AU2005202737B2 - Use of chemotherapeutic agents - Google Patents

Description

53826DIV HKS:DIA:JPH P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE

SPECIFICATION

FOR A STANDARD

PATENT

ORIGINAL

Name of Applicant: HANS-HERRMANN SCHULZ AND GUNTHER SCHLIMBACH Actual Inventors: HANS-HERRMANN SCHULZ AND GUNTHER SCHLIMBACH Address for Service: COLLISON CO., 117 King William Street, Adelaide, S.A. 5000 Invention Title: USE OF CHEMOTHERAPEUTIC

AGENTS

Divisional Application Details This is a Divisional of AU Application No. 21716/01 Dated: 22 December 2000 The following statement is a full description of this invention, including the best method of performing it known to me/us: 18/06 '02 DI 15:09 FAX +49 221 97311110 KUTZENBERGER WOLFF I@005

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C WO 01/456 79 SWO 14979 PCT/EP00/13 se of chemotherapeutic agents Cl The present invention relates to the use of chemotherapeutic agents fcor the preparation of a medicament for the topical and/or local treatment of di;.eases n >5 caused by bacteria and/or for prophylaxis in humans or animals.

lCo Bacteria can be the cause of a large number of diseases and can moreover iLapair Cl wound healing. In the oral region, for example, tooth decay (caries) is caus :d by microbes specific to the mouth. Oral bacteria convert dietary carbohydrat, s to C 10 acids capable of dissolving the tooth enamel (enamelum) and dentin (dentinun). If the enamel surface is broken, the bacteria penetrate further into the under ying deatin. The radial dentinal tubules contain pulp processes, so partial or total infection and hence inflammation of the pulp occurs as the situation develops. The effect of inflammation of the pulp is to increase the congestion of blood. A the pulp is located in the rigid pulp cavity, it cannot expand and pain occurs. I' the situation is left untreated, the consequences are necrosis of the pulp tissue and bacterial decomposition (gangrene). If the gangrenous matter is not removed, this is followed by inflammations outside the root tip. Granulomas, cysts, fistulaticn or abscesses may develop. Gas formation also exacerbates the pain at this stage.

Inflammation of the periodontium also involves bacteria. The periodoni um consists of the gingiva, the annular ligament of the radius, the periodc tal membrane and the intermediate Sharpey's fibres. An inflammation, periodon itis can affect individual regions or the entire periodontium. Periodontitis, like car ies, is caused by dental plaque at the margins of the gingiva, which hardens to t rtar due to calcareous infiltrations. Bacteria living in the plaque form metabolic products which cause periodontal disease. The gingiva gradually recedes and the periodontal membrane and alveolar bone begin to disintegrate. Sites of infeci ion form in the surrounding tissue. The consequences are continued destruction of the bones and loosening of the teeth, which ultimately fall out. Damage in the oral region can also lead to diseases in other body organs.

Calcium hydroxide preparations or zinc oxide/clove oil (eugenol) are used for he treatment of caries profunda, both in the case of exposed pulp and when the dentin covering is still unbroken. An infected and necrotized pulp is removed as far as 18/06 '02 DI 15:09 FAX +49 221 97311110 KUTZENBERGER WOLFF ]006

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WO I/4$679 WO 01/479 PCT/EPOO/13L55 possible and the pulp cavity is filled with suitable root fillers. If the p 1lp is n gangreous, success can only be expected if the contaminated root canal s /stem and the dentin near the canal can be disinfected. The main problems a:e the inaccessibility of the bacterially infected apical delta of the root canals, wh ch is difficult to clean, and also the infected canal wall system, which has to be ren toved with cotsiderable effort using instruments. A gangrene treatment is therefore Snormally a compromise solution and is wholly rejected by some schoolh. In Sprinciple, contraindications for a gAngrene treatment are multirooted teet and 0 apical processes visible by X-ray. Extraction of the tooth is indicated in tese C1 10 cases. Periodontal diseases are treated by the removal of subgingival concren ents.

Other treatments use medicaments such as caustic agents, anti-inflammatori s or vitamins.

Infections in the oral region are treated using antibiotics and chemotherap ~tic agents with aa antibacterial action, although these should only be adminis!sed after critical diagnosis. The preferred agents are antibiotics such as penicillin 3 or oral penicillins. Possible alternatives are erytbromycin, lincomycin, clindarrycin and, if appropriate, sulfonamides. The preferred agents in the case of m oed infections with Gram-negative microbes are broad-spectrum penicillins suc as ampicillin, which can optionally be replaced by tetracyclines. Antibiotics and chemotherapeutic agents are always administered systemically. According to the prevailing school of thought, agents used for sys:emic chemotherapy should not be used as local antibiotics- The current use of antimicrobial substances in dental medicine is described by B.M. Owens and N.J. Schuman (Journal of Clinical Pediatric Dentistry, 1994 (Winter), 18, 129-134; cited in Medline, AN 94331337). According to tlese authors, there ate two distinct categories of antimicrobial substances, nan:ely naturally occurring substances from fungi (penicillins and cephalosporins), bact ia and actinomycctes (amiloglycosidea), and their derivatives, which are caled antibiotics, and compounds of synthetic origin (sulfanilamides and quinolon s), which are called chemotherapoutic agents. The group of antibiotics which are important for dental medicine are penicillins, cephlosporins and aminoglycosic.es, as well as erythromycin. Because of their good efficacy, low costs and ease ofr se, these antibiotics are the preferred agents for many if not most odontogen ms 18/06 '02 DI 15:09 FAX +49 221 97311110 KUTZENBERGER WOLFF ]007

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c WO 01/4679 PCT/EPOO/3 infections. The substances of synthetic origin are less valuable in dental me icine.

C According to the prevailing school of thought, they are frequently characteried by high costs, lack of efficacy and toxicity for the patient.

S 5 The sensitivity to antimicrobial agents of microbes which cause progr sive periodontitis or odontogenous abscesses has been studied in vitro by S. Eick et al.

o (Int. J. Antimicrob. Agents, 1999, 12, 41-46) using modem antibiotic and chetrotherapeutic agents, i.e. penicillin, amoxicillin, cefoxitin, clindan ycin, o doxycycline, metronidazole and ciprofloxain. The result was to recom neud Cl 10 clindanycin for antimicrobial treatments.

Antibiotics have been used in dental medicine both systemically and topically to treat patients. U. Wahlmann et al. (Int. J. Antimicrob. Agents, 1999, 12, 253 256) have reported the effects of the systemic administration of cefuroxim ten minutes prior to a dental extraction. Bacteraemtia occurred with a lower frequency it the group treated with cefuroxim than in the untreated group.

K. Kosowska and P.B. Heczko (Med. Dosw. Mikrobiol., 1977, 29, 101-106; :ited in Chemical Abstracts, CA 88:69315) have reported the topical use of a varie.y of antibiotics. They treated infected teeth with various antibiotics, nainely erythromycin, neomycin, chloramphenicol, colistin, nystatin or dexametha one, The aerobic flora in the root canals was eliminated in about 55% of cises.

However, the antibiotic resistance of the microorganisms isolated from the root canals after the treatment had been increased by the treatment. The resistanc:e of Staphylococcus epidermis to erytbromycin or methicillin was increased three fold or two-fold, The majority of Staphylococcus aureus strains were resistart to erythromycin, cbloramphenicol and penicillin.

The authors of the above literature references are all in agreement that the topical use of antibiotics and chemotherapeutic agents administered as sucking tab (ets, throat tablets, lozenges, styli, cones, powders or ointments are only of very 'ittle importance because of the frequent occurrence of increased resistance of the pathogens and because of the high sensitization rate. The therapeutic beneft is generally also limited in wounds with adequate external drainage. The substances used are scarcely absorbed, if at all, so their action cannot be expected to pene rate 18/06 '02 DI 15:10 FAX +49 221 97311110 KUTZENBERGER WOLFF j008 WO 01/45679 g PCT/EPO0/13

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deeper into the tissue.

Accordingly, given the curent state of the art in human and veterinary !ental medicine, there is a great need for agents which have a high activity again ;t the c 5 microbes occurring in the region of the mouth, teeth and jaws or in oral we ands have a rapid bactericidal action, have a good local tolerability, elicit a low tendency o to generate antibiotic resistance, can be applied topically and/or locally and hence are easy to administer, place a minimum systemic burden on the organism vhen O administered topically/locally, and have a good tissue penetration, and whos. use S 10 ensures the preservation of the damaged teeth.

Bacteria are also important in wound care. Wounds are tissue defects on the body surface and can be caused by injuries, operations, infections or pathophysiolo ical processes, Wounds are dangerous inter alia because of possible infections due to penetration by pathogenic bacteria. Bacterial colonization of the wound can ;low down or prevent the healing process or lead to other complications sue i as lymphangitis, sepsis or chronic infections.

Infected wounds must receive an antimicrobial treatment to control pathogenic microbes. Moreover, in a similar way to necrotic wounds, the wound mu t be cleaned to remove foreign bodies and cell detritus so that it can progress to the aext healing phase. The treatment of an infected wound normally consists f a combined systemic and local approach where optionally antibiotics are used a id a suitable dressing is applied which may itself have an antibacterial action. In n tany cases wound infections can be successfully treated by the administratior of systemically active antibiotics, but the systemic administration of an antibiotic necessarily burdens the entire organism. This may be contraindicated in n any cases, for example due to the patient's clinical situation, if the patient has primary diseases or if an allergizing potential exists, It is advantageous in such cas to apply the antibiotic topically and/or locally so that it can also be used in a hi:gher local tissue concentration. Topical/local applications may also be favoured by other factors, as in the case of certain hospital epidemiologies, or economic asp acts such as the amounts needed, the prices of the medicaments and the costs du;: to side effects. However, the use of topical antibiotics is not generally recommended because this can lead to allergic reactions or to the formation of antibiotic-resis ant 18/06 '02 DI 15:10 FAX +49 221 97311110 KUTZENBERGER WOLFF 009 0 0 c WO 01/4S679 F CT/EFOO/1 1155 c, species of bacteria. It is therefore regarded as particularly important to li, oit the F use of topical antibiotics.

Nowadays a local antibiotic treatment is used only for superficial skin inf :ctions C 5 because the antibiotic can act directly on the pathogens. A local applica ion is unsuccessful in the case of deep skin infections because the antibiotics do not penetrate the intact skin. There are three preferred groups of local antibio ics in C use today. These are polypeptides such as bacitracin, tyrothrici, colistia and Spolymyxm B, or aminoglycosides such as neomycin, kanamycin and paromyzin or Cl 10 mupirocia. However, with the presence of local or systemic toxicity atid the danger of the secondary development of bacterial resistance, local antil:iotics should only be used with great restraint In local therapies with gyrase inhil itors, incorporation into plastic materials has been proposed as a possible c nical application in addition to conventional forms of administration such as eye trops, ear drops, instillation solutions, powders and healing ointments :Stille, Fortschritte der antimikrobiellen und antineoplastischen Chemotherapie (Adv;tnces in antimicrobial and antineoplastic chemotherapy), vol. 6-10, 1987, pp. 1:;75 1583).

Accordingly, given the current state of the art, there is also a need in humar and veterinary medicine for topically and/or locally applicable agents with an antitiotic action which have a high activity against the microbes occurring in wounds, hrve a rapid bactericidal action, have a good local tolerability, elicit a low tenden y to generate antibiotic resistance, are easy to administer by topical and/or local application, place a minimum systemic burden on the organism when adminis ered topically/locally, have a good tissue penetration, are also suitable for the treatb ent of deep infections and additionally accelerate the wound healing process.

It has now been found, surprisingly, that certain chemotherapeutic agents, administered locally and/or topically, have an extremely positive effect in a vaiety of ways on the treatment of diseases caused by bacteria in the oral regior of humans and animals, for example dental and periodontal diseases, and on we and healing. Medicaments which contain these chetnotherapeutic agents can be used successfully in dental medicine against microbes encountered in the soft tizsue and/or hard tissue, where they lead to inflammations. The medicaments are 18/06 '02 DI 15:11 FAX +49 221 97311110 KUTZENBERGER WOLFF SWO 01/45679 PCTEP00/13 155 generally suitable for the local treatment of endodontal syndromes such as pilpitis en due to carious diseases, for the prophylaxis of dentin wounds, for the topical treatment of the infected root canal and the periapical tissue, and also f',r the topical treatment of periodontal diseases, of osseomucosal wounds with dis urbed C 5 wound healing, for example after dental extraction, and of soft tissue infec tions.

Such diseases are caused by bacteria in the hard dental tissue, for example in the o case of infections in the crown and root dentin, in the dentin inside the root canal t and in the root cement in the apical region of the root of the tooth. Also inc uded Sare bacterial infections of the jawbone and alveolar bone, They are also :o be 1 0 understood as including infections in the soft tissues, for instance in the pulp, :i n the periodontal tissue, in the gingival mucosa, in the alveolar mucosa, in the labi I and buccal mucosa, in the palatine mucosa and in the periglottis, It has further been found, surprisingly, that the use of these chemotherapcutic agents in humar and veterinary medicine also has a positive effect in a variety of ways on the treat nent and prophylaxis of wounds, This was shown in the treatment of different formis of wounds, for example in surgical infections such as postoperative or posttraum atic wound infections, in perioperative prophylaxis, in infected buns, in :land infections, in postoperative sepsis, in infected ulcers and gangrenes and in skin infections such as acute and chronic bacterial skin infections, secondarily inf cted dermatoses or acne and rosacea. These lists are examples and do not imply a limitation to the areas mentioned, These diseases can be treated according to the invention by the local and/or topical application of chemotherapeutic agents.

