Patent Issued for Inhibitors of bacterial glutaminyl cyclases for use in the treatment of periodontal and related diseases (USPTO 11958871): Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V.

2024 MAY 08 (NewsRx) -- By a News Reporter-Staff News Editor at Insurance Daily News -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Buchholz, Mirko (Halle, DE), Cynis, Holger (Halle, DE), Geissler, Stefanie (Halle, DE), Jager, Christian (Halle, DE), Liebe, Linda (Halle, DE), Linnert, Miriam (Halle, DE), Meitzner, Diane (Wolfen, DE), Piechotta, Anke (Halle, DE), Ramsbeck, Daniel (Halle, DE), filed on February 22, 2019, was published online on April 16, 2024.

The assignee for this patent, patent number 11958871, is Fraunhofer-Gesellschaft Zur Forderung Der Angewandten Forschung E.V. (Munich, Germany).

Reporters obtained the following quote from the background information supplied by the inventors: “BACKGROUND ART

“Periodontal diseases are highly prevalent with about 30% of the human population being affected worldwide, have considerable impact on individuals and society, and are costly to treat. The cost of dental care is the fourth highest of all diseases and consuming between 5 and 10% of all healthcare resources (Batchelor, P. British Dental Journal 2014, 217, 405-409). Representative population studies show that periodontal diseases are widespread and their prevalence has been increasing since 1997 (Micheelis, W. et al. Vierte Deutsche Mundgesundheitsstudie (DMS IV), Deutscher Arzte-Verlag, Koln, 2006). Amongst the adult population in Germany, 52.7% were found to be affected by moderately severe and 20.5% by severe forms of periodontitis. The health insurance expenditure in Germany for the direct treatment of periodontitis amounted to about EUR 1.1 billion (Statistisches Bundesamt, 2008), not including the costs incurred by secondary diseases.

“Periodontitis is a general term describing inflammation condition of the periodontal apparatus which is caused by multi-bacterial induction and has strong relations to various systemic diseases, such as cardiovascular diseases, rheumatoid arthritis, chronic obstructive pulmonary disease and Alzheimer’s disease.

“The currently established therapy of periodontitis, according to the recommendations of the German Society Of Dental, Oral And Craniomandibular Sciences, is generally performed by manual supra and subgingival debridement (removal of the bacterial plaques) along with the application of antiseptic substances (daily disinfection by mouth washes), which disintegrates the entire oral biofilm and provides an opportunity for recolonization by potential pathogens. Furthermore, adjuvant systemic broad-spectrum antibiotic therapy is applied in advanced disease forms. The latter also leads to a non-selective destruction of the biofilm and has to be administered in high doses and over a prolonged period of time in order to reach sufficient therapeutic levels at the particular site of action, i.e. the gingival pocket. Standard adjuvant therapy of periodontitis involves, for instance, systemic administration of doxyciclin (per os) 1 x 200 mg/die for 1 day and 2 x 100 mg/die for further 18 days (Wissenschaftliche Stellungnahme: Adjuvante Antibiotika in der Parodontitistherapie, Deutsche Gesellschaft fur Zahn- Mund- und Kieferheilkunde, DZZ 2003). As a result, resistance development in oral pathogens is observed. Further, the microbiome in the patient’s intestine is destroyed, which leads to a loss of metabolic support, immune modulation, and enables recolonization by potential pathogens. A focused and targeted therapy along with conservation of the remaining biofilm would represent a significant improvement in the treatment of periodontitis and conditions associated therewith.

“The presence of periodontopathogenic bacteria varies among periodontitis patients. Nevertheless, the occurrence of certain bacterial species in the subgingival plaques has been found to be closely associated with the etiology of periodontal diseases (Socransky et al., Journal of Clinical Periodontology, 1998, 25, 134-144).

