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EP-4735432-A1 - INHIBITORS OF HEME OXYGENASE, COMPOSITIONS AND USES THEREOF

EP4735432A1EP 4735432 A1EP4735432 A1EP 4735432A1EP-4735432-A1

Abstract

1, 4-disubstituted-l, 2, 3 triazoles compounds of formula ( I ) : (I) able to inhibit heme oxygenase activity, their use as a medicament in treating and/or preventing pathological conditions associated to alterations in heme oxygenase activity and pharmaceutical compositions containing the same.

Inventors

  • SICA, ANTONIO
  • TRON, GIAN CESARE
  • CONSONNI, Francesca

Assignees

  • Università degli Studi del Piemonte Orientale "Amedeo Avogadro"
  • Humanitas Mirasole S.p.A.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A 1 , 4-disubstituted-l , 2 , 3 triazole compound of formula ( I ) : B N > N A (I) wherein A is selected from B is selected from straight or branched, substituted or unsubstituted Ch-s alkyl, straight or branched, substituted or unsubstituted C 2 -s alkenyl, straight or branched, substituted or unsubstituted Ci-s carbonyl, straight or branched, substituted or unsubstituted Ci-s alkoxy, C3-6 cycloalkyl, Ar 1 , and substituted or unsubstituted (CH 2 ) n -Ar 1 ; n is an integer 1 to 4; Ar 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group.
  2. 2. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to claim 1, wherein, when Ar 1 is a substituted aryl or a substituted heteroaryl, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4 alkyl, 1H- tetrazole, -COOH, -OH, -CH 2 -OH, -NH 2 , -NH-C (0) -NH-R 1 , - COOR 1 , -NO 2 , -CF 3 , -ON, -OR 1 , -CONH 2 , -CONHR 1 , -CONR 1 R 2 , - NHR 1 , -NR 1 R 2 , -NHCOR 1 , -NHSO 2 R 1 , or -SO 2 NHR 1 ; R 1 and R 2 are identical or different from each other and independently selected from H, straight or branched, substituted or unsubstituted Ci-s alkyl, Ar 2 ; Ar 2 is selected from aryl and heteroaryl. 3. The 1 , 4-disubstituted-l , 2 ,
  3. 3 triazole compound according to claim 1 or claim 2, wherein, when B is a substituted Ci-s alkyl, a substituted C2-8 alkenyl, a substituted Ci-s carbonyl, a substituted Ci-s alkoxy, or a substituted (CH2) n -Ar 1 , the one or more substituents are independently selected from aryl and heteroaryl.
  4. 4. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from straight or branched, substituted or unsubstituted C1-4 alkyl, straight or branched, substituted or unsubstituted C2-4 alkenyl, straight or branched, substituted or unsubstituted C1-4 carbonyl, straight or branched, substituted or unsubstituted C1-4 alkoxy, Ar 1 , and substituted or unsubstituted (CH2) n -Ar 1 , and wherein n is 1 to 4.
  5. 5. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from straight or branched, substituted or unsubstituted C1-3 alkyl, straight or branched, substituted or unsubstituted C2-3 alkenyl, substituted or unsubstituted C1-2 carbonyl, substituted or unsubstituted C1-2 alkoxy, Ar 1 , and substituted or unsubstituted (CH2) n - Ar 1 , wherein n is an integer 1 to 3.
  6. 6. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from substituted or unsubstituted (CH2) n -Ar 1 , and wherein n is an integer 1 to 4.
  7. 7. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein n is an integer 1 to 2.
  8. 8. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar 1 is selected from substituted or unsubstituted aryl.
  9. 9. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when B is a substituted (CH 2 ) n -Ar 1 , the one or more substituents are independently selected from aryl.
  10. 10. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the compound of formula (I) is not 4- [ ( IH-imidazol-l- yl ) methyl ] -1- ( 4 -nitrobenzyl )-lH-l,2,3-triazole, 4- [ 4- ( IH-imidazol-l-yl ) methyl- 1H- 1 , 2, 3-triazol-l- yl ] methylbenzophenone, 4- [4- (1H-1, 2, 4triazol-l- yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone .
  11. 11. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar 1 is selected from substituted or unsubstituted benzene, and substituted or unsubstituted naphthalene.
  12. 12. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when Ar 1 is a substituted aryl or a substituted heteroaryl group, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci- 4 alkyl, -NH 2 , -CF 3 , -COOH, -OH, -CH 2 -OH, -NO 2 , -ON, -Ome, -CONH 2 , -COOMe.