In terms of the invention, chemotherapeutic agents are derivatives of quinolnecarboxylic acid or naphthyridonecarboxylic acid of general formula R3 R4 R6 A N

RI

So010 18/06 '02 DI 15:11 FAX +49 221 97311110 KTEBRE OF 11 KUTZENBERGER WOLFF Q011 WO 01/45679 PCTJEflO/13VF S in wicb: A is CH, C-halogen, C-CE 3 C-CN,. C-OCM, C-OCHF 2 or N, RI is C, -C 5 -alkyl, C 1

-C

5 -allcenyl, 2-finoroethyl, bicycloalkyl, 2-fluorocycloprcpyl, I -oxctam-3-yl, optionally sabstitaited phenyl or pyridyl, or A and RI the group C-O-0H 2

-CH(CH,

R2 is hydrogen or C 1

-C

3 -alkyli optionally substituted halogen or amino, cyclo a kI44, methylan ino, together 1'orn by xyl, R(3 is hydrogen, halogen, methyl, amino or NH-NI{ 2 R4 is hydrogen, halogen or amino, and RS is. an optionally monosubstituted or polysubstituted mono-, b: or tricyclic ahicycle which is saturated or has at least one double I ond and which optionally has at least one beteroatom in the ring sys iem,4 or an aromatic miono-, bi- or tricycle optionally having at least one heteroatom, and/or 4H-4-oxoquiuohzines of general formula (0T): 18/06 '02 DI 15:12 FAX +49 221 97311110 KUTZENBERGER WOLFF 012

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wo 01/45679 PCTIEP00/13 in which; c n 5 R1 is hydrogen or C 1

-C

3 -alkyl, and P R2 is an optionally monosubstituted or polysubstituted mono-, bi- or tricyclic alicycle which is saturated or has at least one double bond Sand which optionally has at least one heteroatom in the ring sy tem, or an aromatic mono-, bi- or tricycle optionally having at lea t one heteroatom, and/or their corresponding hydrates and/or their corresponding physiologically compatible acid addition salts and/or optionally the corresponding physiologically compatible salts of the carboxylic acids on which they are based, i.e the compounds of general formula in which R2 is H and/or the compounds of general formula (II) in which RI is H, and/or corresponding enantiomers a:id/or corresponding diastereomers and/or corresponding racemates and/or correspor ding mixtures of at least two of the above-mentioned compounds.

When administered topically and/or locally, these compounds have a bene!icial action in the treatment of diseases caused by bacteria in the oral region of hw ans and animals, especially in the treatment of pulpitis, including infections of the root canal and the periapical tissue, periodontal diseases and odontogenous or oral soft tissue infections, in the prophylaxis of dentin wounds, in the treatment of fom s of wounds in humans and animals arising from surgical infections sucl as postoperative or posttraumatic wound infections, in perioperative prophylaxi;, in infected bums, in hand infections, in postoperative sepsis, in infected ulcers and gangrenes, in acute and chronic bacterial skin infections, secondarily infected dermatoses or acno and rosacea, and in general for the acceleration of wcund healing in humans and animals.

It is preferred to use at least one of these compounds to prepare a pharmaceu ical product, especially a medicament, for the topical and/or local treatment of disc ases caused by bacteria or for the acceleration of wound healing.

18/06 '02 DI 15:12 FAX +49 221 97311110 KTEBRE OF 1 KUTZENBERGER WOLFF Z013 ClWO 01145679 PCTEPOO/13',55 Cl It is Preferred to use the compounds of formula in which A is CHI, CF, CCI, CBr C-CHS, C-ON, C-OCH 3

C-OCHF

2 o r N.

RI is ethyl, 1,1-dimethylethyl, 1-ethenyl, l,l-dimethylprop.2ynAi, 2- 0 ~fuothyl, cytclopropyl, bicyclo(1.l .1)penjt-l -yl, 2fuoro, yclo propyl, I -oxetan-3-yl, ruethylandno, 4 -tluorophenyl, 2,4-difli oroo phenyl, S-atnno-2,4-difluoropheny1, 5-fluoropyridfi-2-yl cr 6anaino-3,5-difiuoropyxidin2yx, or A and Ri together Corn, the group C-0XCII1 2

-CH(CH

3 the -CH(CW3)- part of this grou~p 'ezn~g bonded to theu nitrOgen ato~u of the heterocycie, R2 is hydrogen, methyl or ethyl, R3 is hydrogen, F, CI, Br, mnethyl, amino or NI{-NI{ 2 R4 is hydrogen, F or amnino, and R5 is optionally manosubstituted or Polysubstitutcd oclopr ipyl, azetidinyl, pyrrolidiriyl, pip erildinyl, piperazinyi, maorpho~ nyl, Phenyl, pyrrolyl, pyridyl or inaidazolyl, it optionally also b2 4ng possible far at least two substituents to be coupled together, and/or the compounds of" formusla (LI) in which RI is hydrogen, and R2 is optionally maonosubstituted or polysubstituted cycloprcopyl, azeticlinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholiny t, it optionally also being possible for at least two substituents to be coupled together, It is paxtcularly prefered to use the compounds of formula in which 18/06 '02 DI 15:13 FAX +49 221 97311110 KUTZENBERGER WOLFF Q~i014 ClWO 01/45679 PCT/EIPUO/13 A is Cit OF, 001, C-ON, C-OCH 3 or N, RI is cyclopropyl, 2-flnorocyclopropyl, 4-fluozophenyl or 2,,4-dli lucrephenyl, or A and RI together form the groupOOCH- en 5-the -CH(C11 3 part of this group being bonded to the nitrogen, atom of the heterocycle, IC)R2 is hydrogen, R3 is hydrogen or amino, R4 is hydroget or F. and is optionally monoSUbStitUted Or polysubstituued pyrroltinyl, piid~Iyl, piperazinyl or morphoinyl, it optionally also 3eing possible for at least two suibstituents to be coupled together.

It is very particularly preferred to use the compounds of formula in whc A is CHI, OF, CCI, 0-00113 or N, RI is cyclopropyl or 2 3 4 -diflzorophenyl, or A and RI together fon -i the group C-O-CH 2

-CH(CH

3 the CH(CH3)- part of this gro-up b eing bonded to the nitrogen atom of the heterocycle, R2 is hydrogen, R(3 is hydrogen or arnino, R(4 is hydrogen or F, and is pyrrolidinyl, pip eridinyl, piperazimyl, inorpholinyl or 3 azabicyclo (3.1 .0)hexyl optionally substituted by amino, methyl, an inamnethyl and/or methoxyinino, or PipefidinopyrralidinyI.

Ri- or tricyclic alicycles or aromatic bi- or tricyrCs R_5 in general formula (I and 18/06 '02 DI 15:13 FAX +49 221 97311110 KUTZENBERGER WOLFF (N]WO 01/45679 PCT.EPOO/XS tSS R2 in general formula (111) are also understood as including futsed ring 53 stems (fl which can optionally have at least one double bond and/or at least one heteroatom in the ring system- Examples of radical RS in the compounds of fonnula are l-arnimcyclopn .pyl, 3-hydroxyazetidin-l-yl, 3-arninoazefidin- l-yJ 3 -methylaminioazetiaiw yl, 3o anatino-2-methylazetidin-I1-yl, 3 -axnino-3-.rnethylaz:etdn.1-yl, 3-amnino -2,3tn deaet idi-IY ly3 -aminopyndoidiw. lyb, 3-(2-aniino-I1-oxopropyl)amnim -1o ~pyrrolidin-I1 y1, 3-norvalylnorvalylaniino- 1-pyrrolidin-I -Yl, 3-ax-nino-3 Cl 10 luaormetylpyrrolidin-1I-4, $-amino-4-methylpyrrolidjrn4 -yl, 3-aminofluoromethylpyrroli din- Il-yl, 4 -anino-2-xnethylpyrrolidim 1 -yl, 4-axnino-3,3dixnethyl-l1-pyrrolidin-1-'yl, 3 -an-tino-.3 -phenylpynroipiin- 1-yl, 3-amino-4eyclopropylpyrrolidin- 1-yl, 3 -aminomethylpyrrolidiw -4l 3eth ylalninoznethylpyrrolidizi-yl, 3 -(l-aminloethyl)-1 -pyrrohlin-I -y4 3-(l -anu no- 1 -methylethyl)pyuulidin..; 3 -aminoinethyl3miemylpyrmlidin-1 I 3aminonethyl-3-fluoromnethylpynrolidinq -yl, 3 -axinomaethyl-4-methylpynvlict 3yl, 3 -aminoxnethy1-4-trifluororthylpyrroncjin-l-yl, 3-aminomnethyl-4chloropyrrolidi-1 I-yl, 3 -aminomethy-4-metoxyiiinopyrolidi 2 3-{2methyl- 1W-imaidazol-l1-yl)pyrrolidin- 1-yl, 3 4 -mcthyi- 1,2,3-ttiazol-l -yl)pyrrol. dinl-yl, 3-methylaminopiperidin-l§yl, 4 -hydroxypiperidin-1.y, 4hydroxyriminopiperidin- by!, piperazin-lI-yl, 3-methyl- 1-piperazinyl 7 4rthylpiperazin- 1 -yb 4 -ethylpiperazin..I yl, 4 -acetylpiperaziu- 1 -yl, 4-(5 -meth) 1-2oxo-1 ,3 -dioxol-4-yl)metbylpiperazin-1-yl, 4-(S-earboxy-l1-oxopropyl)piperazin -1yl, 3,5-dirnethylpipersain- I-yl, 2 4 ,5-trimethylpiperazin..i -yl, 3,4,5trimethylpiperazin-i -yl, 2 -aznitomethybnotpholinal..yl, 2dimetylaninomethylmorpholinA..y, 3 -methylaminomethylinoipiolh..4.y 7amino-S -azaspzzQo(2.4)heptan-5-yI, S-axnino-6-azaspir-o(3 .4)oetani-6-yL, 6-amino .3azabicyolo(3.1 .O)hexan-3-yl, 6 -akanylalanylamino-3-azftbicyrlo(3, 1 .0)heltan-3-vyl, 6-amaino- 1 -methyl-3-azabicyclo(3 .20O)heptan-3 y1, 6 -miethy1-2,5-diazabioylo- (2.2.1 )heptan-2-yl, 2,5-diazabicyclo(2.2i1)heptan-z-yl, 8-methyl-3,8-diazabiycloI- (3.21 )Octanu3 -yl, S-anino-Z-aza-2-spixo[4,4]x~ouyy1 1-azninomethyl-8-aza-8bio~yclo-[4.3 .O]nonyl, 5-aminomotYI-7-aza-2-oxo-7.bicycto[3 .3 .0]ootyl 1an~onietIhy1-7-aza-3-oxo.7-bicyclo[3 tetyl, 2,7-diaza-7-bicyclo[3 .3 .0]octy,, 3,7-diaza-3-bicyclo[3.3 .O]ocW1l, Z,S-diaza-8-bioyolo[4 3. 0]nonyl, 5,8-diaza-2-o,' o- 8-bicyclo [4.3-O3nonyl, 3, 8-diaza-8-bicyclo[4.3 .Ononyl, 2.7-diaza-7h0 18/06 '.02 DI 15:13 FAX +49 221 97311110 KUTZENBERGER WOLFF c-IWO 01/45679 PCT/EPOO/131:'5 bioyclo[4.3-Ojnonty], 3 ,9-diaza-9-bicyclo[4.3 .03nonyl, 3,9-diaza-3bicyulo[4.3 .Ojnonyl, 7-aznino-3 -aza-3-bicycko4 I.0)heptyl, azaspiro[2.43hept-5-yl or 7 -methylarnino-.S-azaspiro[24]hept4.-yt 2,7-diaza-2.

bicyclo[3.3 .O)octyl, 4-amaino- 1,3-dihydxo-2Hisoindoh-2Ay, 3 ,4-dihydro-2( imen 5 isoquinolinyl, hexahydropyrolo [3 ,4-bjpyrrol-5(1J1)-yl, ootahydro-6E-pyrro.-;,4bjpyridw-6-yl, hexahydropyroo[3,4-b)-1 4 -oxazin-6(2H)-yl, 2,3-dihydro-1o methyl-1I-isoindo!-5-yl, pyridin-4-yl, 2,6-dimethylpyridin-4-yl, 1H-pyrrol-1-y or tfl IH-irnidazol-1-yl.

ci 10 Examples of radicals R2 in the comnpounids of formula (11) are azetidin-l-yl, 2hydroxyinethylazetidn.-1 -yl, 2-azninomethylazetidin- 1-yl, pyrrolidin- 1-yl, isoxazohn-I1-yl, 2-methylpyrazolidin- l-yl, 3-hydroxypynolidin- 1-yI, 3carboxypyrrolidin-l -yl, 3-atnuiopyrrolidin- 1-yl, 3-amninornethylpyrolidin-l -yl, 3znetlhylaminopyrrolidin- I-yb, 3-ethylaminopyrrolidin-1-yI, 3fluoroothylaininopyrrolidin- 1-yl, 3 -trifluoroethylaminopyrrolidin-1-yl, 3methoxyethiytaxrdnopyrrolidin- i-yl, 3 -(N-methyl-N-cyclopropylamino)pyrolidi.iyl, 3-amino-4-cyclopropylpyrrolidin- l-yl, 4-methyl--3-methylamino-pyzrolldin. I -yI, 3-cyclopropylamino-4-rnethylpyzroidin-l-yI, 3 -(1-ariino-8-aza-8bicyclo [42 .0]nonyl, 3-amninomethxylpyrrolidin-I -yl, 3-ninomethyb-3tdifluxorornethyipyrrolidin- 1-yl. Samino-2-aza-z-spiro(4.4]nonyl, I -aninionethyl-8aza-8-bicyclo[4,3-0)-nonyl, S-aminomethyl-7.-aza-2-oxo-7-bicyolo0[3.3-O]octyl. I1ainlomethyl-7-aza-3-oxo-7-bioyclo[3 -332]octyl, 2,7-diaza-7-bicyclo,[3 .3 .]ooty L., 3 ,7-diaza-3-bicyclo[3 .3 .0]octyl, 2 ,8-diaza-8-bicyclo[4.3.0]uonyl, 5 ,8-diaza-2-o, o- 8-bicyclo[4.3.O]nonyl, 3,.8-diaza-8-bicyclo [4.3 .Ojnonyl, 2,7-diaza-1-bicyclo[43 01nxonyl, 3 ,9-diaza-9..bicyelot4. 3 .Ononyl, 2,74iaza-2-bicyclo[3.3.0]octyl, piperici. n- 1 -yl, 3-aminopipelidin- I -yl, 3-amina-4-mnelhylpipetridin- 1 -yl, 3,9-diaza-3-bicyo o- (4.3 .O]nonyl, 7-amino-3-aza-3-bicyolo[4. 1.0]heptyl, 7-amino-5-azaspiro[2,4jhelitor 7-methylamino-5-azaspiro[2.4]hept.5-yl.

