CN1523987A - Immune response modifiers for the treatment of periodontal disease - Google Patents

Immune response modifiers for the treatment of periodontal disease Download PDF

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CN1523987A
CN1523987A CNA028118715A CN02811871A CN1523987A CN 1523987 A CN1523987 A CN 1523987A CN A028118715 A CNA028118715 A CN A028118715A CN 02811871 A CN02811871 A CN 02811871A CN 1523987 A CN1523987 A CN 1523987A
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alkyl
purposes
imidazo
periodontal
immune response
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苏米塔・B・米特拉
苏米塔·B·米特拉
・E・塞尔伯恩
查尔斯·E·塞尔伯恩
A・托迈
马克·A·托迈
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3M Innovative Properties Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Abstract

The disclosure provides methods for the treatment and prevention of periodontal disease. In preferred embodiments, the invention provides for local treatment of periodontal tissues with a pharmaceutical composition including an immune response modifier (IRM) selected from the group of immune response modifiers comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.

Description

The immune response modifier of treatment periodontal
Invention field
The present invention relates to periodontal treatment of conditions or prevention method.Especially, the present invention includes the new purposes of immune response modifier compounds for treating and prevention periodontal.Preferred immune response modifier is selected from and comprises immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1, the immune response modifier of 2-bridging immidazoquinolinaminas.
Background of invention
Periodontal or periodontitis are the sclerous tissues and all ruined inflammatory diseasess of soft tissue that can cause supports tooth, also are estimated to be the risk factor of cardiovascular disease recently.＂ DentalInfections and atherosclerosis ＂ such as Beck, American Heart Journal, 13: S528-533 (1999).According to estimates, the people who is just accepting more this class disease treatment of severe form at present in the U.S. more than 10,000,000 people, about 8,000,000,000 dollars of annual medical expense.
Clinically, periodontitis is the inflammation of periodontal tissue, will cause the inflammation of gingiva and may cause the absorption of alveolar bone and the degeneration of gingiva.The degeneration of gingiva will cause periodontal ligament to expose, thereby allow microorganism to invade and destroy ligament.
The bacterial infection of some basic kind plays an important role to causing host's inflammatory reaction, and host's inflammatory reaction is the reason that causes disorganization and finally cause the tooth loss.Zambon，J.J.，＂Periodontal?Disease，Microbial?Factors＂， Ann.Periodontol.， 1：879-825(1996)。Be determined with the main pathogens of this disease association, they comprise porphyromonas gingivalis (Porphyromonas gingivalis), good fortune match bacteroid (Bacteroides forsythus) and actinobacillus actinomycetem comitans (Actinobacillus actinomycetemcomitans).Although with regard to pathogenetic essence, antibacterial is not enough to separately cause a disease.The easily ill body constitution of host factor such as heredity and environmental factors such as smoking are considered to influence coequally the outbreak and the deterioration of disease.
The form of periodontitis comprises early onset thereof periodontitis (EOP), chronic adult's periodontitis (AP) and periodontitis rambunctious (RP).Local juvenile periodontitis is a kind of of EOP, and it betides the teenager that seems healthy in addition, and infects relevant with actinobacillus actinomycetem comitans." chronic adult's periodontitis " is usually with good fortune match bacteroid, porphyromonas gingivalis, (asaccharolytic) bacillus separated by the non-sugar of many Gram-negatives and the oral cavity spirillum is relevant.It betides the patient more than 35 years old usually.Clinically, its similar acute necrosis ulcer gingivitis of following in rapidly progressive periodontitis.The patient will lose 9～12 millimeters gingivas and adhere in short six months.
The method of current treatment periodontal is nothing more than the method for machinery and be the method for surgery in essence, generally include stripping scrape with the root of the tooth leveling to remove the calculus deposit.Yet the Therapeutic Method of machinery can not influence the potential cause of disease.Antibiotic also is used as auxiliary treatment means, Loesche etc., and ＂ Treatment paradigms in periodontal disease ＂, Compend.Contin.Educ Dental, 18(3): 221-6,228-30 (1997).Unfortunately the result is always gloomy, because antibiotic can not be eliminated the antibacterial of causing inflammatory factor, the patient will suffer to infect again.
Accordingly, constantly need be at new, the effectively treatment and the preventive measure of periodontal.The present invention needs at this just.
Summary of the invention
The invention provides periodontal treatment of conditions or prevention method, comprise that immune response modifier (IRM) chemical compound with the treatment effective dose directly is applied to the patient's who suffers from the periodontal disease periodontal tissue.Preferred IRM chemical compound is selected from immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1,2-bridging immidazoquinolinaminas.
The accompanying drawing summary
Fig. 1 is the analysis sketch map of periodontal;
Fig. 2 is the figure that shows the interior porphyromonas gingivalis ratio of bacterial plaque of infected mice;
Fig. 3 is the figure that shows the bone loss of infected mice;
Fig. 4 a is the sketch map that the degree of depth is examined in bleeding index, gingival index and the spy of Canis familiaris L. before the treatment;
Fig. 4 b is the sketch map that the degree of depth is examined in bleeding index, gingival index and the spy of Canis familiaris L. after two weeks of treatment.
Detailed Description Of The Invention
The present invention openly provides the method for use immune response modifier (IRM) compounds for treating or prevention oral condition such as periodontal disease. " immune response modifier compound " as used herein refers to impel from hematopoietic cell and comprises the compound that produces one or more cell factors such as interferon (α), TNF and interleukin-12 dendritic cells and/or the monocyte/macrophage. The example of such compound comprises CpG oligonucleotide, lipopolysaccharides, polyinosinic acid-polycytidylic acid complex compound and polypeptide, protein, known they will impel from dendritic cells and/or monocyte/macrophage and produce cell factor.
In the preferred embodiment, the IRM chemical compound is selected from immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1,2-bridging immidazoquinolinaminas.The method for preparing these IRM chemical compounds is disclosed in following document with the pharmaceutical composition that comprises them: United States Patent (USP) 4,689,338; 5,389,640; 5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916; 5,482,936; 5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296; 5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; 6,194,425; 6,245,776 and 6,331,539 and PCT publication WO 00/76505 and WO00/76518.These disclosed patents and patent application are hereby incorporated by reference.
Here used " periodontitis " is meant the periodontal tissue, alveolar bone, cementum of tooth and the inflammation and/or the degeneration of contiguous gingiva tissue.As review, each tooth is made up of three parts: corona 1, neck 2 and root of the tooth 3 with reference to Fig. 1.Corona 1 is the part of protruding in the tooth on gingiva 4, and with to one or more other dental articulations in the jaw.Neck 2 is parts between corona 1 and root of the tooth 3 in the tooth.Cementum-enamel meet (CEJ) the 5th, the position that the cementum 6 of root of the tooth 3 and the enamel 7 of corona 1 meet.Root of the tooth 3 is fixed in alveolus 8 or " teeth groove ".The tooth overwhelming majority is made up of dentine 10, and it is covered by enamel 7 on corona 1, is covered by cementum 6 on root of the tooth 3.Cementum 6 on the root of the tooth 3 links to each other with alveolar bone 11 by periodontal ligament 13, thereby forms fibrous binding site between tooth and alveolus 8.
Therefore, used here " periodontal tissue " be around and the tissue of supports tooth and comprise periodontal ligament, alveolar bone and gingiva." periodontal pocket " is the inductive space that extends under cementum-enamel meet (CEJ) of pathology, and owing to alveolar bone and/or pericemental fracture produce.
Although proposed a large amount of models, the inflammatory essence of periodontitis is not still understood completely, Page etc., ＂ Advances in the pathogenesis of periodontitis:summaryof developments, clinical implications and future directions ＂ Periodontology 2000, 14: 216-248 (1997).A kind of hypothesis is, variation has taken place in the pre-morbific normal immunoreaction for initial antibacterial of bacteriological protection, thereby becomes the not exclusively invalid formation that helps disease, Mathur etc., ＂ Cell-mediated immune system regulationin periodontal disease ＂ Critical Rev.Oral.Bio.Med., 8: 76-89 (1997).According to this hypothesis, in the minimal people who suffers from or do not have periodontal, the TH1 immunoreation is tended in immunoreation, and this reaction is general viral relevant with tumor with control.And in the patient of carrying out property periodontal, immune response pathway is tended to the TH2 reaction, thereby it is characterized in that activating B cell secretory antibody.It is believed that antibody response is invalid to antibacterial, and short-term normally, immunity " memory " can not be caused.In addition, the cytokine of TH2 emiocytosis can activate unsuitable host tissue and reinvent enzyme, and these enzymes help to destroy the connective tissue that tooth and jaw are close to, and these enzymes also cause the absorption again of periodontal alveolar bone.