  13. 13. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein, when Ar 1 is a substituted aryl, the one or more substituents are independently selected from halogen atom, substituted or unsubstituted Ci-4 alkyl, -NH 2 , CF 3 .
  14. 14. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein B is selected from substituted or unsubstituted (CH2) n -Ar 1 , n is an integer 1 to 4, Ar 1 is selected from substituted or unsubstituted aryl and wherein the compound of formula (I) is not 4- [ ( IH-imidazol-l-yl ) methyl ] -1- ( 4- nitrobenzyl )-lH- 1,2, 3-triazole, 4 — [ 4 — ( IH-imidazol-l- yl ) methyl- 1H- 1 , 2, 3-triazol-l-yl] methylbenzophenone, 4- [4 - (lH-l,2,4triazol-l-yl) methyl- 1H- 1 , 2, 3-triazol-l- yl ] methylbenzophenone .
  15. 15. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein Ar 2 is selected from benzene, furan, thiophene, pyrrolidine, pyrrole, 1 , 2 , 3-triazole, pyrazole, imidazole, oxazole, isooxazole, thiazole, isothiazole, 1.2.3-oxadiazole, 1 , 2 , 4-oxadiazole, 1 , 2 , 5-oxadiazole, pyridine, pyrididazine, pyrimidine, pyrazine, naphthalene, indole, IH-indazole, IH-benzo [d] imidazole, benzo [d] thiazol-2-amine, isoindole, indolizine, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, or carbazole.
  16. 16. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from: - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH- 1.2.3-triazole (#1) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH- 1,2, 3-triazole (#6) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole ( #9) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ; - l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ; - 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ; - 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ; - 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ; - 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ; - 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- phenethyl-lH-1 , 2 , 3-triazole (#18) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#22) ; - 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#23) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- phenoxy ethyl )-lH- 1,2, 3-triazole (#24) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#25) ; - 4 — ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH- 1.2.3-triazole (#27) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ; - 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ; - 2- (4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1H- 1.2.3-triazol-l-yl ) -1-phenylethan-l-one (#35) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2- phenoxyethyl ) -1H-1, 2, 3-triazole (#36) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-cinnamyl- 1H-1, 2, 3-triazole (#39; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ; - 4- (2 - (4- ( (lH-l,2,4-triazol-l-yl) methyl )-lH- 1.2.3-triazol-l-yl) ethyl ) aniline ( #42 ) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) - 1 - ( 3 , 4 - dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -1H-1, 2, 3-triazole (#45) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ; - 2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) -1-phenylethan-l-one (#47) ; - 1- ( ( 1- ( 2 -phenoxy ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#48) ; - 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ; - 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ; - 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ; - 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ; - 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ; - 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ; - 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ; - 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ; - 1- ( ( 1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .
  17. 17. The 1 , 4-disubstituted-l , 2 , 3 triazole compound according to any one of the preceding claims, wherein the 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) is selected from: - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-benzyl-lH- 1,2,3-triazole (#1) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-phenethyl-lH- 1,2,3-triazole (#6) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- chlorophenethyl ) -1H-1, 2, 3-triazole (#7) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- phenylpropyl ) -1H-1, 2, 3-triazole (#8) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (naphthalen-1- ylmethyl )-lH- 1,2, 3-triazole ( #9) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 2 , 