CN1939917A

CN1939917A - Cannabinol derivatives and pharmaceutical use thereof

Info

Publication number: CN1939917A
Application number: CN 200610100189
Authority: CN
Inventors: C·R·特拉维斯
Original assignee: Immugen Pharmaceuticals Inc
Current assignee: Immugen Pharmaceuticals Inc
Priority date: 1999-03-22
Filing date: 2000-03-22
Publication date: 2007-04-04
Also published as: ZA200107773B

Abstract

The invention provides cannabinol derivatives and pharmaceutical preparations thereof.

Description

Cannabis derivative and medicinal

The application is that application number is 200410062002.X, the applying date to be the dividing an application of patent application on March 22nd, 2000.

The invention technical field

The present invention relates to treat the disease relevant, particularly HIV disease and true tumor disease with immunodeficiency disease.

Background of invention

Retrovirus human immunodeficiency virus 1 and 2 (HIV) is modal AIDS pathogenic agent.By a part of virus envelope protein (gp120), HIV with high-affinity specifically in conjunction with the CD4 molecule on the T-lymphocyte.In conjunction with after, virus merges and internalization with cytolemma.In cell, virus produces reversed transcriptive enzyme, and reversed transcriptive enzyme is transcribed into DNA with geneome RNA.Should be incorporated in the cell DNA by contrary HIV transcript afterwards, for cells survival, it exists as " provirus " in cell DNA.Provirus can hide between not timing, perhaps can be " activated " with transcript mRNA and geneome RNA, causes albumen to synthesize, assemble, form new virion, go out virus and necrocytosis from the cell surface blastogenesis.

Though as if fully do not understand as yet causing the accurate incident of activated, they can cause the release/generation of the endogenous cell factor, these cytokines and HIV genome interact to promote translation.In this respect, need cell SP1 and HIV to promote son (containing the several SP1 of series connection consensus sequence binding sites) to transcribe in conjunction with the genomic high level of HIV of hiding.In addition, in the time of on one or two (depending on the HIV strain) the consensus sequence binding site in being attached to HIV enhanser (with promoting that son is adjacent), NF κ B plays potent transcriptional activator.Transcription factor CREB/ATF, NF-AT and AP1 also strengthen HIV and transcribe.For all retrovirus, when provirus is activated, can produce structure and enzyme gag, pol and env gene product.HIV at first transcribes gag-pol as fusion rotein, this fusion rotein finally by the hiv protease cracking to generate sophisticated viral protein.HIV also adopt other modulin (being tat and rev gene product specifically) as transcriptional enhancer to induce high-caliber genetic expression.Nef is another HIV gene of regulating the virus replication level.

Though these factors for the initiating activity virus replication only have part to understand, there are some to comprise modulin, inflammatory cytokine (for example IL1, IL2, IL4, IL6, IL10, tumor necrosis factor alpha (TNFa), platelet activating factor, interferon-gamma (IFN γ)) and the nitrogen oxide of heat shock, uv-radiation, other (for example superinfection) virus in the middle of them.Many these factors are T-cell activator (for example their promote the cell cycle and the clonal expansion of T-cell colony), and they by many B-cells as the direct reaction of infectious agent (for example HIV) is discharged.These factors are the interior signal conduction of trigger cell incident also, promotes generation and its (IkB) disassociation from its inhibitor of NF κ B.Active NF κ B is that to activate the DNA that many cytogenes and HIV genome transcribe conjugated protein.In this respect, for example TNF α and IL-1 strengthen NF kB activity in the T-cell of cultivating to cytokine.

Conceal more proviral cell expressing HIV gp41, gp120 and other possible viral protein, this is by carrying out from transcribing of the genomic basic horizontal of provirus according to supposition.Though produced anti-so proteic immune response of HIV (part is because the glycosylation pattern of these proteic height volatilities and change thereof), but such immune response is normally incomplete, cause latent virus to converge, thereby effectively avoided immunological surveillance.In addition, the HIV gp120 that exists on the cytolemma of cells infected can enter the reaction mediated infection cell of non-infected cells and not infect fusion event between the antigen presenting cell (for example dendritic cell) by being similar to virus.Such fusion event does not resemble destroys cells infected the cell immune response, but causes forming short-life multinucleated syncytia " giant cells " usually, and such " giant cells " in fact promotes virus replication.In this respect, though the monocyte of latent infection and T-lymphocyte immobilized normally, and without any active NF κ B, other cell (for example dendritic cell) generally contains high-caliber active NF κ B.Yet dendritic cell does not produce SP1, and the Sp1 of T-cell and monocytes activity form.Therefore, between T-cell that infects and dendritic cell, form synplasm and make active NF κ B and SP1 enter same cell, thereby promoting that HIV is genomic transcribes.

When ripe HIV from host cell when " blastogenesis is come out ", viral life cycle finishes, and keeps a certain amount of cytolemma as its part coating.These blastogenesis incidents often take place in following cytolemma zone: the zone of fusion takes place in adhesion molecule in the cell (ICAMs) and other surface receptor in the cell-stimulating process.Because such albumen is positioned at the iuntercellular contact area, this phenomenon (being called polarity covering or polarization) can be by " concentrating viral blastogenesis " on flanking cell or promoting synplasm to form the diffusion of helping virus infection.In addition, the virion of release often contains some membrane-bound ICAMs (for example ICAM-1), and such virus can be by not relating to the interactional interaction of gp120-CD4 in conjunction with cell (for example peripheral blood monocyte).Such ICAM-1 ⁺The infectivity of HIV virus compares ICAM-1 ^-HIV is strong, and because they are covered by the glycoprotein of host animal, it is littler that they are recycled host's antibody neutral possibility.HIV can strengthen for example generation of ICAM-1 of cell adhesion molecule by the phosphorylation that promotes STAT1 α (it is in conjunction with the ICAM-1 genetic enhancer and promote the SP1-dependent transcription).What is interesting is that inflammatory cytokine (for example IFN γ) also promotes the phosphorylation of STAT1 α, and this gene contains the consensus sequence binding site that some relate to identical transcription factor, especially NF κ B that HIV duplicates.

In resting cell, there is the proteic height volatility of the HIV that hides, HIV converge and all makes virus duplicating by the ability that obtains ICAMs and change its tropism in the face of under the situation of aggressive host immune response to the property ignored relatively of immunological surveillance and virus.Along with the prolongation of time, the system that is used to eliminate infection is damaged and constantly destroyed to virus gradually.This virus is lasting to be existed and duplicating process is the HIV disease, and that its sign is that cytokine signaling conducts is out of control, out of control in lymphsystem and finally destroy lymphoglandula particularly.When becoming to host immune system, the HIV disease progression do not have ability so that it can not eliminate the degree of chance disease (for example bacterium, fungi, true tumor etc.) time, has just formed AIDS.Many patients reduce to about 200 o'clock (the CD4+T-cell counting of most of health adults is about 1000) in their CD4+T-cell counting and begin to show the AIDS symptom.

In order to prevent to develop into AIDS, many current therapy stopping on the viral life cycle incident, generally are target tightening that target is directly fixed on the viral protein.For example, produce gp120 antibody and blocked initial cell infection.Yet, ability and its ability that obtains the ICAM molecule that part spreads by synplasm or direct cell-cells contacting owing to virus, such effort has obtained mixing resultant.Other therapies adopts the hiv protease inhibitor to generate sophisticated rep and cap with blocking-up from the rep-cap precursor protein.Other treatment plan has adopted the combination of antiviral compound, and its target is to suppress or the attenuated virus enzyme.Yet, every according to estimates about 10 ⁴A spontaneous mutation (people such as Perelson, Science, 271,1582-86 (1996)) will appear in the inferior HIV of the duplicating gene.Because this virus can be carried out about 1010 times and duplicate general every day, it is recurrent therefore the promoting agent that directly acts on viral protein being developed immunity to drugs.In addition, many treatment plans need the patient to observe the very strict arrangement of taking medicine, and will take a large amount of pills every day.The patient can not observe the failure ratio that such schedule of administration has increased antiviral therapy.Owing to have these problems, need be able to weaken novel method, compound and the composition of the course of disease of HIV disease and other immunodeficiency disease.

There is every year thousands of people to be diagnosed as cancer and other true tumor disease, though and aspect cancer therapy, obtained some progress, existing treatment means can not be succeedd under many circumstances.For example, the many cancer therapy drugs that are administered to the patient often have toxic action to the intravital non-cancer cells of patient.In addition, its growth can be developed immunity to drugs to these medicines sometimes by many new biological cells that some medicines suppress.Certainly, reactive tumour is only being represented the sub-fraction of all kinds true tumor disease, and for example ovarian cancer, mammary cancer, lung cancer etc. have the medicine of high activity quite few to solid tumor.Therefore, the patient who suffers from the broad variety malignant tumour still has recurrence and dead high risk.Therefore need to suppress true tumor growth, the especially promoting agent of solid tumor growth always.

Summary of the invention

The invention provides method, compound and the composition of the treatment disease relevant with immunodeficiency disease.According to the inventive method, the pharmaceutically acceptable composition that will comprise at least a 5-alkyl-resorcinol derivatives compound is administered to the patient being enough to weaken under the condition of immunity system dysfunction, and wherein said 5-alkyl-resorcinol derivatives compound is selected from 5-alkyl resorcinol class, cannabinol derivative, cannabidiol derivative, cannabigerol (cannabigerol) derivative and their combination.The present invention also provides the antiviral cannabinol derivative that can be used in the inventive method.The present invention also provides alkylated resorcinol derivative and has used described alkylated resorcinol derivative to weaken the method for true tumor growth.The inventive method and compound can be used for treating disease of immune system, for example HIV disease and true tumor disease.Can clearly understand these and other advantage of the present invention and other feature of the present invention by following detailed description.

Detailed Description Of The Invention

On the one hand, the invention provides the method for the treatment disease relevant with immunodeficiency disease.According to this method, will comprise that the pharmaceutically acceptable composition of the compound of at least a 5-of being selected from alkyl resorcinol derivative, cannabinol derivative, cannabidiol derivative, cannabigerol derivative and their combination is administered to the patient being enough to weaken under the condition of immunity system dysfunction.

