WO2002102377A1 - Modificateurs de reponse immunitaire pour le traitement de la parodontolyse - Google Patents

Modificateurs de reponse immunitaire pour le traitement de la parodontolyse Download PDF

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WO2002102377A1
WO2002102377A1 PCT/US2002/018944 US0218944W WO02102377A1 WO 2002102377 A1 WO2002102377 A1 WO 2002102377A1 US 0218944 W US0218944 W US 0218944W WO 02102377 A1 WO02102377 A1 WO 02102377A1
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alkyl
use according
amines
carbon atoms
group
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PCT/US2002/018944
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Sumita B. Mitra
Charles E. Shelburne
Mark A. Tomai
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3M Innovative Properties Company
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Priority to EP02742096A priority Critical patent/EP1401437A1/fr
Priority to CA002449754A priority patent/CA2449754A1/fr
Priority to JP2003504964A priority patent/JP2005519849A/ja
Priority to US10/479,109 priority patent/US7226928B2/en
Publication of WO2002102377A1 publication Critical patent/WO2002102377A1/fr

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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

Definitions

  • the invention is directed to methods for the treatment or prevention of periodontal conditions.
  • the invention includes the novel use of immune response modifier compounds to treat or prevent periodontal disease.
  • Preferred immune response modifiers are 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.
  • Periodontal disease or periodontitis is an inflammatory disease that results in the destruction of both the hard and soft tissues supporting the teeth and has recently been hypothesized as a risk factor for cardiovascular disease. Beck et al. "Dental Infections and atherosclerosis, "American Heart Journal, JL3:S528-533 (1999). It is estimated that over 10 million people in the United States are currently being treated for the more serious forms of this disease, with approximately 8 billion dollars spent for treatment each year. Clinically, periodontitis is an inflammation of the periodontium and results in inflammation of the gingiva and may result in resorption of alveolar bone and recession of the gingiva. Recession of the gingiva can lead to exposure of the periodontal ligament allowing microorganisms to invade and destroy the ligament.
  • Periodontitis include early onset periodontitis (EOP), chronic adult periodontitis (AP), and refractory periodontitis (RP).
  • EOP early onset periodontitis
  • AP chronic adult periodontitis
  • RP refractory periodontitis
  • Localized juvenile periodontitis is a form of EOP which occurs in otherwise seemingly healthy adolescents and is associated with infection by A. actinomycetemcomitans.
  • "Chronic adult periodontitis” is commonly associated with the presence of B. forsythus, P. gingivalis, many gram-negative asaccharolytic rods, and oral spirochetes. It typically occurs in patients over 35 years of age. Clinically, it resembles acute necrotizing ulcerative gingivitis imposed on rapidly progressive periodontitis. Patients may lose 9 to 12 mm of gingival attachment in as little as six months.
  • the present invention provides methods for treating or preventing a periodontal condition comprising administering a therapeutically effective amount of an immune response modifier (IRM) compound directly to periodontal tissue in a patient affected by the periodontal condition.
  • IRM immune response modifier
  • the IRM compound is selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
  • FIG. 1 is a diagram illustrating periodontal anatomy
  • FIG. 2 is a graph showing the proportion of Porphyromonas gingivalis in the plaque of infected mice ;
  • FIG. 3 is a graph showing bone loss in infected mice
  • FIG. 4a is a graph of bleeding index, gingival index and probing depth of a dog pre-treatment.
  • FIG. 4b is a graph of bleeding index, gingival index and probing depth of a dog at two weeks post-treatment.
  • immune response modifier means a compound which induces the production of one or more cytokines, e.g., Interferon ( ), Tumor
  • Necrosis Factor and Interleukin-12, from hematopoietec cells including dendritic cells and/or monocyte/macrophages.
  • Examples of such compounds include the CpG oligonucleotides, lipopolysaccharides, polyinosic:polycytidylic acid complexes, and polypeptides and proteins know to induce cytokine production from dendritic cells and/or monocyte/macrophages .
  • the JJRM compound is selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
  • Methods for preparing such JJ Ms and pharmaceutical compositions containing them are disclosed in, for example, U.S. Patent Nos.
  • each tooth consists of three parts, a crown 1, neck 2 and root 3.
  • the crown 1 is the part of the tooth that projects above the gingiva 4 and occludes with one or more other teeth in the opposite jaw.
  • the neck 2 is the part of the tooth between the crown 1 and the root 3.
