WO2010148632A1

WO2010148632A1 - Dihydropyridine compounds and preparation methods, pharmaceutical compositions and uses thereof

Info

Publication number: WO2010148632A1
Application number: PCT/CN2010/000758
Authority: WO
Inventors: 李松; 郭真; 赵国明; 王莉莉; 关华; 肖军海; 钟武; 郑志兵; 谢云德; 李行舟; 王晓奎; 周辛波; 刘洪英
Original assignee: 中国人民解放军军事医学科学院毒物药物研究所
Priority date: 2009-06-25
Filing date: 2010-05-27
Publication date: 2010-12-29
Also published as: CN101575314B; CN101575314A

Abstract

Dihydropyridine compounds and preparation methods, pharmaceutical compositions and uses thereof. Especially, compounds shown as general formula (I) and isomers, salts for medicinal purpose or hydrates thereof, wherein each variable is defined as in the specification. Preparing methods of compounds shown as general formula (I), and uses for preparing drugs of compounds shown as general formula (I) and isomers, salts for medicinal purpose or hydrates thereof, in particular to uses for preparing drugs for curing and/or preventing hepatitis B virus.

Description

Dioxane compound and its preparation method, compound and use

The present invention relates to a hydroquinone compound and a process for the preparation thereof, and a composition comprising the above compound, and a use of a US compound or Hume or a hydrate as an antiviral, especially for the treatment and/or Use of a substance for preventing hepatitis. Background

Chronic hepatitis is a disease caused by the hepatitis B virus (B), which is closely related to cirrhosis and liver cancer. I am a high hepatitis type, 1 1 whole viral hepatitis clear epidemic investigation results show that I am due to hepatitis B virus surface antigen (B g)

. , 1. Chemical B. As a result of my research on the prevalence of viral hepatitis, the hepatitis A AIDS rate increased to 1.1/1. /1, rises (Wang,

Etc. Disease monitoring, , ( ) ). Chronic liver inflammation is not healthy but family, causing heavy

Chronic hepatitis has been a major public worker.

The chronic diseases are mainly caused by the rabbit market and N polymerization inhibition (Loo ba. L ang TJ, nv . The. 1 1 1 ). The former includes dry anti-b FN b, nt on and a Peg F a Pega y Q includes Lamy La vde, Ep v BO A de ov p vox Hep ea,

En ecav , Ba ac udeO) b Te b vud ne, TyzekaQ

(Teno ov ead and not evud ne Levov. In comparison, the available materials are very rare and there is very little, so it is very important not to study new safe and effective anti-virus, especially the new system.

The hydrogen physin has physiological activity and can work as a N-channel antagonist (U5 0 ) and a L-channel antagonism (U5 1 ) with [ [ [ c ) N

1) Hydroquinone compounds have and act (U5 1). However, there is no such thing as a hydroquinone compound hepatitis virus.

Content

The novel hydrogen compounds provided by the present invention have potent antiviral effects, particularly the role of hepatitis B virus. This was done on the top.

This aspect provides compounds

, representing oxygen, ( ), (, , ( ?) or , represents , on behalf of or in one or more of its respective substitutions, substituting hydrogen, halogen, oxy,

, nitro, oxy, , , amino, ( ) amino, ( ) amino, (d, d) amino, ( ), ( ) oxy, (d, d) oxycarbon, (d, d) a gas having 1 carbon atom, a (d, d) oxy group, a (d, d) amino group and an amino group, and

Substituting or substituting for the substitution of hydrogen, aryl, aryl, ketone, nitro, ( ), (, ) oxy, ( ), , ) oxycarbon, ( ) oxy, amino , ( ) amino or ( ) amino, (d, d) amino and (d, d)

,

Or Hugh, can or hydrate.

a compound of the first aspect,

, representing hydrogen, (d, d,), , , benzene,

, benzene or toluene

, on behalf of (d, )

Substituting or substituting a substitute for hydrogen, halogen, oxygen,

, nitro, oxy,,, amino, (d, d) amino, d, d amino, (d, d) amino, (d, d) oxy carbon, (d, d) oxy, (d, d) a group and (d, d) and a representative or a substituent thereof substituted by a hydrogen, a nitro group, an oxy group, an oxy group, an oxy group, a (d, d, oxy) group, ,) Oxygen, Amino, (d, d,) Amino, (0,) Amino, (0,) Base and ( ,).