The inventive method can be treated the HIV disease of philtrum, the SIV disease in the inhuman primate or the FIV in the feline especially effectively.Though do not want to be subjected to the constraint of any particular theory, it is believed that the inventive method may promote T-cell, monocyte and scavenger cell static of active and latent infection by multiple added machinery.The combination of these effects can weaken the ability that HIV duplicates in host immune system.Under the situation that shortage is duplicated, the immune component that do not infect can be removed away the cell of latent infection better in patient's body, and catastrophic event still less can take place.In addition, duplicate by weakening HIV, the inventive method can reduce the probability of interpersonal propagation (for example enclose the living phase and spread through sex intercourse).Really, the inventive method that wherein composition is administered on the mucosal tissue (for example vagina or rectal tissue) can hinder the absorption of virus via such tissue, thereby has reduced the incidence of primary infection.Therefore, the invention provides the method that prevention HIV propagates.In addition, the inventive method can prevent that HIV from infecting the secondary illness of often being followed, for example lymph structure deteriorate, CNS disease, chance disease, true tumor and AIDS wasting syndrome.

The HIV treatment of diseases can be estimated by monitoring its weakening of symptom to the reaction that continues to use the inventive method.For example, the CD4+T-cell counting of most of health adults is about 1200 for about 800-, and HIV+ patient's the stable decline of this counting as mentioned above.Therefore, the inventive method minimizing that can increase CD4+T-cell number among the HIV+ patient (generally measuring) or alleviate the CD4+T-cell number by analyzing the CD4+/CD8+ ratio.For example, by results of regular determination, can be before foundation the inventive method be treated and measure the hypocellular speed of patient CD4+T-afterwards.Advantageously use the inventive method and can slow down lowering speed at least, and preferably increase the actual increase of CD4+ cell number.Similarly, the inventive method can reduce patient's inner virus load (HIV that promptly circulates tires) or weaken its increase.Favourable reaction to treatment also can be monitored by measuring white corpuscle adhesion, lymphocyte transportation and monocyte/macrophage movability (being chemotactic assay).

In one embodiment, at least a compound in pharmaceutically acceptable composition can be a 5-alkyl resorcinol derivative.Such compound can be advantageously used in the inventive method, because they show hypotoxicity (referring to for example U.S. patent 5,859,067) usually.Exemplary 5-alkyl resorcinol class can have following structural formula:

Formula I

Wherein

R ¹Be:

a)H，

B) C _1-4Alkyl or its ester,

c)COOH，

d)OH，

E) O-C _1-5Alkyl or alkanoyl, described group can choose wantonly by one or dimethylamino or ethylamino replace,

F) contain carboxyl or amino O-CO-C _3-10Alkyl,

g)

N=1-8 wherein

H) PAB or C _1-7Aminoalkyl group or its organic or inorganic acid salt, the isocyanic ester of PAB or aminoalkyl group or isothiocyanic acid ester derivative, C-terminal derivative or its salt with aminoalkyl group of 1-7 other carbon atom, the activated derivatives of this C-terminal derivative; Perhaps

I) R ¹And R ²Constitutional formula-O (CH ₂) _3-5Shown in substituting group, wherein R ¹And R ²Carbon atom with their institute's bondings constitutes a ring, and on described ring, have at least a hydrogen atom to choose wantonly by halogen and replace,

R ²Be:

A) H, OH or halogen

B) C _1-6Carboxyl or alkoxyl group, perhaps

C) R ¹And R ²Constitutional formula-O (CH ₂) _3-5Shown in substituting group, wherein R ¹And R ²Carbon atom with their institute's bondings constitutes a ring, and on described ring, have at least a hydrogen atom to choose wantonly by halogen and replace,

R ³Be

A) (W) _m-Y-(Z) _n, wherein

W is C _5-12Alkyl, alkenyl, alkynyl group or its mixture, described group can be chosen wantonly by at least one halogen and replace,

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

I) C _5-12Alkyl, alkenyl, alkynyl group or its mixture, described group can be chosen wantonly by at least one halogen and replace, choose wantonly to be replaced by terminal aromatic ring,

Ii) CN _1-3, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂, the C of each on amide nitrogen atom wherein _1-4Alkyl can be identical or different, perhaps

Iii) phenyl or benzyl, wherein said group can be chosen wantonly by halogen, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkylthio, CN, CF ₃, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different, and wherein

M and n are identical or different, and are respectively 0 or 1,

B) C _5-12Alkyl or haloalkyl, described group can be chosen wantonly by terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different, perhaps

C) C _5-12Alkenyl or alkynyl group, described group can be chosen wantonly by halogen, dithia cyclopentenes (ditholene), terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different;

R ⁴Be:

a)H，

b)OH，

C) C _1-6Alkoxyl group or carboxyl

R ⁵Be H or OH; And

R ⁶Be

A) H or OH;

B) C _1-4Alkyl, alkenyl, alkynyl group or its mixture,

C) O-C _1-4Alkyl, alkenyl, alkynyl group or its mixture, or

D) pryenyl, spiceleaf thiazolinyl (gerenyl) or farnesyl, described group is optional to be replaced by one or more halogens at an arbitrary position,

E) (W) _m-Y-(Z) _n, wherein

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

M and n are identical or different, and are respectively 0 or 1,

F) C _5-12Alkyl or haloalkyl, described group can be chosen wantonly by terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different, perhaps

G) C _5-12Alkenyl or alkynyl group, described group can be chosen wantonly by halogen, dithia cyclopentenes, terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different.

Formula I compound preferably includes OH or OCH ₃As R ¹Substituting group.At R ²Preferred substituted is hydrogen, hydroxyl or methoxyl group.When comprising formula I compound, R ⁶Be preferably methyl or ethyl.Preferred formula I compound is at R ¹, R ⁵Has hydroxyl substituent, at R ⁶Has methyl substituents; Even more preferably, this compound is at R ²The 3rd hydroxyl substituent arranged.At R ³Preferred substituted was discussed in this paper other places; Yet, the invention provides formula I compound, wherein R ³Be:

A) (W) _m-Y-(Z) _n, wherein

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS, Z is:

Iii) phenyl or benzyl, wherein said group can be chosen wantonly by halogen, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkylthio, CN, CF ₃, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different,

Wherein have one in the middle of W and the Z at least and comprise side chain, and wherein

M and n are identical or different, and are respectively 0 or 1,

B) end is the C of side chain _5-12Alkyl or haloalkyl, described group can be chosen wantonly by terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different, perhaps

C) end is the C of side chain _5-12Alkenyl or alkynyl group, described group can be chosen wantonly by halogen, dithia cyclopentenes, terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different.Many such compounds have shown anti-tumor activity, and as described herein can like this use.Though the composition of the inventive method can comprise such compound arbitrarily, some preferred compounds are as follows:

As mentioned above, formula I compound can be at R ⁶Has the spiceleaf alkenyl group.In this respect, at least a compound in the pharmaceutically acceptable composition of the present invention can be the or derivatives thereof of cannabigerol shown in the following formula:

Formula II

Wherein

R ¹Be:

a)H，

B) C _1-4Alkyl or its ester,

c)COOH，

d)OH，

F) contain carboxyl or amino O-CO-C _3-10Alkyl,

g)

N=1-8 wherein

R ²Be:

A) H, OH or halogen

B) C _1-6Carboxyl or alkoxyl group, perhaps

R ³Be:

A) (W) _m-Y-(Z) _n, wherein

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

Ii) CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂, the C of each on amide nitrogen atom wherein _1-4Alkyl can be identical or different, perhaps

M and n are identical or different, and are respectively 0 or 1,

B) C _5-12Alkyl or haloalkyl, described group can be chosen wantonly by terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different,

C) C _5-12Alkenyl or alkynyl group, described group can be chosen wantonly by halogen, dithia cyclopentenes, terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different;

R ⁵Be

a)H

B) C _1-4Alkyl

c)COOH

D) OH, or

E) O-C _1-5Alkyl (ether) or alkanoyl, described group can choose wantonly by at least one one or dimethylamino or ethylamino replace,

R ⁶Be:

A) hydrogen,

B) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl (preferred ethyl) or C _1-6Haloalkyl,

c)CN，

d)CO ₂H，

E) CO ₂-C _1-4Alkyl,

f)C(Y)(Z)-OH，

G) C (Y) (Z)-O-C _1-4Alkyl, or

H) C _1-6Alkyl-CO ₂-Y,

Wherein Y and Z are H or C respectively independently _1-6Alkyl,

R ⁷Be:

A) hydroxyl (preferred beta-hydroxy) or lactone,

B) halogen,

C) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

d)CN，

e)N ₃，

f)CO ₂H，

G) CO ₂-C _1-4Alkyl,

h)C(Y)(Z)-OH，

I) C (Y) (Z)-O-C _1-4Alkyl,

J) C _1-6Alkyl-CO ₂-Y, or

K)=O or=S,

Wherein Y and Z are H or C respectively independently _1-6Alkyl, and R wherein ⁷Can be on the 2-5 optional position.

Formula I and II compound can obtain (referring to people such as for example Dominianni, J.Org.Chem., 42,344-46 (1977) by marketable material is synthetic with currently known methods; People such as Baek, Arch.Pharm.Res., 19,228-30 (1996); People such as Guthrie, J.Org.Chem.47,2369-76 (1982)).For example, under acid catalysis with 2,6-syringol and OH-R ³Condensation can generate 4-alkylphenol intermediate.Phenolic group is changed into the diethyl phosphoric acid ester, in liquefied ammonia, use the lithium metallic reducing then, can generate the dimethoxy benzene derivative.Afterwards this compound is carried out one or two demethylations (for example using boron tribromide) and can generate required methoxyphenol and/or Resorcinol (formula I) respectively.At R ⁶Have the formula I compound of alkyl substituent to make by following method: for example, at first with the dimethoxy benzene derivative at R ⁶Lithiumation (lithiation) (for example in the presence of Bu/THF) is exposed to alkylating agent (for example methyl or ethyl iodide or sulfuric ester) then.Afterwards this compound being carried out one or two demethylations (for example using boron tribromide) can generate required at R respectively ⁶Methoxyphenol and/or Resorcinol (formula I) that alkyl substituent is arranged.Formula II compound can be by for example will be at R under acid catalysis ³Have required substituent methoxyphenol and/or Resorcinol (formula I) and Geraniol condensation (for example at BF ₃, Et ₂O, silicon-dioxide and CH ₂Cl ₂Exist down) and make.Certainly, these compounds can obtain by other proper method (it is known in the art having many) is synthetic.