2- diphenylethyl ) -1H-1, 2, 3-triazole (#10) ; - l- ( (l-benzyl-lH-l,2,3-triazol-4-yl) methyl ) - IH-tetrazole (#11) ; - 1- ( ( 1 -phene thy 1 - 1H- 1 , 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#12) ; - 1- ( ( 1- ( 4 -chlorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#13) ; - 1- ( ( 1- ( 3 -phenylpropyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#14) ; - 1- ( ( 1- (naphthalen-l-ylmethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#15) ; - 1- ( ( 1- ( 2 , 2 -diphenyl ethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#16) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1-benzyl- 1H-1, 2, 3-triazole (#17) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- phenethyl-lH-1 , 2 , 3-triazole (#18) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- chlorophenethyl ) -1H-1, 2, 3-triazole (#19) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3- phenylpropyl ) -1H-1, 2, 3-triazole (#20) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (naphthalen-l-ylmethyl ) -1H-1, 2, 3-triazole (#21) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 2 , 2- diphenylethyl) -1H-1, 2, 3-triazole (#22) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- phenylbutyl) -1H-1, 2, 3-triazole (#25) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#26) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1-cinnamyl-lH- 1.2.3-triazole (#27) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#28) ; - 4 - ( 2 - ( 4 - ( ( IH-imidazol-l-yl ) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#29) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- methylphenethyl ) -1H-1, 2, 3-triazole (#30) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#31) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- ( 3 , 4- dichlorophenethyl ) -1H-1, 2, 3-triazole (#32) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (3- (4- chlorophenyl ) propyl )-lH- 1,2, 3-triazole ( #33) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- f luorophenethyl )-lH- 1,2, 3-triazole ( #34 ) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- phenylbutyl) -1H-1, 2, 3-triazole (#37) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 3 , 3- diphenylpropyl ) -1H-1, 2, 3-triazole (#38) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (2- (naphthalen-l-yl ) ethyl) -1H-1, 2, 3-triazole (#40) ; - 4- ( ( IH-imidazol-l-yl ) methyl ) -1- (4- ( tri fluoromethyl) phenethyl) -1H-1, 2, 3-triazole (#41) ; - 4- (2 - (4 - ( (lH-l,2,4-triazol-l-yl) methyl )-lH- 1.2.3-triazol-l-yl) ethyl ) aniline ( #42 ) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- ( 4- methylphenethyl ) -1H-1, 2, 3-triazole (#43) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) — 1 — ( 3 , 4 — dichlorophenethyl )-lH- 1,2, 3-triazole (#44) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (3- (4- chlorophenyl ) propyl) -lH-l,2,3-triazole (#45) ; - 4- ( (lH-l,2,4-triazol-l-yl) methyl ) -1- (4- f luorophenethyl ) -1H-1, 2, 3-triazole (#46) ; - 1- ( ( 1- ( 4 -phenylbutyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#49) ; - 1- ( ( 1- ( 3 , 3 -diphenylpropyl ) -1H-1, 2, 3-triazol- 4-yl ) methyl ) -IH-tetrazole (#50) ; - 1- ( ( 1-cinnamyl-lH-l , 2, 3-triazol-4-yl) methyl ) - IH-tetrazole (#51) ; - 1- ( ( 1- ( 2- (naphthalen-l-yl ) ethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#52) ; - 4- (2- (4- ( (lH-tetrazol-l-yl) methyl ) -1H-1 , 2 , 3- triazol-l-yl ) ethyl) aniline (#53) ; - 1- ( ( 1- ( 4 -methylphenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#54) ; - 1- ( ( 1- ( 3 , 4 -di chlorophenethyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#55) ; - 1- ( ( 1- ( 3- ( 4 -chlorophenyl ) propyl ) -1H-1 , 2 , 3- triazol-4-yl ) methyl ) -IH-tetrazole (#56) ; - 1- ( ( 1- ( 4- fluorophenethyl ) -1H-1, 2, 3-triazol-4- yl ) methyl ) -IH-tetrazole (#57) .
  18. 18. A 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) according to any one of claims 1 to 17 for use in the treatment and/or prevention of a disease condition in which heme oxygenase is aberrantly over-activated.
  19. 19. The 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) for use according to claim 18, wherein the disease condition in which heme oxygenase is aberrantly overactivated is a neoplastic condition.
  20. 20. A pharmaceutical composition comprising at least one 1 , 4-disubstituted-l , 2 , 3 triazole of formula (I) according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

