone 7 described methods by 2-oxyethyl group-1-methoxyl group-4-.

F7, (±)-cis-1,2-dimethoxy-4 '-(2-nitrocyclohex-4-thiazolinyl) benzene

With 10.0g (±)-anti-form-1,2-dimethoxy-4 '-(2-nitrocyclohex-4-thiazolinyl) benzene (compound G7) and 20.0g potassium hydroxide are dissolved in 150ml ethanol and the 35ml dimethyl formamide.Temperature is no more than the 60ml ethanolic soln that dropwise adds the 17.5ml vitriol oil under 4 ℃ in keeping.After stirring 1h, mixture is added in 1 liter of frozen water, suction filtration obtains precipitation, through water washing and dry, this crude product recrystallization in ethanol.Obtain the 8.6g title compound, m.p.82.5-84 ℃.

G1,3,4-dimethoxy-ω-nitrostyrolene

With 207.0g 3,4-dimethoxy benzaldehyde, 100.0g ammonium acetate and 125ml Nitromethane 99Min. are heated in 1.0 liters of glacial acetic acids and boil, and continue 3-4h.After the cooling, suction filtration obtains precipitation in ice bath, through glacial acetic acid and petroleum ether and dry.M.p.：140-141℃。Yield: 179.0g.

G2,3-oxyethyl group-4-methoxyl group-ω-nitrostyrolene

By initial compounds known in the art, obtain title compound according to the method among the embodiment G1:

By known in the art or can according to currently known methods (such as describe among the WO95/01338 or its similar or similar methods) initial compounds of preparation begins, and obtains following compounds according to the method among the embodiment G1:

G3,4-(1,1-two fluoro-methoxyl groups)-3-methoxyl group-ω-nitrostyrolene

G4,3-(1,1-two fluoro-methoxyl groups)-4-methoxyl group-ω-nitrostyrolene

G5,3-(2,2-two fluoro-oxyethyl groups-4)-methoxyl group-ω-nitrostyrolene

By 3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl aldehyde (compound H 1) beginning, according to the method acquisition title compound of embodiment G1.

M.p.：164-165℃

G6,2-oxyethyl group-1-methoxyl group-4-((1RS, 6SR)-6-nitro-hexamethylene-3-thiazolinyl) benzene

By 3-oxyethyl group 4-methoxyl group-ω-nitrostyrolene (compound G2) beginning, according to the described method of compound G7 is obtained title compound.

G7, (±)-anti-form-1,2-dimethoxy-4 '-(2-nitrocyclohex-4-thiazolinyl) benzene

With 50.0g 3,4-dimethoxy-ω-nitrostyrolene (compound G1) and 1.0g (9.1mmol) quinhydrones are suspended in the 200ml absolute toluene and at-70 ℃ and use 55.0g (1.02mol) liquid 1,3-butadiene to handle.In autoclave, stirred this mixture 6 days, cooling then in 160 ℃.On Rotary Evaporators, remove some solvents, suction filtration gained precipitation and recrystallization in ethanol.

M.p.：113.5-115.5℃.

H1,3-(2,2-two fluoro-oxyethyl groups)-4-methoxyl group-phenyl aldehyde

10.04g isovanillin and 15.5g salt of wormwood are placed autoclave.Add 50mlDMF and 12.44g 2-bromo-1, the 1-C2H4F2 C2H4F2.Close autoclave and heat 20h in 60 ℃.Cross filter solid and use 120ml DMF washing.Steam to remove about 120ml solvent and with residue incline to 200ml ice/waterborne, be settled out product.After stirring this slurry 30min, filtration product and the dry 13.69g desired product that generates.

M.p.：66-68℃

Commercial applicability

Compound of the present invention has the valuable pharmacological characteristic, therefore can be used for commercial applications.As cyclic nucleotide phosphodiesterase (PDE) inhibitor (particularly 4 types) optionally, they are suitable for use as bronchial therapeutical agent on the one hand and (are used for the treatment of airway obstruction, this is based on the effect of their dilating effect and their increase respiratory rates or respiratory drive), and because their vasorelaxation action can be used for eliminating erective dysfunction; On the other hand, they can be used for treating the particularly disease in the tracheal disease of immunity (prevention of asthma), dermatosis, central nervous system disease, intestinal disease, eye and joint, these diseases by histamine, PAF (platelet activation factor), arachidonic acid derivatives such as leukotriene and prostaglandin(PG), cytokine, interleukin, chemokine, α-, β-and gamma-interferon, tumour necrosis factor (TNF) or media such as oxygen-cent red radical and proteolytic enzyme cause.The characteristics of The compounds of this invention are that toxicity is low, intestinal absorption good (bioavailability height), therapeutic domain is wide and do not have significant side effects.