Or Hugh, can or hydrate.

a compound of the first aspect

, representing oxygen, , , , or benzo

, on behalf of , , or

Substituting or substituting for the substitution of hydrogen, , , , , oxy , nitro , oxy , , , amino , amino , dimethylamino , amino , amino , amino , oxy carbon , oxy, oxy, ke, and

Substituting or substituting or substituting for the substitution of hydrogen, , , , , , , , , , oxy , oxy , oxycarbon , oxycarbon , nitro , amino , amino , dimethylamino , amino , amino And or rest, or hydrate.

a compound of the first aspect,

Representing hydrogen or

, representative or

Representing a substituted or polysubstituted sheep substituted for the same or different substitutions of hydrogen, , , , , , , oxy , oxy , and

Representing a substituted or partially substituted phenyl group, or

Wherein the substitutions are the same or different from the lower gene hydrogen, , , , oxy, oxycarbon, nitro, amino, amino, amino and amino groups.

Or rest, or hydrate. According to Ben Youming, on the one hand, the generalized mountainized eight-in-one material is superimposed. . (1) 2o-P-group- 4-phenylene-6-one (

Base one 5-nitro 4-methylbenzene shot one 1 4 a 3"

' an oxygen tt

". bite one

(2) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridin-3-ethyl citrate;

(3) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridin-3-ethyl citrate;

(4) 2-Methyl-4-(2-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dioxopyridin-3- shuttle Acid vinegar

(5) 2-Methyl-4-(3-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridin-3- shuttle Acid ethyl ester

(6) 2-Methyl-4-(2-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyrazine

_ _

Biting ethyl citrate;

(7) 2-methyl-4-(4-fluorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate;

(8) 2-Methyl-4-(2-methoxyphenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate ;

(9) 2-methyl-4-(2- olphenyl)-5-nitro-6-(2-carbophenyl)-1,4 dihydropyridin-3-ethyl citrate;

(10) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridyl-3-oxoate;

(11) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-hexanoic acid;

(12) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6(2-carbophenyl)-1,4 dihydropyrrol-3-ethyl citrate ;

(13) 2-Methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,6-trifluorobenzene

))-1,4-diaminopyridin-3-ethyl citrate; (1) (phenyl) nitro ( , phenyl) 1, hydrogen

(1) 2 (phenyl) nitro ( , phenyl ) 1, hydrogen

(1) 2 (phenyl) nitro (phenyl) 1, hydrogen

(1) 2 (phenyl) nitro, phenyl) 1, hydrogen

(1) (phenyl) nitro ( , , benzene

Base), hydrogen

(1) (phenyl) nitro ( ) 1, hydrogen and

( ) (phenyl) nitro

) 1 hydrogen,

Or Hugh, can or hydrate.

The second aspect provides a method of each of the compounds of the first aspect, which comprises

Step) in the absence or acidity of the inert compound (n) in this case

(D)

D)

And the compound of (V),

Obtaining the hydrogen compound and

Step B) In the remainder, in the inertia, the compound of the above step, the compound is obtained, and the compound is obtained.

Wherein, the prime examples and , , , , , , and are each of the compounds of the first aspect of the invention.

The third aspect provides a composition comprising a compound which is useful in the treatment and/or prevention of a quantity of the compound of any of the above aspects, and other active compounds.

The first aspect provides the use of a compound according to any of the above aspects in the treatment and/or prevention of an acute or chronic viral disease.

The fifth aspect provides the use of the compound of any of the above aspects in the treatment and/or prevention of acute or chronic hepatitis virus infection.

The sixth aspect provides a method of treating and/or preventing an acute or chronic viral disease comprising administering a therapeutically and/or prophylactically effective amount of a compound of any of the above aspects to a subject in need thereof.

The present invention provides a method of treating and/or preventing an acute or chronic hepatitis virus infection comprising administering a therapeutically effective and/or prophylactic amount of a compound of any of the above aspects.

All of the texts, their contents are quoted in this article, and the results of this article are not of. In addition, the various woods used in this field and the woods of this field, even if this, I still hope that the wood times and the more reconciliation mentioned in this wood and the times are not inconsistent.

This, wood times "or" refers to , , , and .

"Mid" (d, d) refers to a straight or carbon atom having a carbon atom, including but not limited to ethylene, propylene, and .

In the description of the present invention, wood "(d, d)" means a straight or a carbon atom having a straight or a carbon atom.

This specification states that wood "" generally refers to a system of 1, or may include, or is not limited to, phenyl and .

The description of the term "牛木倍" usually refers to the atomic N, , etc., or may contain a combined OR.

Ben, wood "(d, )" refers to a straight or a gene containing one carbon atom, including but not limited to , , , , , , , and .