Another report proposes the periodontal model based on T-cell two way classification, it is characterized in that IL-4 produces cell at high proportion in the periodontitis tissue, and infers the role of TH2 cell in disease progressive injury process.Seymour G.J. etc., ＂ Cellular immunity andhypersensitivity as components of periodontal destruction ＂, Oral Dis, 2(1): 96-101 (1996).This report is supported by people's such as Bartova work recently.Bartova etc., ＂ TH1 and TH2 cytokine profile in patients with early onset periodontitisand their healthy siblings ＂, Mediators Inflamm., 9(2): 115-20 (2000).
A different hypothesis that has obtained progress is that the TH1 reaction that activates some typical cells factors will cause bone resorption because of osteoclast activates.Assuma etc., ＂ IL-1 and TNFantagonists inhibit the inflammatory response and bone loss inexperimental periodontitis ＂, J.ofImmunology, 160: 403-409 (1998).
Another report claims to observe cumulative cytokine situation in periodontitis, this with pathological tissue in TH1 type cell preponderate and conform to, also under suitable stimulation, can be conformed to by rise with TH2 type cell (if existence).Takeichi etc., ＂ Cytokine profiles of T-lymphocytes from gingival tissues with pathological pocketing ＂, J.Dent. Res., 79(8): 1548-55 (in August, 2000).CD4 and CD8+ lymphocyte all show can express TH1-and TH2-cytokines courier.
Generally speaking, the report of front has been emphasized causing also lacking consistent mechanism aspect the periodontal pathogeny, and also lacks consensus on the Medical Treatment method of disease.
A lot of immidazoquinolinaminas, imidazopyridine amine, 6; the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1; it is being effectively aspect immunomodulating, antiviral and the antitumor (comprising anticancer) that 2-bridging immidazoquinolinaminas compound exhibits goes out, and demonstrates strengthening can be used as useful vaccine adminicle aspect the protective immunity system response of vaccine.The a lot of such IRM chemical compounds of recent findings can suppress the TH2 immunoreation, and strengthen the TH2 immunoreation.Can be referring to U.S. Pat 6,039,969; The disclosure is incorporated by reference in the lump in full at this.
Although still there is dispute in the immunology aspect of periodontal, inventor's discovery is treated with immunoreation adjusting chemical compound and is helped patients with periodontitis, and can treat potential infection.Especially, can reduce alveolar bone or pericemental destruction with the IRM compounds for treating.If the suitable time that begins before destroyed in periodontal tissue applies treatment, the present invention also can be used to regulate patient's immunoreation to prevent the clinical symptom of periodontal effectively.Therefore the IRM compositions has the value of treatment and prevention concurrently.
" patient " comprises the human and animal.
Useful pharmaceutical composition comprises immune response modifier (IRM) chemical compound in the inventive method.Preferred compositions comprises being selected from and comprises immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1, the chemical compound of immune response modifiers such as 2-bridging immidazoquinolinaminas.
Preferred immune response modifier chemical compound comprises 1H-imidazo [4, the 5-c] quinoline-4-amine of one of the formula I-V by hereinafter definition:
Figure A0281187100111
Wherein
R 11Be selected from the alkyl that contains 1 to 10 carbon atom; The hydroxyalkyl that contains 1 to 6 carbon atom; Acyloxy alkyl, acyloxy wherein are the alkanoyloxy or the benzoyloxys of 2 to 4 carbon atoms, and alkyl wherein contains 1 to 6 carbon atom; Benzyl; Phenylethyl; And phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the alkyl that contains 1 to 4 carbon atom, the alkoxyl that contains 1 to 4 carbon atom and halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups;
R 21Be selected from hydrogen; The alkyl that contains 1-8 carbon atom; Benzyl; Phenylethyl; And phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the alkyl that contains 1 to 4 carbon atom, the alkoxyl that contains 1 to 4 carbon atom, halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups; With
Each R 1Is independently selected from alkoxyl, the halogen that contains 1 to 4 carbon atom and contains the alkyl of 1 to 4 carbon atom, and n is 0 to 2 integer that prerequisite is if n is 2, so said two R 1The carbon atom number that group contains lumps together and is no more than 6;
Wherein
R 12Be selected from the straight or branched thiazolinyl that contains 2 to 10 carbon atoms and the straight or branched thiazolinyl that contains 2 to 10 carbon atoms of replacement, the cycloalkyl that wherein said substituent group is selected from the straight or branched alkyl that contains 1 to 4 carbon atom and contains 3 to 6 carbon atoms; And the cycloalkyl that contains 3 to 6 carbon atoms that is contained the straight or branched alkyl replacement of 1 to 4 carbon atom; With
R 22Be selected from hydrogen; The straight or branched alkyl that contains 1-8 carbon atom; Benzyl; Phenylethyl and phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the straight or branched alkyl that contains 1 to 4 carbon atom, the straight or branched alkoxyl that contains 1 to 4 carbon atom and halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups; With
Each R 2Be independently selected from the straight or branched alkoxyl that contains 1 to 4 carbon atom; Halogen; With the straight or branched alkyl that contains 1 to 4 carbon atom; N is 0 to 2 integer, and prerequisite is if n is 2, so said two R 2The carbon atom number that group contains lumps together and is no more than 6;
Wherein
R 23Be selected from hydrogen, contain the straight or branched alkyl of 1-8 carbon atom; Benzyl; Phenylethyl and phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the straight or branched alkyl that contains 1 to 4 carbon atom, the straight or branched alkoxyl that contains 1 to 4 carbon atom and halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups; With
Each R 3Be independently selected from the straight or branched alkoxyl that contains 1 to 4 carbon atom; Halogen; With the straight or branched alkyl that contains 1 to 4 carbon atom; N is 0 to 2 integer, and prerequisite is if n is 2, so said two R 3The carbon atom number that group contains lumps together and is no more than 6;
Wherein
R 14Be-CHR xR y, R wherein yBe hydrogen and carbon-carbon bond, prerequisite is to work as R yWhen being hydrogen, R xIt is the alkoxyl that contains 1 to 4 carbon atom; The hydroxy alkoxy base that contains 1 to 4 carbon atom; The 1-alkynyl that contains 2 to 10 carbon atoms; THP trtrahydropyranyl; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 4 carbon atom; 2-, 3-or 4-pyridine radicals; Further prerequisite is to work as R yWhen being carbon-carbon bond, R yAnd R xForm tetrahydrofuran base together, it can be independently selected from hydroxyl by one or two and contain optional replacement of group of the hydroxyalkyl of 1 to 4 carbon atom;
R 24Be selected from hydrogen; The alkyl that contains 1 to 4 carbon atom; Phenyl; With the phenyl that replaces, substituent group wherein is selected from the alkyl that contains 1 to 4 carbon atom, alkoxyl and the halogen that contains 1 to 4 carbon atom; With
R 4Be selected from hydrogen; The straight or branched alkoxyl that contains 1 to 4 carbon atom; Halogen; With the straight or branched alkyl that contains 1 to 4 carbon atom;
Wherein
R 15Be selected from hydrogen; The straight or branched alkyl and the substituted straight or branched alkyl that contains 1 to 10 carbon atom that contain 1 to 10 carbon atom, substituent group wherein are selected from the cycloalkyl that contains 3 to 6 carbon atoms and are contained the cycloalkyl that contains 3 to 6 carbon atoms of the straight or branched alkyl replacement of 1 to 4 carbon atom; The straight or branched thiazolinyl or the substituted straight or branched thiazolinyl that contains 2 to 10 carbon atoms that contain 2 to 10 carbon atoms, substituent group wherein are selected from the cycloalkyl that contains 3 to 6 carbon atoms and are contained the cycloalkyl that contains 3 to 6 carbon atoms of the straight or branched alkyl replacement of 1 to 4 carbon atom; The hydroxyalkyl that contains 1 to 6 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 6 carbon atom; Acyloxy alkyl, acyloxy wherein are the alkanoyloxy or the benzoyloxys of 2 to 4 carbon atoms, and moieties contains 1 to 6 carbon atom; Benzyl; Phenylethyl and phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the alkyl that contains 1 to 4 carbon atom, the alkoxyl that contains 1 to 4 carbon atom and halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups;
R 25Be
Wherein
R sAnd R TBe independently selected from hydrogen; The alkyl that contains 1 to 4 carbon atom; Phenyl; With substituted phenyl, substituent group wherein is selected from the alkyl that contains 1 to 4 carbon atom, alkoxyl and the halogen that contains 1 to 4 carbon atom;
X is selected from the alkoxyl that contains 1 to 4 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 4 carbon atom; The hydroxyalkyl that contains 1 to 4 carbon atom; The haloalkyl that contains 1 to 4 carbon atom; Alkyl amido, alkyl wherein contain 1 to 4 carbon atom; Amino; The amino that replaces, substituent group wherein is alkyl or the hydroxyalkyl that contains 1 to 4 carbon atom; Azido; Chlorine; Hydroxyl; The 1-morpholino; 1-pyrrolidine generation (pyrrolidino); The alkylthio group that contains 1 to 4 carbon atom; With
R 5Be selected from hydrogen; The straight or branched alkoxyl that contains 1 to 4 carbon atom; Halogen; With the straight or branched alkyl that contains 1 to 4 carbon atom;
Pharmaceutically acceptable salt with aforesaid any material.