  • the cemento-enamel junction (CEJ) 5 is the location where the cementum 6 of the root 3 and enamel 7 of the crown 1 meet.
  • the root 3 is fixed in the tooth socket 8, or "alveolus”.
  • tooth Most of the tooth is composed of dentin 10 that is covered by enamel 7 over the crown 1 and cementum 6 over the root 3.
  • the cementum 6 over the root 3 is attached to the alveolar bone 11 by periodontal ligament 13 to form a fibrous joint between the tooth and its alveolus 8.
  • peripheral tissues are the tissues surrounding and supporting a tooth and include the periodontal ligament, alveolar bone and gingiva.
  • periodontal pocket is a pathologically induced space extending below the cemento- enamel junction (CEJ) and resulting from break down of the alveolar bone and/or periodontal ligament.
  • cytokines that are secreted by TH2 cells can activate inappropriate host tissue remodeling enzymes that contribute to the destruction of the connective tissue that holds the teeth to the jaw, and enzymes that cause the resorption of the alveolar bone around the teeth.
  • imidazoquinoline amine imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amine compounds have demonstrated potent immunomodulating, antiviral and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants to enhance protective immune system response to vaccines. Recently, it has been found that many of these IRM compounds can inhibit TH2 immune responses, as well as enhance
  • treatment with IRM compounds can reduce the destruction of the alveolar bone or periodontal ligament. If treatment is administered at an appropriate time before destruction of periodontal tissues begins, the invention can also be used to modulate the patient's immune response to effectively prevent clinical signs of periodontal disease.
  • the IRM compositions can have both therapeutic and prophylactic value.
  • a "patient” includes humans and animals
  • a pharmaceutical composition useful in the method of the invention includes an immune response modifier (IRM) compound.
  • IRM immune response modifier
  • Preferred compositions include compounds 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
  • Preferred immune response modifier compounds include lH-imidazo[4,5- c]quinolin-4-amines defined by one of Formulas I-V below:
  • R ⁇ is selected from the group consisting of alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms;
  • R 21 is selected from the group consisting of hydrogen, alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and each R ⁇ is independently selected from the group consisting of alkoxy of one to four carbon atoms, halogen, and alkyl of one to four carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said R ⁇ groups together contain no more than six carbon atoms;
  • R 12 is selected from the group consisting of straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of straight chain or branched chain alkyl containing one to four carbon atoms and cycloalkyl containing three to six carbon atoms; and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; and
  • R 22 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl containing one to four carbon atoms, straight chain or branched chain alkoxy containing one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R 2 is independently selected from the group consisting of straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and n is an integer from zero to
  • R 23 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from the group consisting of straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy of one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R 3 is independently selected from the group consisting of straight chain or branched chain alkoxy of one to four carbon atoms, halogen, and straight chain or branched chain alkyl of one to four carbon atoms, and n is an integer from zero to 2, with the provis
  • R 14 is -CHR x R y wherein R y is hydrogen or a carbon-carbon bond, with the proviso that when R y is hydrogen R x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R y is a carbon-carbon bond R y and R x together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxy alkyl of one to four carbon atoms;
  • R 24 is selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and
  • R is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms; V wherein
  • R 15 is selected from the group consisting of: hydrogen; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxy
  • Rs and Rx are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
  • X is selected from the group consisting of alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1- pyrrolidino, alkylthio of one to four carbon atoms; and R 5 is selected from the group consisting of hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms; and a pharmaceutically acceptable salt of any of the foregoing.
  • Preferred 6,7 fused cycloalkylimidazopyridine amine IRM compounds are defined by Formula VI below:
  • R 16 is selected from the group consisting of hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing three to six carbon atoms and cycloal
  • R y is hydrogen or a carbon-carbon bond, with the proviso that when R y is hydrogen R x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1- alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when R y is a carbon-carbon bond R y and R x together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to four carbon atoms,
  • R 26 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to six carbon atoms, morpholinoalkyl, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and
  • R s and R ⁇ are independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
  • X is selected from the group consisting of alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms, and R 6 is selected from the group consisting of hydrogen, fluoro, chloro, straight chain or branched chain alkyl containing one to four carbon atoms, and straight chain or branched chain fluoro- or chloroalkyl containing one to four carbon atoms and at least one fluorine or chlorine atom; and pharmaceutically acceptable salts
  • R 27 is selected from the group consisting of hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, straight chain or branched chain hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from the group consisting of methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms;
  • R 67 and R 77 are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms, with the proviso that R 67 and R 77 taken together contain no more than six carbon atoms, and with the further proviso that when R 77 is hydrogen then R 67 is other than hydrogen and R 27 is other than hydrogen or morpholinoalkyl, and with the further proviso that when R 67 is hydrogen then R 77 and R 27 are other than hydrogen; and pharmaceutically acceptable salts thereof.