In the cattle, wood "(d d)oxy" means a straight or oxy group containing 1 carbon atom, having a straightness of 1 carbon atom or

The oxy group includes, but is not limited to, an oxy group, an oxy group, an oxy group, an oxy group, an oxy group, an oxy group, an oxy group and the like.

In this example, wood "(d, d)" means a straight or 1 carbon atom straight or

. In the description, wood "( ) oxycarbon" means a straight or oxygen carbon with 1 carbon atom, a straight or oxygen carbon with 1 carbon atom, including but not limited to oxygen, oxygen, oxygen, oxygen , oxygen carbon, oxygen and carbon, and oxygen.

The compound may exist in the form of an optical hoop in the form of a Hugh or a Hugh. This involves

Hugh or no rest and a mixture of them. The method of non-external rest can be divided into optical components of the sheep, the method of rest and relaxation of the compound and respectively dissolved, then mixed, placed, precipitated solid rest.

The solid solution can be extracted separately.

Hugh.

Acidity includes, but is not limited to, fatty acids, sulfonic acids, or L-forms, lactic acid, natural or non-natural amino acids, and derivatives thereof.

The methods used in the above methods include, but are not limited to, ethanol, , , , petroleum, and the like.

Or in the molecule of the compound, the gene is introduced into the molecule, so that it can be annihilated, and the method of removing the introduced gene can be taken.

In the case of 1), in this inert state, the compound (in which hydrogen) is at least in the medium of the acid or the reverse, or the compound (of which, hydrogen) is present in at least the intervening The reverse is reversed to obtain a mixture of (V) and (V). Crystallized in this solution, or precipitated and differentiated, respectively (V) and (V).

Where , , , , and above represent at least a medium or a sulfonic acid

2) (V) or (V) in this solution reverses (1) the oxime of the compound.

or

Where , , , , ibid , , hydrogen ,

Among the at least mediators of the molecule include, but are not limited to, fatty acids, sulfonic acids, or L-forms, lactic acid, natural or unnatural amino acids, and derivatives thereof.

These include but are not limited to carbon ( ), carbon ( ), N N carbon (D, 3 3 (dimethyl)) carbon (, B P (Carter) and the like.

Hand-based method for the present compound using the following reverse scheme

This compound can be in the form. It is available. Among the materials that may be used include, but are not limited to, phosphoric acid, phosphoric acid, hydrogen, and nitric acid, and each of which has not, , , , , , , , lactic acid, benzoic acid, sulfonic acid, sulfonic acid, sulfonic acid, toluenesulfonic acid, etc. Made of.

Useful gold, including but not limited to the present compound , or, or, or, diethyl, diethanol, ethanol, dimethylaminoethanol, , , or phenyl.

Some of the compounds in the present invention may be crystallized with water or various families, and in some cases, various compounds may be formed. These include the amount of solvate, including hydrates, which are also included in the low-profile process.

However, some of the compounds of this first aspect are still in this step. Hugh , the compound of the present invention or their hydrate or hydrate is

, representing hydrogen, ( , , ), , , , benzene ,

, benzene or toluene

, representative ( )

Substituting or substituting a substitute for hydrogen, a sulphur, an oxy group,

, a nitro group, an oxy group, an amino group, an amino group, an amino group, an amino group, an oxy group, an oxy group, an oxy group, an amino group, an amino group, an oxy group, an oxy group, an alkyl group, and a hydrazine Alkyl, oxy, , , , ( , , oxy, oxycarbon, amino, amino, ( , , amino, (d, d,) amino and ( ).

Further compounds or their hydrates or hydrates are special,

, representing hydrogen, , , , or benzo , representative, , or

Substituting or substituting or substituting for the substitution of hydrogen, , , , , oxy , , nitro , oxy , , , amino , amino , dimethylamino , amino , amino , amino , oxy , oxy , oxy, base, and

Substituting or substituting for the substitution of hydrogen, , , , , , , , , , oxy , oxy , oxy carbon , oxycarbon , nitro , amino , amino , dimethylamino , amino , The amino group and the compound under the step or the hydrate or their hydrate are very special

, representing hydrogen or

, representative or

Representing a substituted or substituted substituted sheep , which replaces the same or different self - lowering hydrogens , , , , , , oxy , oxy , and

Representing a substituted or partially substituted phenyl group, or

Wherein the substitutions are the same or different, from the lower gene hydrogen, , , , oxy, oxycarbon, nitro, amino, amino, amino and amino.

