CN106432226A

CN106432226A - Prodrug of 1H-imidazo[4,5-c]quinoline-4-amine and related compound

Info

Publication number: CN106432226A
Application number: CN201610481539.2A
Authority: CN
Inventors: 于崇曦
Original assignee: 于崇曦
Current assignee: Taifeier biomedical (Suzhou) Co.,Ltd.
Priority date: 2007-01-31
Filing date: 2007-01-31
Publication date: 2017-02-22
Anticipated expiration: 2027-01-31
Also published as: CN106432226B

Abstract

The invention relates to design and synthesis of a prodrug of 1H-imidazo[4,5-c]quinoline-4-amine and the related compound, wherein the prodrug has a general formula 1 'structural formula 1' or a general formula 2 'structural formula 2', and is prepared by reacting the 1H-imidazo[4,5-c]quinoline-4-amine and the related compound with proper acetic anhydride or acetyl chloride. Experimental results indicate that more than 90 percent of the prodrug can return a mother drug structure within a few minutes, can be used for treating any 1H-imidazo[4,5-c]quinoline-4-amine and the related compound treatable states of human or animals, and avoids most of side effects generated by the 1H-imidazo[4,5-c]quinoline-4-amine and the related compound. The concentration of the 1H-imidazo[4,5-c]quinoline-4-amine and the related compound can be stabilized at the optimal treatment concentration by a controlled release transdermal delivery system of the prodrug, the curative effect is improved and side effects are reduced.

Description

1H-imidazo [4,5-c] quinolin-4-amines class and the prodrug of related compound thereof

The application is the divisional application of No. 200780050660.9 Chinese invention patent application.The filing date of original application On January 31st, 2007, invention entitled " have rapid skin penetration speed positively charged water miscible 1H-imidazo [4, 5-c] prodrug of quinolin-4-amines class and related compound thereof ".

Technical field

The present invention relates to 1H-imidazo [4,5-c] quinolin-4-amines class and related compound thereof with positive charge, and water The synthesis of the prodrug of dissolubility, and in any 1H-imidazo [4,5-c] quinolin-4-amines class for the treatment of human or animal and related Application on compounds-treatable conditions.Especially, the present invention makes 1H-imidazo [4,5-c] quinolin-4-amines class and relatedization thereof Compound energy fast skin penetration.

Technical background

1H-imidazo [4,5-c] quinolin-4-amines class described here and related compound thereof in United States Patent (USP) 4,689, As antiviral drugs and interferon inducer disclosure in 338.The method that Gerster, J.F. Kem et al. proposes (Antimicrob.AgentsChemother.14,817-823,1978) demonstrates 1-isobutyl group-1H-imidazo [4,5-c] quinoline Quinoline-4-amine and related compound thereof have anti-bleb effect (United States Patent (USP) to the primary lesion being caused by herpes simplex virus Numbers 4,689,338).

Multiple external preparations of this compound are also described.United States Patent (USP) the 4,751,087th, the 4,411,893rd, 4,722, 941st, 4,746,515 and 5,736,553 disclose and utilize ethyl oleate and glyceryl monolaurate, N, N-dimethyl dodecyl Amine-n-oxides, glyceryl monolaurate and aliphatic acid are used for improving the transdermal transfer of medicine as dermal osmosis accelerator. 3M company has had been developed that Aldara (Aldara) emulsifiable paste (1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines) is used for controlling Treat actinic keratoma, superficial basal cell carcinoma, outer reproduction wart and perianal wart.

Content of the invention

Technical problem

3M company has been developed for Aldara emulsifiable paste (1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines) and is used for treating Actinic keratoma, superficial basal cell carcinoma, outer reproduction wart and perianal wart.

But, 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines and related compound thereof are in water and organic solvent In solubility very low, so the speed that they penetrate skin is very slow.This emulsifiable paste can make the medicine of high concentration long on skin Time stops, and causes many side effects to include rubescent, swelling, shouting pain, blister or ulcer, hardening thickening, the skin peeling of skin, Scab spot and the dermatodyschroia crusted, itch, burn and possibly cannot recover.Another problem is that skin is penetrated by they Not enough, it is impossible to for treating other cancers in addition to superficial basal cell carcinoma.

Solution

The present invention relates to novel 1H-imidazo [4,5-c] the quinolin-4-amines class with positive charge and related compound thereof Prodrug and in application pharmaceutically.These 1H-imidazo [4,5-c] quinolin-4-amines classes and the prodrug of related compound thereof There is formula (1) " structural formula 1 " or the structure of formula (2) " structural formula 2 "：

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；At-(CH₂)_n- In, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute； R₁And R₂Respective independent Shi Ke represents identical or different group, can be H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, Thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_M,-, wherein m= 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or its He substitutes ring system group；R₃Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, alkyl halide Base or alkynyl, aryl or heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or Other ring system groups of person substitute；X represents O, NH or S；Y represents C, S=O or P-OR11；R₄Selected from by following member's group The group becoming：The alkyl of 1 to about 10 carbon atoms, the hydroxyalkyl of 1 to about 10 carbon atoms, acyloxyallcyl (acyloxylalkyl) wherein acyloxy moieties is alkanoyloxy (alkanoyloxy) or the benzoyl of 2 to about 5 carbon atoms Epoxide, and moieties can be containing the alkyl of 1 to about 8 carbon atoms, benzyl, phenethyl and phenyl, described benzyl, phenethyl, Or phenyl substituent optionally has 1 or 2 substituents on phenyl ring, substituent can be independently selected from by following member The group of composition：The alkyl of 1 to about 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen, its principle is, if described Phenyl ring is replaced by 2 described groups, then the total number of carbon atoms of described group is less than 8；R₅Selected from by following member composition Group：Hydrogen, the alkyl of 1 to about 10 carbon atoms, benzyl, phenethyl, and phenyl, described benzyl, phenethyl, or phenyl substituent can Optionally having 1 or 2 substituents on phenyl ring, substituent can be independently selected from the group by following member composition：1 to about The alkyl of 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen, its principle is, if described phenyl ring is by 2 described bases Group replaces, then the total number of carbon atoms of described group is less than 8；R₆Selected from by the group of following member composition：Hydrogen, 1 to about 5 carbon The alkyl of atom, the alkoxyl of 1 to about 5 carbon atoms and halogen；R₇Selected from by the group of following member composition：Oxygen, 1 to about 5 The alkyl of carbon atom, the alkoxyl of 1 to about 5 carbon atoms and halogen；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_aIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or Person's heteroaryl, or other ring system groups replacement；R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_bIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl Base, or other ring system groups replacement；R₁₀Represent side chain or straight chain ,-(CH₂)_c-, c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other rings Shape group replaces；R₁₁Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynes Base, aryl or heteroaryl, wherein, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other rings Shape system radical substitutes；R₁₂Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl, Or alkynyl, aryl or heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other Ring system group substitutes；A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion；All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,-(CH₂)_m-,-(CH₂)_a-,-(CH₂)_b-or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N atom, can have singly-bound, double or triple bonds.