“Thus, there is a high demand for the development of new treatments for periodontitis and related conditions capable of selectively targeting pathogens which induce a periodontal disease, while being essentially inactive on homologous human target proteins and preferably substantially preserving the rest of the naturally occurring biofilm. Such treatment would provide significant improvement to patients and healthcare systems.

“Problems to be Solved by the Invention

“In view of the above, the present invention aims at the object of identifying and providing compounds and/or pharmaceutical compositions useful in the treatment of periodontal and related diseases. Said compounds and/or pharmaceutical compositions should be preferably capable of selectively targeting pathogens which induce a periodontal disease. More preferably, the rest of the naturally occurring biofilm should be substantially preserved; homologous human target proteins should not be substantially inhibited. Even more preferably, the compounds and/or pharmaceutical compositions should exhibit high in vivo activities against the targeted pathogens.

“A further object is the preparation of a crystal and/or co-crystal of therapeutic target protein(s), which can be used for identifying inhibitors capable of targeting pathogens which induce a periodontal disease, e.g., by means of structure-based drug-design.

“A further object is to provide a method for identifying a candidate compound which may associate with a binding pocket of said therapeutic target protein(s), which compound is preferably an inhibitor of said therapeutic target protein.

“A further object of the present invention is to provide an inhibitor of said therapeutic target protein(s), and a pharmaceutical composition comprising such inhibitor. Said inhibitor should be preferably a selective inhibitor, i.e. selectively killing or selectively inhibiting the growth of (a) target bacterial pathogen(s) while being substantially inactive towards other bacterial and/or human protein targets.

“A further object of the present invention is to provide a method for treatment of the human or animal body, and/or a compound or a pharmaceutical composition for use in such method.

“A further object of the present invention is to provide a method for therapy or prophylaxis of a bacterial infection, and/or a compound or a pharmaceutical composition for use in such method, preferably by selectively killing or selectively inhibiting the growth of the pathogenic bacterial species.

“A further object of the present invention is to provide a method for therapy or prophylaxis of an acute, chronic or recurrent periodontal disease and/or a compound or a pharmaceutical composition compound for use in such method.

“In the methods for treatment according to the above objects, the route of administration should be preferably topical administration or systemic administration, and the methods are preferably non-surgical methods.”

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors’ summary information for this patent: “As a solution to the above-formulated problems, the present disclosure provides a compound according to one of the following Formulae I or II,

“its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein L, A and R¹ are defined according to the appended claims.

“The present disclosure further provides a pharmaceutical composition comprising the compound as defined above and a pharmaceutically acceptable excipient.

“The present disclosure further provides a compound as defined above and/or a pharmaceutical composition as defined above for use in a method for treatment of the human or animal body; for use in a method for therapy and/or prophylaxis of a bacterial infection; and for use in a method for therapy and/or prophylaxis of an acute, chronic or recurrent periodontal disease.

“The present disclosure further provides a crystal comprising a bacterial glutaminyl cyclase (bacQC) selected from PgQC and TfQC, and a co-crystal further comprising a candidate compound, preferably a bacQC inhibitor; as well as methods for preparing said crystal and/or co-crystal.”

The claims supplied by the inventors are:

“1. A compound according to the following Formula I, its individual enantiomers, its individual diastereoisomers, its hydrates, its solvates, its crystal forms, its individual tautomers or a pharmaceutically acceptable salt thereof, wherein: A is selected from the group consisting of optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl and optionally substituted alkenyl; R¹ is independently selected from the group consisting of H and optionally substituted alkyl; L is R^a and R^b are the same or different from each other and are independently selected from the group consisting of H, halo, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalkyl and optionally substituted heteroaryl, and wherein R^a and R^b can optionally be joined together to form a carbocyclic or a heterocyclic ring.