  • Preferred 1,2-bridged imidazoquinoline amine IRM compounds are defined by Formula Vffl below:
  • Z is selected from the group consisting of: -(CH 2 ) P - wherein p is 1 to 4;
  • R D is hydrogen or alkyl of one to four carbon atoms
  • R E is selected from the group consisting of alkyl of one to four carbon atoms, hydroxy, -OR F wherein Rp is alkyl of one to four carbon atoms, and -NR G R G wherein R G and R' G are independently hydrogen or alkyl of one to four carbon atoms;
  • Suitable thiazolo- and oxazolo- quinolinamine and pyridinamine compounds include compounds of Formula LX:
  • R 19 is selected from the group consisting of oxygen, sulfur and selenium;
  • R 29 is selected from the group consisting of
  • R 39 and R 49 are each independently: -hydrogen; -X-alkyl; -halo; -haloalkyl;
  • R 39 and R 9 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
  • X is selected from the group consisting of -O-, -S-, -NR 59 -, -C(O)-, -C(O)O-
  • each R 59 is independently H or C 1-8 alkyl; and pharmaceutically acceptable salts thereof.
  • Suitable imidazonaphthyridine and tetrahydroimidazonaphthyridine IRM compounds are those of Formulae X and XI below:
  • R110 is selected from the group consisting of:
  • R 410 is
  • each R310 s independently selected from the group consisting of hydrogen and C ⁇ . 10 alkyl; and each R is independently selected from the group consisting of hydrogen, ⁇ o alkyl, C 1-10 alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof.
  • R 111 is selected from the group consisting of: - hydrogen;
  • Y is -N- or -CR-;
  • R 211 is selected from the group consisting of: -hydrogen; -d.io alkyl;
  • each R 311 is independently selected from the group consisting of hydrogen and Q. 10 alkyl; and each R is independently selected from the group consisting of hydrogen, C MO alkyl, Ci-io alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof.
  • Additional preferred lH-imidazo[4,5-c]quinolin-4-amines and tetrahydro- 1H- imidazo[4,5-c]quinolin-4-amines include compounds defined by Formulas XII, XIII and XrV below:
  • R112 is -al yl-NRs ⁇ -CO-R ⁇ or -alkenyl-NR 312 -CO- R 1 wherein R 4 ⁇ 2 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: -alkyl;
  • R 512 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
  • R 212 is selected from the group consisting of: -hydrogen; -alkyl;
  • each R 3 i 2 is independently selected from the group consisting of hydrogen; C 1-10 alkyl-heteroaryl; C 1-10 alkyl-(substituted heteroaryl); C 1-10 alkyl-aryl; C 1-10 alkyl- (substituted aryl) and C ⁇ _ ⁇ o alkyl; v is 0 to 4; and each R i2 present is independently selected from the group consisting of C 1-10 alkyl, C ⁇ -10 alkoxy, halogen and trifluoromethyl;
  • R ⁇ i3 is -alkyl-NR 313 - SO 2 -X-R 413 or -alkenyl-NR 313 - SO 2 -X-R413 ;
  • X is a bond or -NR 513 -;
  • R 413 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
  • R 213 is selected from the group consisting of:
  • each R31 3 is independently selected from the group consisting of hydrogen and . 1 0 alkyl;
  • R 513 is selected from the group consisting of hydrogen and - 10 alkyl, or R 413 and R 513 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4 and each R 13 present is independently selected from the group consisting of Ci-io alkyl, C 1-10 alkoxy, halogen and trifluoromethyl;
  • R ⁇ i4 is -alkyl-NR 314 -CY-NR 514 -X-R4 1 or -alkenyl-NR 3 ⁇ -CY- NR 514 -X- R 414 wherein
  • X is a bond, -CO- or -SO 2 -;
  • R t ⁇ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
  • R 414 can additionally be hydrogen;
  • R 214 is selected from the group consisting of:
  • each R 314 is independently selected from the group consisting of hydrogen and . 10 alkyl;
  • R 514 is selected from the group consisting of hydrogen and C 1-10 alkyl, or R 414 and R 514 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4 and each R 14 present is independently selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, halogen and trifluoromethyl, and a pharmaceutically acceptable salts thereof.