Based on its PDE rejection characteristic, compound of the present invention can be used for people and medicine and therapeutical agent for animals, for example, they can be used for treatment and prevent following disease: the tracheal disease (bronchitis, allergic bronchitis, bronchial asthma, pulmonary emphysema, COPD) of the various causes of acute and chronic (particularly inflammation and allergy cause); Tetter (particularly proliferative, inflammatory and hypersensitive), for example itch, alopecia areata, hyperplastic scar, discoid lupus erythematosus, folliculus and large-area pyoderma, endogenous and exogenous acne, acne erythematosa and other proliferative, inflammatory and the anaphylaxis dermatosis in psoriasis (ordinary psoriasis), poisoning or supersensitivity contact eczema, atopic eczema, seborrheic eczema, haplolichen, sunburn, anogenital region territory; The disease that excessively discharges based on TNF and leukotriene, for example inflammation (Crohn disease and ulcerative colitis) widely in reaction, transplant rejection, shock symptom [septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)] and other gastrointestinal regional of the disease of sacroiliitis type (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis illness), disease of immune system (AIDS, multiple sclerosis), graft antagonism host; Upper respiratory tract zone (pharynx, nose) and the disease in the adjacent area (nasal side hole, eye), for example allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, anaphylaxis conjunctivitis and nasal polyp based on irritated and/or chronic, bad immunological response; And the heart disease that can treat by PDE inhibitor heart function deficiency for example, or the disease that can treat based on organizational slack's effect of PDE inhibitor for example erective dysfunction or kidney and the ureteral colic relevant with urinary stone disease.In addition, compound of the present invention also can be used for treating the diabetic urine flooding and with brain metabolism disorder diseases associated, for example brain aging, senile dementia (Alzheimer's disease), the impairment of memory function relevant with Parkinson's disease or multi-infarct dementia; The disease that equally also can be used for the treatment of central nervous system, the dementia that causes as melancholia or arteriosclerosis.

The invention still further relates to treatment and suffer from the Mammals of above-mentioned a kind of disease, comprise people's method.Present method is characterised in that to ill administration therapeutic activity of the present invention, pharmacology is effective and one or more compounds of tolerance dose.

The invention still further relates to and be used for the treatment of and/or preventing disease, particularly the The compounds of this invention of above-mentioned disease.

The invention still further relates to The compounds of this invention and be used to prepare the purposes of the pharmaceutical composition that treats and/or prevents above-mentioned disease.

The invention still further relates to The compounds of this invention and be used to prepare the purposes of treatment by the pharmaceutical composition of the disease of the particularly PDE4-mediation of phosphodiesterase mediation, disease wherein such as be those or those skilled in the art of mentioning in this specification sheets obviously visible or known those.

The invention still further relates to The compounds of this invention is used to prepare and has the purposes that PDE4 suppresses active pharmaceutical composition.

The invention still further relates to and be used for the treatment of the pharmaceutical composition that treats and/or prevents above-mentioned disease, contains one or more The compounds of this invention.

The invention still further relates to the composition that contains one or more The compounds of this invention and pharmaceutically acceptable carrier.Described composition can be used for treatment, such as being used for the treatment of, preventing or improving one or more above-mentioned diseases.

The invention still further relates to the PDE of having of the present invention particularly PDE4 suppress active pharmaceutical composition.

In addition, the product that the present invention relates to produce, this product comprises wrapping material and the medicament that is included in the described wrapping material, wherein said medicament for the effect of antagonism 4 type cyclic nucleotide phosphodiesterases (PDE4), to improve the disease mediated symptom of PDE4-effective in cure, and wrapping material wherein comprise label or package insert, it indicates medicament is the disease that is used to prevent or treat the PDE4-mediation, and wherein said medicament contains the compound of one or more formula I of the present invention.These wrapping material, label and package insert others and the medicament that is used to have associated uses to be generally known as standard pack material, label and package insert same or similar.