Examples of compounds of formula or fonnula (IQ) are 1-cyolopropyl-6-fluo!-o- 1 4 diliydro-8-mehoxy-7-(3-(ethyanino)-pipdinyJ-4-oxo3.qunhnecarboxylic acid (b~alofloxacin), 8-chloro-1 -cyclopropyl-6-f luoro-1 ,4-dihydno-7- ,laS)-octahydra- 6 H-pyolo[3A-bpyidn6yl..&oxo.3qunoljnecatboxruc avid monobydrochioride (BAY Y31 18), l -cyclopropyb-6-tluoroadifluoromethoxy-l ,4-dihydro-7-((3S)-mcthy-1-piperaziny)-4-oxo-3.

14 0 16 181/06 '02 DI 15:14 FAX +49 221 97311110 KTEBRE OF 1 KUTZENBERGER WOLFF Q017 WOO01/45679 rcTEPOU(1315 en quinolinecarboxylic acid hydrochloride (caderofloxacin). I -cyclopropyl-6-fluorc Cl1 ,4-dihydro-4-oxo-7-(1 -pipcazinyl)-3 -quinolinecarboxylic acid (ciprofloxacin), 7- (3-amino-i -pyrrolidiayl)-8-c-hloro-I-cyclopropyl-6-flutoro- 1,4-dilaydro-4-oxo-3quinoiinecarboxylic acid (clinnffloxacin), (cc,~-+--6ann--mtyazabicyclo 0)hept-3-yf)l- cyclopropy1-6-fluar-o- 1,4-dihydro-4-oxo- 1,8- Cl naphthyridine-3-carboxylic acid (ecenofloxacin), I-ethyl-6-fluoro-1,4-dibydr-o-4 Clo~ro-7-(1 -piperazinyl)- 1,8-niaphthyridiae-3 -carboxylir, acid (enoxacin), 1o oCyciopropy1-7-(4-ethy1-1-piperazinyl)-6-flnoro- I ,4-dihydro-4-oxo-3- Cl quinolinecarboxylic acid (enrotloxacin), 6-fluoro-l1-(5-fluoro-2-pyridinyl)- 1,4dihydro-7-(4-rnethyl- 1-piperaziniyl)-4-oxo-3-.quinolinecarboxylic acid (fandofloxaciny, 6,8-clifluoro- 1-(2-fl-uoroethyl> I ,4-dihydro-7-(4-mettyl-1 piporazinyl)-4-oxo-3-qainoliniecatboxylv, acid (ileroxacin), 1 -cyclopropyl-6tluoro-i ,4-dihydra-8-inethoxy-7-(3-inethyl- I-piperazinyl)-4-oxo-3-quinolilnecarboxylic acid (gatifloxacin), 74[(42)-3-(nninomethyl)>4-(mcthoxyimino)-1 pyroalidinylJ-lI-cyclopropyl-6-fluoro-1I,4-dihydro-4-oxo-1,-naphthyrdine-3- Qarboxylic acid (gernifloxaoin), 1-cyclopropyi-6-fluoro- 1,4-dihydro-5-tmethyl-7- '3methyl-i -piperazinyl)-4-oxo-3-quinolinecarbo-xylic acid (grepafloxacin). (3S)-9.

fluoro-2,3-.dihydrao-3-metyl-I O-(4-niethyl- 1-piper-azinyl)-7-oxo-7E-pyrido[1 1del-i ,4-bcfloxazine-6-catboxylic acid (lovofloxacin), 1 -etliyl-6, 8-diflucro- 1,Adihiydro-7-(3 -me-thyl- l-piperazinyl)-4-oxo-3-qui-noliniecaxboxylic acid (komefloxacin), 1 -cyclopr-opyl-6-flnoro- 1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahy& 6H-pyrrolo[3 ,4-b~pyridin-6-yl]-4-oxo-3-quinoinecarboxylic acid (moxifloxaciri), 9-flutoro-6,7-dihydro-S-(4-hydroxy- 1-pipeidinyl)-5-methylI -oxo-1W4SFIbenzolijjquinolizine--2-cazboxylic acid (nacliRoxacin), 1 -ethyl-6-fluoro-1 p4dihydro-4-oxo-7-(1 -piperazinyl)-3-quinoiinearboxylio acid (norfioxacin), 9fluoro-2,3 -dihydto-3 -methyl-i O-(4-nwthyl- I-piperazinyl)--7-oxo-7H-pyrido[l 3de]- 1,4-b enzoxazine-6-carboxylic acid (ofloxaoinj, 5-arno-7-[(7S)-7-anino-5 azaapiro[2A4]ept-5-y]-1-cyclopropy-6-fluoro-1I 4cdhhYdroSnlethyi-0x0-3quinolinecaxboxylic acid (olamufloxacin), (3S)-lO-(1 -aninocyclcpropyI)-9-flacro- 2,3-dihydro-3-metbyl-7-oxo-7H-pyrido[1 1,4-benzoxazine-6-carboxylic acid (p azufloxacin), 1 -ethyl-6-fluoro- 1,4-dihydxo-7-(4-mthyl-1-piperazinyl)-4oxo-3-quinoiinecarboxylic acid (pefloxacin), 6-fluoro-1 -xethyl-7-[4-{(5-nietbyl -2oxo-i ,3-dioxol-4-yl)methyl]- l-piperazinyl]-4-oxo-liH4H-[ 1,3)thiazeto(3 ,2a) quinoline-3-carboxylic acid (prulifloxacin), i-ethyl -i,4-dlhydro-4-axo-7-(4pyridinyl)-3-quinoinecarboxylic acid (rosoxacin), 7.-[(7S)-7-amino-5- 18/06 '02 DI 15:14 FAX +49 221 97311110 KUTZENBERGER WOLFF Z018 0 0 Wa 01/45679 PCTIEP00/131 azaspiro[2, 4]ept-5-yl}--chloro-6-fluoro--[(1 R,ZS)-2-fluorocyclopropyl]- 1,4 en dihydro-4-oxo-3-quinolinecarboxylic acid (sitafloxacin), 5-amino- -cycloprop ,1-7- [(3R,5S)-3,5-dimethyl-1 -piperazinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3quinolinecaboxylic acid (sparfloxacin), 7-(3-amino- 1 -pyrrolidinyl)- 1 Mn 5 difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic ac: d (tosufloxacin) or 7-(1a,5c,6ct-6-amino-3-azabicyclo(3 .1.0]hex-3-yl)- 1-(2,4difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboylic ac d (trovafloxacin).

If corresponding physiologically compatible acid addition salts of the compo mds of general formula and/or of general formula (II) are used, these can prefer ably be selected from the group comprising hydrochloride, hydrobrorikide, methanesulfonate and toluenesulfonate. If corresponding physiologially compatible salts of the carboxylic acids on which said compounds are base are used, these can preferably be selected from the group comprising alkali metal alts, alkaline earth metal salts, ammonium salts, guanidinium salts and silver salts. It is also possible to use mixtures of at least two of the above-mentio-ed physiologically compatible salts.

The above-mouentioned compounds of formula or formula (II) are known ani can be prepared by conventional processes familiar to those skilled in the art. It is also known that the compounds of formula or formula have an antibiotic ac tion and have an antibacterial spectrunm against Gram-positive and Grata-neg; tive microbes. It is also known that it is possible to use the compounds of formul a (1) or formula for the systemic treatment of diseases which can be cause(. by Gram-negative, Gram-positive or bacterioid microorganisms. It is also known that ciprofloxacin can be used in topical forma in ophthalmology.

The compounds of general formula or of general formula (II) can be used fo' the topical and/or local treatment of a variety of diseases caused by bacteria ant for prophylaxis in humans and animals.

The compounds of formula or formula can be used particularly in dental medicine and/or for improving wound healing in general medicine or veteriiary medicine. The uses according to the invention of the compounds of formula or 18/06 '02 DI 15:15 FAX +49 221 97311110 KUTZENBERGER WOLFF n 019 0 c- WOO0I/45679 Pr~onl; c W 01145679 PCTAEP00/131 n formula (II) preferably involve a) endodontal treatmnts such as the tc pical treatment ofpulpitis due to carious diseases, the prophylaxis of dentin wounds or the topical treatment of the iufected root canal and the periapical region, b) the topical treatment of periodontal diseases, c) the topical treatment of oral osseomucosal wounds with disturbed wound healing, or prophylactic treatmen;, for example after extractions, cystectomy or incisions due e.g. to phlegmotls or o parulides, d) the topical and/or local treatment of postoperative or posttraur2-latic wound infections, e) perioperative prophylaxis, f) infected bums, g) and infections, h) postoperative sepsis, i) infected ulcers and gagrenes, j) acutt and C 10 chronic bacterial skin infections, k) secondarily infected dermatoses, 1) acie and rosacea, or m) mucosal ulcerations.

Preferred uses according to the invention are described below using the are; s of dental medicine and wound healing as examples.

18/06 '02 DI 15:15 FAX +49 221 97311110 KUTZENBERGER WOLFF @020

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SWO 01/45679 FCT/EP00/133 SS C, Topical treatment oflpulpitis due to carious diseases The particular problems associated with treatment of the pulp are the small I:rmph supply, its position as a terminal organ with a small collateral circulation, an I the c 5 influence of external stimuli given its location in a rigid, inflexible cavity, i1 the case of carious defects, the microorganisms advance in the direction of the nulp, o cross the enamel-dentin interface and soften the dentin cone. If the carious process in reaches half of the total dentin layer, the pulp is already histologioally mod fied, o even though clinical symptoms are often still absent If the caries advances ft rther C 10 without penetrating the remainder of the dentin covering, symptoms of pulpiti are normally experienced. If the caries reaches the pulp, different histopatholo ical forms arise. These consequences of the carious process are attributable to the fact that dentin has radial channels, called dentinal tubules, running through it, said tubules containing pulp processes. These processes of the dentinogenic :ells (odontoblasts), which are located at the periphery of the pulp, serve inter al a to conduct stimuli. It is known that the microorganisms and their toxins follov the dentinal tubules. If the caries extensively penetrates the dentin layer or reaches the pulp, the condition is referred to as caries profwuda.

The particular problem associated with the diagnosis of a pulp disease is thai the histological and clinical pictures are often quite different. As pain is sensed and interpreted differently by different patients, there is always the risk of a ialse diagnosis. The pulp infection has often progressed further than is clinially ascertainable. Under the conventional treatment, there is then the dange- of residual microbes being left behind In the conventional treatment of caries normally used today, the carious matt:r is first removed. Then the cavity is disinfected, for example with hydrogen peroxide, and, depending on the degree of pulp inflammation, is indircotly or directly cap >ed.

This means that a thin residual dentin covering is left untouched or the exposed pulp is coated with a medicament, This is done using either calcium hydroxid e or zinc oxide/eugenol. Both medicaments are strongly alkaline, have an antibact. al action and induce caustic necrosis in a local region of the pulp. This has the effect of building secondary dentin, depending on the extent of the previous damage and the resistance situation. The capping agent is covered with a reliner, for exaz:ple 18/06 '02 DI 15:16 FAX +49 221 97311110 KUTZENBERGER WOLFF [021

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c WO 01/45679 rPCT/Poo/ls3i zinc phosphate cement. In the same session or at a later time, the definitive fi ling is prepared, for example with a composite cement. In cases of particular iain symptoms or where the pulp no longer reacts to external stimuli, it is assumed that the pulp can no longer regenerate or that it is dead. In these cases the pulp is en 5 removed and a root treatment is carried out.

l O The topical treatment of infected dentin and pulpitis with antibiotics has hitierto n been described in the scientific literature as unsuccessful. As the main argu lent Sagainst this method of treatment, it is stated that the microbes in que: tion C 10 (anaerobes and aerobes) were only dealt with to a very limited extent by the antibiotics tested. It was further established that the antibiotics tested earlie: for these indications generally have only a bacteriostatic action and not a bacteri idal action. This allows resistant microbes to get out of control and hypersensit vity reactions against a particular antibiotic can be triggered.

It has now been found, surprisingly, that, when applied topically and/or locally to the periodontal interstice in dentistry, the antibiotics of formula or fonnula, (II) completely control the bacteria occurring in odontogenous infections, and additionally that the disadvantages of the conventional treatment described ab ove do not arise. It has further been found that the compounds of formula or formula have a high tissue penetration in the odontogenous region. It has also been found that, under treatment with the compounds of formula or formula the microbes of odontogenous infections have no tendency to develop resistince.

This is of great importance because, for example in the case of caries profunda, it is always necessary to decide whether softened residual dentin can be left ove. the pulp. By virtue of complete elimination of the microbes present, there is now a novel method of treatment wherein a thin softened dentin covering can be left i Fthe compounds of formula or formula (II) are used. This method of treat aent makes it possible to free infected dentin layers of microbes and to stop pulp infections. This means that pain reactions are eliminated and pulp infections a.:e to a certain extent cured. The pulp remains vital- The topical application of the compounds of formula or formula (II) foll(wed the removal of the carious dentin. The compounds of formula or formul; (1) were applied for example in aqueous solution, in a form of gelatinous consist mncy 18/06 '02 DI 15:16 FAX +49 221 97311110 KUTZENBERGER WOLFF Z022

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WO 01/45679 PCT/EP00/13155 or on an inert carrier, for example by means of a cotton wool plug. The overly:ng cavity was occluded with a cement to seal the margins. The cotton wool plug was left in the cavity for three to six days. The compounds of formula or fornm la can be used in concentrations of 0.005 mg/ml to 200 mg/ml, Prefer -ed concentrations are those ranging from 0.5 mg/ml to 150 mg/ml and particul;-rly C preferred concentrations are those ranging from 10 to 100 mg/ml.

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o Surprisingly, it was observed in a large number of cases that the action of O compounds of formula or formula (If) even resulted in a regeneration of the r alp tissue. This was shown by the fact that, after extirpation of the infected :nd inflamed pulp, the nerve needle could be introduced as far as the foratien physiologicum. About two weeks after the topical application of a compouni of formula or formula a burgeoning of fresh pulp tissue was observed wl:ich was characterized in that the vertical canal volume was found to have shrunk w len inspected with instruments, and fresh pulp tissue had grown out again into the canal in the direction of the crown. This pulp tissue was vital.