Medicine either absorbs through intestines and stomach or other approach, is required for medicine and passes through barrier film with molecular forms. First medicine need to dissolve, and if medicine there is preferable biopharmaceutical properties, it can be from the regional diffusion of high concentration to low dense The region of degree, strides across biomembrane and enters blood or systemic circulation system.All of biomembrane contains lipid as Main Ingredients and Appearance.Raw In thing membrane structure, active molecule all has phosphatic highly polar head construction, and, in most of the cases, Also has the hydrocarbon tails of two very hydrophobic.Biomembrane has double-decker, and hydrophilic head construction is towards the aqueous phase district of both sides Territory.Very hydrophilic medicine cannot be by the very hydrophobic medicine through biomembranous hydrophobic layer because the reason that similar compatibility making Stop wherein for a biomembranous part, thus the cytoplasm of inside can not be efficiently entering.

It is an object of the invention to by improving 1H-imidazo [4,5-c] quinolin-4-amines class and related compound thereof at skin Solubility in surface moisture and improve their penetration speeds to biomembrane and skin barrier, so that it can pass through transdermal It is administered (external application).The novel prodrugs of these 1H-imidazo [4,5-c] quinolin-4-amines classes and related compound thereof has two jointly Design feature：They with the presence of a lipophilic part and one under physiological ph conditions with the one-level of protonated form, Two grades, or tertiary amine group (water-soluble portion, its pKa is 9.5-10.7) is [in 1H-imidazo [4,5-c] quinolin-4-amines class Aromatic amine is very weak alkali (pKa=6.5-6.7), and only fraction exists with protonated form under physiological ph conditions].This The balance of the water-soluble-oil soluble of sample be medicine effectively pass through biomembrane necessary [Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993)].Amino with positive charge substantially increases solubility in water for the medicine.Permitted In the case of Duo, the dissolving of medicine is the slowest in absorption process and rate-limiting step.1H-imidazo [4,5-c] quinolin-4-amines class and Solubility in skin surface moisture for the related compound is very little, and they can not effectively pass through skin barrier with the form of molecule. Even and if they have passed through skin membrane, cannot efficiently enter cytoplasm (because poorly water-soluble), half liquid of a kind of cell interior The concentrated aqueous solution of state or suspension.When these prodrugs are given with formulation transdermals such as solution, spray, emulsion, ointment, latex or gels During medicine, they can be quickly soluble in the moisture of skin surface.Positive charge meeting on amino and cell membrane in these prodrugs The negative electrical charge of phosphate head structure combine, [due to alkalescence weak (pKa=6.5-6.7) and there is steric hindrance (amino and aromatic ring It is joined directly together) the phosphate head knot of positive charge on the aromatic amine of 1H-imidazo [4,5-c] quinolin-4-amines class and cell membrane The combination of the negative electrical charge of structure is more weak], therefore, local concentration outside biomembrane for the medicine is very high thus contributes to these prodrugs and leads to Excessive concentrations region is to the region of low concentration.After these prodrugs enter cell membrane, its hydrophilic parts can promote prodrug to enter Enter cytoplasm.When these prodrugs are outside skin, they simply do not have a bioactive prodrug, Just because of this and because Its residence time outside skin is short, and therefore prodrug does not results in rubescent, swelling, shouting pain, blister or skin ulcer, skin Hardening thickening, skin peeling, scab spot and crust, itch, burn or dermatodyschroia.These prodrugs penetrating in human body skin Speed is in vitro by the measurement of improved Franz pond, and wherein human body skin is isolatable from the human body skin of thigh position above or below Skin tissue (360-400 micron is thick).Accept solution by 2 milliliters containing 2% the physiological saline of bovine serum albumin(BSA)s form and with The speed stirring of 600 revs/min.The transdermal accumulation total amount of these prodrugs and female medicine thereof passes through specific high performance liquid chromatography Method measures.Donor solution by containing 3% 1H-imidazo [4,5-c] quinolin-4-amines class some before drug solns or by containing The suspension composition of 1H-imidazo [4,5-c] the quinolin-4-amines class of 3%, is all dissolved in the phosphate of 0.5 milliliter of ethanol and pH7.4 In the mixed liquor of cushioning liquid (0.2M) (v/v, 70/30), result is as shown in Figure 1.Calculating penetrates the apparent of human body skin and penetrates Value, obtains 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride, 1-butyl-1H-imidazo [4,5-c] Quinoline-4-amide hydrochloride, 1-benzyl-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride, 1-isobutyl group- 1H-imidazo [4,5-c] quinolin-4-amines hydrochloride, 1-butyl-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride, 1-benzyl The apparent penetrating value of base-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride is 0.15 milligram, 0.13 milligram, 0.16 milligram, 0.005 milligram, 0.005 milligram and 0.005 milli gram per centimeter²/ hour.Prodrug penetrates the speed of human body skin than 1H-imidazo Fast about 25 times of [4,5-c] quinolin-4-amines class.Result explanation di-alkyaminoethyl group on positive charge to medicine pass through biomembrane and Skin barrier is extremely important.

Spread effect or uncomfortable reaction to mouse skin for these novel prodrugs is evaluated, by the following method by 0.05 The various testing drug external applications that milliliter is dissolved in the 3% of the PBS (0.2M) of pH7.4 are applied to nude mice back, every day two Secondary, spread effect or discomfort to mouse skin for these the novel prodrugs of post-evaluation in a week is reacted.1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride, 1-butyl-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride, 1- Benzyl-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride does not finds spread effect or uncomfortable reaction.