This special compound or Hugh or

Or hydrate

Phenylnitro(phenyl) 1 hydrogen ( ) (phenyl) nitro (phenyl) 1, hydrogen Adjacent to ethyl citrate;

(3) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydro-peri-p-ethyl fumarate;

(4) 2-Methyl-4-(2-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridin-3-浚Acid ethyl ester

(6) 2-methyl-4-(2-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate;

(9) 2-methyl-4-(2-phenylphenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-carboxylate;

(10) 2-methyl-4-(3-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate;

(11) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4 dihydropyridin-3-propanoic acid ethyl ester;

(12) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-carbophenyl)-1,4 dihydropyridin-3-pyruvic acid Ester

(13) 2-Methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,6-trifluorobenzene

Base)-1,4-dihydropyrazine? Ethyl citrate;

(14) 2-Methyl-4-(2-phenylphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridin-3-浚Acid ethyl ester

(15) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorobenzene

Ethyl)-1-dihydropyridin-3-ethyl citrate; (1) (phenyl) nitro ( , phenyl ) 1 hydrogen

(1) (phenyl) nitro ( , benzene

Base) 1, hydrogen

1) phenyl) nitro ( , benzene

Base) 1, hydrogen

(1) phenyl) nitro ( ) 1, hydrogen and

(phenyl) nitro (

) 1, hydrogen.

The compound (1) compound can be prepared by the following methods.

In the case of or not acid, the complex of (n) in 1 inertness

Among them, the same as above,

, ( D)

Among them, the same as above

To pass (V),

Which is the same as above

Inverse compound

Among them, hydrogen

B) Under, in the inertia, the above steps , the inverse of the compound, which is the same as the prime, , , and .

The following inverse method can be used

On the contrary, the solution used is all inert. Including alcohol, ethanol, propanol, dihydrogen, hydrogen, methyl, dimethyl or acetic acid, dimethyl, dimethyl, and hexamethyl.

The reverse temperature can be internalized. Usually the nuclear counter is in 1 C but in each.

The reverse can be, but it can also be raised. Usually reversed.

The opposite may or may not be acid. Have

, acetic acid, sulfonic acid, toluenesulfonic acid, elemental, sulfuric acid, phosphoric acid, nitric acid, etc. But this is in the presence of phase or acid.

Nuclear anti-use includes, diethyl, hydrogen, potassium carbonate, potassium carbonate, hydrogencarbonate, acetic acid, sodium hydroxide, potassium hydroxide. The D) used as the starting point is already in some cases, or it can be found in accordance with the methods in the text. See Ma a B. F. B. , Hugo. B. Lau , ea . y he 1 )

The ( ) used as the starting point is already, or it can be made according to the methods in the text ( av d . Bake , e ng . yn he , 1 , .).

The compounds of the present invention can be synthesized by a conventional method, or by a combined method or a parallel synthesis method.

Or 1 is preferably a compound of 1 10). It can be synthesized in liquid phase or in solid phase synthesis.

More information on each compound.

The antiviral action of this compound e et al ( . . e M. L. he , P oc Na . cad. c. , 1 ) and o ba et al. B. E. o ba, J. The method of L. e n n v a e ea ch 1 , 1 ) was determined.

Anti-virus in micro titration. The only strange growth base and ep . . 1 cell, used as a blank.

First dissolve each ( ) of the compound in , ep . . 1 The cells are not diluted in each step. Usually, the compound is diluted to 1 u / m ( 1 ) to the micro-titration of each of the second strange growth bovine serum u diluted, each time diluted the most

High times.

Will be 2 Hep . 2. 1 Cells in microbodies (cells) in microbodies.

The test mixture is available under C 0 . However, in the new, each new growth. once again This compound, the solution is closed. The mixture was again found. Before the determination of the antiviral effect, light micromirror or biochemical method aa B ue dye or T ypan B ue staining was used to investigate ep . . Cytotoxicity.

However, the collection of the utensils will be received.

In accordance with the use of students).

Cytotoxicity assay

By Hep . . 1 Toxicity in cells or inhibition of cell formation. Photo-season micro-mirror was not measured and expressed as cells. In Hep . . 1 cells are compared to unreasonable cells, such as cells that dissolve, form, or cells. Cell disease, microscopic, cell disease, complete

I have a sickness. The average degree of cell disease and the percentage of inhibition under each degree. Eed ench half is poisonous T,), maximum T).

T, is a cell with a phase of cells similar to the shape of this compound.

Antiviral activity assay

The special move to the device (see above) will be ep. . 1 The cells above (1. Na. M Na ), neutralized (Na., pH.) and (X) will be baked at 1 C insulation N.