In another embodiment, at least a compound in the pharmaceutically acceptable composition of the present invention is the derivative of cannabinol shown in the following formula:

Formula III

Wherein

R ¹Be:

a)H，

B) C _1-4Alkyl or its ester,

c)COOH，

d)OH，

E) O-C _1-5Alkyl (ether) or alkanoyl, described group can choose wantonly by one or dimethylamino or ethylamino replace,

F) contain carboxyl or amino O-CO-C _3-10Alkyl,

g)

N=1-8 wherein, or

H) PAB or C _1-7Aminoalkyl group or its organic or inorganic acid salt, the isocyanic ester of PAB or aminoalkyl group or isothiocyanic acid ester derivative, C-terminal derivative or its salt with aminoalkyl group of 1-7 other carbon atom, the activated derivatives of this C-terminal derivative;

R ²Be:

A) H, OH or halogen

B) C _1-6Carboxyl or alkoxyl group (preferred methoxyl group), perhaps

C) R ¹And R ²Constitutional formula-O (CH ₂) _3-5-shown in substituting group, wherein R ¹And R ²Carbon atom with their institute's bondings constitutes a ring, and on described ring, have at least a hydrogen atom to choose wantonly by halogen and replace,

R ³Be:

A) (W) _m-Y-(Z) _n, wherein

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

M and n are identical or different, and are respectively 0 or 1,

R ⁶With R ^{6 '}Together formation=O or=S, perhaps be independently selected from respectively:

A) hydrogen,

B) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

c)CN，

d)CO ₂H，

E) CO ₂-C _1-4Alkyl,

f)C(Y)(Z)-OH，

G) C (Y) (Z)-O-C _1-4Alkyl and

H) C _1-6Alkyl-CO ₂-Y,

Wherein Y and Z are H or C respectively independently _1-6Alkyl,

R ⁷Be:

A) hydroxyl or lactone,

B) halogen,

C) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

d)CN，

e)N ₃，

f)CO ₂H，

G) CO ₂-C _1-4Alkyl,

h)C(Y)(Z)-OH，

I) C (Y) (Z)-O-C _1-4Alkyl,

J) C _1-6Alkyl-CO ₂-Y, or

K)=O or=S,

Wherein Y and Z are H or C respectively independently _1-6Alkyl;

Q is:

A) O or S, or

B) N-W, wherein W is:

I) hydrogen,

Ii) C _1-6Alkoxyalkyl, C _1-6Alkyl or C _1-6Haloalkyl

Iii) OC _1-6Alkyl or OC _1-6Haloalkyl,

iv)CN，

V) C _1-6Alkyl,

Vi) (Z) C of C (Y) _1-4Alkyl, or

Vii) C _1-6Alkyl-CO ₂-Z,

Wherein Y and Z are H or C respectively independently _1-6Alkyl.

More known in the art formula III compound spiritedness activity are arranged, this mainly is to work by excited CB1 acceptor.In some applications, in formula III, can preferably adopt and preferentially to promote CB2 agonist activity rather than the active substituting group of CB1 (R for example ¹-R ⁷, Q and ring C), more preferably adopt the substituting group can promote selectivity CB2 agonist activity.In some embodiments, in order to alleviate or eliminate the spiritual active function of some hemp ester (cannabinaoid), the inventive method adopts selectivity CB2 agonist, and such selectivity CB2 agonist acts preferentially on CB2 acceptor rather than CB1 acceptor.Most preferably, selectivity CB2 agonist debond CB1 acceptor under the concentration of its activation CB2 acceptor.Various selectivity CB2 agonists are known in this area.Such examples for compounds comprises typical case and atypia hemp ester, two ring hemp esters, aminoalkyl indole and eicosanoids (eicosanoid) (referring to for example Pertwee, Pharmacol.Ther., 74 (2), 129-80 (1997)).Whether in order to estimate given compound is selectivity CB2 agonist, can use the method for any appropriate to estimate its relative affinity, for example use cell engineering to come expressed receptor (people such as Ross, Br.J.Pharmacol. CB2 and CB1 acceptor, 126,665-72 (1999)).Such value generally is with binding constant K _iExpression is by K _iCan calculate K _I-CB1/ K _I-CB2Ratio.Ideal situation is that selectivity CB2 agonist is for the K of CB2 acceptor _iBe the about 0.1nM of about 100nM-, be preferably the about 0.2nM of about 25nM-, for example be the about 0.5nM of about 15nM-.In addition, K _I-CB1/ K _I-CB2That ratio is at least is about 1.5, more preferably at least about 5 (for example at least about 10).Known chemical compound lot has appropriate C B2 selectivity, is suitable in the methods of the invention as the CB2 agonist.For example, JWH-015 has the K of 13.8 ± 4.6nM _I-cB2And 27.5 K _I-CB1/ K _I-CB2Ratio; WIN-55,212-2 have the K of .028 ± 0.16nM _I-cB2And 6.75 K _I-CB1/ K _I-CB2Ratio; 5-F Δ B-THO has the K of 8.7 ± 3.5nM _I-cB2And 6.55 K _I-CB1/ K _I-CB2Ratio; JWH-018 has the K of 2.94 ± 2.65nM _I-cB2And 3.23 K _I-CB1/ K _I-CB2Ratio; CP-56,667 have the K of 23.6 ± 6.5nM _I-cB2And 2.61 K _I-CB1/ K _I-CB2Ratio; L759656 has the K of 11.8 ± 2.5nM _I-cB2And 414.24 K _I-CB1/ K _I-CB2Ratio; L759633 has the K of 6.4 ± 2.2nM _I-cB2And 162.97 K _I-CB1/ K _I-CB2Ratio (referring to above-mentioned reference).Those of ordinary skills know these values of how measuring still undeterminate (or new) compound.In conjunction with the CB2 acceptor, preferred selectivity CB2 agonist shows the directed physiological response of the CB2-stronger than the CB1 reaction except preferentially.Being used for the active standard analysis of difference and measuring the ability that compound generates at cell engineering inhibition medicine inductive ring AMP (cAMP), to express acceptor separately, generally is with EC ₅₀(per-cent of maximum effect) expression people such as (, Br.J.Pharmacol., 126,665-72 (1999)) Ross.Preferably, selectivity CB2 agonist generally show greater than about 10, more generally greater than the EC of about 100 (for example greater than about 500) _50-CB2/ EC _50-CB1Ratio.Known chemical compound lot has appropriate C B2 selectivity, and therefore can be used as the CB2 agonist in the methods of the invention.For example, the EC of L759656 _50-CB2/ EC _50-CB1Ratio＞3000; The EC of L759633 _50-CB2/ EC _50-CB1Ratio＞1000.Those of ordinary skills know these values of how measuring still undeterminate (or new) compound.

For the CB2 selectivity, the R in the formula III ¹Preferably be not OH, OH is present in natural cannabinol and the tetrahydrocannabinol compound.R in the formula III ¹Be preferably H, O-C _1-4The half ester of alkyl (methoxyl group more preferably) or succsinic acid, propanedioic acid or the alanine ester and the salt thereof of L-Ala.In another embodiment preferred, R ¹And R ²Constitutional formula-O (CH together ₂) _3-5-shown in substituting group, wherein R ¹And R ²Carbon atom with their institute's bondings constitutes a ring, has at least a hydrogen atom can choose wantonly by halogen on the described ring to replace (for example O, Bridge 2 propylidene (propano) ring).In addition, the R in the formula III ²Be halogen, be preferably iodine.R ⁶And R ⁶' preferred formation=O or be respectively methyl, ethyl or methoxyl group together.

Though R ⁷Can be on the optional position of 7-10 position of ring C, but they are preferably on 9 of this ring.When hope improves the CB2 selectivity, R ⁷Be preferably electronegative (for example COOH, halogen, beta-hydroxy or lactone), and in order to improve activity, it can be replaced by lactone or beta-hydroxy.

Ring C in the formula III can be arbitrary following ring (the dotted line representative is at two keys of Δ 6a-10a, Δ 8-9 or Δ 9-10 position):

Yet in order to improve the CB2 selectivity, this ring is preferably aromatic nucleus.In this respect, the preferred embodiments of the invention provide the new antiviral cannabinol derivative of formula III, and wherein encircling C is aromatic nucleus.In such compound, R ⁷Preferably electronegative, more preferably on C9.In addition, R ¹Not OH preferably, and be preferably deoxidation, ester or ether.The example of cannabinol derivative compound comprises:

Many formula III compounds are well-known, and other formula III compound can make according to disclosed method (referring to, for example, International Patent Application WO 99/20268 (Burstein) and United States Patent (USP) 2,509,386 (Adams), 3,799,946 (Loev), 3,856,821 (Loev), 3,897,306 (people such as Vidic), 4,064,009 (people such as Fukada), 4,087,545 (people such as Archer), 4,142,139 (Bindra), 4,309,545 (Johnson), 4,599,327 (people such as N  gr á di), 4,833,073 (people such as McNally), 4,876,276 (people such as Mechoulan), 4,973,603 (Burstein), 5,338,753 (people such as Burstein), 5,389,375 (ElSohly), 5,440,052 (people such as Makriyannis), 5,605,906 (Lau), with 5,635,530 (people such as Mechoulam); With people such as Charalambous, Pharm.Biochem.Behav., 40,509-12 (191), people such as Gareau, Bioorg.Med.Chem.Lett., 6 (2), 189-94 (1996), people such as Griffin, Br.J.Pharmacol., 126,1575-84 (1999), people such as Huffman, Bioorg.Med.Chem.Lett., 6,2281-88 (1998), people such as Lemberger, Clin.Pharmacol.Ther., 18 (6), 720-26 (1975), people such as Loev, J.Med.Chem., 16 (11), 1200-06 9 (1973), people such as Loev, J.Med.Chem., 17 (11), 1234-35 (1974), people such as Martin, Pharm.Biochem.Behav., 46,295-301 (1993), people such as Papahatjis, J.Med.Chem., 41 (7), 1195-1200 (1998), people such as Pars, J.Med.Chem., 19 (4), 445-53 (1976), people .Pharmacol.Ther. such as Pertwee, 74 (2), 129-80 (1997), people such as Razdan, J.Med.Chem., 19 (4), 454-60 (1976), Razdan.Pharmacol.Reviews, 38 (2) 75-149 (1980), people such as Reggio, J.Med.Chem., 40 (20), 3312-18 (1997), people such as Reggio, Life Sci., 56 (23/24), 2025-32 (1995), (people such as Ross, Br.J.Pharmacol., 126,665-72 (1999), people such as Thomas, J.Pharm.Exp.Ther., 285 (1), 285-92 (1998), people such as Wiley, J.Pharm.Exp.Ther., 285 (1), 995-1004 (1998), people such as Winn, J.Med.Chem., 19 (4), people such as 461-71 (1976) and Xie, J.Med.Chem., 41,167-74 (1998)).