Prophylaxis of dentin wounds In the treatment of carious defects or after the preparation of dentin surface: to receive e.g. fillings, inlays, onlays, crowns or bridges, dentinal tubules which are directly connected to the pulp, and hence provide access to the pulp, are cut Each prepared dentin surface is covered by an organic layer and preparation resict es (smear layer), If the preparatory work is also carried out in dentin modifiec by caries, said surface normally contains microorganisms. The usual practice i5 to flush the dentin wound with hydrogen peroxide and then carefully dry it with the air syringe. Even when the cavity walls are 'hard to the probe' aftet removal of the caries and preparation of the cavity, and the cavity has been treated wvith disinfectants, there is still the possibility that microbes have already adva ced further in the dentinal tubules in the direction of the pulp and are unreachabl: by disinfectants. This can cause dentin hypersensitivities and subsequently secondary caries.

It has now been found that the prophylactic topical use of the compound s of formula or formula (11 after every preparation associated with carious defec s in 18/06 '02 DI 15:17 FAX +49 221 97311110 KUTZENBERGER WOLFF S0z23 F WO 01/45679 PCT/ER00/1315.

the dentin region can also destroy microbes which have advanced well into the Cl dentinal tubules, and that said compounds thus have an advantageous effect on the tooth-preserving procedures. For this reason, after removal of the carious regio ,s, r. the compounds of formula or formula (II) are applied to the prepared cav ties S and rubbed in. Said compounds are applied in the form of solutions, gelt or tC suspensions to form a local depot with an antibiotic action before the reliner is CN placed on and/or in the fundament of the inlays, onlays, crowns or bridges. "'his o results in the effective destruction of the residual pathogens not only on the sur:ace o of the cavity, but also in the dentinal tubules. A further advantage is that the tulbule structure is not modified or denatured here, as is frequently the case with the current procedures using dentin protecting agents and impregnating agents- The microbe-free conditions achieved in this way have a permanent beneficial effec on prosthetic procedures since dentin hypersensitivities and subsequently secondary caries are effectively avoided- The application of the compounds of formula or formula can either rep lace or complement the disinfecting treatment with hydrogen peroxide. The compo rids of formula or formula (II) can be applied in dissolved form or as a gel, optionally in the presence of solubilizers to promote a deep penetration of the chemotherapeutic agents into the dentinal tubules. Gels are used in the provisional care of dentin wounds and solutions are preferably used before the definitive fi:ting of e.g. crowns and bridges. The solutions or gels of the chemotherapeutic agents used are applied to the prepared dentin surfaces and gently rubbed in. Residue; are then removed, for example with a cotton wool swab or air jet. Inlays, onlays, crowns or bridges can then be fixed. The compounds of formula or formul; can be used in concentrations of 0.005 mg/ml to 200 mg/ml. Preftrred concentrations are those ranging from 0.5 mg/ml to 150 mg/ml and partic arly preferred concentrations are those ranging from 10 to 100 mg/m.

Topical treatment of the infected root canal and the periapical region in the conventional method normally used nowadays for the topical treatment of the infected root canal and the periapical region, failures can be expected if, ifter extensive infections of the pulp and hence of the root canal, the extremely difficult diagnosis was established incorrectly. In these cases pathogenic microbe: are 18/06 '02 DI 15:17 FAX +49 221 97311110 KUTZENBERGER WOLFF Z 024 0 0 WO 01/45679 PCT/EP00/1315; c' present in the lateral branches of the pulp, in the apical delta, in the poriapical r region and in the outer dentin layer of the pulp cavity. It is known that infected tissue cannot be completely removed with instruments in many of these c inal regions because of the anatomical conditions. The diverse branches, for exam ple Cn 5 an apical delta or lateral branches, and the medullary canals cannot norrally, be Ci reached and prepared with instruments. The usual disinfectants are also often Sunsuccessful. A particularly difficult situation arises when the microbes 1ave n advanced beyond the root canal aperture (foramen apicale). This periapical re; ,ion Scannot be reached with root canal instruments or disinfectants in the form of :oot C" 10 canal inserts.

In the conventional treatment, the pulp is removed with a nerve needle and the canal is prepared using root canal cutting instruments. This is to be understoo i as meaning the widening of the canal lumen and the removal of the infected c mal wall. The mechanical preparation is combined with the use of chemical agints.

The definitive root filling is carried out after completion of this treatment.

It has now been found, surprisingly, that the compounds of formula or fornula (II) can also be used for the topical treatment of the infected root canal and the periapical region. It was found that the compounds of formula or formula (I) destroy all the microbes occurring in the root canal and in the periapical refion, including those in all the mechanically inaccessible branches of the root canal and beyond the root tip in the periapical region. No bacterial resistances were f(und when using the compounds of formula or formula This behaviour o-i the compounds of formula or formula (II) makes it possible to dispense witj an extensive preparation in the form practised hitherto.

In the clinical use of the compounds of formula or formula the pulp residues are removed first. The preparation of the canals is carried out xwith minimum discomfort for the patient. The canals are then flushed with hydrogen peroxide. Other methods of disinfection can be omitted. The compound 3 of formula or formula in a liquid form of administration, are then introduced into the root canal under pressure using a cannula. The compounds of formul (1) or are then injected in dissolved form or in a gelatinous form of administra ion.

The root canal is subsequently occluded in the crown region, first with a cc-tton 18/06 '02 DI 15:18 FAX +49 221 97311110 KUTZENBERGER WOLFF @025

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WO 01/45679 PCT/EP00/131 c, wool plug and then with zinc phosphate cement to seal the margins. If the CE 1als Cl are not gangrenous, the antibiotics remain in the canals for 3 days. If the canal; are gangrenous, it has proved advantageous to renew the application for a further t .ree days. This treatment results in a successful therapy of infected root canals an I of e 5 the apical region. The compounds of formula or formula can be use in C- concentrations of 0.005 mg/ml to 200 mg/mI. Preferred concentrations are tlose C ranging from 0.5 mg/ml to 150 mg/ml and particularly preferred concentration- are t n those ranging from 10 to 100 mg/ml Topical application to the root canal can also advantageously be complemented. by the local injection of a solution of the compounds of formula or formula into the periodontal interstice. In this application technique, which is known I rom intraligamental anaesthesia, the tooth is completely flooded with the antibact, :rial solution of the compounds of fomnula or formula (II) in the entire root reg ion.

This effectively destroys the microbes which have invaded the periodontal interstice and the periapical region. Preferred forms of administration of the intraligamental injection are solutions of the compounds of formula or forriula (11) in concentrations of 0,005 mg/ml to 200 mg/ml. Preferred concentrations are those ranging from 0.5 mg/ml to 150 mg/ml and particularly prefe red concentrations are those ranging from 1 to 100 mg/ml.

One particular advantage of using the compounds of formula or formula is that it is possible to preserve teeth which in the past often had to be extracted o: on which a root tip resection had to be performed. The consequential costs, of preparing a dental prosthesis, can be expected to fall markedly.

Topical treatment of periodontal diseases Periodontal diseases are often the consequence of poor oral hygiene and in n any cases are completely cured by local procedures, e.g. tartar removal, However, the success depends on the pocket depth and on whether the pathogenic microbes can be removed by supragingival scaling. If this treatment procedure is not succesful, combination with the local application of antibiotics is recommended The usual procedure is the local application of tetracyclines by means of threads. These are pushed into the gingival pocket for several days. The advantage of this methc d is 18/06 '02 DI 15:18 FAX +49 221 97311110 KUTZENBERGER WOLFF 0026 Cl WO 01/45679 PCT/EPOO/131$S c. that an operative intervention can be avoided in many cases.

Cn It has now been found, surprisingly, that the compounds of formula or fon ula are also suitable for the treatment of periodontal diseases. To do this, tht oads e 5 or so-called chips impregnated with solutions or gelatinous preparations ol the compounds of formula or formula (II) are inserted in the gingival pockel A Spossible alternative is to use medicament cariers in the form of trays coverin the rn teeth and gingiva. Before they are applied, the gelatinous applications oJ the o compounds of formula or formula are instilled into the gingival pocket In CN 10 addition, the gel containing the compounds of formula or formula (II) can also be placed in the medicament carrier. This use of medicament carrieis is advantageous because the treatment time can be reduced by the rapid ons t of action to about 15 to 30 minutes, so the treatment can be carried out directly b the surgery. The compounds of formula or formula (II) can be use!t in concentrations of 0.005 mg/ml to 200 mg/mL Preferred concentrations are tiose ranging from 0.5 mg/ml to 200 mg/ml and particularly preferred concentration are those ranging from 10 to 150 mg/ml.

Periodontal diseases can also be treated by administering the compound, of formula or formula by intraligarnental injection, it being possible to use concentrations ranging from 0.005 mg/ml to 200 mg/ml, preferably from 0.5 m :ml to 200 mg/mI. For the antibiotics commonly used nowadays, such as tetracyclines, an intraligamental injection is not reasonable since these compounds wih a predominantly bacteriostatic action are quickly washed out due to the rapid iluid exchange in the periodontal interstice, and cannot develop their action. T7tracyclines can therefore only develop their effects via depot formulations. By contrast, the compounds of formula or formula (II) have a very rapid and also bactericidal action, so their residence time in the periodontal interstice is suffi ient to destroy the microbes.

The treatment procedures were characterized by being very effective in that they covered the entire bacterial spectrum involved in periodontal diseases. The cure rates were very high. As a rule, the treattent procedure was also markedly quicker than those conventionally used hitherto. Satisfactory clinical results were gene -ally obtained after only the third rest period. The prospects of success of this rovel 18/06 '02 DI 15:19 FAX +49 221 97311110 KUTZENBERGER WOLFF I027

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l WO 01/45679 PCT/EPO0/131 3 tamethod of treating periodontal diseases have been substantially improved b) the Suse of compounds of formula or formula In many cases this approach can avoid an operative intervention.

C 5 It was found, surprisingly, that when the compounds of formulae and verc applied to the gingival pocket, the gingival tissue regenerated very rapidly, rea, hed o a firm consistency and no longer bled. Accordingly, the topical and/or I scal i/ application of the compounds of formulae and (11) leads to a rapid regeneration 1 of the periodontal tissues. This in turn leads to a rapid regrowth of the tooth- 10 supporting tissues and a reattachtment of the teeth.

Topical treatment of osseomucosal wounds Bacterial infections of the bone and soft tissues in the mouth and jaw region at d in the face often have odontogenous causes. The origin is usually pulp-dead tereth, root residues, odontogenous cysts, dentitio difficilis and progressive period: ntal diseases. Odontogenous abscesses are usually exposed surgically and drained imtil the cause has been eliminated. The various infections in the oral region require different therapeutic procedures. Thus it is generally possible to dispense with a systemic chemotherapy, for example in the case of infections near alvi olar processes, whereas e.g. the treatment of phlegmons always requires the syst:i;mic administration of antibiotics. As a rule, however, combination with the to qical application of antibiotics is advisable.

It has been found that the compounds of formula or formula can als' be used for the topical treatment of osseomucosal wounds, having a beneficial e Tect on the therapy. Topical use of the compounds of formula or formula (I) normally effects a rapid subsidence of the inflammatory symptoms and an ,:,arly onset of healing. It has been observed that the healing process normally occurs much more rapidly than in the methods in common use today. The compounds of formula or formula thus have an extremely positive effect, i.e. acceler;.ting effect, on the wound healing process.

Application is effected by flushing and/or by means of strip inserts impregtrated with compounds of formula or formula They are to be used for exampl for 18/06 '02 DI 15:19 FAX +49 221 97311110 KUTZENBERGER WOLFF 1028 Cl WO 01/45679 PCT/EP00/1315 c. postoperative infections following dentosurgical interventions (extractions). For eC this purpose the gel containing the compound of formula or formula 01) is syringed directly into the extraction wound or onto a collagen sponge which remains in the extraction wound. The wound is closed for about half an ho: r by biting on a tampon. Prophylactic applications have been particularly succe:;sful after the extraction of teeth with focal infections.

Ctl tr Liquid forms of administration suitable for flushing fistulae are those contaning 0 the compounds of formula or formula in concentrations of 0.005 tg/ il to NC 10 250 mg/mn. Preferred concentrations are those ranging from 0.5 to 100 m;/ml, Forms suitable for coating strips are gels containing the compounds of formula (I) or formula as well as aqueous solutions or suspensions. These applica ions can contain the compounds of formula or formula (II) in concentrations of .005 mg/ml to 200 mg/ml. Preferred concentrations for solutions are those ranging rom 0.1 to 50 mg/ml. Gelatinous forms of administration in concentrations of 25 150 mg/ml are preferred in the case of strip inserts, Wound care Postoperative wound infections can generally occur in cases of inad&iuate infection prophylaxis following surgical interventions. Posttraumatic wound infections can arise due to cuts, stings, bruises, bites or gunshot wounds. ]Local perioperative prophylaxis can be carried out in the case of aseptic operations v ith a slight risk of infection. It is also possible to use local perioperative prophylaxis in addition to systemic perioperative prophylaxis, for example in the case of infections with an increased risk of infection, such as implantations, heart operations, transplantations, neurosurgical operations, operations in a highly contaminated area such as the oral cavity, oesophagus, rectum or c lon, hysterectomy, bile duct operations, operations on patients with lowered resis ance, or amputations. The local treatment of first, second or third degree bums cm be administered prophylactically or after infection. Antibacterial local treatment is of great benefit especially in the case of severe bums, Examples of hand infec tions are panaritiun cutaneum, panaritium subcutaneum, panaritium ossale, panalitium articulare or tendovaginitis purulenta. In postoperative sepsis the infected wounds can be rendered substantially or completely free of microbes by the t. pical 18/06 '02 DI 15:20 FAX +49 221 97311110 KUTZENBERGER WOLFF Q029 0 0 CNWO 01/45679 PCTAEP00/131;5 n- application of antibacterial agents. Gangrenes can be handled by local treat neat r n with antibiotics in addition to therapy with parenteral antibiotics, Exampl s of acute bacterial skin infections are pyoderma, erysipelas, fuurncles, carburcles, phlegmons, abscesses, ulcus cruris, diabetic foot, infected decubital ulcers, lood S 5 blisters, erysipeloids or erythrasma. Examples of chronic bacterial skin infec ions are lupus vulgaris, swimming-pool granuloma, Buruli ulcers or actinomycosis.

o Secondary bacterial infections occur for example in virus infections such as h:rpes tn simplex, herpes zoster or chicken-pox. Secondary bacterial infection; of Sdermatoses occur for example in eczema, the exudation stage ofneurodermtitis, l 10 vesicular dermatoses or contact dermatitis. Milder and moderate forms of actu and rosacea can also be treated locally. In all the cases mentioned, local applicati n of the compounds of formula or formula (II) can be used either on its own in addition to systemic application.