One good prodrug should be able to be easily returned to female medicine.Carry out external plasma hydrolysis studies in accordance with the following methods.Will 10 milligrams of prodrugs are dissolved in the PBS of 0.1 milliliter of 0.2M pH value 7.4.1 milliliter of human plasma is preheating to 37 DEG C, Add to mixture.Mixture is incubated in the water-bath of 37 DEG C.Every two minutes intervals, take out 0.2 milliliter of sample and add 0.4 ml methanol makes plasma protein precipitate.Sample centrifuges 5 minutes and uses efficient liquid phase chromatographic analysis.1-isobutyl group-1H-imidazoles And the half-life of [4,5-c] quinoline-4-amide hydrochloride hydrolysis is 18 ± 1 minutes, 1-butyl-1H-imidazo [4,5-c] The half-life of quinoline-4-amide hydrochloride hydrolysis is 18 ± 2 minutes, 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4- The half-life of amide hydrochloride hydrolysis is 19 ± 1 minutes.

1H-imidazo [4,5-c] quinolin-4-amines class is known antiviral drugs, and it also can the biology of inducing interferon Synthesis (Gerster, J.F., U.S. Patent number 4,689,338).This compounds is that this fact of interferon inducer carries Showing, perhaps they may be used for treating a lot of disease, such as rheumatoid arthritis, genitals or other position wart, eczema, liver Inflammation, psoriasis, multiple sclerosis, primary thrombocytosis, cancer, acquired immunodeficiency syndrome (AIDS) and its Its virus disease.Aldara emulsifiable paste (1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines) is developed by 3M company, is used for controlling Treat actinic keratoma, superficial basal cell carcinoma, external genital organs wart and perianal wart.

In order to evaluate the active anticancer of these prodrugs, by the breast cancer cell of people, (BCAP-37, every mouse uses 4-5 milli Rice³Tumor tissues) implant nude mice (BALB) subcutaneous.After 3 hours, implanting region (near the foreleg) external application of human breast cancer cell Smear 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride and the 1-isobutyl group-1H-miaow of 50 microlitres 3% Azoles simultaneously [4,5-c] quinolin-4-amines hydrochloride, be all dissolved in ethanol/0.2M pH value 7.2 PBS (v/v, 70/ 30), smear once every day.After 28 days, control group (n=7, average tumor size is 15 ± 2 millimeters × 13 ± 2 millimeters) and use 1- The group of isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride treatment (n=7, average tumor size is 12 ± 2 millimeters × 11 ± 2 millimeters) Tumor incidence be 100%, and with 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide salt The group (n=7) of hydrochlorate treatment does not observe tumour.1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloric acid The average weight of the group small mouse of salts for treating is 22 ± 2 grams, 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride The average weight of the group small mouse for the treatment of is 22 ± 2 grams, and control group is 24 ± 2 grams.The pair of these prodrugs of the results show Act on very slight.

In second anti-tumor experiment, by the colon cancer cell of people, (LS174J, every mouse uses 4-5 millimeter³Tumour Tissue) implant nude mice (BALB) subcutaneous.After 3 hours, smear 50 in region (near the foreleg) external application implanting human colon cancer cell 1-isobutyl group-1H-imidazo [4, the 5-c] quinoline-4-amide hydrochloride of microlitre 3% and 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride, is all dissolved in the PBS (v/v, 70/30) of ethanol/0.2M pH value 7.2, often It is smeared twice.After 28 days, control group (n=7, average tumor size is 20 ± 3 millimeters × 18 ± 3 millimeters) and use 1-isobutyl (n=7, average tumor size is 17 ± 2 millimeters × 154 to the group of base-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride treatment ± 2 millimeters) Tumor incidence be 100%, and with 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloric acid The group (n=7) of salts for treating does not observe tumour.1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride The average weight of the group small mouse for the treatment of is 21 ± 2 grams, and 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride is controlled The average weight of the group small mouse treated is 21 ± 2 grams, and control group is 23 ± 2 grams.

In the 3rd anti-tumor experiment, by the breast cancer cell of people, (BCAP-37, every mouse uses 3-4 milli Rice³Tumor tissues) implant nude mice (BALB) subcutaneous.After 21 days, tumor size length is to 13 ± 2 millimeters × 12 ± 3 millimeters.Then exist 1-isobutyl group-1H-imidazo [4,5-c] of 50 microlitres 3% is smeared in region (near the foreleg) external application implanting human breast cancer cell Quinoline-4-amide hydrochloride and 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride, be all dissolved in ethanol/ The PBS (v/v, 70/30) of 0.2M pH value 7.2, every day smears twice.In control group (n=7), tumour is big Little at the 45th day duration to 21 ± 3 millimeters × 19 ± 3 millimeters, all dead to mouse when the 60th day.With 1-isobutyl group-1H- In the group of imidazo [4,5-c] quinolin-4-amines hydrochloride treatment (n=7), tumor size was 17 ± 2 millimeters when the 45th day × 15 ± 2 millimeters, all dead to mouse when the 70th day.With 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide In the group of hydrochloride treatment (n=7), tumor size narrowed down to 11 ± 2 millimeters × 10 ± 2 millimeters when the 45th day, by the 70th day When still without dead mouse.When the 45th day, 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride was treated Group small mouse average weight be 21 ± 2 grams, 1-isobutyl group-1H-imidazo [4,5-c] quinolin-4-amines hydrochloride treatment The average weight of group small mouse is 22 ± 2 grams, and control group is 23 ± 2 grams.

According to Kern et al. describe method [Antimicrob.Agents Chemother.14,817, (1978) .] comment The valency anti-bleb effect of these prodrugs.In first experiment, anesthesia Female guinea pigs (n=5).Use in cavy vagina 1-isobutyl group-1H-imidazo [4, the 5-c] quinoline-4-amide hydrochloride solution of 100 microlitres 3%, its be dissolved in ethanol/ The PBS (v/v, 70/30) of 0.2M pH value 7.4, uses 3 days.Then cavy vagina is made to infect by cotton rod Herpes simplex virus (I type or II type, about 10⁵Individual bacterial plaque forms unit).After being infected by detection the 1st, the 2nd, the 3rd, 5 or 7 days cloudy Viral load in the cotton rod of road collection monitors the duplication of virus.In second experiment, anesthesia Female guinea pigs (n=5). 1-isobutyl group-1H-imidazo [4, the 5-c] quinoline-4-amide hydrochloride using 200 microlitres 3% in cavy vagina is molten Liquid, it is dissolved in the PBS (v/v, 70/30) of ethanol/0.2M pH 7.4, then makes cavy vagina by cotton rod Infection herpes simplex virus (1 type or II type, about 10⁵Individual bacterial plaque forms unit).In the 3rd experiment, anaesthetize Female guinea pigs (n=5).With cotton rod make cavy vagina infection herpes simplex virus (I type or II type, about 10⁵Individual bacterial plaque forms unit).5 After it, use 1-isobutyl group-1H-imidazo [4, the 5-c] quinoline-4-amide hydrochloric acid of 100 microlitres 5% in cavy vagina Salting liquid, it is dissolved in the PBS (v/v, the mixed solution of 70/30) of ethanol/0.2M pH 7.4, once a day, Use 10 days continuously.Result proves, 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride is in cavy sense Before dye, infect simultaneously or use all effective after infection.