N pay

Usually the non-active digoxigenin type hepatitis C specific N probe has not been determined especially in ep 2. . 1 cell virus N, each time, the instructions for use the probe with digoxin

And harmony. Amnioticization is in, closed, and . 1 N Laurel, . And g to sperm N

with . In C, ng 1 high-octyl B-specific N staining (1 small, ). However, the B DN of the ground is high.

The rabbit of Gao Xin's N is born. Sheep, and (manufacturer's), but use the prior to the phosphoric acid

. Phosphoric acid P, the filter starts, but in the plastic film, in C again. Exposing the filter to x measures the specific N of the hepatitis (intensity 1 to the gods), inhibition, .

Inhibition (,) means that the compound is not specifically reduced compared to hepatitis.

The antiviral effect of this compound. American compound hepatitis (B has unexpected antiviral activity, so it is caused by various diseases caused by untreated virus, especially diseases caused by acute and chronic persistent HB virus infection. Chronic viral diseases caused by B can be gods Different degrees of syndromes are too weeknt, and chronic hepatitis virus infection can be cirrhosis and/or cells.

What can be done with this compound

Governance can be an acute and chronic viral infection of infectious hepatitis, a case of hepatitis virus infection. In particular, the treatment of chronic hepatitis infection and the treatment of acute hepatitis virus infection.

The composition of the compound can be administered orally, straight, nasal, clear, local, parenteral subcutaneous, intradermal, intraperitoneal, internal, indoor, sternum in any of the following ways.

9 Or inject or, or with the aid of an external reservoir, which is served, intraperitoneally or internally.

The present compound or a composition containing the same may be in the form of a sheep. It can be Hugh and Solid. Hugh can be solution, rest, particles, , . Other examples, , , , , , solutions , , , particles , , , , , , , etc.

The composition of the present invention may contain a commonly used rest, including but not limited to sub-exchange, alumina, aluminum, serum serum, phosphoric acid, glycerin, potassium acetate, a mixture of partial glycerin of saturated vegetable fatty acids, water or Acid to protein hydrogen phosphate, sodium hydrogen phosphate, oxidation, Sangui, vinyl hydride, polypropylene, wool, and the like. The content of the composition of the composition may be 1 weight, usually about the weight. Seeing local anesthesia, anti-corruption, etc., can be directly in the rest.

And may contain a complex , , arabic , or ethylene , filled , lactose sucrose corn , calcium phosphate , , amino ,

, talc, earth, , potato, or acceptable, lauric sulfuric acid. You can use the public method.

Serve water and solution oil or pre-water or other combination. The system can contain regular additions. Sugar, aluminum, hydrogenated edible oils, emulsified, , sheep, arabic or non-aqueous (may contain edible oils), fat or glycerol or ethanol, benzo or. Need to add flavor or look.

It may contain conventional cocoa or other glycerin. External injection, usually by compound and family disinfection. Drinking water. Depending on the degree of rest, the compound is soluble in both the rest and the solution. The compound is dissolved in water, sterilized or encapsulated in the injection solution.

For topical application, the compound may be in the form of an ointment, or , wherein the active ingredient is dissolved in or at rest. Among the ointments that can be used are, but are not limited to, oils, Vaseline, Vaseline, ethylene oxide, propylene oxide, emulsification and water, and available Hugh, including but not limited to oils, dehydrated sheep, and 16 carbons.

Octyl twelve and water.

The presence of the active compound in the upper part of the mixture . 1 . Than . ~ (weight).

In addition to the compounds contained, other active compounds can be included in the near step.

In general, it has been advantageous to be in the vicinity of the active compound. g

g kg Hugh, fruity, multiple sheep, to the desired effect. 1 g of the active compound in sheep, more than 1 g kg, but it can also not follow the above, that is, depending on the treatment of Komi and Hugh, the nature and extent of the disease, The way of the thing, as well as the cycle or the same. Hugh way

The following is a step-by-step explanation, but comprehension is used to explain the use and not to limit it in any way.

The materials used in this test and the test methods are described in terms of generality and / or Hugh. However, the multiple materials and methods of operation used for the purposes of this disclosure are in the art, but are still described herein. The wood in the art is clear, and in the following, the materials and methods of operation are not specifically described in the art.