  • Particularly preferred compounds include l-(2-methylpropyl)-lH-imidazo[4,5- c]quinolin-4-amine (imiquimod), 4-amino-2-ethoxymethyl- ⁇ , ⁇ -dimethyl-lH-imidazo[4,5- c]quinoline-l-ethanol (resiquimod), 2-propyl[l,3]thiazolo[4,5-c]quinolin-4-amine, N-[4- (4-amino-2-butyl- lH-imidazo[4,5-c] [ 1 ,5]naphthyridin- l-yl)butyl]-N' -cyclohexylurea; 2- methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine, and l-(2- methylpropyl)- lH-imidazo[4,5-c] [ 1 ,5]naphthy
  • the pharmaceutical compositions can be provided in a form suitable for systemic application or in a form suitable for local delivery to the affected site. The latter mode is presently preferred.
  • the pharmaceutical compositions can be formulated to provide for delivery of the IRM compound to the treatment site at a predetermined rate, for a predetermined duration, alone, or in combination with other therapeutic or prophylactic agents, for example antibiotics, fluoride sources etc.
  • Excipients commonly used to formulate drugs into a suitable vehicle can be incorporated as necessary provided that the excipient does not substantially interfere with the function or stability of the composition.
  • Non-limiting examples of forms suitable for the pharmaceutical compositions include enhanced viscosity formulations such as disclosed in U.S. Patent Nos.
  • transmucosal patches such as disclosed in U.S. Patent Nos. 5,780,045 and 5,750,134 and PCT Publication WO 00/19987
  • microcapsules such as disclosed in U.S. Patent No. 5,500,228
  • biodegradable cross-linked hydrolyzed gelatin matrices such as those used in the PerioChipTM (available from Perio Products Ltd., Jerusalem, Israel); dental rinses and dentifrices.
  • Excipients such as flavorings, colorants, surfactants, binders can be employed as needed.
  • a “treatment site” means the site where the pharmaceutical composition is delivered to the patient.
  • Treatment sites are typically local sites proximate to a lesion and generally include the gingival surfaces, periodontal pockets, or any other site that the drug could be delivered to the maxillary or mandibular tissue.
  • the composition is typically delivered topically or by placing the composition in the subgingival space (periodontal pocket).
  • therapeutically effective amount means an amount of an
  • IRM compound sufficient to prevent, reduce or reverse periodontal disease.
  • the therapeutically effective amount of an IRM compound for periodontitis will vary depending on such things as the activity of the particular compound, the particular composition administered, the duration of delivery, the frequency of administration, the treatment site, and any other therapeutic agents being coadministered.
  • a pharmaceutical composition useful for practicing the methods of the invention can contain from about 0.001% to 5.0% of an IRM compound based on total weight of the pharmaceutical composition. Typically the composition will contain from about 0.01% to 1% of an IRM compound.
  • the IRM compound may be present in the pharmaceutical composition as the sole therapeutically active ingredient or in combination with other therapeutic agents such as antibiotics, e.g., penicillins, tetracycline; antiseptics, e.g., chlorhexidine; corticosteroids, e.g., hydrocortisone, betamethasone; nonsteroidal antiinflammatories, e.g., flurbiprofen, ibuprofen, naproxen.
  • antibiotics e.g., penicillins, tetracycline
  • antiseptics e.g., chlorhexidine
  • corticosteroids e.g., hydrocortisone, betamethasone
  • nonsteroidal antiinflammatories e.g.,
  • Treatment regimens may include administration at least one time per week, typically two to three times per week, or even daily for at least one week, typically two weeks and in some cases three to four weeks.
  • the patient can be rechecked according to the common standards of care. Thus recalls can be monthly, every two months and typically every three months. Repeated administration can be provided as needed.
  • the IRM compound can be applied to a treatment site in some type of sustained release formulation, such as gels, capsules, patches, biodegradable matrices, etc. for delivery of the IRM compound to the treatment site over a period of about 1-24 hours, typically about 1-8 hours, and in some embodiments, about 1-3 hours. It is also foreseen that in certain situations, a burst of IRM compound can be provided by direct administration, such as by subgingival placement, use of a dentifrice or mouth wash, etc. at the discretion of the clinician.