1H-imidazo [4,5-c] quinolin-4-amines can be according to United States Patent (USP) 4, and disclosed in 689,388 prepared by method.On State the compound represented by formula (1) " structural formula 1 " or formula (2) " structural formula 2 " can by 1H-imidazo [4,5-c] quinoline- 4-amine and related compound thereof, under the effect of coupling agent, react with the compound in formula (3) " structural formula 3 " and prepare, even Mixture has：N, N '-dicyclohexylcarbodiimide, N, N '-DIC, O-(BTA-1-base)-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, O-(BTA-1-base)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, benzene And triazole-1-base-epoxide-three (dimethylamino) phosphorus hexafluorophosphoric acid ester etc..

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；At-(CH₂)_n- In, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute； R₁And R₂Respective independent Shi Ke represents identical or different group, can be H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, Thiazolinyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_M,-, wherein m=2, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replace Generation；X represents O, NH or S；Y represents C, S=O or P-OR11；R₄Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, Thiazolinyl or alkynyl, aryl or heteroaryl；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_aIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other Ring system group substitutes；R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., At-(CH₂)_bIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system bases Group substitutes；R₁₀Represent side chain or straight chain ,-(CH₂)_c-, c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, appoint One CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups；R₁₁Represent H, appoint The alkyl of one 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, Arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；R₁₂Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, its In arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；A^-Generation Table Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,-(CH₂)_m-,- (CH₂)_a-,-(CH₂)_b-or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N atom, Ke Yihan Have singly-bound, double or triple bonds.

Compound represented by above-mentioned formula (1) " structural formula 1 " or formula (2) " structural formula 2 " can be by 1H-imidazo Compound in [4,5-c] quinolin-4-amines class and related compound thereof, with formula (4) " structural formula 4 " reacts and prepares.

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；Any CH₂Can By O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute；R₁And R₂Each solely Identical or different group can be represented immediately, can be H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluor alkane Base, haloalkyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_m-, wherein m=2, the 3rd, the 4th, the 5th, the 6th, the 7th, 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system bases Group substitutes；R₃Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, virtue Base or heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring-type systems System group substitutes；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ... ,- (CH₂)_aIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system bases Group substitutes；R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_b- In, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replacement；R₁₀ Represent side chain or straight chain ,-(CH₂)_c-, c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, arbitrary CH₂Permissible By O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups；R₁₁Represent H, arbitrary 1-12 carbon The alkyl of atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Permissible By O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；R₁₂Represent H, arbitrary 1-12 The alkyl of individual carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, any of which CH₂ Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,-(CH₂) m-,-(CH₂)_a-,- (CH₂)_b-or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N atom, can be containing singly-bound, double Key or three keys.

Advantage

In the present invention, the prodrug of these 1H-imidazo [4,5-c] quinolin-4-amines classes and related compound thereof has a fat Insoluble portion and a water-soluble portion (amido existing with protonated form under physiological ph).The ammonia of these prodrug positively chargeds Base has two big advantages.First, it drastically increases solubility in water for the medicine, when these novel prodrugs with solution, spray, During the formulation cutaneous penetrations such as emulsion, ointment, latex or gel, they can rapidly and skin, eyes, genitals, face, nose or The surface moisture mixing of other body parts.Second, the amino of these prodrug positively chargeds can be with biomembranous electronegative phosphorus Hydrochlorate head construction combines.Therefore, the local concentration outside biomembrane can be very high, thus promote medicine from area with high mercury through to Low concentration region.After these prodrugs enter into biomembrane, hydrophilic parts will promote prodrug to enter cytoplasm, Yi Zhongnong In the semi liquid state aqueous solution of contracting or suspension.Due to prodrug skin, eyes, genital area, face, nose or health other The time of staying at position is very short, itches thus without causing, burns or pain.Experiment proves that the prodrug more than 90% can divide youngster Female medicine is returned in clock.Because prodrug has more preferable absorptivity, and cutaneous penetration can be avoided " first-pass metabolism ", therefore at equal dose During amount, the curative effect of prodrug is more higher than 1H-imidazo [4,5-c] quinolin-4-amines class and related compound thereof.

Brief description

Fig. 1 is 1-isobutyl group-lH-imidazo [4,5-c] by the human skin tissue separating in Franz pond (n=5) Quinoline-4-amide hydrochloride (3% solution, A), 1-butyl-lH-imidazo [4,5-c] quinoline-4-amide hydrochloride (3% solution, B), 1-benzyl-IH-imidazo [4,5-c] quinoline-4-amide hydrochloride (3% solution, C), 1-isobutyl group- LH-lH-imidazo [4,5-c] quinolin-4-amines hydrochloride (3% suspension, D), 1-butyl-lH-imidazo [4,5-c] quinoline- 4-amine hydrochlorate (3% suspension, E) and 1-benzyl-IH-imidazo [4,5-c] quinolin-4-amines hydrochloride (3% suspension, F) Accumulative total spirogram.In each example, carrier solution be all ethanol/pH value 7.4 PBS (0.2M) (v/v, 70/30).