Preferably use 6 of following formula VI definition, the condensed cycloalkyl imidazopyridine of 7-amine IRM chemical compound:
Figure A0281187100151
Wherein m is 1,2 or 3;
R 16Be selected from hydrogen; The cycloalkyl that contains 3,4 or 5 carbon atoms; The straight or branched alkyl and the substituted straight or branched alkyl that contains 1 to 10 carbon atom that contain 1 to 10 carbon atom, substituent group wherein are selected from the cycloalkyl that contains 3 to 6 carbon atoms and are contained the cycloalkyl that contains 3 to 6 carbon atoms of the straight or branched alkyl replacement of 1 to 4 carbon atom; The fluoro or the chloro alkyl that contain 1 to 10 carbon atom and one or more fluorine atoms or chlorine atom; The straight or branched thiazolinyl and the substituted straight or branched thiazolinyl that contains 2 to 10 carbon atoms that contain 2 to 10 carbon atoms, substituent group wherein are selected from the cycloalkyl that contains 3 to 6 carbon atoms and are contained the cycloalkyl that contains 3 to 6 carbon atoms of the straight or branched alkyl replacement of 1 to 4 carbon atom; The hydroxyalkyl that contains 1 to 6 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 6 carbon atom; The acyloxy alkyl, acyloxy wherein is the alkanoyloxy or the benzoyloxy of 2 to 4 carbon atoms, moieties contains 1 to 6 carbon atom, prerequisite be any such alkyl, replacement alkyl, thiazolinyl, replacement thiazolinyl, hydroxyalkyl, alkoxyalkyl or acyloxy alkyl not directly and nitrogen-atoms key carbon atom that connect, that full carbon replaces; Benzyl; Phenylethyl; And phenyl; Its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be replaced by one or two group that is independently selected from the alkyl that contains 1 to 4 carbon atom, the alkoxyl that contains 1 to 4 carbon atom and halogen, prerequisite is that the carbon atom number that so said two groups contain lumps together and is no more than 6 if said phenyl ring is replaced by two said groups;
With-CHR xR y
Wherein
R yBe hydrogen or carbon-carbon bond, prerequisite is to work as R yWhen being hydrogen, R xIt is the alkoxyl that contains 1 to 4 carbon atom; The hydroxy alkoxy base that contains 1 to 4 carbon atom; The 1-alkynyl that contains 2 to 10 carbon atoms; THP trtrahydropyranyl; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 4 carbon atom; 2-, 3-or 4-pyridine radicals; Further condition is to work as R yWhen being carbon-carbon bond, R yAnd R xForm tetrahydrofuran base together, it can be independently selected from hydroxyl by one or two and contain optional replacement of group of 1 to 4 carbon atom hydroxyalkyl;
R 26Be selected from hydrogen; The straight or branched alkyl that contains 1-8 carbon atom; The straight or branched hydroxyalkyl that contains 1-6 carbon atom; The morpholino alkyl; Benzyl; Phenylethyl; And phenyl; The group that its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be selected from methyl, methoxyl group and halogen replaces; With
-C (R S) (R T) (X), R wherein sAnd R TBe independently selected from hydrogen; The alkyl that contains 1-4 carbon atom; Phenyl; The phenyl that replaces, its substituent group is selected from the alkyl that contains 1-4 carbon atom, the alkoxyl that contains 1-4 carbon atom and halogen;
X is selected from the alkoxyl that contains 1-4 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 4 carbon atom; The haloalkyl that contains 1 to 4 carbon atom; Alkyl amido, alkyl wherein contain 1 to 4 carbon atom; Amino; The amino that replaces, substituent group wherein is alkyl or the hydroxyalkyl that contains 1 to 4 carbon atom; Azido; The alkylthio group that contains 1 to 4 carbon atom; With the morpholino alkyl, wherein alkyl contains 1 to 4 carbon atom; With
R 6Be selected from hydrogen; Fluorine; Chlorine; The straight or branched alkyl that contains 1 to 4 carbon atom; With contain 1 to 4 carbon atom and contain the straight or branched fluoro-alkyl or the chloro alkyl of a fluorine atom or chlorine atom at least;
With their pharmaceutically acceptable salt.
The preferred imidazopyridine amine IRM chemical compound that is defined by following formula VII:
Wherein
R 17Be selected from hydrogen;-CH 2R w, R wherein wBe selected from the straight or branched alkyl or cycloalkyl that contains 1 to 10 carbon atom; The straight or branched thiazolinyl that contains 2 to 10 carbon atoms; The straight or branched hydroxyalkyl that contains 1 to 6 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 6 carbon atom; And phenylethyl; And-CH=CR zR z, each R wherein zBe independently selected from the straight or branched alkyl or cycloalkyl that contains 1 to 6 carbon atom;
R 27Be selected from hydrogen; The straight or branched alkyl that contains 1 to 8 carbon atom; The straight or branched hydroxyalkyl that contains 1 to 6 carbon atom; Alkoxyalkyl, alkoxyl wherein contain 1 to 4 carbon atom, and alkyl contains 1 to 6 carbon atom; Benzyl; Phenylethyl; And phenyl; The group that its phenyl ring of said benzyl, phenylethyl or phenyl substituent can randomly be selected from methyl, methoxyl group and halogen replaces; With the morpholino alkyl, alkyl wherein contains 1 to 4 carbon atom;
R 67And R 77Be independently selected from hydrogen; With the alkyl that contains 1 to 5 carbon atom, prerequisite is R 67And R 77The carbon atom number that contains lumps together and is no more than 6, and further prerequisite is to work as R 77When being hydrogen, R 67Not hydrogen and R 27Be not hydrogen or morpholino alkyl, further prerequisite is to work as R 67When being hydrogen, R 77And R 27Not hydrogen;
With their pharmaceutically acceptable salt.
Preferably by following formula VIII define 1,2-bridging immidazoquinolinaminas IRM chemical compound:
Wherein
Z is selected from following groups:
-(CH 2) p-, wherein p is 1-4;
-(CH 2) a-C (R DR E) (CH 2) b-, wherein a and b are that integer and a+b are 0-3; R DBe hydrogen or the alkyl that contains 1-4 carbon atom; R EBe selected from the alkyl that contains 1 to 4 carbon atom, hydroxyl ,-OR F, R wherein FBe contain 1 to 4 carbon atom alkyl and-NR GR ' G, R wherein GAnd R ' GBe hydrogen or the alkyl that contains 1 to 4 carbon atom independently; With
-(CH 2) a-(Y)-(CH 2) b-, wherein a and b are that integer and a+b are 0-3, Y is O, and S, or-NR J-, R wherein JBe hydrogen or the alkyl that contains 1 to 4 carbon atom;
Wherein q is 0 or 1 and R 8Be selected from the alkyl that contains 1 to 4 carbon atom, alkoxyl and the halogen that contains 1 to 4 carbon atom;
With their pharmaceutically acceptable salt.