Local application of the compounds of formula or formula (II) has proved advantageous because the broad efficacy of these compounds also mak,:s it possible to treat mixed infections- Previous topical antibiotics have on y a restricted spectrum of action and hence are less effective. Another advantage of the compounds of formula or formula is the very rapid onset of the antibacterial action. This allows a therapeutic response while the patient is sti11 in the surgery. These compounds of formula or formula have an exce lent bactericidal action and hence are superior to the current topical antibiotics, which often have only a bacteriostatic action and accordingly have to be used much ilore frequently and for much longer periods. Another advantage of the compounms of formula or formula (II) compared with current local antibiotics is their 1ood tissue penetration. Their penetration through the intact skit also allows the successful local treatment of deeper skin infections. The fact that the compoitnds of formula or formula (II) have a considerably lower potential than conventi mal local antibiotics for the generation of bacterial resistance is to be regarded is a further advantage. This enables them to be used much more safely. Another advantage of the compounds of formula or formula (II) is a generally obser ible accelerating effect on wound healing. An additional advantage of the local use of compounds of formula or formula is the prevention of complications such as lymphangitis, sepsis or chronic local ihfections, 18/06 '02 DI 15:20 FAX +49 221 97311110 KUTZENBERGER WOLFF 030

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NC WO 01/45679 PCTEF00/131 Surprisingly, topical application of the compounds of formula or formul t (II) c has also proved particularly effective in the therapy of diabetic foot sync ome.

According to current medical practice, any lesion found to have local inflammation, with or without signs of systemic infection, demands immn diate C 5 treatment with a broad-spectrum antibiotic. It has to be taken into account here ,i that the inflammatory process normally involves a mixed infection with CrTam- O positive and Gram-negative microbes and with anaerobes and aerobes. Initially, Ll the systemic administration of amoxicillin, clavlanic acid or clindamycin, ech i o combination with a gyrase inhibitor, proved effective. According to the result of C' 10 the wound smear taken prior to the administration of antibiotics, the antibiosi s can then be targeted. However, the time required for antibiotic therapy, especia lly in the case of osteomyelitic defects, is the subject of controversial discussion. The systemic administration of high doses of antibiotics for a period of months c eems pointless if the X-ray examination shows no detectable tendency of the oste'llysis to heal; a surgical intervention will become unavoidable in such a case.

In the therapy currently used for diabetic foot, an essential prerequisite for cure without complications is a wound free of infection. Therefore, if the wond is infected, rapid and reliable treatment of the infection is of the highest priori'y. A local or systemic antibiotic therapy involves the risk of allergy anl the development of resistance. Dressings consisting of active charcoal and elentental silver have proved particularly satisfactory. Non-toxic elemental silver ccatrols local infection very effectively. Active charcoal binds microorganisms a I cell detritus and makes it possible to remove the unwanted particles when the dr :ssing is changed. Local irritations or allergies and the development of resistan:e arm excluded and the necessary moist environment is assured at the same tim. In modem wound treatment, dyes, with the exception of PVP/iodine complexc S, are no longer important as disinfectants. Potassium permanganate has dosage problems and can cause severe skin bums. Ethacridine lactate has a high tllergy rate and only a limited antimicrobial efficacy. Merbromin, which ccntains mercury, is highly toxic, impairs granulation and has disposal problems. Other dyes, e.g. brilliant green, methyl violet and fuchsin, are obsolete because o f their low efficacy and especially because of their damaging effect on the epithelium.

Accordingly, in the current state of the art, the treatment of diabetic foot is :dso in 18/06 '02 DI 15:21 FAX +49 221 97311110 KUTZENBERGER WOLFF [031

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c WO 01/45679 PCT/EP00/1311':5 need of topical and/or local antibiotics which have a high activity againsi the cn microbes occurring in wounds, have a rapid action, have a good local tolerab ility, elicit a low tendency to generate antibiotic resistance, are easy to admitister topically and/or locally, place a minimum system burden on the organism whbe applied topically/locally, have a good tissue penetration, are also suitable for the treatment of deep infections and furthermore accelerate the wound healing process.

l It has now been found that topical application of the compounds of formula or 1 formula (II) can also achieve a satisfactory outcome in the therapy of diabetic foot C 10 syndrome. This was demonstrated particularly by the fact that, in patients with severe rnicroangiopathies of the feet accompanying diabetic foot syndromnes, attempted systemic treatments with Avalox 400 (moxifloxacin) and/or Clont 400 brought no significant changes, in findings since these active ingredients were only able to achieve very low ti ssue concentrations after systemic administration because of pronounced microangiopathies. Surprisingly, however, topical application of the compound of formula or formula (II) led to significant improvements in the patholo:jical process. Ulcers of different degrees of severity (D I to D V ulcers) coulb be treated. Greasy ulcers became clean, encrusted and smaller in size and even he led completely. This treatment was successful after several topical applications o: the compounds of formula or formula at weekly intervals, said compoi ids being applied to the wound directly in dissolved form or, for example, as a gi1 or by means of impregnated compresses or dressings. These compounds of fonmula or formula can be applied to the wound in concentrations of 0.005 mg/ni to 200 mg/ml, preferred concentrations for solutions or gels being those ranging 1:,om 0-1 to 150 mg/ml- In the case of impregnated compresses or dressings, gelati.ous forms of administration can be used in concentrations of 25 150 mg/ml.

It has further been found that local and/or topical application of the compouncs of formula or formula (1J) is also beneficial in veterinary medicine. Recent stu ies have shown that, in many countries, two-thirds of dogs and more than 80% of cats over four years of age require dental treatment. Moreover, more than 10% of cats and 7.5% of dogs over 4 years of age suffer from severe periodontitis, which can lead to renal, hepatic and cardiac infections. It has now been found, surprisitgly, that the compounds of formula or formula (IT) are also suitable for the treatr tent 18/06 '02 DI 15:21 FAX +49 221 97311110 KUTZENBERGER WOLFF Q032

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Swe ol0/4S679 PCT/EPOO/1315:; of dental diseases in animals. Endodontal treatments can be carried out using, the Ce same methods and the same active ingredient concentrations of the compounc s of ci formula or formula as those explained above for treatments in human de ntal medicine. For the treatment of periodontal diseases, threads impregnated vith cM 5 solutions or gelatinous preparations of the compounds of formula or formuli (I) are inserted in the animal's gingival pooket. An alternative possibility is to use o silicone trays. The compounds of formula or formula (II) an be used in t concentrations of 0.005 mg/inl to 200 mg/ml. Preferred concentrations are tllose Sranging from 0.5 rg/tml to 200 mg/ml and particularly preferred concentration; are C1 10 those ranging from 10 to 150 mg/ml.

When foreign bodies are introduced into the oral region of an animal J r a prolonged period of time, reaction episodes can ensue, so it is often advantag aous to treat periodontal diseases with compounds of formula or formula (II) by direct instillation into the gingival pocket, by intraligamental injection or by nieans of a medicament carrier, for example a silicone tray. In the last case the anim al to be treated is anaesthetized and a lump of workable silicone impression materi. as conventionally used in human dental medicine, is pressed against the upper jaw.

After the mouth has been closed, an impression of the lower teeth is made an 1, by pressing the still plastic material, the entire marginal regions of the gingiv i are covered so as to overlap in the buccal cavity. After curing, the total impressim of the upper and lower teeth and the gingival areas is removed and a compourid of formula or formula (II) is instilled into the gingival pockets and optionally placed in the cavities of the impression. The mould is placed on the animal's jaws again. The mouth is kept closed for a further 15 to 30 minutes, allowin e the compounds of formula or formula (II) to make topical contact with the tissi e.

Topical and/or local application of the compounds of formulae aud efft cts a rapid destmrution of the bacteria and a rapid regeneration of the periodontal ti;:sues.

This leads to a rapid regrowth of the tooth-supporting tissues and a reattachm mt of the teeth. A further advantage of this method of treatment is that the ae amal's strong mouth odour is effectively and causally controlled. The compourds of formula or formula (II) can be used as solutions or gels in concentx ttions ranging from 0.005 mg/ml to 200 mg/ml, preferably from 0.5 mg/ml to 200 rrig/ml.

18/06 '02 DI 15:22 FAX +49 221 97311110 KUTZENBERGER WOLFF []033

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C WO 01/45679 PCT/EP00/131 S The compounds of formula or formula (II) can also be used in combination with CC) other anti-infective agents such as antibacterial, antifungal or antiviral substanc The compounds of formula or formula (II) can be used in concentratior.s of 0.005 mg/ml to 200 mg/ml. Preferred concentrations are those ranging froir mg/m to 200 mg/ml and particularly preferred concentrations are those ran ing Sfrom 10 to 150 mg/ml.

o The compounds of formula or formula can be used as solutions, :els, N- 10 suspensions, emulsions or liposomes or in micelles. Examples of solutions are aqueous solutions in the presence of solubilizers. Examples of solubilizer are salts, polyols, sugar alcohols, polyglycols or co-solvents such as glycerol, ethy 'ene glycol, propylene glycol, furfiral, N,N-dimethylformamide, methanol, ethantl ipropauol, n-propanol or acetone. Aqueous gels are prepared by the additio of gelling agents such as pectins, ethylene glycol monomethacrylate gel, algin:tes, hydroxyethyl cellulose, carboxytnethyl hydroxyethyl cellulose, polyglyceryl methacrylates or polysacchaides. Other suitable additives are thickeners suc' as cellulose, alkyl cellulose, hydroxyethyl cellulose, agar-agar, carboxymethyl .,,ar and cellulose ethers, or hydrotropic solubilizers such as ethylenediarnine, ure i or cyclodextrins. The galenical forms can also contain solubilizers such as surfactants, of preservatives. Examples of possible suspension constituents are tragacanth, cellulose, wetting agents, glycols, polyols, mucins or cellulose etl era.

Possible emulsion constituents are emulsifiers such as polysorbates, surfact; nts, lecithins, mucins, gelatin or carboxymethyl cellulose. Other suitable form: of administration are dental pocket inserts consisting of an inert carrier mate:ial, which are impregnated with the active ingredient and optionally other auxilary substances and gradually release the active ingredient by dissolution. Example 3 of possible forms of administration for root fillings are tampons, cotton wool plug or foam pellets. Application in the case of soft tissue infections can be effected ,Vith strips or thread inserts. It is also possible to use pharmaceutical substance.; or auxiliary substances for osmotic adjustment, Other possible auxiliary substa .:ces for formulating the compounds of formula or formula (It) are antioxidi ats, chelating agents, disinfectants, dispersants, emulsion stabilizers, hydrocollc.ids, preservatives, solubilizers, wetting agents, quaternary ammonium compounxds, stabilizers, suspending agents or thickeners. The above-mentioned constituents can 18/06 '02 DI 15:22 FAX +49 221 97311110 KUTZENBERGER WOLFF ]034

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c WO 01/45679 rCT/EP00/1315 c- also be used in combination with one another.

Suitable stable gelatinous fonmulations are those which, apart from the oompol nds of formula or formula are composed ofpolycthes, modified celluloses and M 5 water. Preferred gel formulations are those containing the compounds of formula or formula (11) in mixtures of propylene glycol, Tween 20 solution and r:uc.

o hydroxyethyl cellulose. Preferred compositions consist of compounds of fortrula ir or formula (II) in amounts of 0.001 to 100 mg/ml, polypropylene glycol in amounts of S to 250 mg/ml, 1% Tween 20 solution in amounts of 5 to 200 tM Aml and muc. hydroxyethyl cellulose ad 1 g/ml, Particularly preferred gelati ous formulations consist of the compounds of formula or formula (11) in amoun s of 1 to 100 mg/ml, propylene glycol in amounts of 50 to 200 mg/ml, 1% Tweet solution in amounts of 3 to 150 mg/ml and muc. hydroxy cellulose ad 1 g/ml.

The Examples which follow serve to illustrate the present invention without however limiting the general spirit of the invention, 18/06 '02 DI 15:23 FAX +49 221 97311110 KUTZENBERGER WOLFF 035 WO 01/45679 PCT/EP00/131!

EXAMPLES

Examples ofdifferent formulations Example 1: Moxifloxacin HC1 solution moxifloxacin hydrochloride aqua pro injectione 500 mg ad 100 ral Example 2: High-viscosity formulation moxifloxacin HCI gel moxifloxacin hydrochloride hydxoxyethyl cellulose propylene glycol distilled water ad .0 g 0.5 g s. g 10.0 g Example 3: Low-viscosity formulation with stabi lzer: moxifloxacin HC1 gel moxifloxacin hydrochloride L .0 g hydroxyethyl cellulose 0.25 g propylene glycol 1.5 g 1% Tween 20 solution 1.0 g distilled water ad 10,0 g 18/06 '02 DI 15:23 FAX +49 221 97311110 KUTZENBERGER WOLFF 036 In

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C WO 01/45679 PCT/E00/131 ;Z Example 4; Moxfltoxacin HC1 gel e 5 moxifloxacin hydrochloride 0.1 g hydroxyethyl cellulose 0.25 g 0 propylene glycol 1.5 g It 1% Tween 20 solution 1.0 g N A. Endodontal diseases A.1. Topical treatment ofpulpitis due to carious diseases Patiext A 1.1 (male, 43 years). Clinical diagnosis: tooth 24, mesial carious defect (enamel/dentin), tooll vital, increased sensitivity to cold. Course of treatr tent: removal of caries- Residual dentin covering very slightly softened. Pellet ii:sert impregnated with moxifloxacin hydrochloride gel (25 mg/ml), provisional c:vity occlusion- Check-up after 4 days: patient was symptom-free. Relining with dropsin, final filling with composite. Check-up after 3 weeks; tooth vital, p2 tient symptom-free.