Fig. 2 is structural formula 1 and the figure of structural formula 2.Wherein, R represents side chain or straight chain ,-(CH₂)_n-, n=0, the 1st, the 2nd, the 3rd, the 4th, 5、6、7、8、9、10……；At-(CH₂)_nIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl Base, or other ring system groups replacement；R₁And R₂Respective independent Shi Ke represents identical or different group, can be H, appoints The alkyl of one 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, or R₁ And R₂Common representative-(CH₂)_m,-, wherein m=2, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C、CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute；R₃Represent H, the alkane of arbitrary 1-12 carbon atom Base, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, any of which CH₂Can be by O, S, CH= CH、C≡C、CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute；X represents O, NH or S；Y represents C, S =O or P-OR11；R₄Selected from by the group of following member composition：The alkyl of 1 to about 10 carbon atoms, 1 to about 10 carbon atoms Hydroxyalkyl, acyloxyallcyl wherein acyloxy moieties is alkoxy carbonyl group or the benzoyloxy of 2 to about 5 carbon atoms, and alkyl Part can contain alkyl, benzyl, phenethyl and phenyl, described benzyl, the phenethyl of 1-8 carbon atom, or phenyl substituent can Optionally having 1 or 2 substituents on phenyl ring, substituent can be independently selected from the group by following member composition：1 to about The alkyl of 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen, its principle is, if described phenyl ring is by 2 described bases Group replaces, then the total number of carbon atoms of described group is less than 8；R₅Selected from by the group of following member composition：Hydrogen, 1 to about 10 The alkyl of carbon atom, benzyl, phenethyl and phenyl, described benzyl, phenethyl, or phenyl substituent is optionally at phenyl ring On there are 1 or 2 substituents, substituent can be independently selected from the group by following member composition：The alkane of 1 to about 5 carbon atoms Base, the alkoxyl of 1 to about 5 carbon atoms and halogen, its principle is, if described phenyl ring is replaced by 2 described groups, then described The total number of carbon atoms of group is less than 8；R₆Selected from by the group of following member composition：Hydrogen, the alkyl of 1 to about 5 carbon atoms, 1 Alkoxyl and halogen to about 5 carbon atoms；R₇Selected from by the group of following member composition：Hydrogen, 1 to about 5 carbon atoms alkyl, The alkoxyl of 1 to about 5 carbon atoms and halogen；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, 8th, the 9th, 10 ..., at-(CH₂)_aIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or Other ring system groups substitute；R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_bIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other rings Shape system radical substitutes；R₁₀Represent side chain or straight chain ,-(CH₂)_c-, c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ... ,- (CH₂)_cIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups； R₁₁Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or miscellaneous Aryl, wherein, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replace Generation；R₁₂Represent H, the alkyl of arbitrary 1-12 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or Heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups Substitute；A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion；All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,- (CH₂)_m-,-(CH₂)_a-,-(CH₂)_b-or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N are former Son, can have singly-bound, double or triple bonds.

Preferred forms

The preparation of tertbutyloxycarbonyl-1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide

1-isobutyl group-1H-imidazo [4, the 5-c] quinolin-4-amines of 32.2 grams (0.1 moles) is dissolved in 500 milliliters of acetic acid In ethyl ester.Add 36 grams of (0.1 mole) N-tertbutyloxycarbonyl-sarcosine acid anhydride [(Boc-N-Me-in the reactive mixture Gly)₂O] and 20 milliliters of triethylamines.Mixture refluxes 2 hours.Solution with water washes 1 time, 100 milliliters every time, 10% lemon pickling 1 Secondary, 100 milliliters every time, wash 1 time, 100 milliliters every time, 5% sodium bicarbonate solution is washed 1 time, 100 milliliters every time, is washed with water 3 Secondary, 100 milliliters every time.Ethyl acetate layer anhydrous sodium sulfate is dried.It is evaporated ethyl acetate solvent.After drying, obtain 36 grams of mesh Mark product (productivity is 87.5%).Elementary analysis：C₂₂H₂₉N₅O₃, molecular weight：411.50.Calculated value %：C：64.21；H：7.10； N：17.02；O：11.66；Measured value %：C：64.17；H：7.15；N：16.97；O：11.71.¹H-NMR (400MHz, CDCl₃)： δ：1.12 (d, 6H), 1.52 (d, 9H), 2,37 (m, H), 3.05 (s, 3H), 4.30 (d, 2H), 4.78 (m, 2H), 7.60-7.70 (m, 2H), 7.85 (s, H), 8.02-8.20 (m, 2H), 9.01 (b, H).

The preparation of 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride

35 grams of tertbutyloxycarbonyl-1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-amide are dissolved in 200 milliliters In ethanol.It is slowly introducing 20 minutes hydrogen chloride gas in reactant mixture.Mixture is stirred at room temperature 1 hour.Mixture 500 milliliters of ether of middle addition.Solid product is collected by filtration, washes 3 times with ether.After drying, obtain 27 grams of target product (productivity It is 91.2%).Elementary analysis：C₁₇H₂₂ClN₅O；Molecular weight：347.84.Calculated value %C：58.70；H：6.37；Cl：10.19；N： 20.13；O：4.60；Measured value %C：58.67；H：6.41；Cl：10.17；N：20.11；O：4.64.

Embodiment

The preparation of tertbutyloxycarbonyl-1-butyl-1H-imidazo [4,5-c] quinoline-4-glycine amide

32.2 grams of (0.1 mole) 1-butyl-1H-imidazo [4,5-c] quinolin-4-amines are dissolved in 300 milliliters of ethyl acetate In.Reactant mixture adds 33.3 grams of (0.1 mole) N-tertbutyloxycarbonyl-glycine anhydrides [(Boc-N-Gly)₂O] and 20 millis Rise triethylamine.Mixture refluxes 2 hours.Solution with water is washed 1 time, and 100 milliliters every time, 10% lemon pickling 1 time, 100 in the least every time Rising, washing 1 time, 100 milliliters every time, 5% sodium bicarbonate solution washes 1 time, 100 milliliters every time, washes 3 times, 100 milliliters every time. Ethyl acetate solution anhydrous sodium sulfate is dried.Ethyl acetate solution is evaporated.After drying, obtain 37 grams of target product (productivity It is 93.1%).Elementary analysis：C₂₁H₂₇N₅O₃；Molecular weight：397.47.Calculated value %C：63.46；H：6.85；N：17.62；O： 12.08；Measured value %C：63.42；H：6.87；N：17.60：O：12.11.¹H-NMR (400MHz, CDCl₃)：δ：0.93 (t, 3H), 1.27 (m, 2H), 1.45 (d, 9H), 1.68 (m, 2H), 4.30 (m, 2H), 4.76 (m, 2H), 7.60-7.71 (m, 2H), 7.85 (s, H), 8.02-8.17 (m, 2H), 8.62 (b, H), 9.02 (b, H).