Suitable thiazole and-He oxazoles and quinolinamine and pyridine amines comprise formula IX chemical compound:
Wherein
R 19Be selected from oxygen, sulfur and selenium;
R 29Be selected from following groups:
-hydrogen;
-alkyl;
-alkyl-OH;
-haloalkyl;
-thiazolinyl;
-alkyl-X-alkyl;
-alkyl-X-thiazolinyl;
-thiazolinyl-X-alkyl;
-thiazolinyl-X-thiazolinyl;
-alkyl-N (R 59) 2
-alkyl-N 3
-alkyl-O-C (O)-N (R 59) 2
-heterocyclic radical;
-alkyl-X-heterocyclic radical;
-thiazolinyl-X-heterocyclic radical;
-aryl;
-alkyl-X-aryl;
-thiazolinyl-X-aryl;
-heteroaryl;
-alkyl-X-heteroaryl; With
-thiazolinyl-X-heteroaryl;
R 39And R 49Be independently:
-hydrogen;
-X-alkyl;
-halogen;
-haloalkyl;
-N(R 59) 2；
Maybe when lumping together, R 39And R 49Form condensed aromatic ring, hetero-aromatic ring, cycloalkyl or a heterocycle;
X is selected from-O-,-S-,-NR 59-,-C (O)-,-C (O) O-,-OC (O)-and key; With
Each R 59Be hydrogen or C independently 1-8Alkyl;
With their pharmaceutically acceptable salt.
As shown in the formula X and formula XI is suitable imidazo benzodiazine and imidazolidine and benzodiazine IRM chemical compound:
Wherein
A is=N-CR=CR-CR=;=CR-N=CR-CR=;=CR-CR=N-CR=; Or=CR-CR=CR-N=;
R 110Be selected from following groups:
-hydrogen;
-unsubstituted or be selected from the C that following substituent group replaces by one or more 1-20Alkyl or C 2-20Thiazolinyl:
-aryl;
-heteroaryl;
-heterocyclic radical;
-O-C 1-20Alkyl;
-O-(C 1-20Alkyl) 0-1-aryl;
-O-(C 1-20Alkyl) 0-1-heteroaryl;
-O-(C 1-20Alkyl) 0-1-heterocyclic radical;
-C 1-20Alkoxy carbonyl;
-S (O) 0-2-C 1-20Alkyl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-aryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heteroaryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heterocyclic radical;
-N(R 310) 2；
-N 3；
Oxo;
-halogen;
-nitro;
-hydroxyl; With
-SH; With
-C 1-20Alkyl-NR 310-Q-X-R 410Or-C 2-20Thiazolinyl-NR 310-Q-X-R 410, wherein Q be-CO-or-SO 2-; X is a key ,-O-or-NR 310-; And R 410It is aryl; Heteroaryl; Heterocyclic radical; Perhaps unsubstituted or be selected from that following one or more substituent groups replace-C 1-20Alkyl or-C 2-20Thiazolinyl:
-aryl;
-heteroaryl;
-heterocyclic radical;
-O-C 1-20Alkyl;
-O-(C 1-20Alkyl) 0-1-aryl;
-O-(C 1-20Alkyl) 0-1-heteroaryl;
-O-(C 1-20Alkyl) 0-1-heterocyclic radical;
-C 1-20Alkoxy carbonyl;
-S (O) 0-2-C 1-20Alkyl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-aryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heteroaryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heterocyclic radical;
-N(R 310) 2；
-NR 310-CO-O-C 1-20Alkyl;
-N 3；
Oxo;
-halogen;
-nitro;
-hydroxyl; With
-SH; Or R 410Be
Figure A0281187100221
Wherein Y be-N-or-CR-;
R 210Be selected from following groups:
-hydrogen;
-C 1-10Alkyl;
-C 2-10Thiazolinyl;
-aryl;
-C 1-10Alkyl-O-C 1-10Alkyl;
-C 1-10Alkyl-O-C 2-10Thiazolinyl; With
-be selected from the C that following one or more substituent groups replace 1-10Alkyl or C 2-10Thiazolinyl:
-hydroxyl;
-halogen;
-N(R 310) 2；
-CO-N(R 310) 2；
-CO-C 1-10Alkyl;
-N 3；
-aryl;
-heteroaryl;
-heterocyclic radical;
-CO-aryl; With
-CO-heteroaryl;
Each R 310Be independently selected from hydrogen and C 1-10Alkyl; With
Each R is independently selected from hydrogen, C 1-10Alkyl, C 1-10Alkoxyl, halogen and trifluoromethyl,
With their pharmaceutically acceptable salt.
Wherein
B is-NR-C (R) 2-C (R) 2-C (R) 2-;-C (R) 2-NR-C (R) 2-C (R) 2-;-C (R) 2-C (R) 2-NR-C (R) 2-; Or-C (R) 2-C (R) 2-C (R) 2-NR-;
R 111Be selected from following groups:
-hydrogen;
-unsubstituted or be selected from the C that following one or more substituent groups replace 1-20Alkyl or C 2-20Thiazolinyl:
-aryl;
-heteroaryl;
-heterocyclic radical;
-O-C 1-20Alkyl;
-O-(C 1-20Alkyl) 0-1-aryl;
-O-(C 1-20Alkyl) 0-1-heteroaryl;
-O-(C 1-20Alkyl) 0-1-heterocyclic radical;
-C 1-20Alkoxy carbonyl;
-S (O) 0-2-C 1-20Alkyl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-aryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heteroaryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heterocyclic radical;
-N(R 311) 2；
-N 3；
Oxo;
-halogen;
-nitro;
-hydroxyl; With
-SH; With
-C 1-20Alkyl-NR 311-Q-X-R 411Or-C 2-20Thiazolinyl-NR 311-Q-X-R 411, wherein Q be-CO-or-SO 2-; X is a key ,-O-or-NR 311-; And R 411It is aryl; Heteroaryl; Heterocyclic radical; Perhaps unsubstituted or be selected from that following one or more substituent groups replace-C 1-20Alkyl or-C 2-20Thiazolinyl:
-aryl;
-heteroaryl;
-heterocyclic radical;
-O-C 1-20Alkyl;
-O-(C 1-20Alkyl) 0-1-aryl;
-O-(C 1-20Alkyl) 0-1-heteroaryl;
-O-(C 1-20Alkyl) 0-1-heterocyclic radical;
-C 1-20Alkoxy carbonyl;
-S (O) 0-2-C 1-20Alkyl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-aryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heteroaryl;
-S (O) 0-2-(C 1-20Alkyl) 0-1-heterocyclic radical;
-N(R 311) 2；
-NR 311-CO-O-C 1-20Alkyl;
-N 3；
Oxo;
-halogen;
-nitro;
-hydroxyl; With
-SH; Or R 411Be
Figure A0281187100241
Wherein Y be-N-or-CR-;
R 211Be selected from following groups:
-hydrogen;
-C 1-10Alkyl;
-C 2-10Thiazolinyl;
-aryl;
-C 1-10Alkyl-O-C 1-10Alkyl;
-C 1-10Alkyl-O-C 2-10Thiazolinyl; With
-be selected from the C that following one or more substituent groups replace 1-10Alkyl or C 2-10Thiazolinyl:
-hydroxyl;
-halogen;
-N(R 311) 2；
-CO-N(R 311) 2；
-CO-C 1-10Alkyl;
-N 3；
-aryl;
-heteroaryl;
-heterocyclic radical;
-CO-aryl; With
-CO-heteroaryl;
Each R 311Be independently selected from hydrogen and C 1-10Alkyl; With
Each R is independently selected from hydrogen, C 1-10Alkyl, C 1-10Alkoxyl, halogen and trifluoromethyl,
With their pharmaceutically acceptable salt.