“2. The compound according to claim 1, wherein: said aryl is independently a C_6-10, preferably C₆ aryl group; said heterocyclyl is independently a monocyclic or bicyclic C_1-11, preferably C_2-8, more preferably C_4-5 heterocyclic group comprising 1 to 4 ring heteroatoms selected from N, S and O; said alkyl is independently a linear or branched, open-chained or cyclic C_1-6, preferably C_1-4, more preferably C_1-3, even more preferably C_1-2 alkyl group; said cycloalkyl is independently a cyclic C_3-6, preferably C_4-6, more preferably C_5-6 alkyl group; said alkenyl is independently a linear or branched, open-chained or cyclic C_2-6, preferably C_2-4, more preferably C₂ group comprising at least one C═C bond; said heteroaryl is independently an aromatic monocyclic or bicyclic C_1-11, preferably C_2-8, more preferably C_4-5 heterocyclic group comprising 1 to 4 ring heteroatoms selected from N, S and O; and said heteroalkyl is independently a linear or branched, open-chained or cyclic C_1-5, preferably C_1-3, more preferably C_1-2 heteroalkyl group comprising 1 to 4 heteroatoms selected from N, S and O.

“3. The compound according to claim 1, which is represented by the following Formula Ia, wherein A is selected from optionally substituted aryl and optionally substituted heteroaryl; and R¹, R^a and R^b are H.

“4. The compound according to claim 1, wherein R^a and R^b are independently selected from ¹H and D.

“5. The compound according to claim 1, wherein A is substituted by at least one substituent represented by the following structure B: wherein n=1, 2, 3, 4, 5 or 6; and R⁷ and R⁸ are independently selected from alkyl, aryl, heteroalkyl, heteroaryl, carbamimidoyl, formyl, alkylacyl and arylacyl, each of which can optionally be further substituted and wherein R⁷ and R⁸ can be optionally joined together to form a carbocyclic or a heterocyclic ring.

“6. The compound according to claim 5, wherein R⁷ is represented by the following structure E: wherein M is selected from Fe²⁺ and Fe³⁺ or is absent; R^c and R^d are independently selected from -H, -CH₃, -CH═CH₂, -SO₃H and -CH(OH)CH₂OH; and X is selected from a covalent bond, an alkylene, aralkylene, heteroalkylene, carbocyclene, heterocyclene, heteroarylene, heteroaralkylene, aminoalkylene, alkylamino and carbonyl-alkylamino group; wherein each of these may have up to 12 carbon atoms and up to 11 heteroatoms in the main chain, and may be substituted by one or more C_1-6 alkyl group(s), C_1-6 heteroalkyl group(s), C_1-6 carbocyclyl group(s), C_1-5 heterocyclyl group(s), C_1-5 heteroaryl group(s), halogen atom(s), hydroxyl group(s), cyano group(s), primary, secondary or tertiary amino group(s), carboxyl group(s) and side chain(s) derived from proteinogenic or non-proteinogenic aminoacid(s).

“7. The compound according to claim 6, wherein X is represented by the following structure: wherein m=0, 1, 2 or 3, and R^e is a side chain derived from a proteinogenic amino acid.

“8. The compound according to claim 1, wherein A is substituted by a substituent represented by the following structure F: wherein M is selected from Fe²⁺ and Fe³⁺ or is absent; and R^c and R^d are independently selected from -H, -CH₃, -CH═CH₂, -SO₃H and -CH(OH)CH₂OH.

“9. A pharmaceutical composition comprising the compound according to claim 1, or an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

“10. The compound according to claim 1, wherein optionally substituted refers to optional substitution by one or several groups independently selected from: C_1-6 alkyl, C_1-6 heteroalkyl, C_1-6 carbocyclyl, C_1-5 heterocyclyl and C_1-5 heteroaryl group, each of which may be substituted by one or several halogen atoms and/or hydroxyl groups; a halogen atom; a cyano group; a primary, secondary or tertiary amino group; a hydroxyl group; and a carboxyl group.