The preparation of 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-glycyl amide hydrochloride

36 grams of tertbutyloxycarbonyl-1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-glycine amides are dissolved in 200 milliliters In ethanol.It is slowly introducing 20 minutes hydrogen chloride gas in reactant mixture.Mixture is stirred at room temperature 1 hour.In mixture Add 500 milliliters of ether.Solid product is collected by filtration, then washes 3 times with ether.After drying, (productivity is to obtain 28 grams of target products 92.6%).Elementary analysis：C₁₆H₂₀ClN₅O；Molecular weight：333.82.Calculated value %C：57.57；H：6.04；Cl：10.62；N： 20.98；O：4.79；Measured value %C：57.52；H：6.08；Cl：10.67；N：20.95；O：4.78.

1-butyl-1H-imidazo [4,5-c] quinoline-4-N, the preparation of N-dimethylglycylamide hydrochloride

27 grams of 1-butyl-1H-imidazo [4,5-c] quinoline-4-glycyl amide hydrochlorides are dissolved in 50 milliliters of 2N hydroxides In sodium solution.50 milliliter of 40% formaldehyde and 50 milliliters of acetic acid are added in reactant mixture.Reactant mixture is slowly added to 30 Gram sodium borohydride.After addition, mixed liquor stirs 30 minutes.Another 25 milliliter of 40% formaldehyde and 10 milliliters of adding in reactant mixture Acetic acid.It is slowly added to 20 grams of sodium borohydrides in reactant mixture.Mixture is evaporated.Residue over silica gel column chromatography purifies.? To 20 grams of H mark product (productivity is 68.8%).Elementary analysis：C₁₈H₂₄ClN₅O；Molecular weight：361.87.Calculated value %C：59.74； H：6.68：Cl：9.80；N：19.35：O：4.42：Measured value %C：59.72；H：6.72；Cl：9.75；N：19.37；O：4.44.

The preparation of tertbutyloxycarbonyl-1-benzyl-1H-imidazo [4,5-c] quinoline-4-amide

It is dissolved in 18.9 grams of (0.1 mole) N-tertbutyloxycarbonyl-sarcosines in 300 milliliters of dichloromethane.Instead Answer 20.6 grams of N of addition, N '-dicyclohexylcarbodiimide in mixture.Mixture stirs 1 hour at 0 DEG C.Reactant mixture adds Enter 32.2 grams of (0.1 mole) 1-benzyl-1H-imidazo [4,5-c] quinolin-4-amines and 20 milliliters of triethylamines.Mixture is in room temperature Stir 3 hours.Solids removed by filtration.Dichloromethane solution washes with water 1 time, and 100 milliliters every time, 30% citric acid solution is washed 1 time, 100 milliliters every time, washing 1 time, 100 milliliters every time, 5% sodium bicarbonate solution washes 2 times, 100 milliliters every time, washes 3 times, every time 100 milliliters.Organic solution anhydrous sodium sulfate is dried.It is filtered to remove sodium sulphate.Organic solution is evaporated.After drying, obtain 33 grams Target product (productivity is 74.1%).Elementary analysis：C₂₅H₂₇N₅O₃；Molecular weight：445.51.Calculated value %C：67.40；H： 6.11；N：15.72；O：10.77；Measured value %C：67.35；H：6.14；N：15.70；O：10.81.¹H-NMR (400 MHz, CDCl₃)：δ：1.52 (d, 9H), 3.02 (s, 3H), 4.68 (m, 2H), 4.98 (m, 2H), 7.10-7.16 (m, 5H), 7.60- 7.70 (m, 2H), 7.85 (s, H), 8.02-8.20 (m, 2H), 8.91 (b, H).

The preparation of 1-benzyl-1H-imidazo [4,5-c] quinoline-4-amide hydrochloride

32 grams of tertbutyloxycarbonyl-1-benzyl-1H-imidazo [4,5-c] quinoline-4-amide are dissolved in 200 milliliters of second In alcohol.Reactant mixture is slowly introducing 20 minutes hydrogen chloride gas.Mixture is stirred at room temperature 1 hour.Mixture adds 500 Milliliter ether.Solid product is collected by filtration, then washes 3 times with ether.After drying, (productivity is to obtain 25 grams of target products 85.7%).Elementary analysis：C₂₀H₂₀ClN₅O；Molecular weight：381.86.Calculated value %C：62.91；H：5.28；Cl：9.28；N： 18.34；O：4.19；Measured value %C：62.87；H：5.31；Cl：9.30；N：18.32；O：4.20.

Industrial applicibility

These prodrugs in formula (1) " structural formula 1 " are better than 1H-imidazo [4,5-c] quinolin-4-amines class and relatedization thereof Compound.They may be used for treating any 1H-imidazo [4,5-c] quinolin-4-amines class and the related compound thereof of human or animal Treatable state.They can be used for treating actinic keratoma, basal-cell carcinoma, cancer, AIDS, bird flu, reproduction Wart and perianal wart, and other virus diseases.

Claims

1. by the compound represented by formula (1) " structural formula 1 " or formula (2) " structural formula 2 ",

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, wherein n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；At-(CH₂)_n- In, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute； R₁And R₂Respective independent Shi Ke represents identical or different group, can be H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, Thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_m-, wherein m= 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or its He substitutes ring system group；R₃Represent H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, alkyl halide Base or alkynyl, aryl or heteroaryl, wherein, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, Or other ring system groups substitute；X represents O, NH or S；Y represents C, S=O or P-OR11；R₄Selected from by following member The group of composition：The alkyl of 1 to about 10 carbon atoms, the hydroxyalkyl of 1 to about 10 carbon atoms, acyloxyallcyl wherein acyl-oxygen base portion It is divided into alkoxy carbonyl group or the benzoyloxy of 2 to about 5 carbon atoms, and moieties can contain alkyl, the benzyl of 1-8 carbon atom Base, phenethyl and phenyl, described benzyl, phenethyl, or phenyl substituent optionally have 1 or 2 on phenyl ring and take Dai Ji, substituent can be independently selected from the group by following member composition：The alkyl of 1 to about 5 carbon atoms, 1 to about 5 carbon atoms Alkoxyl and halogen, its principle is, if described phenyl ring is replaced by 2 described groups, then the total number of carbon atoms of described group Less than 8；R₅Selected from by the group of following member composition：Hydrogen, the alkyl of 1 to about 10 carbon atoms, benzyl, phenethyl and benzene Base, described benzyl, phenethyl, or phenyl substituent optionally have 1 or 2 substituents on phenyl ring, and substituent can Independently selected from the group by following member composition：The alkyl of 1 to about 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen Element, its principle is, if described phenyl ring is replaced by 2 described groups, then the total number of carbon atoms of described group is less than 8；R₆ Selected from by the group of following member composition：Hydrogen, the alkyl of 1 to about 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen； R₇Selected from by the group of following member composition：Hydrogen, the alkyl of 1 to about 5 carbon atoms, the alkoxyl of 1 to about 5 carbon atoms and halogen Element；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_aIn-, appoint What CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute；R₉Represent Side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_bIn-, arbitrary CH₂Permissible By O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replacement；R₁₀Represent side chain or straight Chain ,-(CH₂)_c-, wherein c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, arbitrary CH₂Can be by O, S, CH =CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups；R₁₁Represent H, the alkane of arbitrary 1-15 carbon atom Base, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can be by O, S, CH =CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；R₁₂Represent H, arbitrary 1-15 carbon atom Alkyl, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, any of which CH₂Can by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion；All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,-(CH₂)_m-,-(CH₂)_a-,-(CH₂)_b- Or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N atom, can have singly-bound, double or triple bonds.