The ring C of formula III is in the preferred embodiment of aromatic nucleus therein, such compound can also by with currently known methods suitable tetrahydrocannabinol (THC) derivative molecular aromizing is made (referring to, for example, people such as Adams, J.Am.Chem.Soc., 62,23401 (1940); People such as Ghosh, J.Chem.Soc., 1393 (1940); With people such as Adams, J.Am.Chem.Soc., 70,664 (1948)).For example, can by with such compound and sulphur about 238-240 ℃ under nitrogen atmosphere heating made its aromizing people such as (, J.Med.Chem., 40 (20), 3228-33 (1997)) Rhee in about 4 hours.Other suitable method comprise the aromizing of using catalyzer (for example palladium carbon) or chemical dehydrogenating agent (for example 2,3-two chloro-5,6-dicyano quinone) to carry out (referring to, for example United States Patent (USP) 3,799,946 (Loev)).

As mentioned above, in some of the inventive method were used, particularly wherein at least a compound in the composition was during the inventive method of cannabinol derivative is used, to wish to alleviate harmful spirit activity that some such compound institute may have.As another selection of in composition, using outside the active cannabinol derivative of non-spirit (for example selectivity CB2 agonist), can use other pharmacologically active agent except the therapeutical agent that can alleviate spiritual active function.For example, because some above-claimed cpd may apply some activity to the CB1 acceptor, so often wish the auxiliary selectivity CB1 antagonist of using to the patient.Really, in some applications, wish the non-selective CB2 agonist (for example Δ 8-or Δ 9-THC and derivative thereof) of co-administered low dose, in these cases, it is preferred using the CB1 antagonist.Many suitable selectivity CB1 antagonists are (people such as Rinaldi-Carmona, FEBS Lett., 350,240-44 (1994) known in the art, also referring to United States Patent (USP) 5,624,941 (people such as Barth), 5,747,524 (people such as Cullinan), 5,925,768 (people such as Barth)).SR-1241716A is virtuous especially, is the preferred selectivity CB1 antagonist that can be used for the inventive method therefore.Other preferred selectivity CB1 antagonist be cannabidiol and derivative thereof (referring to, for example United States Patent (USP) 2,304,669 (Adams); People such as Razdan, Pharmacol.Reviews, 38 (2), 75-149 (1986); People such as Reggio, Life Sci., 56 (23-24), 2025-32 (1995)), they are antagonism CB1 acceptor effectively.Except antagonism CB1, cannabidiol and many its derivatives can also advantageously weaken the cytochrome p450 system in the liver, thereby have improved the bioavailability of other compound in the composition (people such as Bornheim for example, Chem.Res.Toxicol., 11,1209-16 (1998)).Therefore, in some embodiments of the inventive method, at least a compound in the pharmaceutically acceptable composition is the or derivatives thereof of cannabidiol shown in the following formula:

Formula IV

Wherein

R ¹Be:

a)H，

B) C _1-4Alkyl or its ester,

c)COOH，

d)OH，

E) O-C _1-5Alkyl (preferred methoxyl group) or alkanoyl, described group can choose wantonly by one or dimethylamino or ethylamino replace,

F) contain carboxyl or amino O-CO-C _3-10Alkyl,

g)

N=1-8 wherein, or

R ²Be:

A) H, OH or halogen

B) C _1-6Carboxyl or alkoxyl group, perhaps

R ³Be

A) (W) _m-Y-(Z) _n, wherein

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

M and n are identical or different, and are respectively 0 or 1,

R ⁵Be

a)H

B) C _1-4Alkyl

c)COOH

D) OH, or

R ⁶Be:

A) hydrogen,

B) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

c)CN，

d)CO ₂H，

E) CO ₂-C _1-4Alkyl,

f)C(Y)(Z)-OH，

G) C (Y) (Z)-O-C _1-4Alkyl, or

H) C _1-6Alkyl-CO ₂-Y,

Wherein Y and Z are H or C respectively independently _1-6Alkyl,

R ⁷Be:

A) hydroxyl or lactone,

B) halogen,

C) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl, C _1-6Carboxyl or C _1-6Haloalkyl,

d)CN，

e)N ₃，

f)CO ₂H，

G) CO ₂-C _1-4Alkyl,

h)C(Y)(Z)-OH，

I) C (Y) (Z)-O-C _1-4Alkyl,

J) C _1-6Alkyl-CO ₂-Y, or

K)=O or=S,

Wherein Y and Z are H or C respectively independently _1-6Alkyl, and R wherein ⁷Can be on any position of 1,2,5 or 6 of ring C.

Except having pointed substituting group, the R among the Italian type I-IV in office ³Be preferably:

W wherein ₁Be H, methyl or ethyl, W ₂And W ₃Be H or methyl, wherein W independently respectively ₁, W ₂And W ₃In the middle of have at least one not to be H and/or by halo, and W ₄Be C _1-4Alkyl or haloalkyl, described group can be chosen wantonly by aromatic ring and replace.R ³Be preferably and contain at least one two key (more preferably at C ₄-C ₁₀The position) side chain C _6-12Alkyl, and this chain preferably has the carbon atom of odd number.R ³Be more preferably that end is side chain or contain terminal double link, and the invention provides and have so substituent formula I-IV compound.More preferably, R ³Be preferably dimethyl heptyl (DMH) (for example 1 ', 1 ' DMH or 1 ' R, 2 ' S DMH), dimethyl hexyl or dimethyl amyl group.For example, R ³Can be two-, three-or the tetramethyl-amyl group ,-hexyl or-chains such as heptyl (for example 1,1,5-trimethylammonium hexyl, 1,1,5,5-tetramethyl-hexyl or 1,1,5-trimethylammonium-heptan-4-thiazolinyl).In some instances, R ³Substituting group can have huge terminal portions, for example methyl, dimethyl, (CH ₂) _1-6-CON (CH ₃) ₂, or have the C of halo terminal carbon (preferred bromine) _6-12Haloalkyl.

In the context of the invention, halogenated alkane, alkene and alkynes can have the halogenic substituent of arbitrary number.In preferred embodiments, halogenated alkane, alkene or alkynes have at least one halogen atom (CX for example endways on the carbon atom _1-3, wherein X is a halogen).Alkyl (ethyl alkene and alkynes) can be a straight or branched.In addition, compound can be used as single steric isomer or stereoisomer mixture (for example racemic mixture) or single geometrical isomer (for example E, Z, cis or trans) or the existence of geometrical isomer mixture, and the compound of all these forms all within the scope of the present invention.

When implementing the inventive method, the time that composition can be used any length with any amount that is suitable for producing required curative effect to the patient, those skilled in the art can determine acceptable dosage regimen.For example, when using the inventive method to treat the HIV disease, can be by analyzing along with dose,optimum is determined in dosage increase circulating virus particle (viral load) number and/or CD4+ cell counting.If not by transdermal or sustained release preparation successive administration, composition is generally given about 6 times of patient's administration every day 1-.Yet in some applications, it is suitable using composition with lower frequency.Each dosage is generally the about 1000mg/m3 of about 2mg/m3-, and more preferably about 0.01mg/kg/ days, about 1mg/kg/ days, for example about 10ng/kg/ days-Yue 10mg/kg/ days, and can be up to about 100mg/kg/ days (for example about 250mg/kg/ days).As described herein, unite when using when composition and other therapeutical agent, especially work as cytochrome P ₄₅₀When system is weakened (for example weakening by the cannabidiol derivative), these dosage can be reduced.In addition, when using selectivity CB1 antagonist, it can or use in different preparations or dosage regimen with dosage identical with the present composition or composition.In some applications, preferably (for example at least before 1-4 days) begin to use selectivity CB1 antagonist before using the present composition, with the CB1 receptor activation of any remnants of further reduction, and prevent degradation in the composition.Certainly, because some patient may produce tolerance to one or more compounds in the composition during treating, so can regulate dosage and/or dosage regimen as one sees fit.In addition, when the patient has sound response and/or notices any toxic side effects treatment, can reduce dosage and administration.

Owing to have its multiple effect, can use the inventive method to treat relevant disease or the obstacle of many and immunodeficiency disease except that the HIV disease.For example, the inventive method can be treated autoimmune disorder (for example systemic lupus erythematous, Hashimoto thyroiditis, myasthenia gravis, rheumatoid arthritis, multiple sclerosis, acute febrile polyneuritis, glomerulonephritis etc.).The inventive method also can be used for treating the disease (for example regional ileitis, ulcerative colitis, various forms of asthma) that causes or depend on inflammatory conditions, and it can treat multiple true tumor disease especially effectively, microorganism (for example mycobacterium, fungi) infects or virus infection, especially HSV, Epstein-Barr virus, cytomegalovirus genus, HIV and B-mode and infection with hepatitis C virus.The inventive method also can be used for treating unusual immune response, unusual cicatrization (for example surgical adhesions or keloid), homograft rejection, atherosclerosis and related heart disease.Certainly, the patient can be the animal (for example monkey, cat, dog, horse, ox, pig, goat and sheep etc.) of any kind.

Certainly, when using the inventive method to treat the disease relevant, also can assist and use other suitable therapeutical agent with immunodeficiency disease.For example, the inventive method can comprise auxiliary use antineoplastic agent, carcinostatic agent, microbiotic, anti-mycotic agent, antiviral agent (particularly antiretroviral compound), anthelmintic and Parasiticidal compound.Being suitable in the methods of the invention, the example of the auxiliary antiviral agent that uses comprises Abacavir (abacavir), Zidovodine many good fortune of former times Wei (azidothymidine cidofovir), U-90152S (delavirdine mesylate), didanosine, dideoxycytidine, Wei Lan time in accordance with the law (efavirenz), Foscanet (foscarnet), ganciclovir (ganciclovir), sulfuric acid indinavir (indinavir), lamivudine, Viracept (nelfinavir), nevirapine, ritonavir (ritanavir), Saquinavir, saquinavir mesilate, tavudine (stavudine), zalcitabine etc.When the growth of treatment tumour or true tumor, suitable ancillary compound can comprise anthracycline antibiotics (for example Dx, daunorubicin, carinomycin, N-ethanoyl Zorubicin, zorubicin, 5-iminodaunorubicin and N-ethanoyl daunorubicin and epirubicin) and plant alkaloid (for example vincristine(VCR), vinealeucoblastine(VLB), Etoposide, ellipticine and camptothecine), taxol and docetaxol, mitotane, cis-platinum, phenestrine etc.Be suitable in the present invention the auxiliary anti-inflammatory therapeutics that uses and comprise steroidal and nonsteroidal anti-inflammatory compound (for example prednisone, methylprednisolone, dillar, 11-fludrocortisol or fluorine cortisone, triamcinolone, Betamethasone Valerate and dexamethasone, Ibuprofen BP/EP, piroxicam, beclometasone; Methotrexate, azaribine, etretinate, Dithranol, psoralins); Salicylate (acetylsalicylic acid for example; With immunosuppressor cyclosporin A for example).Be suitable for auxiliary in the methods of the invention other pharmacologically active agent that uses and comprise narcotic (for example Methoxyflurane, isoflurane, enflurane, Hal and Benzocaine); Anti ulcer agent (for example Cimitidine Type A/AB); Antiepileptic drug (barbiturate for example; Azathioprine (a kind of immunosuppression and rheumatism); And muscle relaxant (for example dantrolene and diazepam).In addition, the inventive method can be treated unite to make and is used for treating autoimmune disorder with specific antibodies treatment or steroidal compounds.Can unite other composition (for example cannabigerol and derivative thereof, cannabichrome and derivative thereof, cannabinol and derivative thereof, cannabidiolic acid and derivative thereof, terpenoid, Flavonol (for example hemp flavine) etc.) that auxiliary other pharmacologically active agent that uses comprises the natural hemp with antimicrobial or anti-inflammatory activity with the present composition.