“11. The compound according to claim 1, wherein A in Formula I is selected from the group consisting of alkoxyaryl, (alkoxy)(halo)aryl, (alkoxy)heteroaryl, alkylaryl, alkylheteroaryl, aminoaryl, aminoheteroaryl, arylaryl, arylheteroaryl, (aryloxy)aryl, (aryloxy)heteroaryl, haloaryl, haloheteroaryl, (heteroalkyl)aryl, (haloalkyl)aryl, (heteroaryl)aryl, [(heteroaryl)oxy]aryl, [(aminoalkyl)oxy]aryl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each of which can optionally be further substituted.

“12. The compound according to claim 1, wherein A in Formula I is selected from the group consisting of 2-alkoxyphenyl, 3-alkoxyphenyl, 4-alkoxyphenyl, 2,3-dialkoxyphenyl, 2,4-dialkoxyphenyl, 2,5-dialkoxyphenyl, 2,6-dialkoxyphenyl, 3,4-dialkoxyphenyl, 3,5-dialkoxyphenyl, 3,4,5-trialkoxyphenyl, 2,6-dihalo-4-alkoxyphenyl, 2-halo-4-alkoxyphenyl, 3-halo-5-alkoxyphenyl, 4-halo-3-alkoxyphenyl, 2-alkylphenyl, 3-alkylphenyl, 4-alkylphenyl, 3-[(alkyl)(heteroalkyl)amino]phenyl, 3-[(dialkyl)amino]phenyl, 3-[(diheteroalkyl)amino]phenyl, 3-[(monoalkyl)amino]phenyl, 4-[(alkyl)(heteroalkyl)amino]phenyl, 4-[(dialkyl)amino]phenyl, 4-[(diheteroalkyl)amino]phenyl, 4-[(heteroaryl)oxy]phenyl, 4-[(monoalkyl)amino]phenyl, arylphenyl, 2-(aryloxy)phenyl, 3-(aryloxy)phenyl, 4-(aryloxy)phenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 2,3,4-trihalophenyl, 2,3,5-trihalophenyl, 3,4,5-trihalophenyl, 2,4,5-trihalophenyl, 2,4,6-trihalophenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)phenyl, 3-(C5 monoheteroaryl)phenyl, 4-(C5 monoheteroaryl)phenyl, 3-(C4 monoheteroaryl)phenyl, 4-(C4 monoheteroaryl)phenyl, 3-[(heteroaryl)oxy]phenyl, 4-{[amino(alkyl)]oxy}phenyl, 3-{[amino(alkyl)]oxy}phenyl, naphthyl, phenyl, C5 monoheteroaryl, C4 monoheteroaryl, morpholinyl and piperidinyl, each of which can optionally be further substituted.

“13. The compound according to claim 1, wherein A in Formula I is selected from the group consisting of 2-methoxyphenyl, 3-methoxyphenyl, 4-propoxyphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-benzyloxyphenyl, 3,4-dimethoxyphenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 2,2-difluoro-1,3-benzodioxo1-5-yl, 7-methoxy-1,3-benzodioxo1-5-yl, 2,6-difluoro-4-methoxy-phenyl, 3-(1-piperidyl)phenyl, 4-morpholinophenyl, [1,1’-biphenyl]-3-yl, [1,1’-biphenyl]-4-yl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,4,5-trifluorophenyl, 4-(2-pyridyl)phenyl, 4-(2-carbamimidamidoethyloxy)phenyl, 4-(2-aminoethoxy)phenyl, 4-(2-morpholinoethoxy)phenyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl.

“14. The compound according to claim 1, having a structure selected from the group consisting of:”

For more information, see this patent: Buchholz, Mirko. Inhibitors of bacterial glutaminyl cyclases for use in the treatment of periodontal and related diseases. U.S. Patent Number 11958871, filed February 22, 2019, and published online on April 16, 2024. Patent URL (for desktop use only): https://ppubs.uspto.gov/pubwebapp/external.html?q=(11958871)&db=USPAT&type=ids

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