Pharmaceutical composition is produced by method well known to those skilled in the art.As pharmaceutical composition, compound of the present invention (=active compound) directly can be used, perhaps, preferably itself and appropriate drug auxiliary agent and/or mixed with excipients are used with the form of for example tablet, coated tablet, capsule, Caplet, suppository, patch (as TTS), emulsion, suspensoid, gel or solution, the content of active compound is preferably 0.1-95%, wherein, can make form of medication (as slowly-releasing form or enteric form) mate exactly active compound and/or required onset time by suitably selecting auxiliary agent and/or vehicle.

Based on its expertise, those skilled in the art know auxiliary agent, vehicle, carrier, vehicle, thinner or the assistant agent that is suitable for required pharmaceutical dosage form.Desolventize, outside jelling agent, ointment base and other active compound excipients, can also use for example oxidation inhibitor, dispersion agent, emulsifying agent, sanitas, solubilizing agent, pigment, sequestrant or penetration enhancer.

The administration of pharmaceutical composition of the present invention can realize with the feasible any common received administering mode in this area.Exemplary suitable administering mode for example comprises intravenously, oral cavity, nasal cavity, parenteral, part, transdermal and rectal administration.The preferred oral administration.

For the treatment respiratory tract disease, The compounds of this invention is preferably with aerocolloidal form inhalation; The preferred particle diameter of aerosol particles of solid, liquid or blended component is 0.5-10 μ m, advantageously 2-6 μ m.

Aerocolloidal generation can be adopted following method, as pressure-actuated atomizer or ultrasonic atomizatio shower nozzle, certainly more favourable mode is the gageable aerosol with propellant actuated, perhaps adopts no propelling agent to advance, by sucking the micro-capsule administration of micronization active compound.

Difference according to used intake system, except that active compound, form of medication also comprises following required auxiliary material, as propelling agent (for example freonll-11 in gageable aerosol), tensio-active agent, emulsifying agent, stablizer, sanitas, correctives, filler (for example lactose in the powder inhalation) or, if suitable, also comprise other active compound.

In order to reach the purpose of suction, aerosol and the administration that can adopt various equipment to produce optimum grain-diameter, the suction technology of application will make things convenient for patient to use as far as possible.Except using shifting coupling (pad, expander), the container of pyriform (Nebulator  for example, Volumatic ) and be used for the automatic gear metering spray agent, that can produce spray effect (Autohaler ), particularly for powder inhalator, also have a lot of technical schemes can utilize (Diskhaler  for example, Rotadisk , Turbohaler  or at the sucker described in the European patent application EP 0 505 321), use these schemes and can obtain best active compound administration.

For the treatment tetter, The compounds of this invention is especially can be suitable for the medicament forms administration of local application.For the preparation of medicine, The compounds of this invention (=active compound) is preferably mixed with suitable pharmaceutical auxiliary agent, and further processing obtains suitable pharmaceutical preparation then.Suitable pharmaceutical dosage forms is following formulation, as powder, emulsion, suspension, sprays, oil, ointment, fatty ointment, creme, paste, gel or solution.

Pharmaceutical composition of the present invention prepares with known method own.Arrange the dosage of active compound according to the conventional using dosage of PDE inhibitor.Therefore the concentration that contains active compound for treatment dermopathic local application formulation (as ointment) for example is 0.1-99%.The common dose of inhalation is every day 0.01 to 3mg.The common dose of whole body therapeutic (oral or injection) is every day 0.003 to 3mg/kg.In another embodiment, the dosage of inhalation is every day 0.1 to 3mg, and the dosage of whole body therapeutic (oral or injection) is every day 0.03 to 3mg/kg.

Biological study

As everyone knows, second messenger's ring-type AMP (cAMP) can suppress inflammatory and immunocompetent cell.The PDE4 isozyme is wide expression (H Tenor and C Schudt in the cell that can bring out inflammation and propagation inflammation, in " phosphodiesterase inhibitor ", 21-40, " TheHandbook of Immunopharmacology ", Academic Press, 1996), its inhibition can cause the concentration of cAMP in the cell to increase, therefore and suppressed the activation (JESouness etc., Immunopharmacology 47:127-162,2000) of cell.