Also preferred 1H-imidazo [4,5-c] quinoline-4-amine and tetrahydrochysene-1H-imidazo [4,5-c] quinoline-4-amine comprise the chemical compound of following formula XII, XIII and XIV definition:
Figure A0281187100261
Wherein
R 112Be-alkyl-NR 312-CO-R 412Or-thiazolinyl-NR 312-CO-R 412, R wherein 412Be aryl, heteroaryl, alkyl or alkenyl, it can be unsubstituted separately or is selected from following substituent group and replace by one or more:
-alkyl;
-thiazolinyl;
-alkynyl;
-(alkyl) 0-1-aryl;
-(alkyl) 0-1-(aryl of replacement);
-(alkyl) 0-1-heteroaryl;
-(alkyl) 0-1-(heteroaryl of replacement);
-O-alkyl;
-O-(alkyl) 0-1-aryl;
-O-(alkyl) 0-1-(aryl of replacement);
-O-(alkyl) 0-1-heteroaryl;
-O-(alkyl) 0-1-(heteroaryl of replacement);
-CO-aryl;
The aryl that-CO-replaces;
-CO-heteroaryl;
The heteroaryl that-CO-replaces;
-COOH；
-CO-O-alkyl;
-CO-alkyl;
-S (O) 0-2-alkyl;
-S (O) 0-2-(alkyl) 0-1-aryl;
-S (O) 0-2-(alkyl) 0-1-(aryl of replacement);
-S (O) 0-2-(alkyl) 0-1-heteroaryl;
-S (O) 0-2-(alkyl) 0-1-(heteroaryl of replacement);
-P(O)(OR 312) 2；
-NR 312-CO-O-alkyl;
-N 3；
-halogen;
-nitro;
-cyano group;
-haloalkyl;
-O-haloalkyl;
-CO-haloalkyl;
-OH；
-SH; And under the situation of alkyl, thiazolinyl or heterocyclic radical oxo;
Or R 412Be
Figure A0281187100271
R wherein 512Be aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, the heterocyclic radical of heterocyclic radical or replacement;
R 212Be selected from following group:
-hydrogen;
-alkyl;
-thiazolinyl;
-aryl;
The aryl of-replacement;
-heteroaryl;
The heteroaryl of-replacement;
-heterocyclic radical;
The heterocyclic radical of-replacement;
-alkyl-O-alkyl;
-alkyl-O-thiazolinyl; With
-be selected from the alkyl or alkenyl that following one or more substituent groups replace:
-OH；
-halogen;
-N(R 312) 2；
-CO-N(R 312) 2；
-CO-C 1-10Alkyl;
-CO-O-C 1-10Alkyl;
-N 3；
-aryl;
The aryl of-replacement;
-heteroaryl;
The heteroaryl of-replacement;
-heterocyclic radical;
The heterocyclic radical of-replacement;
-CO-aryl; With
-CO-heteroaryl;
Each R 312Be independently selected from hydrogen; C 1-10Alkyl-heteroaryl; C 1-10Alkyl-(heteroaryl of replacement); C 1-10Alkyl-aryl; C 1-10Alkyl-(aryl of replacement) and C 1-10Alkyl;
V is 0-4;
With each R that exists 12Be independently selected from C 1-10Alkyl, C 1-10Alkoxyl, halogen and trifluoromethyl;
Figure A0281187100281
Wherein
R 113Be-alkyl-NR 313-SO 2-X-R 413Or-thiazolinyl-NR 313-SO 2-X-R 413
X be key or-NR 513-;
R 413Be aryl, heteroaryl, heterocyclic radical, alkyl or alkenyl, it can be unsubstituted separately or is selected from following substituent group and replace by one or more:
-alkyl;
-thiazolinyl;
-aryl;
-heteroaryl;
-heterocyclic radical;
The cycloalkyl of-replacement;
The aryl of-replacement;
The heteroaryl of-replacement;
The heterocyclic radical of-replacement;
-O-alkyl;
-O-(alkyl) 0-1-aryl;
-O-(alkyl) 0-1The aryl of-replacement;
-O-(alkyl) 0-1-heteroaryl;
-O-(alkyl) 0-1The heteroaryl of-replacement;
-O-(alkyl) 0-1-heterocyclic radical;
-O-(alkyl) 0-1The heterocyclic radical of-replacement;
-COOH；
-CO-O-alkyl;
-CO-alkyl;
-S (O) 0-2-alkyl;
-S (O) 0-2-(alkyl) 0-1-aryl;
-S (O) 0-2-(alkyl) 0-1The aryl of-replacement;
-S (O) 0-2-(alkyl) 0-1-heteroaryl;
-S (O) 0-2-(alkyl) 0-1The heteroaryl of-replacement;
-S (O) 0-2-(alkyl) 0-1-heterocyclic radical;
-S (O) 0-2-(alkyl) 0-1The heterocyclic radical of-replacement;
-(alkyl) 0-1-NR 313R 313
-(alkyl) 0-1-NR 313-CO-O-alkyl;
-(alkyl) 0-1-NR 313-CO-alkyl;
-(alkyl) 0-1-NR 313-CO-aryl;
-(alkyl) 0-1-NR 313The aryl that-CO-replaces;
-(alkyl) 0-1-NR 313-CO-heteroaryl;
-(alkyl) 0-1-NR 313The heteroaryl that-CO-replaces;
-N 3；
-halogen;
-haloalkyl;
-halogenated alkoxy;
-CO-haloalkyl;
-CO-halogenated alkoxy;
-nitro;
-cyano group;
-OH；
-SH; And under the situation of alkyl, thiazolinyl or heterocyclic radical oxo;
R 213Be selected from following groups:
-hydrogen;
-alkyl;
-thiazolinyl;
-aryl;
The aryl of-replacement;
-heteroaryl;
The heteroaryl of-replacement;
-alkyl-O-alkyl;
-alkyl-O-thiazolinyl; With
-be selected from the alkyl or alkenyl that following one or more substituent groups replace:
-OH；
-halogen;
-N(R 313) 2；
-CO-N(R 313) 2；
-CO-C 1-10Alkyl;
-CO-O-C 1-10Alkyl;
-N 3；
-aryl;
-(aryl of replacement);
-heteroaryl;
-(heteroaryl of replacement);
-heterocyclic radical;
The heterocyclic radical of-replacement;
-CO-aryl;
The aryl that-CO-replaces;
-CO-heteroaryl; With
The heteroaryl that-CO-replaces;
Each R 313Be independently selected from hydrogen and C 1-10Alkyl;
R 513Be selected from hydrogen and C 1-10Alkyl, or R 413And R 513Lump together the heterocycle that forms 3-7 unit's heterocycle or replacement;
V is each R of 0-4 and existence 13Be independently selected from C 1-10Alkyl, C 1-10Alkoxyl, halogen and trifluoromethyl;
Figure A0281187100311
Wherein
R 114Be-alkyl-NR 314-CY-NR 514-X-R 414Or-thiazolinyl-NR 314-CY-NR 514-X-R 414
Wherein
Y is=O or=S;
X is a key ,-CO-or-SO 2-;
R 414Be aryl, heteroaryl, heterocyclic radical, alkyl or alkenyl, it can be unsubstituted separately or is selected from following substituent group and replace by one or more:
-alkyl;
-thiazolinyl;
-aryl;
-heteroaryl;
-heterocyclic radical;
The aryl of-replacement;
The heteroaryl of-replacement;
The heterocyclic radical of-replacement;
-O-alkyl;
-O-(alkyl) 0-1-aryl;
-O-(alkyl) 0-1The aryl of-replacement;
-O-(alkyl) 0-1-heteroaryl;
-O-(alkyl) 0-1The heteroaryl of-replacement;
-O-(alkyl) 0-1-heterocyclic radical;
-O-(alkyl) 0-1The heterocyclic radical of-replacement;
-COOH；
-CO-O-alkyl;
-CO-alkyl;
-S (O) 0-2-alkyl;
-S (O) 0-2-(alkyl) 0-1-aryl;
-S (O) 0-2-(alkyl) 0-1The aryl of-replacement;
-S (O) 0-2-(alkyl) 0-1-heteroaryl;
-S (O) 0-2-(alkyl) 0-1The heteroaryl of-replacement;
-S (O) 0-2-(alkyl) 0-1-heterocyclic radical;
-S (O) 0-2-(alkyl) 0-1The heterocyclic radical of-replacement;
-(alkyl) 0-1-NR 314R 314
-(alkyl) 0-1-NR 314-CO-O-alkyl;
-(alkyl) 0-1-NR 314-CO-alkyl;
-(alkyl) 0-1-NR 314-CO-aryl;
-(alkyl) 0-1-NR 314The aryl that-CO-replaces;
-(alkyl) 0-1-NR 314-CO-heteroaryl;
-(alkyl) 0-1-NR 314The heteroaryl that-CO-replaces;
-N 3；
-halogen;
-haloalkyl;
-halogenated alkoxy;
-CO-halogenated alkoxy;
-nitro;
-cyano group;
-OH；
-SH; And under the situation of alkyl, thiazolinyl or heterocyclic radical oxo;
Condition is when X is key, R 414Can be hydrogen in addition;
R 214Be selected from following groups:
-hydrogen;
-alkyl;
-thiazolinyl;
-aryl;
The aryl of-replacement;
-heteroaryl;
The heteroaryl of-replacement;
-alkyl-O-alkyl;
-alkyl-O-thiazolinyl; With
-be selected from the alkyl or alkenyl that following one or more substituent groups replace:
-OH；
-halogen;
-N(R 314) 2；
-CO-N(R 314) 2；
-CO-C 1-10Alkyl;
-CO-O-C 1-10Alkyl;
-N 3；
-aryl;
The aryl of-replacement;
-heteroaryl;
The heteroaryl of-replacement;
-heterocyclic radical;
The heterocyclic radical of-replacement;
-CO-aryl;
-CO-(aryl of replacement);
-CO-heteroaryl; With
-CO-(heteroaryl of replacement);
Each R 314Be independently selected from hydrogen and C 1-10Alkyl;
R 514Be selected from hydrogen and C 1-10Alkyl, perhaps R 414And R 514Lump together the heterocycle that forms 3-7 unit's heterocycle or replacement;
V is each R of 0-4 and existence 14Be independently selected from C 1-10Alkyl, C 1-10Alkoxyl, halogen and trifluoromethyl;
With their pharmaceutically acceptable salt.