2. a kind of compound as claimed in claim 1, which is 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-flesh aminoacyl Amine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

3. a kind of compound as claimed in claim 1, which is 1-isobutyl group-1H-imidazo [4,5-c] quinoline-4-N, N-bis- Methyl glycine amide HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

4. a kind of compound as claimed in claim 1, which is 1-butyl-1H-imidazo [4,5-c] quinoline-4-flesh aminoacyl Amine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

5. a kind of compound as claimed in claim 1, which is 1-benzyl-1H-imidazo [4,5-c] quinoline-4-flesh aminoacyl Amine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

6. a kind of compound as claimed in claim 1, which is 1-methyl isophthalic acid H-imidazo [4,5-c] quinoline-4-flesh aminoacyl Amine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

7. a kind of compound as claimed in claim 1, which is 1,2,8-trimethyl-1H-imidazo [4,5-c] quinoline-4-fleshes Glutamine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

8. a kind of compound as claimed in claim 1, which is 1-(2-ethoxy)-1H-imidazo [4,5-c] quinoline-4-flesh Glutamine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

9. a kind of compound as claimed in claim 1, which is 1,8-dimethyl-1H-imidazo [4,5-c] quinoline-4-flesh ammonia Acid amides HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

10. a kind of compound as claimed in claim 1, which is 1,2-dimethyl-1H-imidazo [4,5-c] quinoline-4-flesh ammonia Acid amides HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

11. compounds as claimed in claim 1 a kind of, which is 1-(2,3-dihydroxypropyl)-1H-imidazo [4,5-c] quinoline- 4-amide HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

12. a kind of compounds as claimed in claim 1, which is 1-cyclohexyl methyl-1H-imidazo [4,5-c] quinoline-4-flesh Glutamine HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

13. a kind of compounds as claimed in claim 1, which is 1-benzyl-2-methyl isophthalic acid H-imidazo [4,5-c] quinoline-4- Amide HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

14. a kind of compounds as claimed in claim 1, which is 1-n-hexyl-1H-imidazo [4,5-c] quinoline-4-flesh ammonia Acid amides HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

15. compounds as claimed in claim 1 a kind of, which is 1-n-hexyl-2-methyl isophthalic acid H-imidazo [4,5-c] quinoline- 4-amide HA, wherein, A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion.

The design of 16. 1 kinds of prodrugs, in this design, prodrug should have a fat-soluble part and one in physiological ph When can with protonated form exist one-level amine, secondary amine, tertiary amine group (water-soluble portion)；And should only have 1 or 2 The one-level amine that (preferably 1) can exist with protonated form when physiological ph, secondary amine, tertiary amine group (water solubility portion Point)；Any carboxyl in drug molecule, amino, guanidine radicals or other hydrophilic radicals can use alkyl, aryl or heteroaryl ester bond or Acid amides health care is protected, so that medicine more lipophilic.

Formula (1) " structural formula 1 " described in 17. claims 1 to 15 or the conjunction of the compound represented by formula (2) " structural formula 2 " One-tenth method, wherein said compound can be by 1H-imidazo [4,5-c] quinolin-4-amines class and related compound thereof, at coupling agent Effect under, with the compound in formula (3) " structural formula 3 " react prepare；Coupling agent has：N, N '-dicyclohexylcarbodiimide, N, N '-DIC, O-(BTA-1-base)-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, O-(benzene And triazole-1-base)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, BTA-1-base-epoxide-three (dimethylamino Base) phosphorus hexafluorophosphoric acid ester etc.；

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, wherein n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；At-(CH₂)_n- In, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute； R₁And R₂Respective independent Shi Ke represents identical or different group, can be H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, Thiazolinyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_m-, wherein m=2, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replace Generation；X represents O, NH or S；Y represents C, S=O or P-OR11；R₄Represent H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, Thiazolinyl or alkynyl, aryl or heteroaryl；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_aIn-, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other rings Shape system radical substitutes；R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ... ,- (CH₂)_bIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups Substitute；R₁₀Represent side chain or straight chain ,-(CH₂)_c-, wherein c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, Arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups；R₁₁Represent H, The alkyl of arbitrary 1-15 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, its In, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replacement；R₁₂ Represent H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl Base, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement； A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion；All of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,- (CH₂)_m-,-(CH₂)_a-,-(CH₂)_b-or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N are former Son, can contain singly-bound, double or triple bonds.