  • the following Examples are provided to further explain the invention through specific description of some embodiments of the invention. The Examples, however, are not intended to limit the scope of the invention.
  • Example 1 Treatment of Mice with an IRM
  • mice All mice were kept in an animal colony, where they were caged away from other animals. All mice were kept on a 12-hour light/dark cycle and received distilled water ad libitum. Mice within experiments were sex- and age-matched (12-18 weeks at the start of various experiments).
  • mice in Groups I-III were given sulphamethoxazole/trimethoprim, 10 ml per pint in deionized water, ad libitum for 10 days before experimentation, followed by 4 days without antibiotics.
  • the mice of Groups II-HI were then infected by gavage with 10 9 colony-forming units of live P. gingivalis, in 100 ⁇ l of phosphate buffered saline (PBS) with 2% carboxymethylcellulose, three times at 2 to 4 day intervals as described in Klausen et al, "Two complementary methods of assessing periodontal bone level in rats", Scandinavian Journal of Dental Research, 97, 494-9 (1989).
  • PBS phosphate buffered saline
  • Subgingival plaque samples were obtained from the molars of mice from all three groups using sterile fine paper points (Johnson and Johnson Dental Products Co. East Windsor, NJ). The points were placed in 1 ml of water that was then tested for total bacteria and P. gingivalis levels by quantitative PCR similar to that described for Bacteroides forsythus in Shelburne et al, "Quantitation of Bacteroides forsythus in subgingival plaque: comparison of immunoassay and quantitative polymerase chain reaction", J. Microbial. Methods, 39:97-107 (2000).
  • mice of Groups I and II were dosed by oral gavage twice weekly for seven weeks with either 1 mg/kg or 0.1 mg/kg of resiquimod (4-amino-2-ethoxymethyl- ⁇ , -
  • Bone loss around the maxillary molars was assessed by a morphometric method developed for studies of bone loss in mice.
  • Baker P.J., et al. "Oral infection with Porphyromonas gingivalis and induced alveolar bone loss in immunocompetent and severe combined immunodeficient mice," Arch. Oral Biol., 39(12): 1035-40 (December
  • the sides of the mixing bowl and the mixing blades were scraped.
  • the formulation was mixed under vacuum (about 17 in Hg; 4.3 X 10 4 Pa) for about 10 minutes at 36 rpm.
  • the resulting gel contained 0.05% resiquimod, 5.0% propylene glycol, 9.5% colloidal silicon dioxide, and 85.45% triacetin.
  • Treatment with an IRM gel composition
  • the animal was sedated with xylazine at a dose of about 1 mg/kg and its teeth cleaned of supragingival and subgingival plaque.
  • the teeth affected by periodontitis were scaled and root planed to remove plaque and calculus from both supragingival (enamel) and subgingival (root) tooth surfaces using an ultrasonic Cavitron® (Dentsply, York, PA) and curets.
  • the Cavitron was used to remove gross debris and the curets were used to smooth the root surface. A clean, smooth root surface resulting from the root planing allows epithelial and connective tissue attachment to the root surface during the healing process.
  • Root planing was performed to remove residual embedded calculus and portions of cementum from the roots of the teeth to produce a smooth, hard, clean surface.
  • the primary objective of scaling and root planing is to restore gingival health by completely removing material from the tooth surface that provokes gingival inflammation; that is, plaque, calculus and altered cementum.
  • Scaling and root planing were not done as separate procedures in this Example. The difference between scaling and root planing is only a matter of degree. The nature of the tooth surface determines the degree to which the root surface is scaled or planed.
  • gel composition prepared as described above was applied to sites affected by periodontitis.
  • composition was placed in the periodontal pocket adjacent to each site using a blunt 27 ga. needle and syringe filled with the composition. In this example a single application of the gel was used.
  • the animal was treated with yohimbine at about 0.1 mg/kg to reverse the sedation and the animal was returned to its cage.