Particularly preferred chemical compound comprises 1-(2-methyl-propyl)-1H-imidazo [4,5-c] quinoline-4-amine (imiquimod), 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (resiquimod), 2-propyl group [1,3] thiazole [4,5-c] quinoline-4-amine also, N-[4-(4-amino-2-butyl-1H-imidazo [4,5-c] [1,5] benzodiazine-1-yl) butyl]-N '-cyclohexyl urea; 2-methyl isophthalic acid-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine and 1-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine.
The pharmaceutical compositions that provides has and is suitable for that whole body uses, or is suitable for the topical form at infected point.A kind of form in current preferred back.Pharmaceutical composition can be made into the preparation that is used for following purpose: be used for predetermined speed, predetermined continuous action time the IRM chemical compound being transported to the treatment site, it combines administration separately or with other treatment agent or preventive drug such as antibiotic, fluoride source etc.Be generally used for the excipient that medicine is formulated in the suitable vehicle can be introduced when needed, prerequisite is function or the stability that this excipient does not hinder compositions in fact.The non-limitative example of the dosage forms of pharmaceutical composition comprises among the enhanced preparation of viscosity such as U.S. Pat 5,939,047 and the US 6,123,957 disclosed; Saturating mucosa paster such as US5,780,045 and US 5,750,134 and the open WO 00/19987 of PCT etc. disclosed; Disclosed among microcapsule such as the US 5,500,228; The gel-type vehicle of biodegradable crosslinked hydrolysis is as with PerioChip TM(derive from Perio Products Ltd., Jerusalem Israel) uses; Tooth irrigation and dentifrice.Excipient such as flavoring agent, coloring agent, surfactant and binding agent can use as required.
" treatment site " is meant that pharmaceutical composition will be sent to patient's site.The treatment site generally includes the surface of gingiva typically near the localized site of infringement place, periodontal pocket, or the medicine upper jaw bone that can be delivered to or any other position of mandibular bone tissue.Compositions generally is that the part is carried or carried by compositions being placed on space under the gum (periodontal pocket).
Terminology used here " treatment effective dose " is meant that the IRM chemical compound is enough to prevent, alleviate or reverse the amount of periodontal.Treatment effective dose at the IRM chemical compound of periodontitis is different because of situation, and this depends on the persistent period of the activity of specific compound, the particular composition of using, conveying, the frequency of using, treatment site and the factors of using simultaneously such as other any therapeutic agent.
General, the useful pharmaceutical composition that uses in the method for the present invention can contain about 0.001% to 5.0% IRM chemical compound based on the pharmaceutical composition gross weight.Typically, compositions contains about 0.01% to 1% IRM chemical compound.
The IRM chemical compound can be unique therapeutic activity composition in pharmaceutical composition, also can with other therapeutic agent such as antibiotic such as penicillin, tetracycline; Antiseptic such as chlohexidine; Corticosteroid such as hydrocortisone, betamethasone; Non-steroidal anti-inflammatory drug such as flurbiprofen, ibuprofen, naproxen etc. share.
The frequency of administration and duration decide according to the needs of disease prevention or treatment.Therapeutic scheme can comprise administration weekly at least once, typically weekly two to three times, perhaps in addition at least one week, normally two weeks, sometimes three to around in administration everyday.According to common nursing standard the patient is verified.Can every month, per the bimester, once verify normally per March.Repetitive administration as required.
Typically, the IRM chemical compound can put on the treatment site by a few class extended release preparations, these extended release preparations for example have gel, capsule, paster, biodegradable substrate or the like, being used for approximately is being 1-24 hour, usually approximately being 1-8 hour, is in about 1-3 hour the IRM chemical compound to be transported to the treatment site sometimes.Also can predict in some cases, can provide the IRM that uprushes chemical compound, as under gum under clinician's the guidance, placing, use dentifrice or collutory by direct administration.
By specifically describing embodiments more of the present invention, provide following embodiment, further to illustrate the present invention.But they also do not mean that qualification the present invention.
Embodiment 1
Handle mice with IRM
Mice is studied to determine that the IRM chemical compound is in the potential utility aspect this disease these mices by the known bacterial infection that causes periodontitis.
The preparation of bacterial cultures and preservation
Use is from following bag of porphyromonas gingivalis separator that obtains of gum of adult's periodontitis and non-insulin-dependent diabetes mellitus patient.This separator is at American Type Culture Collection, 10801 University Blvd., Manassas, VA 20110-2209 USA preservation, preserving number 53977 (strains A 7A1-28).At 5%CO 2, 10%H 2And 85%N 2Atmosphere under, at 37 ℃, at PRAS (sterilization of prereduction anaerobic) cloth Lu Shi agar plate (Anaerobe Systems, Morgan Hill, CA) on, at anaerobic jar (Becton Dickinson Microbiology Systems, Cockeysville, MD) middle breeding organism.Broth culture is grown on the BHTS culture medium, the BHTS culture medium is 50% mixture of Tripticase Semen sojae atricolor and Brain Heart Infusion meat soup, wherein be added with 5% yeast extract (all deriving from Becton Dickinson MicrobiologySystems), 10 μ g/ rise hemin, 1 μ g/ rise metadione and 5% horse serum (SigmaChemical, St.Louis.MO).Keep biological species by shifting weekly onboard.Preserve the several months down by resuspension logarithmic (log) phase culture in glycerol/BHTS of 15% and at-70 ℃, make refrigerated raw material.
The porphyromonas gingivalis oral area of mice infects
(Charles River Labs, Wilmington MA) are divided into three groups to 90 specified-pathogens free mices of common BALB/c, every group of about 30 mices.As shown in table 1, group II and III is as described below is infected by porphyromonas gingivalis, and group I is not infected.As described below, give IRM chemical compound to group I and II.
Table 1. experimental program
Group/treatment Infected by porphyromonas gingivalis
????I/IRM Not
????II/IRM Be
III/ does not have Be
All mices remain an animal population, and they are being closed by cage and are separating with other animals therein.All mices keep 12-hour illumination/dark cycle and freely draw distilled water.Sex of mice and age be complementary (when various experiments begin, being age in 12-18 week) in the experiment.
In ten days, freely organize I-III mice Sulfamethoxazole/trimethoprim before the experiment, 10 milliliters every pint in deionized water, and then four days to antibiotic.Make group II-III mice infected then, mode is by raising 10 by force 9The porphyromonas gingivalis alive of colony-forming units, it is arranged in the phosphate buffered saline (PBS) that 100 microlitres contain 2% carboxy methyl cellulose, gives three times with 2-4 days intervals.Can be with reference to Klausen etc. at ＂ Two complementarymethods of assessing periodontal bone level in rats ＂, Scandinavian Journal Of Dental Research, 97, the mode described in the 494-9 (1989).