Patient A 1.2 (male, 33 years). Clinical diagnosis: teeth 11, 13, major dista: and mesial carious defects (enarnel/dentin), all teeth vital, tooth 11 sensitive to ;old, tooth 13 slightly sensitive to heat. Course of treatment: removal of c;ries.

Residual dentin covering hard. Pellet inserts with moxifloxacin hydrochlorid,: gel mg/ml), provisional cavity occlusion. Cheek-up after 1 week: teeth 11 ar d 13 symptom-free. Relining with dropsin, final filling with composite. Check-up after 14 days: teeth vital, patient symptom-free.

Patient A 1.3 (female, 18 years). Clinical diagnosis: tooth 24, major distal calious defect (enamel/dentin), tooth vital, sensitive to cold, sweet and sour. Coun .e of treatment: removal of caries. Residual dentin covering hard. Pellet insert with moxifloxacin hydrochloride gel (25 mg/ml), provisional cavity occlusion. Cl eckup after one week; still slight discomfort of unknown origin, repetition of ii sert.

18/06 '02 DI 15:24 FAX +49 221 97311110 KUTZENBERGER WOLFF E037

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WO 01/45679 FCT/EF00/1315 Check-up after 3 days: tooth vital, patient symptom-free, Relining with dro' sin, Sfinal filling with glass ionomer.

Patient A 1.4 (male, 23 years). Clinical diagnosis: tooth 11, major mesial car ous M 5 defect, tooth vital, sensitivity to heat and cold, night pain. Course of treatrent: C- removal of caries. Residual dentin covering slightly softened. Pellet inserts 'vith 0 moxifloxacin hydrochloride gel (50 mg/ml), provisional cavity occlusion. Ch::ck- T up after 7 days: patient symptom-free, tooth vital. Relining with zinc phosp iate o cement, final filling with glass ionomer Patient A 1.5 (male. 43 years). Clinical diagnosis: tooth 13, major distal car ous defect, tooth weakly vital, sensitivity to cold, night pain Courae of treattrient: removal of caries. Residual dentin covering hard. Pellet insert with moxiflox icin hydrochloride gel (50 mg/ml), provisional cavity occlusion. Check-up after 4 d 3yse patient symptom-free, tooth vital. Relining with dropsin, final filling with composite.

Patient A 1.6 (female, 42 years). Clinical diagnosis: tooth 36, major me.sial carious defect, tooth with reduced vitality, sensitivity to cold and heat, night fain.

Course of treatment: removal of caries, pellet insert with moxiflox win hydrochloride gel (50 mg/mi), provisional cavity occlusion. Check-up after 6 d iys: still slight sensitivity to heat and cold. Repetition of insert. Check-up after 7 d6ys: patient symptom-free, tooth vital. Relining with zinc phosphate cement, :inal filling with composite- Patient A 1.7 (female, 18 years). Clinical diagnosis: tooth 44, major musial carious defect, tooth with reduced vitality, sensitivity to cold, night pain. Couxf; e of treatment: removal of caries. Residual dentin covering slightly softened. P,llet inserts with moxifloxacin hydrochloride gel (50 mg/ml), provisional csvity occlusion. Check-up after 4 days: patient symptom-free, relining with inc phosphate cement, final filling with composite.

Patient A 1.8 (male, 38 years). Clinical diagnosis: tooth 36, major distal catm oti defect, tooth with reduced vitality, sensitivity to cold, heat, sweet and sour, slightly sensitive to percussion, night pain. Course of treatment: removal of caies.

0/~0 rhn ~T Io/uo uc ui 1 :Z4 FAA +49 22 97311110 KUTZENBERGER WOLFF 0O38

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C WO 01/45679 PCT/Poo/13155 Residual dentin covering slightly softened. Pellet insert with moxiflo acin eC hydrochloride gel (50 mg/ml), provisional cavity occlusion. Check-up axter 3 weeks: patient symptom-free, tooth vital, relining with zinc phosphate, final J illing with composite.

Patient A 1.9 (female, 50 years). Clinical diagnosis; tooth 27, major distal cetious 0 defect, tooth vital, sensitivity to cold, slight sensitivity to heat, slight night pain.

Course of treatment: removal of caries. Residual dentin covering softened. 'ellet insert with moxifloxacin hydrochloride gel (25 mg/ml), provisional occlusion- NC 10 Check-up after 7 days: patient symptom-free, tooth vital, Patient A 1.10 (male, 17 years). Clinical diagnosis: teeth 16, 17, 27, 36, 3 1 46 with occlusal caries, teeth vital, sensitivity to cold, sweet and sour, sometim zs to heat, not localizable. Course of treatment; removal of caries. Residual d ntin coverings hard. Pellet inserts with moxifloxacin hydrochloride gel (50 mg/ml), provisional cavity occlusion. Check-up after 14 days: patient symptom-free, :eeth vital. Relining with dropsin, final filling with composite.

Patient A 1.11 (male, 33 years). Clinical diagnosis: tooth 22, distal carious d fect (enamel/dentin), tooth vital, slight sensitivity to heat. Course of treatment: ren oval of caries, residual dentin covering very slightly softened. Pellet insert impregi ated with grepafloxacin gel (25 mg/ml), provisional cavity occlusion, Check-up af:er days: patient was symptom-free. Relining with zino phosphate cement, final 65 ding with composite, Check-up after 4 weeks: tooth vital, patient symptom-free.

Patient A 1.12 (male, 38 years). Clinical diagnosis: teeth 22, 23 with major distal carious defects (enamel/dentin), teeth vital, sensitivity to cold. Course, of treatment: removal of caries, residual dentin covering hard. Pellet inserts with grepafloxacin gel (50 mng/ml), provisional cavity occlusion. Check-up aft r 1 week; teeth symptom-free. Relining with dropsin, final filling with composite.

Check-up after 14 days: teeth vital, patient symptom-free.

Patient A 1.13 (female, 48 years), Clinical diagnosis: tooth 14, major m::sial carious defect (enamel/dentin), tooth vital, sensitivity to cold and sour. Courne of treatment: removal of caries, residual dentin covering hard. Pellet insert w'ith 18/06 '02 DI 15:25 FAX +49 221 97311110 KUTZENBERGER WOLFF Q039 0 0 c- WO 01/45679 PCT/EP00/131 ;Z gemifloxacia mesylate gel (25 mg/ml), provisional cavity occlusion. Chec k-up after 3 weeks: still slight discomfort. Repetition of insert. Check-up after 4 lays: tooth vital, patient symptom-free. Relining with dropsin, final filling with glass ionomer.

3- Patient A 1.14 (male, 53 years). Clinical diagnosis: tooth 13, major mesial ca ious o defect, tooth vital, sensitivity to heat, night pain. Course of treatment: removal of caries, residual dentin covering slightly softened. Pellet inserts with levoflo, acin Sgel (50 mg/ml), provisional cavity occlusion. Check-up after 14 days: pztient N 10 symptom-free, tooth vital. Relining with dropsin, final filling with composite.

Patient A 1.15 (male, 22 years). Clinical diagnosis: tooth 44, major mesial Co ious defect, tooth vital, sensitivity to cold, night pain. Course of treatment; remov i of caries, residual dentin covering leathery. Pellet insert with trovafloxacin mesffate gel (50 mg/ml), provisional cavity occlusion. Check-up after 9 days: pa ient symptor-free, tooth vital. Relining with dropsin, final filling with composite.

Patient A 1.16 (female, 15 years). Clinical diagnosis: tooth 46, major d istal carious defect, tooth with reduced vitality, sensitivity to cold and heat. Coun;e of treatment: removal of caries, pellet insert with sparfloxacin gel (25 mgml), provisional cavity occlusion. Check-up after 4 days: still slight sensitivity to 1.eat.

Repetition of insert. Check-up after 14 days: patient symptom-free, tooth vital.

Relining with dropsin, final filling with composite.

A 2, Prophylaxis of dentin wounds Patient A 2,1 (male, 30 years). Clinical diagnosis: teeth 33 and 36, carious delfsets on both teeth. Teeth vital. Course of treatment: preparation of teeth 33 and 36.

Maing-up of provisional bridge. Application of nmXifloxacin hydrochlcride solution (25 mg/ml) to cavity, drying in gentle air jet. Fixing of bridge with provisional cement. After 8 days, definitive insertion of bridge with :anc phosphate cement. Check-up after 3 weeks: patient symptom-free, Patient A 2.2 (male, 48 years). Clinical diagnosis: teeth 22, 23, 24 with sm all distal carious defects (enamel/dentin), all teeth vital, sensitivity to cold. Course of 18/06 '02 DI 15:25 FAX +49 221 97311110 KUTZENBERGER WOLFF 040

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C WO 01/45679 PCT/EPOD/1315 treatment: removal of caries, smear with moxifloxacin hydrochloride solution c mg/ml), provisional cavity occlusion. Check-up after 2 weeks: teeth symptom-: ee.

Relining with dropsin, final filling with composite. Check-up after 4 weeks; It eth vital, patient symptom-free.

SS

Patient A 2.3 (female, 28 years). Clinical diagnosis: teeth 14, 15, 16, 17 with o cervical erosions (enamel/dentin), sensitivity to cold and sweet. Cours: of Ci ln treatment: preparation, smear with moxifloxacin hydrochloride solution Smg/ml), gentle drying in air jet. Adhesive restoration with composite. Check-up C 10 after 3 weeks: patient symptom-free.

Patient A 2.4 (male, 33 years). Clinical diagnosis: teeth 11, 12, 21, 22 with carious defects in first third of dentin, teeth vital, Course of treatment; prepar;tion for ceramic crowns. Smear with moxifloxacin hydrochloride solution (25 mg ml), drying in gentle air jet, insertion of provisional crowns. After 14 days, inserticn of definitive crowns with zinc phosphate cement. Check-up after 3 weeks: pa ient symptom-free.

Patient A 2.5 (male, 62 years). Clinical diagnosis: tooth 44, mesial carious d :fect in first third of dentin, sensitivity to cold. Course of treatment: removal of c, des, smear with moxifloxacin hydrochloride solution (25 mgtml), provisional c; vity occlusion. Cheek-up after 9 days: patient symptom-free. Relining with dropsin, final filling with composite.

Patient A 2.6 (female, 18 years). Clinical diagnosis: tooth 43, distal carious defect in first third of dentin. Course of treatment: removal of caries, smear with moxifloxacin hydrochloride solution (25 mg/ml), relining with dropsin, final fi fling with composite. Patient failed to attend check-up, Patient A 2.7 (female, 28 years). Clinical diagnosis: teeth 15, 14, 13, 12, 11, 21, 22, 23, 24, 25 with cervical erosions, severe hypersensitivity. Course oftreatrient: cleaning of eroded regions, smear with sparfloxacin solution (50 mg/ml), g ntle drying in air jet. Adhesive restoration with composite.

Patient A 2.8 (female, 33 years). Clinical diagnosis: teeth 13, 14, 15 with mesial 18/06 '02 DI 15:25 FAX +49 221 97311110 KUTZENBERGER WOLFF 4041

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c WO 01/45679 PC PCTIEPOO/J31 Sand distal carious defects in fist third of dentin, sensitivity to cold. Cor ;e of m treatment: preparation of cavities, removal of caries, smear with trovaflo acin mesylate solution (25 mg/ml), drying in gentle air jet. Adhesive restoration with glass ionomer cement.

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A.3. Topical treatment of the infected root canal and the periapical region 0 c Patient A 3.1 (female, 40 years), Clinical diagnosis: tooth 45, apical periodo titis due to pulpitis purulenta, slight bite discomfort. Slightly widened period ,ntal N 10 interstice in X-ray, not gangrenous. Course of treatment: canal preparation clown to apex. Canal insert with moxifloxacin hydrochloride solution (100 mg/m by syringe then topping-up with moxifloxacin hydrochloride gel (100 mg ml), provisional occlusion. Check-up after 3 days: patient symptom-free, root fi ling with endomethasone. Check-up after 14 days: patient still symptom-free, inal filling with composite.

Patient A 3.2 (male, 70 years). Clinical diagnosis: tooth 23, gangrenous, bite discomfort. X-ray normal. Course of treatment: canal preparation down to a 'ex, canal insert with moxifloxacin hydrochloride solution (100 mg/ml) by syringe, hen topping-up with moxifloxacin hydrochloride gel (100 mg/ml), provisi mal occlusion. Check-up after 14 days: patient symptom-free, canal odourless. Ioot filling with endometbasone.

Patient A 3.3 (female, 22 years). Clinical diagnosis: tooth 11, apical periodontitis due to gangrene, bite discomfort. Widened periodontal interstice in X-ray, Course of treatment: canal preparation down to apex, canal insert with moxifloxtcin hydrochloride solution (50 mg/ml) by syringe, then topping-up with moxifloxtcin hydrochloride gel (50 mg/ml) and intraligamental injection of moxifloxa:cin hydrochloride solution (50 mg/ml). Provisional occlusion. Check-up after 3 d:ays: patient symptom-free, canal odourless, Patient A 3.4 (male, 40 years). Clinical diagnosis: tooth 11, apical periodon'tis due to pulpitis purulenta, not gangrenous, bite discomfort. Widened periodoxtal interstice in X-ray. Course of treatment: canal pteparation down to apex, root catal insert with moxifloxacin hydrochloride gel (50 mg/ml), provisional 18/06 '02 DI 15:26 FAX +49 221 97311110 KUTZENBERGER WOLFF [1042

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c WO 01/45679 PCTEPona/317 occlusion. Check-up after 3 days: patient symptom-free. Root filling vith Sendomethasone, provisional occlusion. Check-up after 3 weeks: patient still symptom-free. Final filling with composite.

Ce 5 Patient A 3.5 (female, 43 years). Clinical diagnosis: tooth 35, apical periodoi titis due to gangrene, slight bite discomfort. Weak translucence visible in X ray.

0 Course of treatment canal preparation down to apex not possible. Root c mal insert with moxifloxacin hydrochloride solution (50 xng/ml) by syringe, hen o topping-up with moxifloxaoin hydrochloride gel (50 mg/ml) and intraligamcntal N 10 injection of moxifloxacin hydrochloride solution (50 mg/ml). Check-up aflr 7 days: no gangrenous odour, no bite discomfort. Root filling with N2 med cal.