  • the pockets were examined at weekly intervals for the indicies measured at the time of treatment. Measurement of attachment loss was performed using a standard North Carolina Periodontal probe marked at 1 mm intervals. The probe, which is about 1mm in diameter was inserted into the periodontal pocket to the base. The depth of the pocket
  • FIGs. 4a and 4b there was an over all improvement in PD, Bl and GI as a result of the mechanical cleaning of the teeth (compare left hand panels of Baseline graph (FIG. 4a) and 2 Week Post-Treatment graph (FIG. 4b). There was improvement in the Bl and GI of the treated sites compared to untreated sites that is statistically significant (p ⁇ 0.01). (Compare left and right panels of the 2 Week Post-Treatment graph, FIG. 4b). This is due to the IRM treatment.
  • a human patient affected with chronic adult periodontal disease can be identified by clinical signs typically including Bl, GI, Probing Depth.
  • the human can be treated with a transmucosal patch containing an IRM, prepared as described in Example 4 below, in addition to the standard treatment of scaling and root planing.
  • the patient's teeth can be cleaned of supragingival plaque.
  • the teeth affected by periodontitis can be scaled and root planed to remove plaque and calculus from both supragingival and subgingival tooth surfaces using known instruments, such as, for example, an ultrasonic Cavitron and curets.
  • the Cavitron is used to remove gross debris and the curets are used to smooth the root surface
  • transmucosal patch containing about 0.05 -1.0 % of IRM per patch, and prepared, for example, as described in Example
  • the transmucosal patches can remain adhered to the gingiva for about 1-24 hours. In a typical situation the patch will remain adhered for about 1-3 hours.
  • the patches can be applied two times a week for three weeks. The patient can be reexamined at 1 month after completion of treatment and at three month intervals thereafter. Treatment can be repeated as necessary.
  • IRM compound 4-amino-2-ethoxymethyl- , -dimethyl- 1 H-imidazo [4,5-c]quinoline- 1 -
  • polyoxyethylene 10 oleyl ether (21.78 g of Brij® 97), propylene glycol (10.00), water (2.89 g), resiquimod (0.10 g) and 2-hydroxy-l-(4-(2-hydroxyethoxy)phenyl)-2-methyl-l-
  • propanone (0.55 g of Irgacure® 2959) were combined in a glass jar and then mixed on a platform shaker until a clear liquid composition was obtained.
  • the composition contained 0.10% by weight of resiquimod.
  • the liquid was knife coated at a wet thickness of 25 mil (635 ⁇ M) onto the non- woven polypropylene side of a trilaminate backing and the exposed surface was covered with a clear polyester ( 1.5 mil, 38 ⁇ M) silicone coated release liner.
  • the coated composition was then exposed to UVA light for 8 minutes so that the composition was exposed to a total energy of 2677 mJ/cm 2 .
  • the release liner was removed and the exposed surface of the cured composition was laminated to a silicone coated polyester release liner ( 5mil, 127 ⁇ M). Patches (2.05 cm 2 ) were cut from the laminate.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés de traitement et de prévention de la parodontolyse. Selon des formes d'exécution préférées, l'invention concerne le traitement local de tissus périodontiques par une composition pharmaceutique comprenant un modificateur de réponse immunitaire (IRM) sélectionné dans le groupe des modificateurs de réponse immunitaire comprenant les imidazoquinoléine amines, imidazopyridine amines, cycloalkylimidazopyridine-6,7 condensée-amines, imidazonaphthyridine amines, oxazoloquinoléine amines, thiazoloquinoléine amines et imidazoquinoléine-1,2-pontée-amines.