The present composition can comprise biologically active agent, for example many other promoting agents such as lymphokine or cytokine, anti-inflammatory agent, antiseptic-germicide, antiviral agent, anti-mycotic agent, antiparasitic, antimetabolite, anti-inflammatory agent, vasoactive agent, antineoplastic agent, segmental bronchus agent, local anesthetic, immunomodulator, enzyme, hormone, growth and regenerator and neurotransmitter and cell receptor protein and part etc.The example of other biological promoting agent has analgesic agent (paracetamol for example, anileridine, acetylsalicylic acid; buprenorphine; butalbital; butorphanol; choline salicylate; morphine monomethyl ether; Wy-16225; diclofenac; diflunisal; paracodin; Turbocalcin; R-ETODOLAC; fenoprofen; hydrocodone; hydromorphone; Ibuprofen BP/EP; Ketoprofen; ketorolac; levorphanol; magnesium salicylate; Meclofenamate; meclofenamic acid; pethidine; methadone; Levopromazine; morphine; nalbuphine; Naproxen Base; opium; oxycodone; oxymorphone; pentazocine; phenylethyl barbituric acid; the third oxygen sweet smell; salsalate; sodium salicylate; tramadol; and the anesthesia class analgesic agent except that above-mentioned analgesic agent).Also antianxiety agent be can use, alprazolam, Bromazepam, buspirone, zeisin, chlormezanone, chlorine nitrogen father-in-law, diazepam, halazepam, hydroxyzine, ketazolam, lorazepam, miltown, oxazepam and prazepam etc. comprised.Other biologically active agent comprises the antianxiety agent relevant with anti-spirit depressing for example zeisin, amitriptyline, loxapine, maprotiline and trilafon etc.The example of other active ingredient comprises for example non-rheumatic acetylsalicylic acid of anti-inflammatory agent, choline salicylate, diclofenac, diflunisal, R-ETODOLAC, fenoprofen, floctafenine, flurbiprofen, Ibuprofen BP/EP, INDOMETHACIN, Ketoprofen, lidomide, magnesium salicylate, Meclofenamate, meclofenamic acid, nabumetone, Naproxen Base, the  promazine, Phenylbutazone, piroxicam, salsalate, sodium salicylate, sulindac, tenoxicam, tiaprofenic acid, Thalidomide, linomide, and tolmetin, and the anti-inflammatory agent (diclofenac for example that is used for eye therapy, flurbiprofen, INDOMETHACIN, ketorolac, and trimexolone (generally being used for post-operative treatment)), with be used for the anti-inflammatory agent that non-infection nose uses (beclometasone for example, budesonide, dexamethasone, flunisolide, triamcinolone etc.); Soporific (anti-insomnia/sleep derivation agent), the therapeutical agent that for example is used for the treatment of insomnia comprises alprazolam, Bromazepam, diazepam, diphenhydramine, doxylamine, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, prazepam, Selepam, temazepam, triazolam, zolpidem and sopiclone etc.; Tranquilizer comprises diphenhydramine, hydroxyzine, Levopromazine, promethazine, propofol, melatonin, temaril etc.; Be used for the treatment of minor epilepsy and tremble and wait the tranquilizer of other illness, for example Warner); Zeisin, Amobarbital; Somatarax, aprobarbital, Secbutabarbital, ethyl .beta.-chlorovinyl ethynyl carbinol, glutethimide, L-tryptophane, Mephogarbital, Methohexitone sodium salt, midazolam hydrochloride, oxazepam, vetanarcol, phenylethyl barbituric acid, secobarbital sodium salt, thiosezonal etc.Other active compound can comprise the therapeutical agent hydrochloric acid enadoline (for example being used for the treatment of several head injuries) for example that is used for the treatment of head trauma (brain injury/local asphyxia); cytoprotective; with be used for the treatment of menopause; the therapeutical agent of symptoms of menopause (treatment) is Ergotamine for example; belladonna alkaloids and phenylethyl barbituric acid, the therapeutical agent that is used for the treatment of the menopause vasomotor symptoms is clonidine for example; premarin and medroxyprogesterone; estradiol; estradiol cypionate; Estradiol Valerate; oestrogenic hormon; premarin; esterification oestrone; piperazine estrone sulfate; and lynoral.The example that is used for the treatment of the therapeutical agent of premenstrual tension syndrome (PMS) has progesterone, progestogen, gonadotropin releasing hormone, oral contraceptive, danazol, luprolide acetate, vitamin B6; The therapeutical agent that is used for the treatment of emotion/psychiatric treatment, for example tricyclic antidepressants comprises Warner) (Elavil), Warner), trilafon (Triavil) and doxepin hydrochloride (Sinequan).The example of sedative, antidepressive and antianxiety agent has diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), SSRI ' s (selective serotonin reuptake inhibitor), fluoxetine Hydrochloride (Prozac), sertraline hydrochloride (Zoloft), hydrochloric acid Paroxetine (Paxil), fluvoxamine maleate (Luvox), hydrochloric venlafaxine new (Effexor), thrombotonin, combination of serotonin agonist (Phenfluoramine); Microbiotic (for example fluoroquinolone and tsiklomitsin); Antihistaminic; The katabolism steroidal compounds; And vasoactive agent (for example Beta receptor blockers and pentoxifylline (Trental)).Other compound comprises hemp ester for example CT-3 and HU-210.

As mentioned above, for use in the methods of the invention, compound is incorporated into comprise suitable carrier, and the optional pharmaceutically acceptable composition that contains other nonactive or active ingredient in.Such composition is suitable for using by multiple route of administration commonly used, for example in the cheek, hypogloeeis, skin, intraocular, ear, lung, in skin, lymph, in the tumour, in the chamber, in the nose, subcutaneous, implantation, suction, intradermal, rectum, vagina, saturating mucous membrane, intramuscular, intravenously and intraarticular approach etc.According to required method of application, composition can comprise auxiliary material, biliary salts, biodegradable polymer and multipolymer, buffer reagent, chelating, tinting material, thinner, softener, emulsifying agent, enzyme inhibitors, hydrogel, hydrophilizing agent, lipoprotein and other derivative of fatty acid, liposome and other micelle, microporous membrane, mucoadhesive, neutrality and hydrophobic polymer and multipolymer, microparticulate systems, spices, the salify bronsted lowry acids and bases bronsted lowry, semi-permeable membranes, single or many enteric coatings, solvent is (for example pure, methyl-sulphoxide (DMSO) etc.), tensio-active agent, virus envelope protein or other component.

In a kind of its form, the present composition can be the suction preparation that comprises liquid or solid particulate aerosol, suction preparation for example known in the art.Use the present composition by suction and can treat the segmental bronchus illness (for example flu (rhinovirus), influenza, Cysticfibrosis etc.) that inflammation is brought.Such preparation also can comprise for example materials known in the art such as sanitas, antioxidant, correctives, volatile oil, buffer reagent, dispersion agent, tensio-active agent of other material.Such preparation can also or allow that its reusable form provides with inhalation or in inhalation with unit form.

The present composition can also be topical application preparation (for example paste, creme, lotion, paste, gelifying agent, sprays, an aerosol wet goods), wherein carrier is the thinner that is suitable for the topical application promoting agent, for example Vaseline, lanolin, polyoxyethylene glycol, alcohol etc., described carrier can be chosen wantonly and comprise dermal penetration enhancer.In topical formulations, carrier can be the form that is suitable for preparing creme, gelifying agent, paste, sprays, aerosol, patch, solution, suspension agent and emulsion.

The present composition oral Preparation be can also be mixed with, capsule, cachet, lozenge, tablet, pulvis, granula, solution, suspension agent, emulsion, volatile oil (particularly cannabis seeds oil) etc. for example are mixed with.Such preparation generally comprises water or on-aqueous liquid solution and suspension (for example oil-in-water or water-in-oil emulsion).Usually such oral preparations is wrapped in the enteric coating.The example of oral preparations has cheek or sublingual formulation, comprise the lozenge that can also contain correctives and other known component, the pastille that maybe can also contain inert base, described matrix contain for example gelatin, glycerine, sucrose, gum arabic and other component and weighting agent well known by persons skilled in the art.

The present composition can also be the parenteral route administered formulation, for example Injectable solution and suspension.Such preparation generally also comprises material for example antioxidant, buffer reagent, antiseptic-germicide, for example direct acting replication inhibitors of other antiviral agent and make solution or suspension and recipient's the isoosmotic solute of blood.Such solution or suspension generally are sterilized water or non-water Injectable solution or suspension, and can comprise suspension agent and thickening material.Such preparation generally provides in ampoule that seals or bottle.

The present composition can also be a sustained release preparation, and when administration or when being administered to the curee, such preparation can discharge the compound of aequum in the given time.Perhaps, the present composition can be a percutaneous preparation, and carrier wherein is suitable for promoting the dermal delivery promoting agent.Example has water and alcoholic solution, DMSO, oil solution and suspension and oil-in-water or water-in-oil emulsion.Percutaneous preparation can also be the iontophoresis percutaneous preparation, and wherein carrier generally can be water and/or alcoholic solution, oil solution or suspension and oil-in-water or water-in-oil emulsion.Such preparation also can comprise through skin transmission promotor, and can provide with the kit form with transdermal delivery device, preferred ion electric osmose delivery apparatus, and many modification of iontophoretic delivery device are known in the art.