Determination of the composition, the temperature is not comparable. Determined by c o a ab pec high resolution (resolution 1). N is determined by JN B N, operating frequency N z 1 phenyl nitro ( benzene

Step Synthesis of Nitrotoluene B

will. 9 o ) Nitro is slow. gNa o ) in water TF solution, at the end, room temperature no longer emerges, set each. Will be 2. 729 吋 toluic acid (mmol), 3. 899 carbon milling dimi wow (mmol) in 5Oml water THF reflux h, TLC bolt test reverse seat completely. Slowly add the anti-sit solution to the above liquid, and add the end of the dropwise addition to reflux 16 . Cold state, sputum filtration, 15Oml water is dissolved, acid is adjusted to H to about 3. 0. The ethyl acetate was extracted and the wells were mixed, and the wells were pulverized and the crude products were obtained. The crude product was dissolved in ethyl acetate, and the oil puzzle was added to precipitate crystals. Drying with hydrazine gives a yellowish twin crystal of 1.799. Yield: 50%. Molten fish: 145-1471C Step 2: Synthesis of 3-amino-2-decenoic acid ethyl vinegar

Will 13.O9 ugly ethyl acetate, 3. 9 montmorillonite k-0 was added to the counter-seat bottle and mixed at room temperature. Slowly drip into 10.O9 ammonia water and mix well. The mixture was washed with dichloromethane and added to MgSO. dry.迂 Filter, wave shrink, get a yellowish solid 10.o9. Yield: 79. Melting fish: 107C.

Step 3: 2-Methyl-4-phenyl-5-nitro-6-(4.methylphenyl)-1,4 dihydro _ _

Synthesis of ethyl hexanoate

2_nitroguanidine toluene 5, 0

苯 Benzyl ketone 8mmo, pJ alanine. 079 was added to 40 ml of toluene, and 4 ml of glacial acetic acid was added dropwise thereto, followed by reflux. Reverse seat 3, the wave shrinkage, the weight of the residue, add 5 mmol of 3-amino-2-Tenoic acid ethyl ester, 5 ml of glacial acetic acid, and mix at room temperature for 2Oh. Wave shrinkage, yellow crystals precipitated in the column 0.79 (yield 38.9%) m.p. 193-194 1

o NMR (DMS-) (Pp): 1.169-1.204(3H, t, CH), 2.311(3H, s, CH), 2.37 (3H, s, ArCH), 4.070-4.088 (2H, m, CH) , 5.312 (lH, s, CH), 7.285-7.313 (9H, m, ArH), 9.758 (lH, s, NH) MS (FAB) 379.1 (M). Example 2: 2-Methyl-4-(2-chlorophenyl)-5-nitro-6-(4-methylphenyl)-1,4-dihydropyridin-3-pyruvic acid B ester

1 method, which will be the benzophenone. 9 yellow crystal, 1. , .p. 1

C o N ( ) p . 1. ( ) . , H , . H .00 .01 H H . H, ) . . , . , N ). F B) 1. ( ). 2 (phenyl) nitro (benzene

The method of 1, the benzene toluene, which gives 19 yellow crystals, 1. p. 1 1 CN ( d ) Pp ) . 1 1. , ) . ( HH) . ( , ), . 1 . , ), H , , ), . . 1 , , ), . 1 HN ) FB) 1. ( ). (phenyl) nitro (

Phenyl) 1 hydrogen

Will be benzoic , nitrophenyl , . 9 of toluene, 1 acetic acid refluxed. a small amount of amino groups such as residues □

. o , 1 acetic acid, room temperature h. , get yellow powder . 9 1 7 .p. 1 C.

( d ) pp .111 1. .

. 1 . , . ), . .

, H 1. 1 H NH F B 4 . M). (phenyl) nitro (

Phenyl) 1

The method, which will be chlorobenzene toluene, get. 9 yellow crystals, 1. , . p. 1 1 N ( d ) (Pp ) 1. 1 1. 1 ( ), . , ) .11 , ), . ( , ), . . , ), 1.1 H , N ) MFB) . Phenylnitro group

Will be benzoyl o, nitro, 0. 9

In toluene, 1 acetic acid was refluxed. Reverse, residue, equal amount of amino

1 acetic acid at room temperature. , get yellow crystals .

0 .p. 1 1

1C NM DM pp 1. 1. , ), . 01 , , ) . 0 . ( , q, . , ), . . , . . q H) . , N ) F B) .1 . (phenyl) nitro (

) 1 hydrogen

The method of which will be chlorobenzyl, obtained . 9 yellow crystals, 1.6, .p. 1 6C 1

o NM ( d ) ( pp . 1. H, , , . , ) . . , ) . ), . . , , H ) . . . ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Phenyl) nitro

The method of which will be the benzyloxybenzene , which is obtained . 9 crystallization, 1 , .p.1 1 C 1 N ( d ) (Pp . 1.1 ( H , ), . , , ), . , ), . . H q, )

), .1 .21 , , H), . 1 .1 d, ) . . , d, ), . 0 , , N ). FB) 1.1).