Formula (1) " structural formula 1 " described in 18. claims 1 to 15 or the compound represented by formula (2) " structural formula 2 " Synthetic method, wherein said compound can be by 1H-imidazo [4,5-c] quinolin-4-amines class and related compound thereof, with formula (4) the compound reaction in " structural formula 4 " prepares；

Wherein, R represents side chain or straight chain ,-(CH₂)_n-, n=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ...；Any CH₂Can by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute；R₁And R₂Respective independent when Identical or different group can be represented, can be H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, halogen Substituted alkyl or alkynyl, aryl or heteroaryl, or R₁And R₂Common representative-(CH₂)_m,-, wherein m=2, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replace Generation；R₃Represent H, the alkyl of arbitrary 1-15 carbon atom, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or Heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system bases Group substitutes；R₈Represent side chain or straight chain ,-(CH₂)_a-, wherein a=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_a- In, any CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups substitute； R₉Represent side chain or straight chain ,-(CH₂)_b-, wherein b=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_bIn-, arbitrary CH₂Can be by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or other ring system groups replacement；R₁₀Represent and prop up Chain or straight chain ,-(CH₂)_c-, c=0, the 1st, the 2nd, the 3rd, the 4th, the 5th, the 6th, the 7th, the 8th, the 9th, 10 ..., at-(CH₂)_cIn-, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CR₁₁R₁₂, aryl or heteroaryl, or the replacement of other cyclic groups；R₁₁Represent H, arbitrary 1-15 carbon atom Alkyl, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, wherein, arbitrary CH₂Can by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；R₁₂Representing H, arbitrary 1-15 carbon is former The alkyl of son, alkoxyl, thiazolinyl, perfluoroalkyl, haloalkyl or alkynyl, aryl or heteroaryl, any of which CH₂Can be by O, S, CH=CH, C ≡ C, CR₁R₂, aryl or heteroaryl, or other ring system groups replacement；A^-Represent Cl^-, Br^-, F^-, I^-, AcO^-, citrate or any anion, all of R, R₁, R₂, R₃, R₄,-(CH₂)_n-,-(CH₂)_m-,-(CH₂)_a-,-(CH₂)_b- Or-(CH₂)_c-group can be side chain or straight chain, it may include C, H, O, S, P or N atom, can contain singly-bound, double bond or three Key.

19. as described in claim 1-15 formula (1) " structural formula 1 " or a kind of chemical combination represented by formula (2) " structural formula 2 " Thing, or one at least contains the compound represented by a kind of formula (1) " structural formula 1 " or formula (2) " structural formula 2 " as activity The composition of composition, its can by way of administered orally or transdermally, for treat human or animal any 1H-imidazo [4, 5-c] quinolin-4-amines class and the treatable state of related compound thereof, these states include but is not limited to acquired immunity and lack Sunken syndrome (AIDS), bird flu, hydrophobia (rabies), wart, Severe Acute Respiratory syndrome (SARS), eczema, Hepatitis, psoriasis, multiple sclerosis, primary thrombocytosis and other virus diseases, actinic keratoma, basal cell Knurl, cutaneum carcinoma, breast cancer, colon cancer, lung cancer, carcinoma of mouth and other kinds cancers.

Any 1H-imidazo [4,5-c] quinolin-4-amines class of 20. treatment human or animals and the shape of related compounds-treatable thereof The method of state, the method by any part of health with cutaneous penetration by way of give formula as described in claim 1-15 (1) " structural formula 1 " or the compound represented by formula (2) " structural formula 2 " reach to treat effective PC, wherein transdermal Administering mode includes solution, spray, emulsion, ointment, latex or gel.

The wart of 21. external curing human or animals, Severe Acute Respiratory syndrome (SARS), it is thus achieved that property immunologic deficiency syndrome (AIDS), bird flu, hydrophobia (rabies) and other virus diseases, actinic keratoma, basal cell tumor, cutaneum carcinoma, The method of breast cancer, colon cancer, lung cancer, carcinoma of mouth and other cancers, by controlling at disease pathogenetic specific region cutaneous penetration Chemical combination represented by the formula as described in claim 1-15 (1) " structural formula 1 " for the treatment of effective dose or formula (2) " structural formula 2 " Thing is as the composition of active component.

22. external curings or the method for prevention acquired immunodeficiency syndrome (AIDS), the method is by the upper respiratory tract And/or men and women's genital area transdermal medicine for treating effective dose formula as described in claim 1-15 (1) " structural formula 1 " or Compound represented by formula (2) " structural formula 2 " is as active component, and wherein Transdermal delivery systems includes solution, spray, breast Liquid, ointment, latex or gel.

23. prevention acquired immunodeficiency syndrome (AIDS) methods, the method by treatment effective dose as power Profit requires that the compound represented by formula described in 1-15 (1) " structural formula 1 " or formula (2) " structural formula 2 " mixes as active component Enter in the material of sheath or the coating of sheath (with solution, spray, emulsion, ointment, the formulation such as latex or gel).

24. skin-penetrating therapeutic application systems, containing formula (1) " structural formula 1 " or formula (2) " structural formula as described in claim 1-15 2 " compound represented by, as active component, can be used for treating any 1H-imidazo [4,5-c] quinoline-4-of human or animal Amine and the state of related compounds-treatable thereof, system above can be bandage or paster, and it contains one and comprises activity The hypothallus of material and the protective layer of an impermeable, most preferred system is an active substance reservoir, contains a permeable face To the bottom of skin；By control rate of release, this system can make 1H-imidazo [4,5-c] quinolin-4-amines class and relatedization thereof Compound is stablized in optimal treatment blood concentration thus is improved curative effect and reduce 1H-imidazo [4,5-c] quinolin-4-amines class and phase thereof The side effect of related compounds.

The method of 25. treatment cancers, the method is by formula (1) " structural formula described in administered orally or transdermally claim 1-15 1 " compound or represented by formula (2) " structural formula 2 ", or at least contain formula (1) " structure described in a kind of claim 1-15 Compound represented by formula 1 " or formula (2) " structural formula 2 " is as the composition of active component, and wherein, these novel prodrugs can With any non-steroid anti-inflammatory drug and its prodrug use in conjunction, such as 2-(to isobutyl group) benzenpropanoic acid lignocaine ethyl ester acetic acid Salt, 1-(to chlorobenzoyl)-5-methoxyl group-2 methyl indole-3-acetate. AcOH, the fluoro-2-of (Z)-5- Methyl isophthalic acid-[(4-first thionyl) phenylmethylene-1H-indenes-3-acetate. AcOH, 1-methyl-5-(4- Toluyl)-1H-pyrroles's-2-acetate. AcOH, 5-(4-chlorobenzoyl)-Isosorbide-5-Nitrae-dimethyl-1H-pyrrole Cough up-2-acetate. AcOH, 1,8-diethyl-1,3,4,9-oxolanes-[3,4-b] indoles-1-acetic acid two Ethylamino ethyl ester acetate or other medicines.

26. treatment cancers methods, the method before tumor resection or/and Post operation by administered orally or transdermally as power Profit requires a kind of compound represented by formula described in 1-15 (1) " structural formula 1 " or formula (2) " structural formula 2 ", or one is at least Contain the composition as active component for the compound represented by a kind of formula (1) " structural formula 1 " or formula (2) " structural formula 2 ".