Other preparation of the present composition includes but not limited to implantable capsule or cartridge case (for example being used for tissue implants), patch, implant or suppository (for example being used for rectum or transmucosal administration).

The present composition generally can be distributed to doctor or patient in giving medicine box, and the invention provides such immunomodulatory medicine box.Such medicine box comprises the above-mentioned composition of doser (for example syringe and pin, sucker, pill, suppository, transdermal delivery device etc.) and a plurality of unitary doses in the container of separating.In some medicine boxs, compositions formulated in advance.Other medicine box comprises the separate components that is used for compositions formulated.Medicine box can also comprise carrier or thinner, tr, compositions formulated (if applicable) how is described and use the specification sheets of suitable doser.

As mentioned above, formula I compound have antitumor or cytotoxic active, and the invention provides the method that suppresses true tumor (for example new biological cell or tumour) growth, be included under the condition that is enough to suppress the true tumor growth such compound is delivered in the true tumor.Do not want to be subjected to the constraint of any particular theory, 5-alkyl resorcinol class can cause the DNA division, thereby may inducing cell program death in new biological cell.For this, preferably under being enough to strengthen the condition of apoptosis, the alkylation resorcinol derivatives is delivered in the true tumor.The dead required accurate dosage of inducing cell program depends on the kind of compound used therefor and whether also uses additional compounds.For this method, can unite and use at least a other antineoplastic agent (for example above-mentioned therapeutical agent) to assist administration.

In many application, the inventive method (for example in the patient) is in vivo used, and for example uses in tumour or blood dyscrasia.In using in some such bodies, the alkylation resorcinol derivatives can be by being introduced in the body circulation, for example is incorporated in the body circulation via stomach, intestines, oral or rectal wall approach or via intravenous injection to be delivered on the true tumor.True tumor is or comprises in other application of tumour therein, can be by injected delivery alkylation resorcinol derivatives in the tumour.In some cases, such administering mode can improve the possible partial concn of compound.For using in such body, can depend on the circumstances is formulated into compound in the pharmaceutically acceptable composition described herein.

Can use the inventive method to treat tumor growth, described tumor growth does not preferably need to eliminate tumour or reduce tumor quality.In this respect, can use the inventive method to weaken tumor growth.Such effect can for example make that the resistance new biological cell is easier to be subjected to the influence of other antineoplastic agent, and this method can be assisted and be used other such compound, many such compounds is (rIL-2s for example known in the art, altretamine, Amifostine, asparaginase, azathioprine, bicalutamide, bicalutamide, bleomycin, busulfan, capecitabine, carboplatin, carmustine, Chlorambucil, the cis-platinum injection, cladibrine, endoxan, cyclosporin A, cytarabine, the injection of cytarabine liposome, Dacarbazine, gengshengmeisu, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel, Zorubicin, doxorubicin hydrochloride, estramustine phosphate sodium, Etoposide, the phosphoric acid Etoposide, the floxuridine pegaspargase, fludarabine phosphate, flutamide, gemcitabine hydrochloride, Coserelin, the hydrochloric acid Granisetron, hydroxyurea, the hydrochloric acid darubicin, ifosfamide, Intederon Alpha-2a, Interferon Alfa-2b, U 101440E, formyl tetrahydrofolic acid, leuprorelin acetate, LEVAMISOLE HCL, chlorethyl cyclohexyl nitrosourea, L-PAM, Phenylalanin-Lost, mustargen, melphalan, purinethol, methotrexate, mitomycin, mitotane, mitoxantrone hydrochloride, Nilutamide, Nilutamide, Sandostatin, Ondansetron Hydrochloride, taxol, Pamidronate, pentostatin, melphalan, Plicamycin, polifeprosan 20 with carmustine implant, porfimer sodium, procarbazine hydrochloride, rituximab, Sargramostim, U-9889 2-deoxidation-2-[[(methyl nitroso-group amino), the citric acid tamoxifen, teniposide, testolactone, Tioguanine, the injection thiophene is for group, Topotecan Hydrochloride, the citric acid Toremitene, trastuzumab, vitamin A acid, the glucuronic acid Trimetrexate, valrubicin, Vinblastine sulphate, vincristine sulphate, tartrate Vinorelbine etc.).In addition, even when the tumour continued growth, such weakening can be used for slowing down the process of disease, and striven for the more time to other treatment.In fact, combination therapy makes can use other littler or more heavy dose of shorter or longer time of antineoplastic agent treatment, has thus to help improve curative effect and reduce side effect.

Embodiment

Though those skilled in the art can fully implement the present invention after having read above-mentioned detailed description, following embodiment can help to illustrate some features of the present invention.Certainly, because these embodiment only are illustration purposes for example, so they are not to be used for explaining the scope of the invention with ways to restrain, but the expansion that the invention described above explanation is carried out as a whole.

Embodiment 1

This embodiment has proved the synthetic of formula I compound.

With 2, the 6-syringol (73.4g, 0.48mol), 2,6-dimethyl-2-enanthol (69.0g, 0.48mol) and the mixture of methylsulfonic acid (95mL) stirred 3 hours at 50 ℃, then in stirred overnight at room temperature.Under agitation this mixture is poured in the frozen water (600mL).(2 * 200mL) extract this mixture with methylene dichloride.With this extraction liquid water, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, use anhydrous sodium sulfate drying.This solution decompression is concentrated, obtained product, be oily matter (130g, 96%).The analysis of this material (MS (FAB) m/z 281 (MH) ⁺ ¹HNMR (CDCl ₃) δ 0.80 (d, 6H), 1.0-1.1 (m, 4H), 1.27 (s, 6H), 1.40-1.60 (m, 3H), 3.89 (s, 6H), 5.36 (s, 1H), 6.54 (s, 2H)) have shown that it is 4-(1,1,5-trimethylammonium hexyl)-2, the 6-syringol:

Embodiment 2

This embodiment has proved the synthetic of formula I compound.

To derive from the 4-(1,1,5-trimethylammonium hexyl)-2 of embodiment 1, (130g is 0.46mol) at anhydrous CCl for 6-syringol crude product ₄Solution (100mL) cools off in ice bath, and the adding diethyl phosphite (70mL, 0.54mol).In this stirs the mixture with the temperature of keeping reaction mixture be lower than 10 ℃ speed drip triethylamine (75mL, 0.54mol).This reaction mixture was stirred in ice bath 2 hours, and in stirred overnight at room temperature.Then this mixture is diluted water, 4N aqueous sodium hydroxide solution (100mL), 1N aqueous hydrochloric acid (125mL), water and saturated sodium-chloride water solution washing with methylene dichloride (200mL).With the extracting solution anhydrous sodium sulfate drying, and concentrating under reduced pressure.By silica column chromatography purification crude product, use hexanaphthene: EtOAc (7: 1-3: 1 gradient) wash-out, obtained 103g (54%) product, be colourless wax shape oil.The analysis of this material (MS (FAB) m/z 417 (MH) ⁺. ¹H NMR (CDCl ₃) δ 0.81 (d, 6H), 1.0-1.1 (m, 4H), 1.26 (s, 6R), 1.35-1.6 (m, 9H), 3.86 (s, 6H), 4.25-4.38 (m, 4H), 6.53 (s, 2H)) show that it is 4-(1,1,5-trimethylammonium hexyl)-2,6-Dimethoxyphenyl diethyl phosphoric acid ester:

Embodiment 3

This embodiment has proved the synthetic of formula I compound.

To derive from the 4-(1,1,5-trimethylammonium hexyl)-2 of embodiment 2, (82g is 0.197mol) at Et for 6-Dimethoxyphenyl diethyl phosphoric acid ester ₂Solution among O (175mL) and the THF (35mL) is added in the liquefied ammonia (450mL) that is included in the three-necked flask that is equipped with mechanical stirrer, thermometer, dry-ice condenser and pressure balance type addition funnel lentamente, simultaneously to keep the lithium silk small pieces (2.8g, 0.40g-atom) that blue speed adds new cutting.With this reaction mixture restir 1 hour, then by adding saturated NH ₄The Cl aqueous solution (22mL) comes stopped reaction.Add ether (220mL), the ammonia evaporation is spent the night.Water (220mL) is handled this resistates.Separate each layer, with ether layer with 4N NaOH (200mL), water (2 * 200mL) and the saturated sodium-chloride water solution washing.With organic extract liquid drying (MgSO ₄) and concentrating under reduced pressure.By silica column chromatography purification crude product, use hexanaphthene: EtOAc (95: 5) wash-out, obtained 43g (83%) product, be colorless oil.The analysis of this material (MS (FAB) m/z 265 (MH) ⁺ ¹H NMR (CDCl ₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 4H), 1.26 (s, 6H), 1.4-1.6 (m, 3H), 3.79 (s, 6H), 6.30 (m, 1H), 6.49 (m, 2H)) show that it is 4-(1,1,5-trimethylammonium hexyl)-2, the 6-dimethoxy benzene:

Embodiment 4

This embodiment has proved the synthetic of formula I compound.

The 4-(1 of embodiment 3 will be derived from, 1,5-trimethylammonium hexyl)-2,6-dimethoxy benzene (10g, 0.038mol) solution in anhydrous methylene chloride (100mL) cools off in ice bath, (100mL 1M solution 0.10mol) was handled to the dichloromethane solution that wherein drips boron tribromide with 1 hour then.This mixture was stirred in ice bath 2 hours, then in stirred overnight at room temperature.This reaction mixture is cooled off in ice bath, and water (100mL) is handled carefully.The gained mixture is diluted with methylene dichloride (100mL), and handle with the semi-saturation sodium bicarbonate aqueous solution.Separate each layer, organic layer is evaporated to half volume, and (2 * 75mL) extract with the 2N aqueous sodium hydroxide solution.This alkaline water extraction liquid is cooled off, and be acidified to pH 3.0 with the 1N aqueous hydrochloric acid.Use Et ₂(2 * 100mL) extract this acidifying mixture to O.Ether layer is washed with saturated sodium-chloride water solution, use anhydrous magnesium sulfate drying, and concentrating under reduced pressure.By silica column chromatography purification gained crude product, use hexanaphthene: EtOAc (8: 1-4: 1 gradient) wash-out, obtained 8.0g (90%) product, be the colorless solid crystallization.The analysis of this material (Mp 95-96 ℃ .MS (FAB) m/z237 (MH) ⁺ ¹H NMR (CDCl ₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 4H), 1.23 (s, 6H), 1.40-1.58 (m, 3H), 4.65 (s, 2H), 6.17 (m, 1H), 6.38 (m, 2H)) show that it is 4-(1,1, a 5-trimethylammonium hexyl) Resorcinol:

Embodiment 5

This embodiment has proved the synthetic of formula I compound.