There has been document to set forth the PDE4 inhibitor in the intravital potential anti-inflammatory ability of various animal models (MM Teixeira, TIPS 18:164-170,1997).In PDE4 at cell levels inhibiting (external) research, measured a large amount of scorching reactions that causes.Be for example neutrophilic granulocyte (C Schudt etc., Arch Pharmacol 344:682-690,1991) or eosinophilic granulocyte (A Hatzelmann etc., Brit J Pharmacol 114:821-831, the generation of super-oxide 1995), it can pass through luminol,3-aminophthalic acid cyclic hydrazide enhanced chemical luminescent detecting, perhaps pass through at monocyte, synthetic mensuration (the Gantner etc. of tumor necrosis factor-alpha in scavenger cell or the dentritic cell, Brit J Pharmacol 121:221-231,1997, with PulmonaryPharmacol Therap 12:377-386,1999).In addition, from the restraining effect of the t cell responses of the synthetic of similar cytokine or propagation, can obviously find out the potential immunoregulation capability (DM Essayan, Biochem Pharmacol 57:965-973,1999) of PDE4 inhibitor.Can suppress above-mentioned pro-inflammatory mediator excretory material is those materials that can suppress PDE4.Therefore The compounds of this invention is the main indicator that inflammatory process is suppressed to the restraining effect of PDE4.

Suppress the active measuring method of PDE4

PDE4B2 (GB no.M97515) given in Prof.M.Conti (StanfordUniversity, USA).It uses primer via pcr amplification by original plasmid (pCMV5).Rb9 (5 '-GCCAGCGTGCAAATAATGAAGG-3 ') and Rb10 (5 '-AGAGGGGGATTATGTATCCAC-3 ') be cloned into the pCR-Bac carrier (Invitrogen, Gron-ingen, NL).

Be binned in the SF9 insect cell by the source and prepare recombinant baculovirus.With standard rule (Pharmingen, Hamburg) through Bac-N-Blue (Invitrogen, Groningen, NL) or Baculo-Gold DNA (Pharmingen, Hamburg) transfection plasmid expression.Use plaque assay to select Wt virus-free recombinant virus supernatant liquor.After this, prepare the infectious titer supernatant liquor by increasing 3 times.In not containing the SF900 media of serum, PDE expresses in the SF21 cell, through the MOI of 1-10 (multiplicity of infection) transfection 2 * 10 ⁶Individual cell/ml (LifeTechnologies, Pais-ley, UK).In 28 ℃ of culturing cell 48-72 hours, they were in 1000g and 4 ℃ of compacting 5-10min thereafter.

(20mM Tris, pH8.2 comprise following additive: 140mM NaCl, 3.8mM KCl, 1mM EGTA, 1mM MgCl in ice-cold homogenizing damping fluid ₂, 10mMp-mercaptoethanol, 2mM benzenyl amidine, 0.4mM Pefablock, 10RM leupeptin, 10pM Pepstatin A, 5FM trypsin inhibitor) resuspending SF21 insect cell, concentration about 10 ⁷Individual cell/ml, and use ultra-sonic dispersion.In centrifugal this homogenate of 1000xg 10min, store supernatant liquor in-80 ℃ and use (referring to following) then until the back.Use BSA to determine protein content by Bradford method (BioRad, Munich) as standard substance.

In improved SPA (scintillation proximity assay) test that Amersham Biosciences (referring to program description " phosphodiesterase [3H] cAMPSPA enzyme test; coding TRKQ 7090 ") is provided, the PDE4B2 activity is suppressed by described compound, and this test (is carried out in the MTP ' s) at 96-hole microplate.Test volume is 100 μ l and comprises 20mM Tris damping fluid (pH7.4), 0.1mg BSA (bovine serum albumin)/ml, 5mM Mg ²⁺, the DMSO diluent of 0.5 μ M cAMP (comprise about 50,000cpm[3H] cAMP), 1 each material of μ l and enough reorganization PDE (the 1000xg supernatant liquor is on seeing) to be to guarantee to transform the cAMP of 10-20% under described test conditions.The ultimate density of DMSO (1%v/v) does not influence the activity of the PDE that is studied basically in the test.Behind 37 ℃ of preincubate 5min, begin reaction by adding substrate (cAMP), continue to give tester 15min; After this, stop by adding SPA pearl (50 μ l).According to the explanation of manufacturers, with the SPA pearl in advance resuspending in water, in water, dilute 1: 3 (v/v) then, diluent also comprises 3mM IBMX to guarantee the stopping PDE activity fully.The globule sedimentation (＞30min) after, on commercially available fluorescence detection device, analyze MTP ' s.According to determining that by the concentration-response curve of nonlinear dependence compound suppresses the active corresponding IC of PDE ₅₀Value.