Check-up after 7 days: patient symptom-free. Final filling with composite.

Patient A 3.6 (male, 29 years). Clinical diagnosis: tooth 36, apical periodor titis due to gangrene, bite discomfort. X-ray normal. Course of treatment: c:mal preparation down to apex, root canal insert with moxifloxacin hydrochloride gel mg/ml) and intraligamental injection of moxifloxacin hydrochloride solu ion mg/ml), Check-up after 8 days: no gangrenous odour, patient symptom- ree- Root filling with N2 medical. Check-up after 3 weeks: patient symptom- ree.

Final filling with composite.

Patient A 3.7 (female, 50 years). Clinioal diagnosis: tooth 14, apical periodon titis due to gangrene. Slight bite discomfort. Weak translucence in X-ray. Cours of treatment: canal preparation down to apex, root canal insert with moxifloxtcin hydrochloxide gel (100 mg/ml) and intraligamental injection of moxifloxicin hydrochloride solution (50 mg/ml), provisional occlusion. Check-up after 7 d iys: patient symptom-free. Root filling with endomethasone. Check-up after 3 weAks: patient still symptom-free. Final filling with composite.

Patient A 3.8 (female, 42 years). Clinical diagnosis: tooth 34, apical periodo titis due to gangrene, bite discomfort. Weak translucence visible in X-ray. Cours 3 of treatment: canal preparation down to apex not possible. Root canal insert 'vith moxifloxacin hydrochloride gel (50 mg/ml) and intraligamental injectior of moxifloxacin hydrochloride solution (50 mg/ml), provisional occlusion. Cheo .up after 13 weeks: patient symptom-free, canal odour-free. Root filling with 18/06 '02 DI 15:26 FAX +49 221 97311110 KUTZENBERGER

WOLFF

S043 W 01/45679 PCT/EP00/13:i ;Z endomethasone, final filling with glass ionomer.

Patient A 3.9 (female, 17 years). Clinical diagnosis tooth 46, apical period( ntitis due to pulpitis purulenta, slight bite discomfort, tooth not gangrenous. SIlghtly widened periodontal interstice at mneial root in X-ray. Course of trealment: c anals prepared down to apex, root canal insert with moxifloxacin hydrochloxide gel (100 mg/ml) and intraligamenta injection of moxifloxacin hydrochloride solutio1 Nmg/ml). Check-up after 7 days: patient symptom-free. Root filling with endomethasone, final filling. Patient failed to attend subsequent check-up.

Patient 3.10 (female, 24 years). Clinical diagnosis: tooth 14, fistula in ro t tip region, tooth gangrenous. Slight bite discomfort Course of treatment: canal preparation down to apex, Canal and tistula flushed with moxiflo, acin hydrochloride solution (50 mg/ml) by syringe, canal insert with moxiflo)acin hydrochloride gel (50 mg/ml) and intraligametal injection of moxiflo, acin hydrochloride solution (50 mg/ml). Canal occluded only with cotton wool plug.

Check-up after 3 days: patient still not completely symptom-free. Canal still had very slight gangrenous odour. Repetition of flushing with moxifloxacin hydrochloride solution (50 mg/mi) and canal insert with moxiflo aci hydrochloride gel (50 mg/ml). Check-up after 8 days: patient symptom-free- I ot filling with endomethasone. Check-up after 3 weeks; patient symptom-free. linal flling with composite.

Patient A 3.11 (male, 51 years). Clinical diagnosis: tooth 34, apical periodor titis due to pulpitis purulenta, not gangrenous, no bite discomfort. Fistula in roo tip region. Weak translucence in X-ray. Course of treatment: canal preparation down to apex not possible at palatinal root. Root canal insert with moxifloxAcin hydrochloride gel (100 mg/ml), provisional occlusion. Check-up after 10 d ys: patient symptom-free. Root filling with endonAethasone. Patient failed to at and check-up.

Patient A 3.12 (femnale, 34 years). Clinical diagnosis: tooth 44, fistulation, bite difficulties, gangrenous. Course of treatment; canal preparation down to a:ex, Root canal insert with moxifloxacin hydrochloride solution (50 mg/mnl) using paiper point and intraligamental iqjection of moxifloxacin hydrochloride solution 18/06 '02 DI 15:27 FAX +49 221 97311110 KUTZENBERGER WOLFF ]044

O

c WO 01/45679 _^PCT/EPO/13:; c- mg/ml), provisional occlusion. Check-up after 8 days: patient symptom-free. Root m filling with endomethasone, final filling with composite, Patient A 3.13 (female, 78 years). Clinical diagnosis: tooth 15, apical period.atitis due to pulpitis purlenta, slight bite discomfort, not gangrenous. Cour;e of Streatment: canal preparation down to apex, canal insert with moxiflotacin o hydrochloride solution (50 mg/ml) by syringe and then topping-up with n moxifloxacin hydrochloride gel (50 mg/ml) and intraligamental injectica of o moxifloxacin hydrochloride solution (50 mg/ml), provisional occlusion. Chei k-up after 9 days: patient symptom-free, root filling with endomethasone. Che k-up after 10 days: patient still symptom-free, final filling with composite.

Patient A 3.14 (male, 30 years)_ Clinical diagnosis: tooth 13, gangrenous, bite discomfort, X-ray normal. Course of treatment: canal preparation down to ;pex, canal insert with moxifloxacin hydrochloride solution (50 mg/ml) by syring( and then topping-up with moxifloxacin hydrochloride gel (50 mg/ml) and intraligamental injection of moxifloxacin hydrochloride solution (50 mg'ml), provisional occlusion. Check-up after 10 days: patient symptom-free, anal odourless, root filling with endomethasone.

Patient A 3.15 (female, 32 years). Clinical diagnosis: tooth 31, apical periodo: ttitis due to gangrene, bite discomfort, widened periodontal interstice in X-ray. Ccurse of treatment: canal preparation down to apex, canal insert with moxiflo,,acin hydrochloride solution (50 mg/ml) by syringe, then topping-up with moxiflo:iacin hydrochloride gel (50 mg/tul) and intraligamental injection of moxiflo~acin hydrochloride solution (50 mg/ml), provisional occlusion. Check-up after 9 cays: patient symptom-free, canal odourless.

Patient A 3.16 (male, 40 years). Clinical diagnosis: tooth 46, apical periodor titis due to pulpitis purulenta, not gangrenous, widened periodontal interstice visib e in X-ray. Course of treatment: canal preparation down to apex, root canal insert with grepafloxacin gel (50 mg/tnl), provisional occlusion. Check-up after 3 wceks: patient symptom-free- Root filling with endomethasone, provisional occhuion.

Check-up after 1 week: patient still symptomn-free, final filling with composite.

18/06 t02 DI 15:27 FAX +49 221 97311110 KUTZENBERGER WOLFF Q4 045 ci WO 01/4$679 PCT/EPooII 315.- ;Z ~Patient A 3.17 (femnale, 33 years), Clinical 'diagnosis:, tooth 32, apical penio'lontitis due to gangrenae, slight bite discomnfort weak translucence visible in X-ray. ,-outgo ci ~Of treatment:- canal preparation down~ to Vpex not possible, Root ca"a inse t with grepafoxacjn solution (20 mg/i) by Syringe, then tpping',up with grepafl xacin (20 mng/mI) and ttraligarnentaj injection Of grcpafloxacjn solution (50 ag/rnI).

r-Check-up after 6 days; no gangrenous odour, no bite cbscornoron Root iln N2 medical. Check-np alter 4 days: Patient syxnpom-free- Final fillinW with composite.

ci 10 Patient A 3.18 (female, 55 years). Clinical d ciagnosis. tooth 34, apical periodtntitis dlue to gate, slight bite disconfort, weak translucence visible in X-ray. C 'urse of treatment: canal preparation down to apex, root canlaj itsert with trovallo (Scin mesylate gel (100 mg/mi) anid intraligaruental injection oftrvfoameyle Sol tio 0 m /m rov si nal oclus jon C hleck-up after 12 days: tient symptommfee. Root filling wjth tndomietjazone Check-up after 3 weeks: pa;ienxt Still symptom-ffte 0 Final filling with composite Patient A 3.19 (female, 22 years) Clinical1 dia&gnosis: tooth 11, apical periodoi titis due to ganglrena, simaplex- Course Of treatme~nt; canal preparaton down to ape): not possible, Root canal insert with trovafloxacin niesylate solution (50 mg W), pr7ovisional occlusion. Check-up after 3 weeks;: patient sytaptoin-Irege, canal od,-ur- free. Root filling wvith endomethasone, final filling wvith glass ioflomer.

Patient A 3.20 (femnale, 77 yeaz,7), Clinical diagnosis: tooth 47, apical Perfodonjitig due to pulpitis purulenta, tooth not gangreu®is slightly widened periodontai interstice at mesiat root visible in X-ray. Coureot tetet aasprp.e down to apex. R~oot canal insert with tou xofn tosylma: gels 0nrai) Check-UP alter 8 days;, Patient syMptom..free 0 Root filling with endomethaso ie, final filling. Patient failed to attend subsequent check-up.

Patient A 3.21 (female, 54 years). Clinical diagnosis:- tooth 22, fistula in root lip region, tooth gangrenous, slight bite discomfort Course, of treatment. cac a] preParaliOn cloN to apex, canal and fistula flushed with moxtflox&.in hyd cfro~~ so uti n 0 m /mI bys yrge, ca al inse t w ith mioxifloxac n hydrochloride gel (50 rag/m) anid intra-9ligamenita injection of moxifloxa 18/06 '02 DI 15:28 FAX +49 221 97311110 KUTZENBERGER

WOLFF

0 WQ 0114:5679 PCTTpfo, t3155 ;Z h~dX-Q~h ol oution (50) mg/rmu. CanalI occluded only with cotton W 'I plug Check-up after 8 daya: patient still not Muly SYflPtomn.free, caastlVidv c-i slight odour. Repotition oIf flushing and insert. Chc pae t1 das patebt sympoinii-e R ot illng with endo mne wasone. C heok-up after I week: patient S YMPtom..fr 6 e, Final filling with composite.

CiPatienlt A 3.2.2 (male, 50) year-s). Clinical diagnosis: toot 35, apical perloc ontitjs c-idue to p'4Piti,, putulenta, not gangrenous, no bite discomnfort, Course of treitment. canal Prep-aration down tQ apex, root canal insert withL tosufioxacin tosylate l(0 o 10 Mg/mI), ProvisionA4 occlusorL Check-up after 10 days: pain(rpo, -re ciO -Ro tflling with endomnetl-asone, a s Patient taile to tten che keup Patient A 3.23 (tamnale, 64 years), Clinical diagnosis' toothi 34, flstulatio 1 bite diffcujtjes 8 gangenous. Course of treatment. c-anal Preparation down to apm., root canal insert with grepafloxacjn solution (50 mg/cu) using paper point, ntraligamental injection of geafioxacin solution (50 mnglia!), Provisional occlision.

Chec-upafter 10 days: patient sympton-fie Root filling With endomnetia,;one, final fiflig with composite.

B. Toicat fratrnent c/periodonztal iseases7 -Patient IB I (female, 3.3 years), Clinical diagnlosis: teeth 26 and 27, mari'inal Periadontitis with exposed root cement, pocket depths of 4 to 5 mm, strong to notr ex ore. Course of treatrnent: reazoval Of concremont by ultratsond and nana1 fl, thread insert with Zuoxifloxacin hydrooblolider ue (5 mgm)yoeig't Gingipac gffgival dressing, Check-up after 3 days: patient symptom-rnft &ulgrval reginS and pockets inflaanmation.free.

]Patient B 2 (female, 60 yeatt). Cida igoi:teh1 o1,sVr ag a periodontitis with exposed root ceMent, pocket depthsq of 5 to 6 mm. Course of teatment: removal of concrement by ulfrasotj thread insert With inoxifoxaj in after oo4 d gatelt (50 mn l o vc i wIh G ingipac gingival dressing. Che k- V p afte 4 ays pat ent a i pto fi-e o g in g iv al reg io nas an d p o ck ets in flam nzatio u..f t. e.

Patient BR 3 (male, 49 years). Clinical diagnosis, teeth 24 to 28, Margin -11 t046 18/06 '02 DI 15:28 FAX +49 221 97311110 KUTZENBERGER WOLFF Ej047 o WO 01/45679 P ro o t 5 wil ex o e ro t e enpocket depths of 4 to 6 nun. Cc: ursge of treatmnt: removal of cncrement by Ultra sund and maUaly, thedins( rt wit m'oXinOxaCin hydrochloride (50 mIn), covering wVit Gingipac gingival d~essing.

Check-up atbor 5 days: patient SYxnptora-free gingiVal regions and I ocke-ts SIUnflaxmnationfree Ci Patient B 4 (femnale, 20 years). Clinical diagnosis: raarginal periodontti in entire 0 ~~upper- and lower jaw region, stron2g foetor exc or)eocedptsf4to nm CouIrse of treatment: r~emoval of "cOlrerent by ultrasound, Medicinal spln: -with 0 10 moxifloxac, 0 hydrocbaoxide gel (0.25 Mg/nd) worn for 10 Minutes/day for 4 days.

ci Check-up after 3 days: patient MYnptorn-free no0 more iZnflarrUnatory phenCmea present.

Patient U 5 (female, 53 years), Cliical diagnosis' toot 37, Tnagr periodc rititis With exposed root cement, Pocket depths of 5 mmi, strong foetor cxoreCw eo treatment; removal of concrement by ultrasound and manulally, thread insert with moxifloxacin hydrochloride gel (50 rng/mI), cOve-tng with CJingipac ginijval dr~essing. Check-up after 8 days: patient symptom-fiee, gingival regions and Pockets inflammnation-free.

-Patient IS 6 (feumale, 30 years)- Clial diagnosis' teeth 25 28, severe Inert cue! periodontiuis with exposed root cement, pocket depths of 4 runt Coust of trleatment: removalJ of concrement by ultraoun± hedise ihmxfo;c hydrochloride gel rag/mi), ifltra~igamental injiection of *fOXifloxL tin hydro chloride solution (50 rug/mI), covering with 3 ingipao gingival dress;, rg.