- (phenyl) (

The method of which will be chlorobenzyl , which will be . 19 red crystals 1.o 0 . p. 1 C 1 N (D ) Pp . 1. 1( , H), . ( , ), .01 . ), .6 , , , .1 . , , ), . . 1 , d ) . . 1 H q, H . , NH FB) 4 1. M . 1 (phenyl) nitro (

The method of which will be benzene toluene, 9 red crystal, . , .p. 1 1C N DM d P . 1.210 HH , .3 H , , . . . , . . . , . . . , HHH , . 1 . 1 H , HH , 0.01 H, , N ) FB) . 11 phenyl) nitro

The method of obtaining the benzamidine . 9 yellow crystals , , . p. 1 C 1

N

( d ) pp . 1. ( ) . ( ), . . , , ), ), . 0 . 1

H, H H), . . ( H, H H , . ( H , N ) M F B) . 1 phenyl) nitro

Method, which will be the beryl

Benzene got 0. 9 crystallization, 1. .p 1 CN ( ) pp ) . 1. ( H, ), . , H), . . , 1 ) q ) . ), . . ( , , , ), . . ( 1 H, q, H . . ( q, , . HNFB . 1 oxyphenyl nitro

The method of which will be obtained from benzyl benzophenone . 9 yellow crystals, 2 . p. 1 CN ( ) (pp . 1 1. ( , ) . ( , ) . ( , . 1 . , .q H) . H, H) . . . 7 H ) . . . H, d ) .1 . 1 , ) , . 1 . q, ), . , , ) FB) .1 ). 1 (phenyl) nitro (

Chlorobenzoquinone

9 yellow crystals . p. 1 1C.1 N ( d ) Pp ) . 1. H, , , .2 H, s, ), . . ( , ), . , ), . . . , H) . H, H), 1. H, NH).MFB) .

0). 1 2 phenyl nitro

Method, which will be the beryl

.

Benzene, got. 9 yellow crystal. p. 1 1 C. N ( d ) P .11 1. H , ), . , , ), . . H q, H) .7 H , H), . . . H, H) . . . . , NH). FB) 1.1 " 1 (phenyl) nitro(phenyl) 1 hydrogen

Method of separating the berylone

Benzene got . 1 9 yellow crystals, . , . p. 1 ( 1 ) , ( 1 ) , ( 2 ) , . . . ) .1 ). 1 (phenyl) nitro

The method comprises the benzene and amino groups respectively, and the benzyl group is obtained, and the yellow crystal is obtained. 1 , .p. HN d ) Pp ) . , , ) . H) . 1 , , ), . 1 . , ), . . . 10.1 0 N ) FB) . 1 (phenyl) nitro

The method of which will be the benzophenone . 9 yellow , . p. 1 1 CN ( ) pp . 1.1 ( , ), .2 1 , ), . .5 d, ) . . , q, H) 5 1 ), . . , ), . , N ). FB) .1 ) . 1 (phenyl) nitro (

The method of benzene toluene, which gives 9 yellow crystals, .p. 1 1 CN ( d ) Pp . 1 1. H, H), . 1 ) . . d, H), . 12 . , q H ) . H ) . . , , ) . 11 . d H), .81 , NH) FB) 3 .1 ") (phenyl) Nitro) 1 Hydrogen

Will be 1 . In the water hydrogen m1, sodium hydride is no longer emitted. 1, the room temperature is reversed to 1 small, and the water is terminated. The residue is water and has a phase of acid. Get yellowish and rest . 1 .

1 HND (Pp .12 1. HH . H , ) . H) . ( , d, H) . . , q ), H, ) . . , ) . 1 . ( , d ) FB . 1 Determination of cytotoxicity and antiviral activity of the present compound The cytotoxicity and antiviral activity of the present compound were determined according to the above method.

Claims

Claim

1, the compound,

, representing hydrogen, (, ), ( ), (d d) or , representing d, d

Substituting or substituting a substitute for hydrogen, hydrazine, oxy,

, nitro, amino, ,, amino, (d, d) amino, d, d amino (dd) amino, d, d), (d, d) oxy, (d, d) oxycarbon, (d, d) , which may have 1 carbon atom, a halogen, a (d, d) oxy group, a (d, d) amino group and an amino group, and

Substituting or replacing one or more of the respective substituents from hydrogen, aryl, methoxy, , nitro, octyl, (d, d), (d, d,) oxy, (d, d), (d, d) oxycarbon, (d, d) oxy, amino, (d, d) amino or (d, d) amino, (dd) amino and (d, d) Or rest, or hydrate. Compound of claim 1