The 4-(1 of embodiment 4 will be derived from, 1,5-trimethylammonium hexyl) Resorcinol (2g, 0.0076mol) solution in anhydrous methylene chloride (10mL) cools off in ice bath, and drip the solution of boron tribromide in methylene dichloride (2.6mL 1M solution, 0.0026mol).This mixture was stirred in cooling bath 2 hours, then in stirred overnight at room temperature.This mixture is cooled off in ice bath, and water (10mL) handles carefully, use sodium bicarbonate aqueous solution (5mL) to handle then.Isolate organic layer, use dried over mgso, and concentrating under reduced pressure.By silica column chromatography purification gained resistates, use hexanaphthene: EtOAc (8: 1-4: 1 gradient) wash-out, obtained 0.364g (19%) product, be colorless oil.The analysis of this material (MS (FAB) m/z 251 (MH) ⁺ ¹HNMR (CDCl ₃) δ 0.80 (d, 6H), 1.00-1.10 (m, 4H), 1.24 (s, 6H), 1.4-1.6 (m, 3H), 3.78 (s, 3H), 4.67 (s, 1H), 6.23 (m, 1H), 6.40 (m, 1H), 6.47 (m, 1H)) show that it is 3-methoxyl group-5-(1,1,5-trimethylammonium hexyl) phenol:

Embodiment 6

This embodiment has confirmed the antiviral activity of several The compounds of this invention.

Compound: preparation has the listed compound of table 1 of different concns in SDMSA, and takes advantage of fresh use.

The cell of latent infection: with 5 * 10 ³(derive from AIDS Research andReference Reagent Program, Bethesda MD) is layered in the 96-orifice plate with substratum the U1 cell, and described substratum has or do not have 5ng/ml TNF α and test compounds.Cultivate after 3-6 days evaluation supernatant liquor and cell.

PBMC separates and shock treatment: peripheral blood monocyte (PBMC) washing that will derive from healthy HIV-and hepatitis-negative patient is to remove remaining gradient separations material.Count the cell of washing then, and estimate its viability.After this initial preparation, with cell with 1 * 10 ⁶The concentration of individual cell/ml is suspended in RPMI 1640 substratum that are supplemented with following substances: the foetal calf serum of 15% deactivation, 2nM L-glutaminate, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates and 10 μ g/ml gentamicins and 2 μ g/ml PHA.Cultivate (37 ℃, 5%CO ₂) behind the 2-3 days, by centrifugal collecting cell, washing, and be resuspended in the same medium that is supplemented with recombinant il-2.Keep this culture then until use, replaced 1/2 volume with the fresh IL-12 substratum that contains in per 3 days.

PBMC measures: when preparing to use, will derive from minimum 2 donors and mix, counted with the PBMCs of PHA and IL-1 shock treatment and measure its viability by trypanblue exclusion method.Then with cell with 1 * 10 ⁶The concentration of individual cell/ml is resuspended among the RPMI 1640 that is supplemented with following substances: 15% foetal calf serum (hot deactivation), 2mM L-glutaminate, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates, 10 μ g/ml gentamicins and IL-2 (20U/ml).50 μ l cells are assigned in 60 holes, inside of 96 hole flat boards then.Each flat board comprises cell control well (having only cell), virus control hole (cell adds virus), drug toxicity control wells (cell adds test compounds), medicine colorimetric control wells (having only medicine) and experimental port (medicine adds cell and adds virus).The compound that adds dilution in this microlitre flat board adds suitably pre-titrating HIV-1 strain then.Analyze all samples to measure toxicity of compound with sisters' flat board in triplicate mode.The final volume in each hole is 200 μ l.With analyte at 37 ℃, 5%CO ₂Cultivated 7 days under the condition, collect supernatant liquor then to analyze RT activity and sisters' flat board with the evaluation cell viability.

Monocyte separates and cultivates: obtain peripheral blood monocyte (PBM) by Ficoll sea Parker's purifying (the optional reorganization IFN γ that uses) from the HIV-of health and hepatitis-negative donor.After 7 days, the culture washing to remove the not cell of adhesion, is added test compounds, add HIV-1 then.Infect after 24 hours, culture is washed for the last time, add fresh test compounds, culture is continued to cultivate 7 days by removing substratum.Measure virus replication by express supernatant liquor p24 antigen with commercially available elisa assay reagent then.Parallel use AZT is as positive control in each is measured.

Measure the XTT staining of viability:, 3-two (2-methoxyl group-4-nitro-5-sulfo group phenyl)-5-[(phenyl amino by 2) carbonyl] the also original evaluation toxicity of 2H-tetrazolium  oxyhydroxide (XXT) do not exist.The 50 μ l solution that will contain 1mg/ml XTT and 0.06 μ g/ml azophenlyene metilsulfate (PMS) are added in each hole, then flat board are cultivated 4 hours at 37 ℃.Several mixes the soluble reaction product so that the flat board of sealing can reverse to use the dull and stereotyped sealing ply of viscosity to replace lid.After the cultivation, read dull and stereotyped reducing degree by spectrophotometry with the evaluation product at 450nm.

Analyze p24: generate (p24) by standard ELISA evaluation viral protein.

Reverse transcriptase determination: in not celliferous supernatant liquor, measure reversed transcriptive enzyme.Titrating TTP is resuspended in the distilled water with the concentration of 5Ci/ml.Prepare poly-rA and oligomeric dT as stock solution, and remain on-20 ℃.Prepare fresh RT reaction buffer (125 μ l 1M EGTA, 125 μ l dH ₂O, 110 μ l 10%SDS, 50 μ l 1M Tris (pH 7.4), 50 μ l 1M DTT and 40MI 1M MgCl ₂).Then with these three kinds of solution with 2 parts of TTP, 1 part of poly-rA: oligomeric dT is in the same place with the mixed of 1 portion of damping fluid.10 these reaction mixtures of μ l are placed round bottom microlitre flat board, add the supernatant liquor that 15 μ l contain virus.This flat board was cultivated 60 minutes in the water-bath with solid carrier.After the reaction, to the DE81 scraps of paper, washing is 5 times, each 5 minutes in 5% sodium phosphate buffer with volumetric point, and washing is 2 times, each 1 minute in distilled water, and washing is 2 times, each 1 minute in 70% ethanol, and is dry then.In each sample, add Opti-Fluor O then, and the radioactivity of using the scintillometer quantitative assay to mix.

Data analysis:, calculate IC for each mensuration ₅₀(promptly 50% virus replication suppresses), TC ₅₀(50% cytotoxicity) and selectivity index (SI=IC ₅₀/ TC ₅₀).The aggregated data of all test compounds is listed in the table 1.These results show that 11-removes first-Δ 9-tetrahydrochysene cannabidiol-9-formic acid, cannabidiol and olivitol, 5-(1,1,5-trimethylammonium hexyl) Resorcinol and 5-(1,1,5-trimethylammonium hexyl)-2, the 6-syringol shows appropriate antiviral activity.The antiviral activity of olivitol in PBMCs and TNF α inductive U1 cell than at monocyte/macrophage or more not remarkable in the inductive U1 cell.To mention the hemp ester especially, these results are wondrous, because known observation show some such compound can improve rather than suppress HIV and duplicate (referring to, people such as Noe for example, Drug of Abuse, the 25th chapter of Immunomodulation and AIDS, people such as Friedman, Ed., (Plenum Press, NY 1998)).

Embodiment 7

This embodiment has confirmed the anti-tumor activity of formula I compound.

Clone: cell shown in the table 2 is lain in breeding in RPMI 1640 with 10% foetal calf serum, 2mM L-glutaminate and sodium bicarbonate or DMEM (" perfect medium ") under the aseptic condition, and at 37 ℃, 5%CO ₂Cultivate down with 95% humidity condition.Weekly each clone is gone down to posterity and cultivate 1 or 2 time, and periodically screen mycoplasma contamination (positive culture being treated for 3 times in generation) with microbiotic.Only use the culture that does not contain mycoplasma to carry out antitumor evaluation.

Antitumor evaluation: collect the cell of each clone, make agglomeratingly, be resuspended in then in the fresh perfect medium to remove substratum.Determine cell number, and dye to measure viability with iodate third ingot.With perfect medium cell being adjusted to density is 5 * 10 ³Individual cell/ml.Inoculate to tissue culturing plate with each clone sample of 100 μ l, and with these dull and stereotyped overnight incubation to carry out cell fixation and adaptation.

After the adaptation, the listed compound of table 2 is diluted in perfect medium.Use 8 kinds of concentration to handle cell culture.For each dilution, use 8 holes of 100 μ l administration solution-treated respectively.Each culture flat board comprises cell contrast (8 holes are with the mock of perfect medium processing), substratum contrast (having 7 holes that substratum is used to deduct the signal that is produced by culture medium condition), solvent control (8 holes) and air blank (1 hole) to calibrate dull and stereotyped reader.The Dx (1 μ M, 8 holes) that also is used as the single dose of cytotoxicity positive control is handled each clone.In case administration is finished, be about to cell at 37 ℃, 5%CO ₂Cultivate down with 95% humidity condition.

Handle after 5 days, use the antitumor action of SRB assay method analysis of cells, to calculate the IC of each processing ₅₀The gained result is as shown in table 2.These results show that 5-(2,6-dimethyl-2-heptyl) Resorcinol shows the IC of 77-95 μ M in 6 clones ₅₀, this shows that such compound has antitumor action.

Incorporate into as a reference

The document Anywhere mention in any accompanying drawing or all sources (for example the publication of contriver's certificate, patent application, patent, printing, museum register on the books or record, utility model, worldwide webpage etc.) of quoting, sequence table or introduce the present invention with its parallel statement of submitting to and by it with reference to a part as this specification sheets.

Explain and instruct

Above stated specification is to make as a whole complete description of the present invention, and is not only any specific part of its aspect.Specification sheets has been described " preferred embodiment " of the present invention, comprises its best mode of enforcement known to the inventor.Certainly, by reading above stated specification, the modification of these preferred embodiments is conspicuous to those skilled in the art.The inventor wishes that those skilled in the art depend on the circumstances and uses such modification, and the inventor plans to implement the present invention with the mode except that the specifically described mode of this paper.Therefore, the present invention includes as all modification and coordinator by the suitable theme of in appended claims, listing that is allowed by the law.