As shown in Figure 2, at infected the last fortnight, any experimental animal does not all have the porphyromonas gingivalis sign, and this state remains to when infected always.The ratio that infects porphyromonas gingivalis in the sample of collecting in one week of back reaches about 2%.Vide infra.This ratio remains on 2%-5% in the remaining time of experiment.On arbitrary time point in experiment, there is not significant porphyromonas gingivalis level difference between the animal handling or be untreated through IRM.
Separation of bacterial from the bacterial plaque of infected mice
(Johnson and Johnson Dental Products Co.EastWindsor, NJ) molar from whole three groups of mices obtains the subgingival plaque sample to use sterile thin paper point.These paper points are placed in 1 ml water, and the whole antibacterial of do test, with being similar to Shelburne etc. at ＂ Quantitation of Bacteroides forsythus in subgingival plaque:comparisonof immunoassay and quantitative polymerase chain reaction ＂ J.Microbial. Methods, 39: the quantitative PCR method of describing among the 97-107 (2000) that is used for good fortune match bacteroid is measured the level of porphyromonas gingivalis.
Treat with resiquimod
Totally seven weeks group I and II mice were given resiquimod (the 4-amino-2-ethoxymethyl-(α of 1 mg/kg or 0.1 mg/kg weekly for twice with the oral cavity gavage, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol) solution in 100 microlitre PBS.In back 43 days kill animals of treatment beginning.
The measurement of alveolar bone loss
By developing the morphometry method assessment upper jaw bone molar bone loss on every side that is used to study the loss of mice bone.＂ Oral infection with Porphyromonasgingivalis and induced alveolar bone loss in immunocompetent and severecombined immunodeficient mice such as Baker P.J., " Arch.Oral Biol., 39(12): 1035-40 (in December, 1994).Under the pressure of 15p.s.i (1.05 kilograms/square centimeter), in boiling water, handle after 5 minutes, remove the meat in the jaw, soaked overnight in 3% hydrogen peroxide, air dries, and is painted with 1% methylene blue.The bone level, just the distance from cementum-enamel meet (CEJ) to alveolar bone top on the upper jaw bone molar is measured down at anatomic microscope (x30).To every mice, carry out 14 bone horizontal surveies.All carry out three times at random to the measurement of bone level.Obtain the image of lubber-line by camera, utilize computer analysis to obtain the value of the bone level of the level represented with micron in each site from CEJ to the alveolar bone top.
The result
Its bone loss of animal for the treatment of with resiquimod obviously is less than the animal (Fig. 3) of not receiving treatment, and has significance difference (p＜0.01) with the level that is fit to this model.And the animal of accepting 1 mg/kg resiquimod dosage treatment is compared with those animals of accepting 0.1 mg/kg resiquimod dosage treatment, does not have difference.
What is interesting is that the target animal bacterial plaque porphyromonas gingivalis level relevant with bone loss or treatment (or not treated) difference do not reduce.This reduction that demonstrates the bone loss is the adjusting owing to some host response, rather than the elimination of antibacterial, and is essential although they are undoubtedly morbidity.
Embodiment 2
Spontaneous generation periodontal with IRM gel combination treatment Canis familiaris L.
The Canis familiaris L. of a trouble spontaneous generation periodontal is by comprising gingival index (observation scoring 0-3 branch), and bleeding index (observation scoring 0-3 branch), spy are examined degree of depth clinical indices such as (using North Carolina probe measurement to nearest millimeter) and be determined.Scrape except the standard processing that flattens with root of the tooth except stripping, also with the gel combination treatment that contains resiquimod, this gel combination prepares according to following description this animal.Well-trained inspector is according to being determined curative effect by periodontal above-mentioned each the exponential measurement result of invasion and attack.
Contain the preparation of the IRM gel combination of IRM resiquimod
Add in 1000 milliliters of glass beakers propylene glycol (700 gram) and IRM resiquimod (4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol, 7.0g).It is all dissolved up to all resiquimods the mixture that obtains under agitation to be heated (about 56 ℃).The solution of gained is added in the mixing bowl of ROSS LDM-4 agitator.Add glyceryl triacetate (11,963.0 gram) in the bowl toward mixing, and the mixture of gained was mixed 10 minutes under the rotating speed of 36 revolutions per.(from Degussa, Frankfurt Germany) is divided into five parts of addings to silica colloidal for 1,330.0 gram, AEROSIL  200.Every adding is a, the mixture of gained is under atmospheric pressure mixed 1-2 minute under the rotating speed of 36 revolutions per, then (about 18 in Hg under vacuum; 4.0 * 10 4Pa) under the rotating speed of 36 revolutions per, mixed about 9 minutes.Scraping mixes the side and the hybrid blade of bowl.(about 17 in Hg under vacuum at last; 4.3 * 10 4Pa) under the rotating speed of 36 revolutions per, mixed about 10 minutes.The gel of gained contains 0.05% resiquimod, 5.0% propylene glycol, 9.5% silica colloidal and 85.45% glyceryl triacetate like this.
Treat with the IRM gel combination
Feed the xylazine tranquilizer with the dosage of about 1 mg/kg to animal, and remove on the gum with gum under speckle.The tooth that is infected by periodontitis by stripping scrape with the root of the tooth leveling removing (enamel) and the speckle and the calculus of (root of the tooth) dental surface under the gum on the gum, the instrument of use be ultrasound wave Cavitron  (Dentsply, York, PA) and curet.Use this Cavitron to remove pure fragment, and make root surface become smooth with curet.That root of the tooth leveling back obtains is clean, slick root surface makes epithelial tissue and connective tissue be attached to root surface in healing process.
In stripping scraping operation process, painstakingly do not attempting removing tooth body along calculus.Carry out the root of the tooth leveling and remove the residual build-in calculus and the part cementum of tooth root of the tooth, to produce slick, a firm clean surface.It is by removing the material that causes various focusing depths represented fully from dental surface that main purpose with root of the tooth leveling is scraped in stripping, thereby recovers the health of gingiva; Described material just, bacterial plaque, tartar and altered cementum.In the present embodiment stripping scrape with root of the tooth leveling be not to finish as two independent operations.Stripping is scraped with the difference of root of the tooth leveling and only is the different of degree.The character of dental surface has determined root surface to shell to scrape or the degree of root of the tooth leveling.
According to the size of periodontitis infringement, use the resiquimod gel combination of the about 10-50 microlitre for preparing according to above-mentioned steps to put on the site of being infected by periodontitis.Use a blunt 27ga. pin and fill up the syringe of said composition, said composition is placed in the periodontal pocket in contiguous each site.Gel is an applied once in this embodiment.
After treatment, the Yohimbine of animal being used about 0.1 mg/kg reverses calmness, and sends animal back to cage.
Clinical measurement
Measured each index when week about the periodontal pocket inspection being treated.Use is measured attachment loss every the standard North of 1 millimeter marking Carolina periodontal probe.About 1 millimeter of this probe diameter inserts in the periodontal pocket this probe up to the bottom.Record depth of pocket (PD), probe returns to be removed.At this moment write down the degree of depth of probe.Writing down gingival index (GI) simultaneously---gingiva tissue is rubescent measures (0=is not rubescent, and is very red to 3=, expansion), writes down bleeding index (BI) in the lump---and periodontal pocket hemorrhage tendentiousness when spy is examined is measured (0=is not hemorrhage, bleeds profusely to 3=).This all is the canonical measure index during the human periodontal of assessment in the dental practice.
The result
With reference to Fig. 4 a and 4b, after machinery cleaned tooth, PD, BI and GI generally improved (with baseline chart (figure in Fig. 4 left hand plate a) and treatment two weeks of back compares (Fig. 4 b)).With respect to untreated site,, and has statistical significance (p＜0.01) through its BI of site and the GI improvement of treatment.(left plate and the right panel piece that will treat 2 week back figure compare Fig. 4 b).This gives the credit to the IRM treatment.
Treatment does not have tangible difference (left and right sides plate of 2 week of contrast therapy back figure, Fig. 4 b) with its PD value of site of process treatment.The inventor think this be since the deficiency of time in two weeks of treatment back to rebuild tooth attached cell mechanism.
This research is not final research, does not therefore measure the bone loss.