PCT/US2002/018944 2001-06-15 2002-06-14 Modificateurs de reponse immunitaire pour le traitement de la parodontolyse WO2002102377A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP02742096A EP1401437A1 (fr) 2001-06-15 2002-06-14 Modificateurs de reponse immunitaire pour le traitement de la parodontolyse
CA002449754A CA2449754A1 (fr) 2001-06-15 2002-06-14 Modificateurs de reponse immunitaire pour le traitement de la parodontolyse
JP2003504964A JP2005519849A (ja) 2001-06-15 2002-06-14 歯周病の治療用免疫応答調節剤
US10/479,109 US7226928B2 (en) 2001-06-15 2002-06-14 Methods for the treatment of periodontal disease

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US29876801P 2001-06-15 2001-06-15
US60/298,768 2001-06-15

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US6613902B2 (en) 1996-06-21 2003-09-02 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6677349B1 (en) 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6696465B2 (en) 2000-12-08 2004-02-24 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6716988B2 (en) 2000-12-08 2004-04-06 3M Innovative Properties Company Urea substituted imidazopyridines
US6720333B2 (en) 2000-12-08 2004-04-13 3M Innovative Properties Company Amide substituted imidazopyridines
US6747040B2 (en) 1997-12-11 2004-06-08 3M Innovative Properties Company Imidazonaphthyridines
US6780873B2 (en) 1999-06-10 2004-08-24 3M Innovative Properties Company Urea substituted imidazoquinolines
US6784188B2 (en) 1999-06-10 2004-08-31 3M Innovative Properties Company Urea substituted imidazoquinolines
US6797718B2 (en) 2002-06-07 2004-09-28 3M Innovative Properties Company Ether substituted imidazopyridines
US6818650B2 (en) 2002-09-26 2004-11-16 3M Innovative Properties Company 1H-imidazo dimers
US6916925B1 (en) 1999-11-05 2005-07-12 3M Innovative Properties Co. Dye labeled imidazoquinoline compounds
US6921826B2 (en) 2000-12-08 2005-07-26 3M Innovative Properties Co. Thioether substituted imidazoquinolines
US6949649B2 (en) 2000-12-08 2005-09-27 3M Innovative Properties Co. Thioether substituted imidazoquinolines
US6953804B2 (en) 2000-12-08 2005-10-11 3M Innovative Properties Co. Aryl ether substituted imidazoquinolines
US6989389B2 (en) 2000-12-08 2006-01-24 3M Innovative Properties Co. Aryl ether substituted imidazoquinolines
EP1663222A1 (fr) * 2003-09-02 2006-06-07 3M Innovative Properties Company Methodes associees au traitement de pathologies des muqueuses
US7078523B2 (en) 2000-12-08 2006-07-18 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
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US7598382B2 (en) 2002-12-20 2009-10-06 Coley Pharmaceutical Group, Inc. Aryl substituted imidazoquinolines
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US7968562B2 (en) 2001-11-29 2011-06-28 3M Innovative Properties Company Pharmaceutical formulations comprising an immune response modifier
US8110582B2 (en) 2003-03-04 2012-02-07 3M Innovative Properties Company Prophylactic treatment of UV-induced epidermal neoplasia
US8222270B2 (en) 2008-12-19 2012-07-17 Medicis Pharmaceutical Corporation 2×2×2 week treatment regimen for treating actinic keratosis with pharmaceutical compositions formulated with 2.5% imiquimod
WO2013013055A1 (fr) 2011-07-21 2013-01-24 Rubigo Therapeutics, Inc. Système pour l'administration et la surveillance de médicament
EP2572714A1 (fr) 2002-12-30 2013-03-27 3M Innovative Properties Company Combinaisons immunostimulantes
US8426457B2 (en) 2003-03-13 2013-04-23 Medicis Pharmaceutical Corporation Methods of improving skin quality
US8598196B2 (en) 2008-08-18 2013-12-03 Medicis Pharmaceutical Corporation Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy
US8642616B2 (en) 2009-07-13 2014-02-04 Medicis Pharmaceutical Corporation Lower dosage strength imiquimod formulations and short dosing regimens for treating genital and perianal warts
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems and methods
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US8961477B2 (en) 2003-08-25 2015-02-24 3M Innovative Properties Company Delivery of immune response modifier compounds
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
WO2020163118A1 (fr) * 2019-02-07 2020-08-13 Canwell Biotech Limited Dérivés d'amine d'imidazoquinoline de phosphore, compositions pharmaceutiques et procédés thérapeutiques correspondants

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US7026482B2 (en) 1996-06-21 2006-04-11 Gerster John F Process for preparing imidazoquinolinamines
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US6747040B2 (en) 1997-12-11 2004-06-08 3M Innovative Properties Company Imidazonaphthyridines
US7393859B2 (en) 1999-06-10 2008-07-01 Coley Pharmaceutical Group, Inc. Amide substituted imidazoquinolines
US6784188B2 (en) 1999-06-10 2004-08-31 3M Innovative Properties Company Urea substituted imidazoquinolines
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US6921826B2 (en) 2000-12-08 2005-07-26 3M Innovative Properties Co. Thioether substituted imidazoquinolines
US7276515B2 (en) 2000-12-08 2007-10-02 Coley Pharmaceutical Group, Inc. Thioether substituted imidazoquinolines
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US7696159B2 (en) 2003-03-25 2010-04-13 Graceway Pharmaceuticals, Llc Treatment for basal cell carcinoma
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CA2449754A1 (fr) 2002-12-27

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