Provided the representative inhibiting value that The compounds of this invention is measured in the following Table A, wherein the numbering of compound is corresponding to the numbering of embodiment.

Table A

The active inhibition of PDE4

Compound	-log IC50 (mol/ liter)
Compound	-log IC50 (mol/ liter)	1-4,6-10,24-42,45 and 61	The inhibiting value of these described embodiment is 7.52-10.06

Claims

1. formula I compound,

Wherein

Or wherein

R1 and R2 are the 1-2C-alkylene dioxo base together,

R3 is hydrogen or 1-4C-alkyl,

R31 is hydrogen or 1-4C-alkyl,

R4 is-O-R41, wherein

R5 is hydrogen or 1-4C-alkyl,

R4 is hydrogen or 1-4C-alkyl, and

R5 is-O-R51, wherein

R6 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxyl group,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) (R9), wherein

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

2. according to the formula I compound of claim 1, wherein

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is hydrogen or 1-7C-alkyl-carbonyl, and

R5 is a hydrogen,

R4 is a hydrogen, and

R5 is-O-R51, wherein

R51 is hydrogen or 1-7C-alkyl-carbonyl,

R6 is hydrogen or 1-4C alkyl,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) (R9), wherein

R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

3. according to the formula I compound of claim 1, wherein

R3 be hydrogen,

R31 be hydrogen,

R4 is-O-R41, wherein

R41 is 1-4C-alkyl-carbonyl or hydrogen,

R5 is a hydrogen,

R6 is hydrogen or methyl,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) (R9), wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-2-4C-alkyl or 3-7C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-2-4C-alkyl,

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-4C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is halogen or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

4. according to the formula I compound of claim 1, wherein

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is ethanoyl or hydrogen,

R5 is a hydrogen,

R6 is hydrogen or methyl,

In first aspect present invention (aspect 1),

R7 is-S (O) ₂N (R8) (R9), wherein

R8 is 1-4C-alkyl, 1-4C-alkoxyl group-ethyl or 3-5C-cycloalkyl,

R9 is hydrogen, 1-4C-alkyl or 1-4C-alkoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl, piperidyl or 4-N-(R81)-piperazinyl, wherein

R81 is the 1-4C-alkyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or 1-2C-alkylidene group,

R10 is hydrogen or 1-4C-alkyl,

R11 is the 1-4C-alkyl, or the phenyl that is replaced by R111, wherein

R111 is fluorine, chlorine or 1-4C-alkyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl,

5. according to the formula I compound of claim 1, wherein

R1 is a methoxy or ethoxy,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

In first aspect present invention (aspect 1),

R7 is S (O) ₂N (R8) R9, wherein

R8 is methyl, ethyl, propyl group, 2-methoxyl group-ethyl or cyclopropyl,

R9 is hydrogen, methyl, ethyl, propyl group or 2-methoxyl group-ethyl,

Het1 is morpholinyl, pyrrolidyl, piperidyl or 4-N-(R81)-piperazinyl, wherein

R81 is a methyl,

Or, in second aspect present invention (aspect 2),

R7 is-A-N (R10) S (O) ₂-R11, wherein

A is key or methylene radical,

R10 is hydrogen or methyl,

The phenyl that R11 is replaced by R111, wherein

R111 is fluorine, chlorine or methyl,

Or, in third aspect present invention (aspect 3),

R7 is-S (O) nR12, wherein

N is 0,1 or 2,

R12 is the 1-4C-alkyl, such as methyl,

6. according to the formula I compound of claim 1, wherein

R1 is a methoxy or ethoxy,

R2 is methoxyl group, oxyethyl group, 2,2-difluoroethoxy or difluoro-methoxy,

R3 is a hydrogen,

R31 is a hydrogen,

R4 is-O-R41, wherein

R41 is a hydrogen,

R5 is a hydrogen,

R6 is a hydrogen,

R7 is-S (O) nR12, wherein

N is 0 or 1,

R12 is a methyl,

7. according to the formula I compound of aforementioned each claim, contain one or more following groups:

R1 is a methoxyl group,

R2 is oxyethyl group, difluoro-methoxy or 2, the 2-difluoroethoxy and

R3 and R31 all are hydrogen,

R4 is-O-R41, wherein

R41 be hydrogen and

R5 is a hydrogen,

R6 be hydrogen and

R7 is connected in the position of phenanthridines ring system with reference to benzyl ring, position or contraposition between it is connected in,

8. according to the formula I compound of claim 1, be selected from:

N-[4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-4, N-dimethyl-benzsulfamide

4-fluoro-N-[4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-benzsulfamide

N-[4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-2-methyl-phenyl]-4-methyl-benzsulfamide

N-[4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-benzyl]-4-methyl-benzsulfamide

N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-Toluidrin

N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-4-methyl-benzsulfamide

N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-4-fluoro-benzsulfamide

N-{4-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzyl }-4-methyl-benzsulfamide

N-{4-[(2RS, 4aRS, 10bRS)-and 9-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-phenyl }-4-methyl-benzsulfamide

N-{4-[(2RS, 4aRS, 10bRS)-and 9-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzyl }-4-methyl-benzsulfamide

N-[4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-phenyl]-4-methyl-benzsulfamide

4-((2RS, 4aRS, 10bRS)-and 2-hydroxyl-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N, N-di-isopropyl-benzsulfamide

4-((2RS, 4aRS, 10bRS)-and 9-oxyethyl group-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N, N-dipropyl-benzsulfamide

4-((2RS, 4aRS, 10bRS)-and 9-oxyethyl group-2-hydroxyl-8-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N-(2-methoxyl group-ethyl)-N-methyl-benzsulfamide

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(piperidines-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(piperidines-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

4-((2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl)-N, N-dipropyl-benzsulfamide

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[4-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(morpholine-4-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-N, N-dimethyl-benzsulfamide

N-cyclopropyl-3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-benzsulfamide

3-[(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-2-hydroxyl-9-methoxyl group-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-6-yl]-N, N-two-(2-methoxyl group-ethyl)-benzsulfamide

(2RS, 4aRS, 10bRS)-and 8-(1,1-two fluoro-methoxyl groups)-9-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-[4-(tetramethyleneimine-1-alkylsulfonyl)-phenyl]-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 6-(3-methylsulfonyl-phenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl (sulfanyl)-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(4-methyl sulfenyl (sulfanyl)-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-(4-methyl sulfenyl (sulfanyl)-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-(3-methyl sulfenyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

(2RS, 4aRS, 10bRS)-and 9-(2,2-two fluoro-oxyethyl groups)-8-methoxyl group-6-(3-methylsulfinyl-phenyl)-1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol, and

(2R, 4aR, 10bR)-and 9-oxyethyl group-8-methoxyl group-6-(4-methylsulfinyl-phenyl) 1,2,3,4,4a, 10b-six hydrogen-phenanthridines-2-alcohol

The salt of the salt of enantiomorph and these compounds and enantiomorph, N-oxide compound and N-oxide compound.

9. according to the formula I compound of aforementioned each claim, the configuration at its 4a and 10b place is suc as formula I ^*Shown in:

10. according to the formula I compound of aforementioned each claim, 2, the configuration at 4a and 10b place is suc as formula Ia ^{* * * *}Shown in or 3, the configuration at 4a and 10b place suc as formula Ib ^{* * * *}Shown in:

11. the purposes of the described formula I compound of claim 1 in the treatment disease.

12. a pharmaceutical composition contains one or more formula I compounds as claimed in claim 1 and conventional drug excipient and/or carrier.

13. formula I compound as claimed in claim 1 is used to prepare the purposes of the pharmaceutical composition for the treatment of respiratory disease.

14. formula I compound as claimed in claim 1 is used to prepare the purposes of the pharmaceutical composition of the disease for the treatment of the PDE-mediation.

15. a method for the treatment of patient disease comprises the formula I compound as claimed in claim 1 that gives described patient treatment significant quantity.

16. a method for the treatment of the patient airway disease comprises the formula I compound as claimed in claim 1 that gives described patient treatment significant quantity.