Embodiment 3
The human patients of suffering from chronic human adult periodontal disease with the saturating mucosa patch treatment that contains IRM
For the patient who has infected chronic human adult periodontal disease, it can be by typically comprising bleeding index BI, gingival index GI, visiting clinical indices such as examining the degree of depth and determine.Remove stripping and scrape except the standard care that flattens with root of the tooth, also treat this patient with the saturating mucosa paster that contains IRM (making) according to the step of describing among the following embodiment 4.
Can remove the bacterial plaque of washing on this patient's tooth gum.The tooth that is infected by periodontitis can by stripping scrape with the root of the tooth leveling with remove on the gum with gum under the speckle and the tartar of dental surface, available known apparatus such as ultrasound wave Cavitron and curet are operated.Cavitron is used to remove pure fragment, and curet is used to make root surface smooth.
The size that depends on periodontitis infringement, the saturating mucosa paster that contains the every paster of about 0.05-1.0%IRM prepares according to for example the following examples 4 described steps, and it is adhered to the gingiva of the site that is infected by periodontitis near this patient.Allow the mucosa paster adhere to the about 1-24 of gingiva hour.This sheet keeps adhering to about 1-3 hour in a typical situation.These pasters can a week use amount to for three weeks twice.Finish treatment back one month the time to this patient's check, later every three months check is once.But if essential repetitive therapy.
Embodiment 4
Preparation contains IRM 4-amino-2-ethoxyl methyl-α, the alcoholic acid mucosa paster of alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-
Be suitable for that gingiva uses, contain IRM chemical compound 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4, the 5-c] quinoline-saturating mucosa paster of 1-ethanol (resiquimod) is produced and obtains.
Isooctyl acrylate monomer (20.03 gram), acrylic acid (19.98 gram), methoxy poly (ethylene glycol) 550 monomethacrylates (19.07 gram), PEG400 diacrylate (0.72 gram), polyacrylic acid (containing the polyacrylic 5.73 gram aqueous solutions of 17.5 weight %), polyoxyethylene 10 oleyl ethers (21.78 gram Brij  97), propylene glycol (10.00), water (2.89 gram), resiquimod (0.10g) and 2-hydroxyl-1-(4-(2-hydroxyl-oxethyl) phenyl)-2-methyl isophthalic acid-acetone (0.55 gram Irgacure  2959) makes up in a glass jar, mixes on a dull and stereotyped blender up to obtaining limpid fluid composition then.Said composition contains the resiquimod of 0.10 weight %.
This liquid scraper is coated on the nonwoven polypropylene face of three layers of backing, the wet thick 25mil (635 μ M) that reaches, and the surface that exposes is with the release liner covering of a transparent polyester (1.5mil, 38 μ M) silicone coating.The irradiation 8 minutes under ultraviolet light,long wave subsequently of the compositions of coating is so that said composition is exposed under the irradiation that gross energy reaches the 2677mJ/ square centimeter.Remove release liner and the hardening composition exposure is laminated on the polyester release liner (5mil, 127 μ M) of silicone coating.Section (2.05 square centimeters) from this stratiform thing.
By the detailed description in front with illustrate, obviously can be to method improvement of the present invention and variation under the situation that does not depart from spirit of the present invention or scope of the present invention.Therefore, not departing from all improvement of spirit of the present invention and change still falls in the scope of claims and equivalent thereof.

Claims (29)

1. the immune response modifier chemical compound is used for treating or prevents purposes in the pharmaceutical preparation of periodontal in preparation, and preparation is wherein directly put in the patient's who suffers from the periodontal disease the periodontal tissue.
2. according to the purposes of claim 1, immune response modifier chemical compound wherein is selected from and comprises immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1, the immune response modifier of 2-bridging immidazoquinolinaminas.
3. according to the purposes of claim 2, immune response modifier chemical compound wherein is selected from 1-(2-methyl-propyl)-1H-imidazo [4,5-c] quinoline-4-amine; 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol; 2-propyl group [1,3] thiazole is [4,5-c] quinoline-4-amine also; N-[4-(4-amino-2-butyl-1H-imidazo [4,5-c] [1,5] benzodiazine-1-yl) butyl]-N '-cyclohexyl urea; 2-methyl isophthalic acid-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine and 1-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine.
4. according to the purposes of claim 3, immune response modifier chemical compound wherein is 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol.
5. according to the purposes of claim 1, pharmaceutical preparation wherein is biodegradable substrate, gel, liquid, microcapsule, collutory, unguentum, semisolid, the form of saturating mucosa paster or the combination of these forms.
6. according to the purposes of claim 1, pharmaceutical preparation wherein is gel preparation.
7. according to the purposes of claim 1, pharmaceutical preparation wherein is the mucosa patch formulation.
8. according to the purposes of claim 6, pharmaceutical preparation wherein is by putting on gel preparation administration on the periodontal pocket.
9. according to the purposes of claim 6, pharmaceutical preparation wherein is by administration on the gingiva that gel preparation is put on the patient.
10. according to the purposes of claim 7, pharmaceutical preparation wherein is by administration on the gingiva that saturating mucosa patch formulation is put on the patient.
11. according to the purposes of claim 10, saturating mucosa paster wherein contains the immune response modifier chemical compound based on paster gross weight 0.05-0.1%.
12. according to the purposes of claim 10, the about 1-3 of gingiva that saturating mucosa paster wherein puts on the patient hour.
13., wherein put on patient's the gingiva more than the saturating mucosa paster of a slice according to the purposes of claim 10.
14. according to the purposes of claim 1, periodontal tissue wherein is a gingiva.
15. according to the purposes of claim 1, periodontal wherein is a periodontitis.
16. according to the purposes of claim 15, periodontitis wherein is chronic adult's periodontitis.
17. according to the purposes of claim 15, periodontitis wherein is the early onset thereof periodontitis.
18. according to the purposes of claim 1, pharmaceutical preparation wherein and be selected from the therapeutic agent administration together of antibiotic, antiseptic, corticosteroid and non-steroidal anti-inflammatory drug.
19. the immune response modifier chemical compound is used for treating purposes in the pharmaceutical preparation of periodontal in preparation, preparation is wherein directly put in the patient's who suffers from the periodontal disease the periodontal tissue, and preparation is wherein regulated patient's immunoreation.
20. according to the purposes of claim 19, preparation is wherein regulated patient's TH2 immunoreation.
21. according to the purposes of claim 19, preparation is wherein regulated patient's TH1 immunoreation.
22. purposes according to claim 19, pharmaceutical preparation wherein comprises the immune response modifier chemical compound, these immune response modifier chemical compounds are selected from and comprise immidazoquinolinaminas, imidazopyridine amine, 6, the condensed cycloalkyl imidazopyridine of 7-amine, imidazo diaza naphthylamines, oxazole and quinolinamine, thiazole and quinolinamine and 1, the immune response modifier of 2-bridging immidazoquinolinaminas.
23. according to the purposes of claim 19, immune response modifier chemical compound wherein is selected from 1-(2-methyl-propyl)-1H-imidazo [4,5-c] quinoline-4-amine; 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol; 2-propyl group-[1,3] thiazole is [4,5-c] quinoline-4-amine also; N-[4-(4-amino-2-butyl-1H-imidazo [4,5-c] [1,5] benzodiazine-1-yl) butyl]-N '-cyclohexyl urea; 2-methyl isophthalic acid-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine and 1-(2-methyl-propyl)-1H-imidazo [4,5-c] [1,5] benzodiazine-4-amine.
24. according to the purposes of claim 23, immune response modifier chemical compound wherein is 4-amino-2-ethoxyl methyl-α, alpha-alpha-dimethyl-1H-imidazo [4,5-c] quinoline-1-ethanol.
25. according to the purposes of claim 19, periodontal tissue wherein is patient's a periodontal pocket.
26. according to the purposes of claim 19, periodontal tissue wherein is patient's a gingiva.
27. according to the purposes of claim 19, periodontal wherein is chronic adult's periodontitis.
28. according to the purposes of claim 19, pharmaceutical preparation wherein is the form of gel.
29. according to the purposes of claim 19, pharmaceutical preparation wherein is the form of mucosa paster.
CNA028118715A 2001-06-15 2002-06-14 Immune response modifiers for the treatment of periodontal disease Pending CN1523987A (en)

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