Except as otherwise noted, otherwise the odd number that uses in aforementioned specification and following claims indication (for example " ") comprises plural number.The discrete value of listing certain limit is in order to point out each the independent value in this scope independently with the abbreviation mode, and with each separately value list separately just as it and be incorporated in the specification sheets.As for claims particularly, term " basically by ... form " be meant, except the specific component of listing or step, can also use and substantially not go up unlisted component or the step that influences fundamental sum novel feature of the present invention.On the contrary, term " comprises " or " having " is expression, except listed component or step, can also have any component or step.Term " by ... form " be meant and only have listed component or step, but the coordinator of not getting rid of these components or step can substitute component or this possibility of specifically being listed of step.

Table 1

Compound	Monocyte/macrophage evaluation HIV-1 (p24)			PBMC HIV-1(RT)			TNF inductive U1 cell (RT)
	Monocyte/macrophage evaluation HIV-1 (p24)			PBMC HIV-1(RT)			TNF inductive U1 cell (RT)			IC ₅₀	TC ₅₀	TI	IC ₅₀	TC ₅₀	TI	IC ₅₀	TC ₅₀	TI
	AZT (μ M) DdC (μ M) cannabinol (μ g/ml) cannabidiol (μ g/ml) 11-removes first-Δ 9-tetrahydrochysene cannabidiol-9-formic acid (μ g/ml) Δ 8 tetrahydrocannabinol (μ g/ml) Δ 9tetrahydrocannabinaol (μ g/ml) EtOH (%) Olivitol (μ M) Resorcinol (μ M) Orcinol (μ M) 5-(1,1,5-trimethylammonium hexyl) Resorcinol (μ M) 5-(1,1,5-trimethylammonium hexyl)-2,6-syringol (μ M) 5-(1,1,5-trimethylammonium hexyl)-2,6-dimethoxy benzene (μ M) 3-methoxyl group-5-(1,1,5-trimethylammonium hexyl) phenol (μ M)	0.001 0.0061 0.0028 7.7 8.18 7.79 ＞0.1 ＞0.1 0.06 63.7 NA NA NA NA NA NA	＞4 ＞4 ＞10 13.07 22.87 76.73 ＞0.1 ＞0.1 ＞.1 75.9 NA NA NA NA NA NA	＞4000 655.7 ＞3.571 1.7 2.8 9.8 NA NA ＞1.67 1.19 NA NA NA NA NA NA	0.0021 0.0056 0.0034 0.099 0.0876 6.91 1.52 39.09 0.08 0.07 ＞0.1 16.9 ＞200 ＞200 14.8 15.8 ＞200 39.9	＞4 ＞4 ＞4 ＞10 ＞10 7.66 7.76 71.1 ＞0.1 ＞0.1 ＞0.1 ＞100 ＞200 ＞200 44.6 50.9 ＞200 46.4	＞1904 714.2 1176 ＞101.0 114 1.11 5.11 1.82 ＞1.25 1.43 NA 5.9 --- --- 3 3.2 --- 1.2	--- --- 5.14 2.76 6.69 0.06 0.06 ＞0.1 22.5 NA NA NA NA NA NA	--- --- 5.26 7.8 23.71 ＞0.1 0.088 ＞0.1 77.5 NA NA NA NA NA NA	IC ₅₀	TC ₅₀	TI	IC ₅₀	TC ₅₀	TI	IC ₅₀	TC ₅₀	TI	--- --- 1.0 2.8 3.55 ＞1.667 1.47 NA 3.45 NA NA NA NA NA NA

Table 2

	IC ₅₀Value μ g/ml (IC ₅₀The mole value)
	IC ₅₀Value μ g/ml (IC ₅₀The mole value)							Compound	SNB-7 (CNS)	DLD-1 (colon)	NCI-H23 (lung)	ZR-75-1 (breast)	LOX IMVI (melanoma)	PC-3 (prostate gland)	CAKI-1 (kidney)
5-(2,6-dimethyl-2-heptyl) Resorcinol	2.2×10 ¹ (9.5×10 ^-5)	2.1×10 ¹ (9.0×10 ^-5)	1.8×10 ¹ (7.7×10 ^-5)	1.9×10 ¹ (8.1×10 ^-5)	NA	2.0×10 ¹ (8.4×10 ^-5)	2.2×10 ¹ (9.3×10 ^-5)	Compound	SNB-7 (CNS)	DLD-1 (colon)	NCI-H23 (lung)	ZR-75-1 (breast)	LOX IMVI (melanoma)	PC-3 (prostate gland)	CAKI-1 (kidney)
5-(2,6-dimethyl-2-heptyl) Resorcinol	2.2×10 ¹ (9.5×10 ^-5)	2.1×10 ¹ (9.0×10 ^-5)	1.8×10 ¹ (7.7×10 ^-5)	1.9×10 ¹ (8.1×10 ^-5)	NA	2.0×10 ¹ (8.4×10 ^-5)	2.2×10 ¹ (9.3×10 ^-5)	olivetol	4.0×10 ¹ (2.2×10 ^-4)	4.2×10 ¹ (2.3×10 ^-4)	3.3×10 ¹ (1.8×10 ^-4)	3.6×10 ¹ (2.0×10 ^-4)	4.4×10 ¹ (2.4×10 ^-4)	3.7×10 ¹ (2.0×10 ^-4)	4.0×10 ¹ (2.2×10 ^-4)

Claims

1. the cannabinol derivative of following formula:

Formula III

R wherein ¹Be:

a)H，

B) C _1-4Alkyl or its ester,

c)COOH，

d)OH，

E) O-C _1-5Alkyl (preferred OCH ₃) or alkanoyl, described group can choose wantonly by one or dimethylamino or ethylamino replace,

F) contain carboxyl or amino O-CO-C _3-10Alkyl,

g)

N=1 to 8 wherein

J) lactone (for example COCOH); Or

K) CH (CH ₃) CO ₂H or-OCOCH ₃

R ²Be:

A) H, OH or halogen,

B) C _1-6Carboxyl or alkoxyl group, perhaps

C) R ¹And R ²Constitutional formula-O (CH ₂) _3-6Shown in substituting group, wherein R ¹And R ²Carbon atom with their institute's bondings constitutes a ring, and on described ring, have at least a hydrogen atom to choose wantonly by halogen and replace,

R ³Be

A) (W) _m-Y-(Z) _n, wherein

W is C _5-12Straight or branched (preferred 1S ' CH ₃, 2R ' CH ₃Dimethyl) alkyl, alkenyl, alkynyl group or its mixture, described group can be chosen wantonly by at least one halogen and replace,

Y is a key, O, S, SO, SO ₂, CO, NH, N (C _1-6Alkyl) or NCS,

Z is:

Ii) CN _1-3, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _2-4Alkyl or CON (C _1-4Alkyl) ₂, the C of each on amide nitrogen atom wherein _1-4Alkyl can be identical or different, perhaps

M and n are identical or different, and are respectively 0 or 1,

C) C _5-12Alkenyl or alkynyl group, described group can be chosen wantonly by halogen, dithia cyclopentenes (dithiolene), terminal aromatic ring, CN _1-3, NCS, CO ₂H or CO ₂C _1-4Alkyl, CONH ₂, CONHC _1-4Alkyl or CON (C _1-4Alkyl) ₂Replace, wherein the C of each on amide nitrogen atom _1-4Alkyl can be identical or different;

A) hydrogen,

B) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

c)CN，

d)CO ₂H，

E) CO ₂-C _1-4Alkyl,

f)C(Y)(Z)-OH，

G) C (Y) (Z)-O-C _1-4Alkyl and

H) C _1-6Alkyl-CO ₂Y,

Wherein Y and Z are H or C respectively independently _1-6Alkyl,

R ¹Be:

A) hydroxyl or lactone,

B) halogen,

C) C _1-6Alkoxyl group, C _1-6Alkylthio, C _1-6Alkyl or C _1-6Haloalkyl,

d)CN，

e)N ₃，

f)CO ₂H，

G) CO ₂-C _1-4Alkyl,

h)C(Y)(Z)-OH，

I) C (Y) (Z)-O-C _1-4Alkyl,

J) C _1-6Alkyl-CO ₂-Y, or

K)=O or=S,

Wherein Y and Z are H or C respectively independently _1-6Alkyl;

Q is:

A) O or S, or

B) N-W, wherein W is:

I) hydrogen,

Ii) C _1-6Alkoxyalkyl, C _1-6Alkyl or C _1-6Haloalkyl,

Iii) OC _1-6Alkyl or OC _1-6Haloalkyl,

iv)CN，

V) C _1-6Alkyl,

Vi) (Z) C of C (Y) _1-4Alkyl, or

Vii) C _1-6Alkyl-CO ₂Z,

Wherein Y and Z are H or C respectively independently _1-6Alkyl.

2. the cannabinol derivative of claim 1, wherein the ring C in formula III can be any (wherein the dotted line representative is at two keys of Δ 6a-10a, Δ 8-9 or Δ 9-10 position) in the array structure down:

3. the cannabinol derivative of claim 2 wherein encircles two keys among the C in the 6a-10a position.

4. the cannabinol derivative of claim 1, wherein R ⁷Be=O.

5. the cannabinol derivative of claim 1, wherein R ⁶With R ^{6 '}Formation=O together.

6. the cannabinol derivative of claim 1, the wherein R in the formula III ³Be:

W wherein ₁Be H, methyl or ethyl, wherein W ₂And W ₃Be H or methyl, wherein W independently respectively ₁, W ₂And W ₃In the middle of have at least one not to be H and/or by halo, and W wherein ₄Be C _1-4Alkyl or haloalkyl, described group can be chosen wantonly by aromatic ring and replace.

7. the cannabinol derivative of claim 6, wherein the cannabinol derivative can be used as single steric isomer or stereoisomer mixture or single geometrical isomer or geometrical isomer mixture and exists.

8. the cannabinol derivative of claim 6, wherein R ³Be the alkoxyl group side chain:

9. the cannabinol derivative of claim 1, wherein the cannabinol derivative is:

10. the cannabinol derivative of claim 9, wherein the cannabinol derivative has the alkoxyl group carbon side chain that contains an asymmetric carbon, and it comprises racemic modification and corresponding body thereof, or R or S configuration.

11. the cannabinol derivative of claim 9, wherein the cannabinol derivative has the alkoxyl group side chain that does not contain asymmetric carbon.

12. one kind is suppressed the method that HIV duplicates, it uses the cannabinol derivative of claim 9.

13. the cannabinol derivative of claim 1, wherein the cannabinol derivative of claim 9 is as the selective ligands of CB2 acceptor.