, representing hydrogen, d, d,), , , , benzene ,

, benzene or toluene

, representative)

Substituting or replacing each of the following substitutions with hydrogen, aryl, oxy,

, nitro, oxy,,, amino, (d, d) amino, d, d) amino, amino, d, d) oxy carbon, oxy, yl and (d, d) and representative or Substituting or substituting for the substitution of hydrogen, cyano, nitro, oxy, , , (d, ,), d, oxy, d, d, oxy, amino, (d, d,) amino , (d, d,) amino, (d, d,) amino and (d,)

Or Hugh, can or hydrate. Compound of claim 1,

, representing hydrogen, , , , or benzo

, on behalf of , , or

Substituting or substituting one or more of the following substitutions for hydrogen, , , , , oxy , nitro , oxy , , , amino , amino , dimethylamino , amino , amino , amino , oxy , oxy Base, oxy, base, and

Representatives or their mediators or their respective sites Substituted substituted hydrogen, , , , , , , , , , oxy , oxy , oxycarbon , oxycarbon , nitro , amino , amino , dimethylamino , amino , amino , and or oxime , or hydrate . Compound of claim 1

, representing hydrogen or

, representative or

Representing a substituted or polysubstituted one of which replaces the same or different self-lowering hydrogen, , , , , , oxy, oxy, and

Substituted for the substitution of a substituted or polysubstituted phenyl group, or a substituent of the same or different subhydrogen, , , , oxy, oxycarbon, nitro, amino, amino, amino and amino groups.

Or Hugh, can or hydrate. , the compound of claim 1

Phenylnitro(phenyl) 1, hydrogen ( ) (phenyl nitro(phenyl) 1 hydrogen) phenyl nitrophenyl) 1 hydrogen ( ) (phenyl) nitro (phenyl) 1, hydrogen (5) 2-Methyl-4-(3-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl-1.4-dihydropyrazine-3-hexanoic acid ethyl vinegar ;

(7) 2-Methyl-4-(4-fluorophenyl)-5-nitro-6-(2-carbophenyl)-1 4-dihydropyrimidine

_ _

Bite ethyl citrate;

(9) 2-methyl-4-(2- olphenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate;

(10) 2-methyl-4-(3-chlorophenyl) 4 -yl-6-(2-indolyl)-1,4-dihydropyridin-3-ethyl citrate;

(11) 2-methyl-4-(4-chlorophenyl)-5-nitro-6-(2-carbophenyl)-1,4-dihydropyridin-3-ethyl citrate;

(12) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2-indolyl)-1,4-dihydropyrrol-3-oxo acid Ethyl ester

(13) 2-Methyl-4-(2-methoxyphenyl)-5-nitro-6-(2,4,-trifluorobenzene

Base)-1,4-dihydropyridin-3-ethyl citrate;

(14) 2-Methyl-4-(2- olphenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridin-3- shuttle Acid ethyl ester

(15) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,trifluorobenzene

Ethyl)-1,4-dihydrodisindol-3-propanoic acid ethyl ester;

(16) 2-Methyl-4-(4-chlorophenyl)-5-nitro-6-(2,4,6-trifluorophenyl)-1,4-dihydropyridin-3-浚Acid vinegar

(17) 2-Methyl-4-(2-chloro-4-fluorophenyl)-5-nitro-6-(2,4,6-trifluorobenzene

Methyl-1,4 dihydro-p-butanoic acid methyl ester;

(18) 2-Methyl-4-(2-methylphenyl)-5-nitro-6-(2,4,6-trifluorobenzene ) 1, hydrogen

(1) (phenyl) nitro) 1, hydrogen and

( ) (phenyl) nitro (

) 1 hydrogen

Or rest, or hydrate. And a method for requiring each of the compounds of the formula 1, which comprises the step of: in the case of or not, or in the presence of an acid, in the inert compound D)

(D)

h n)

And the compound of (V),

Obtaining the hydrogen compound and

Step B is below, in this inertia, the compound of the above step, the compound is reversed, and the compound is obtained.

Wherein, the expressions of the compounds (examples, , and ), , , , , , and , a composition comprising a therapeutically and/or prophylactically effective amount of a compound of claim 1 It is an active compound. The use of any of the compounds in the treatment and/or prevention of acute or chronic viral diseases. The use of any of the compounds in the treatment and/or prevention of acute or chronic hepatitis virus infection. 1 . A method of treating and/or preventing an acute or chronic viral disease, particularly a method of treating and/or preventing an acute or chronic hepatitis virus infection, comprising administering a desired and/or prophylactically effective amount of the present invention to a recipient in need thereof A compound of any of (1).