Sep 1, 2016 - ventilators, prosthetic heart valves, contact lenses, intrauterine devices ...... hydrotropes derived from isosorbide: endo/exo isomeric effects and ...
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization International Bureau
(10) International Publication Number
(43) International Publication Date 1 September 2016 (01.09.2016)
(51) International Patent Classification: A61K 47/48 (2006.01) C07D 493/04 (2006.01) A61K 9/00 (2006.01) A61P 17/02 (2006.01) A61K 9/06 (2006.01) A61P 31/00 (2006.01) A61K 31/34 (2006.01)
(74) Agents: MULHERN, Declan et al; Hoffmann Eitle Pat ent- und Rechtsanwalte Partmbb, ArabellastraBe 30, 8 1 25 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
(21) International Application Number: PCT/EP2016/053462
(22) International Filing Date: 18 February 2016 (18.02.2016)
(25) Filing Language:
English
(26) Publication Language:
English
(30) Priority Data: 15 156164.4 23 February 2015 (23.02.2015)
WO 2016/135037 Al
PCT
P O
EP
(71) Applicant: NITTO DENKO CORPORATION [JP/JP]; 1-2, Shimohozumi 1-chome, Ibaraki-shi, Osaka, 567-8680 (JP). (72) Inventors: DE TITTA, Alexandre; Ch. Neuf 8, 1028 Preverenges (CH). DE VISSCHER, Geofrey; Grand Rue 15, 1071 Chexbres (CH). TAKEIRI, Mayu; Rue du Centre 44C, 1025 St. Sulpice (CH). SCHUWER, Nicolas; Chemin du Bois-de-Vaux 1 C, 1007 Lausanne (CH).
(84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published:
—
with international search report (Art. 21(3))
(54) Title: DIANHYDROHEXITOL CODRUG
Formula (la)
these compounds,
F
a
b)
Formula (
)
(57) Abstract: The present invention relates to a codrug of a dianhydrohexitol having one of the following structures: For mula (la) Formula (lb) Formula (lc) wherein D l and D2 are drug moieties that are the same or different and are covalently linked to the dianhydrohexitol via a physiologically hydrolyzable bond; Ri and R 2 are selected from the group consisting of hydrogen, -S0 M and a physiologically hydro lyzable chemical group, wherein M is a cation, and the physiologically hydrolyzable chemical group is selected from the group consisting of alkyl, alkenyl, alkylcarbonyl, alkenylearbonyl arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylether, alkenylether, arylether, and heteroarylether groups wherein the alkyl group or moiety consists of unsubstituted or sub sti tuted, straight-chain or branched-chain or cyclic alkyl groups having 1-22 carbon, atoms, wherein the alkenyl moiety con sists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted, phenyl, or phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, and the heteroaryl moiety is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from, the group consisting of n i trogen, oxygen, and sulphur. The invention also relates to the treatment of wounds and biofilm-associated inventions using
Dianhydrohexito) codrug
1.
FIELD O F THE INVENTION
Dianhydrohexitol compounds according to Formula (1) are suitable for use in the treatment o
wounds, for example to reduce scarring, and can be used to treat biofdm associated infections. This invention relates to codrugs of these compounds.
2.
BACKGROUND OF THE INVENTION
Wound healing is a complex process that, when properly orchestrated, leads to reestablishment of tissue integrity with minimal residual scarring. Normal wound healing includes a transition from a proliferative phase, during which extracellular matrix (ECM) proteins are elaborated, to a remodeling phase, during which the wound is strengthened through stromal organization. Abnormal wound healing may result in pathologic scarring, which represents a diverse spectrum
of disorders that range from unsightly scars, to keloids, to life-threatening systemic diseases such as scleroderma. One example of pathologic dermal scarring is hypertrophic scars that are an
unfavorable outcome of burns, trauma, or surgery. Although much has been learned about the pathophysiology of pathologic dermal scarring, most treatment modalities lack a defined mechanism of action, are nonspecific, and have limited efficacy. There is therefore a need for
new compounds that can effectively treat wounds, particularly reduce scarring.
Oftentimes, healing in a wound will be delayed or prevented by the presence of a biofdm. A biofilm is a community of sessile, stably attached microorganisms, especially bacteria, enmeshed in an extracellular polymer matrix, generally a polysaccharide matrix, exhibiting growth
properties that are distinguished from those of planktonic, free-living microorganisms. Antibiotic resistance of bacteria in biofilms has been extensively documented and bacterial bio films play a role in a number of disease settings, including the exacerbation of cystic fibrosis, chronic urinary tract infections, chronic sinus infections, ear infections, acne, dental caries, periodontitis, nosocomial infections, chronic wounds, infections due to medical devices such as catheters, ventilators, prosthetic heart valves, contact lenses, intrauterine devices and dental plaque (see,
e.g., Potera (1999) Science 283(19)1837-1839; Costerton et al. (1999) Science 284(5418)13 1822; Bjamsholt (2013) APMIS
6) -58). Bacterial biofilms in chronic wounds are generally
(s
not resolved by the host's immune system, and these biofilms have an increased resistance to systemic and topical antimicrobial/antibiotic agents and so ar very difficult to eliminate. There is a need for new compounds that can effectively treat biofilm-associated infections.
The inventors have discovered that certain dianhydrohexitol compounds are suitable for treating wounds, and that these compounds reduce scarring in a healing wound. The dianhydrohexitol compounds also inhibit or eradicate biofilms and are therefore also suitable for use in methods to treat biofilm-associated infections. These compounds are particularly suitable for treating wounds containing a bioiilm. This invention relates to codings of those dianhydrohexitol compounds.
3.
SUMMARY OF THE INVENTION
The invention provides codrugs represented by any one of the Formulae (la), (lb) and
Formula ( lb)
Formula ( 1 a)
Formula ( lc)
wherein D and D are drug moieties that are the same or different and are covalently linked to the dianhydrohexitol via a physiologically hydrolyzable bond; and R2 are selected
from the group consisting of hydrogen, -SO 3M and a
physiologically hydrolyzable chemical group,
wherein M is a cation, and the physiologically hydrolyzable chemical group is selected from the group consisting o f alkyl, alkenyl, alkylcarbonyl. alkenylcarbonyl arylcarbonyl, heteroarylcarbonyl,
alkoxycarbonyl,
aryloxycarbonyl,
heteroaryloxycarbonyl,
alkylether,
alkenylether, arylether, and heteroarylether groups wherein the alkyl group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1-22
carbon atoms, wherein the alkenyl moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted phenyl, or phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, a d the heteroaryl moiety is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoras selected from the group consisting of nitrogen, oxygen, and sulphur.
The invention also provides topical formulations a d medical devices comprising these codrags. The invention also relates to the use of the codrags or topical formulations in methods of treating wounds (e.g. reduce scarring) a d/or biofilm-associated infections.
4.
BR EF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic representation of an example of the procedure in the animal model for scar analysis.
Figure 2 shows an example of a H&E image and the corresponding Sirius red image illustrating the measurements that are used for scar size analysis.
Figure 3 shows the results of the quantitative scar index analysis. Isosorbide is significantly different from Control and Vehicle (p