Check-up after 10 days: patient syrnptom..free, gingival regions and pocliets inflammaton-.fre Patieut B 7 (mnale, 35 years). Clinical diagnosis; teeth 14 17, marginal pet odontitj 5 with exposed root cement, pocket depths of 4 mw. Course of treatme It: removal of concremnent by ultrasound and manaually, th~read insert wi th grepafloxacj 1 x gel (50 rug/rai), Infrahgarntal injection of grepafloxaej 0 solutj:,n thg/mI), coveijrig with Gingipac ginagival dressing. CheckCup alter 9 da~s: patient &Ytptom..free. gingival regions and pockets inflanmation..free.

18/06 '02 DI 15:29 FAX +49 221 97311110 KUTZENBERGER WOLFF Qd 048 0W O 01/4567 9 C M 6 Y1 Painn f ma;3 er) Clinical diagnosis: marginal periodontiuis :,ac entire IIpper and lower jaw re'-Ion, Strong t'oetor ex ore, pocktdph f n c iC r s e f o fa i W e a t e t r e m l o f c o c e m n t b y u fr a s o u n d a n d i c i n a l s p l a t w i t h tro afi xacn m sylte el(0-25 mg/nj9 worn for 10 minutes/day r 'i days- S C h ec k -u p after 6 d ay s p ati e nt y pt f fr i f a n a io p h o m lu o ge SYenlfeifaMtinpeo~ olne present.

Ci C Topical freatment Of OsseomlcosaJ wound, Patiejzt C I (male, 14 years). Clinical diagnvsig: teeth 0i1 and 012, woun, I care after extractiom4 reinPianted teeth- Course of treatment: resorption, anilylos is and sequtrut, in X-ray. Excoobleation after wound care. Application of deot of moxifioxacin hyd-roofflodde gel (50 mg/mI) by gauze strip. Check-up after 3 days, patient SYMPtoim-free, good wound m~argin adaptation.

Patent U 2 (male, 16 year), Clinic-al diagnosis: reglo 36, wound care after i -ajor Surgical interventions, slight submueoaj swelling, fistulation on toot] 36 followtg9 PUlpitis purglent&. Course of treament: incision 7 flushilng %it mnoxiflOxacin hydroclofide solution (so rngI1), strip inlsert with moxiflo, acmn hydrochloride gel (5o umg/mi). Checlc tU, after 3 days* patient sYmptom-faee, :ood rapid heating process Patient C 3 (female, 34 Years)- Clinical diagnosis: teeth 26 and 46 with ajical granuloma 8 severe bite discomfort Course of treatmnent: extraction at iaflainmato 0 stage (osteotomy), no Suture, Wound care with gauze impregnit ted with moxifloxacn 1 hydtochlorde gel (50 tmg/ml). Chekup after 2 days: pati ent SYMtptar-free.

Patient C 4 (femat;p 34 years). Clinical diagnosis: tooth 48, impacted ;.o displaced- Course of treattment: wound care following major surgical ilntervxt-lon (osteOtomy), wound care with1 ga"uze impregnated with moxifnoxacin hydrocmoride gel (50 mg/mil). Wour4 cloeure with two button sutures. Check-up after 2 da's: slight wound pai, no POstoperative Cedema, Check-up atroewe:rmvlIo Sutures, good woud margin adaptationl patient symptom-frce.

18/06 '02 DI 15:29 FAX +49 221 97311110 IUTEBRR&WOF j04 KUTZENBERGER WOLFF Q049 0WO 01/45679 PCTIEP00wI, 155 ;Z4Ptient C S (M4ale, -52 years) Clinical digoi:tooth r..lPltzS P14 Jlefla, fiStUltion, SubmucosaJ swelling. Course of' treatment: trepanaion, in :,sjon 1 c-i flushing of root canal and fistula with Inoxifioxacin hydrochloride s;olutii 'n mg/mIl), canal insert wi'th mocxiflo~aCin hydrochloride gel (50 mng/nd), corn; letion with cotton wool Plug, gauze isert imnpregnated with inoxifli 'xacjn R a~~Y&DOchJOYide gel (50 mg/ndl) in affected region, no suture. Ceku le as goo helin prces, p~tint yxptomfroe. Root canal filling with endomethasone. Check-up afterT 3 weeks: patient syinptomnftee, 0 0 P te t( m l, 4 e rj Clinical diagnsis: tooth 36, woud care ater (N]etraction. Course of treatmenrt; dolor post, restoration of alveolus, aipplicati, na of depot of inoxifloxacin hydrochloride gel (50 mng/mil) by gauze strips, Cie- k-up after 3 days:, patient s3hptomnfree, good woundI margin adaptation, Patient C 7 (male, 36 years). Clinical diagnosis: tooth 22, wound care following root tip resection due to cyst- Course of treatment: incision, strip insert with moxifloxacia hydrochloride gel (50 mg/rn!). Check-uip after 3 days: pa dient gymptomn-free. good healing process, Patient C 8 (female, 31 years). Clinical diagnosis: teeth 26 and 26 with apiceal granuloxngs, bite discomfort. Course of treatmnit: extraction at inflammatory s -age (osteotomy), wound care with gauze impregnated with grepatloxacffl gel mg/in!). Chieck-up after 3 days: paltent is symptom-free.

Patient C 9 (imale, 22 years), Clinical diagnosis: tooth 14, pulpitis purule at, fistrtiation, submucosal swelling. Course of treatment;, repanatiou, incision.

Flushing of root canal and fistula with zuoxifloxacin hydrochloride solution mg/mi), cana insert with grepafloxaeii 1 gel mg/mi), completion only wi1th cotton wool plug. Gauze insert impregnated with moxitloxucin hydrochloride gel (z5 mg/mIl) in affected region, no suture. Chuck-up after 6 days: patient Symnptvm- Flee- Root canal tilling with endomethasone. Checkc-up alter 2 weeks., padi ant Sytaptom-free.

A2 Wound care 18/06 '02 DI 15:30 FAX +49 221 97311110 KIJTZENBERGER oWOO0/456 79 r 0135 ;ZPatient DI) (male, 33 years). DiagnoSj 3 conibustia escharjtica on jeft f rearm. Course Of treatment: wound hygiene, application Of inoxifboxacin hydroc itozide en0ge wound co'vering. Regeneraion 1 of skin epithejuln with complete wounad closnse after ono wee-k, R Patient D) 2 (mlale, 25 yeats). Diagnosis: panaritjum ParUnguale on rght I-iidcue c-I ~finager. Couse of treatmnent: coduction anaethesia openiag at nail mnargi*oa 0 a.4tLU5ss with AkJoxi xacin hydrncbhid gel of fa~.

Patient syinptom...fre 0 .inofrbe Patient D 3 (mnale, 70 years), Diagnosis: diabetes mellitus, hospitai stay clue to sevre diabetic wnicroangiapathy Of the feet with diabetic foot syndrome. Thee outpatient foot care. Fidings: a) deep, 2 X 1-5 cm ulcer under right big toe, gy asy; b) large ulcer D IU, 5 mM diAnieter; c) largo fissue D IV/D V; s mre keratinization of entire foot. Course of treatMent: attempted systemic treat' rent with Avalox 400 -ind Giant 400 without significant change in findings. Then application of dirossings; with inoxifioxaoffl hydrochloride gel at wc-ekty intervals. Wound check-up after 1st week: a) ulcer D 1, 1 x 0-5 cmn, cleau; b) ulcer D III clean; c) ulcer D I) V encruisted. Wound chcck-up after 2nd week: a) leer £D I pin~head-size, clean, b) ulcer D) Mi, clean granular tissue; c) ulcer C WeI v healed, Wound check-up after 3rd week: a) ulcer D I unchanged- b) ulcr 1) 111 Pinhead-size, Wound check-up after 4th week: a) ulcer D I healed; b) udoer JJ Ml healed.

Patient D 4 (male, 62 years). Diagnosis: diabetes rnollitus, diabetic mnicroan 1 jo- pathy of right foot with diabetic foot syncroai Findings- I x 1 cm ulcer gre~isy, severe keratinizati on, of entirte foot. Course of treatment; application of dress;tgs with moxifloxacin hydrochloride gel at weekly intervals. Wound check. up AfT 1st week: ulcer 0.2 x 0.4 cm, clean. Would check-up after 2nd week: ul, er healed, ]Patient 1) 5 (female, 67 years). Diagnoaig: diabetic gangrene on left big te'e. Courtse of treatment: wound hygiene, removal oftbyperkera 0 8 j 5 and necrosis, PC Ur aplications Of Iaoxifloxacin hydincb1 0 lide gel at weekly intervals, coveji ig wouud each timne. Regeneration of skin epithelium with complete wound closw2 18/06 '02 DI 15:30 FAX +49 221 97311110 KUTZENBERGER WOLFF W O 1/4 679PCTEPOO/ 1: revasculadizauon.

PAtient D 6 (mole, 34 years). Diagnosis:, eysipelas on right lower leg. Colt Se of imymobilization, local antibiosis with moxifloxacinl hydrchloi&, gel lcal compreSses. Atter 2 days, prevention Of recurrence. Patient syrn;tornfree.

Cl Patient 1) 7 (female, 52 years,). Diagnosis: phiegmonS on palm. of left I ando Co rse of rearnet~ nciionand Wide openling Of affected tis-sue areas, -ocal antibiosis with mnoxifloxaczA hydrochloride gel wound care, After 2 1 ays', repetition of local antibiosis, Patient symptom-fre Patient D) 8 (female, 28 yeazg), Diagnosis: ftiucle on left foreann. Cours a of treatment: incision and open wound treatment with nioxifloXacin hydrochlctjde solution Patient symptomn-free.

Patient D 9 (female, 44 years)- Diagnosis; carbuncle oil back of neck, Cours of treatment: excision of all necrotic areas, open wouind treatment with moxiflox:Ctom hvdrochloride.impregnated comnpress- Patient symptom-free.

Q105

Claims (8)

1. 2. Use according to claim 1, further including
2. 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinoflnecarboxylic acid (clinafloxacin), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1 -piperazinyl)-4-oxo-3- quinolinecarboxylic acid (gatifloxacin), 7 -[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1 -pyrrolidinyi]-1-cyclopropyl-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (gemifloxacin), 5-amino-1 -oydopropyl-7-[(3R,5S)-3,5-dimethy-1 -piperazinyl]-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid (sparfloxacin), 48 COMS ID No: ARCS-216254 Received by IP Australia: Time 16:25 Date 2008-12-08 09/01 2009 15:43 FAX 6182311273 COLLISON IP AUSTRALIA R038/042 0O 0 or a mixture of at least two of these compounds, is used, S3. Use according to one of claims 1 or 2, characterized in that the acid additions salts are selected from the group comprising hydrochloride, hydrobromide, methanesulfonate o 5 and tolylsulfonate. c 4. Use according to one of claims 1 to 3, characterized in that the physiologically compatible salts of the carboxylic acid are selected from the group comprising alkali o metal salts, alkaline earth metal salts, ammonium salts, silver salts and guanidinium in 10 salts. Use according to one of claims 1 to 4, characterized in that the medicament is used for the treatment of humans or animals. 6. Gelatinous formulation comprising 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- [(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid (moxifloxacin) and also physiologically compatible auxiliary substances, said compound(s) being present in concentrations of 0.005 mg/ml to 200 mg/ml, 7. Gelatinous formulation according to claim 6, characterized in that it comprises, as physiologically compatible auxiliary substances, solvents, gel formers, surface-active compounds, thickeners or mixtures of at least two of these auxiliary substances.
3. 8. Gelatinous formulation according to claim 7, characterized in that it comprises modified celluloses, polyalkylene glycols and water, preferably hydroxyethylcellulose, propylene glycol and water, and also, optionally at least one polysorbate.
4. 9. Gelatinous formulation according to claim 8, characterized in that, as the polysorbate, it comprises at least one mono-, di- or triester of oleic acid, lauric acid, palmitic acid or stearic acid and sorbitol and/or its anhydride having up to 20 mol of ethylene oxide units 49 COMS ID No: ARCS-219371 Received by IP Australia: Time 16:19 Date 2009-01-09 08/12 2008 15:47 FAX 6182311273 COLLISON IP AUSTRALIA @023/033 00 g per mole of sorbitol or anhydride, preferably polyethoxysorbitan monolaurate with l ethylene oxide units. 0 0 10. Gelatinous formulation according to one of claims 6 to 9, characterized in that it has 00 o 5 been applied to an inert carrier or an inert carrier material or has been incorporated therein. C
5. 11. Gelatinous formulation according to claim 10, characterized in that the inert carriers are strip inserts, thread inserts, chips, trays, collagen sponges, pads, cotton wool plugs or foam pellets. 0 CN 12. Gelatinous formulation according to claim 6, characterized in that the compound 1 cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrlo[3,4- b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylicacid (moxifloxacin) is used in concentrations of 0-5 mg/ml to 200 mg/ml.
6. 13. Gelatinous formulation according to claim 12, characterized in that the 1-cyclopropyl- 1 -cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylicacid (moxifloxacin) is used in concentrations of 10 mg/ml to 200 mglml.
7. 14. Use according to one of claims 1 to 5, characterized in that the medicament is in the form of a solution, a suspension, an emulsion, liposomes or micelles and has optionally been applied to or incorporated in a carrier material or an inert carrier according to claim 11. Use according to claim 14, characterized in that the medicament is in the form of an aqueous solution.
8. 16. Use according to claim 14 or 15, characterized in that the medicament comprises, as other physiologically compatible auxiliary substances, solvents, solubility improvers, COMS ID No: ARCS-216254 Received by IP Australia: Time 16:25 Date 2008-12-08 08/12 2008 15:47 FAX 8182311273 COLLISON IP AUSTRALIA lai024/033 00 Sthickeners, solubilizers, preservatives, emulsifiers, mucins, osmolality regulators, Cl antioxidants, chelating agents, disinfectants, dispersants, emulsion stabilizers, (U hydrocolloids, wetting agents or a mixture of at least two of the above-mentioned 0 auxiliary substances. 00 0 51 r-- (N- o'- COMS ID No: ARCS-216254 Received by IP Australia: Time 16:25 Date 2008-12-08