Description

"Inhibitors of Heme Oxygenase, compositions and uses thereof" ★ ★ ★ Field of the invention This disclosure concerns compounds able to inhibit heme oxygenase. The disclosure also relates to the use of these compounds for treatment of pathological conditions in which over-expression of heme oxygenase-1 by myeloid cells is associated with disease progression. Background of the invention Although the pathological significance of tumor- associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. We showed that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi) , endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1) , plays a critical role in shaping a prometastatic tumor microenvironment, favoring immunosuppression, angiogenesis and epithelial-to- mesenchymal transition (Consonni F. et al. 2021, DOI: 10.1038/s41590-021-00921-5) . This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-KBl-CSFlR-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy, in models of sarcoma, lung and melanoma. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients . Substituted 1 , 2 , 3-triazole compounds have been disclosed in WO 2014/205414; WO 2018/067615; Khan Sadaf et al. Synthesis (2010) , 2010 ( 15 ) : 2609-2615 ; Vereshchagin L I et al. Russian Journal Of Organic Chemistry (2006) , 42 ( 6) : 912-917 ; Lv Mingxiu et al. Phosphorus , Sulfur, And Silicon And The Related Elements (2018) , 193 ( 4 ) : 206-210 ; Sahbi Azzeddine et al. lucrdata (2017) , 2 (4) ; Boutouil Aziz et al. Journal Of Adhesion Science And Technology (2019) , 34 ( 5 ) : 549-578 ; Narsimha Sirassu et al. Heterocyclic Letters (2015) , 5(4) : 653- 660. Summary of the invention The object of this disclosure is to provide new compounds which exhibit inhibitory activity against the heme oxygenase enzymes, these new compounds being a valuable therapeutic tool for the treatment and/or prevention of disease conditions characterized by an over-activity of these enzymes. According to the invention, the above object is achieved thanks to the subject matter recalled specifically in the ensuing claims, which are understood as forming an integral part of this disclosure. An embodiment of the present disclosure provides 1 , 4-disubstituted-l , 2 , 3 triazoles of formula (I) : wherein A is selected from B is selected from straight or branched, substituted or unsubstituted Ci-s alkyl, straight or branched, substituted or unsubstituted C2-8 alkenyl, straight or branched, substituted or unsubstituted Ci-s carbonyl, straight or branched, substituted or unsubstituted Ci-s alkoxy, C3-6 cycloalkyl, Ar1, and substituted or unsubstituted (CH2)n-Ar1; n is an integer 1 to 4; Ar1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl group. In an embodiment, the disclosure also relates to the compounds of formula (I) for use in the treatment of disease conditions in which heme oxygenase is aberrantly over activated. In an embodiment, the disclosure also provides a pharmaceutical composition comprising at least one compound of formula (I) and a pharmaceutically acceptable excipient. Overall, the results disclosed herein identify heme oxygenase as a therapeutic target for the treatment of disease conditions characterized by an over-activity of this enzyme. Based on these results, the inventors of the present application were able to develop novel HO-1 inhibitors that can prevent metastatic activity of various human tumors . Brief description of the drawings The invention will now be described in detail, purely by way of illustrative and non-limiting example, with reference to the attached figures, wherein: - Figure 1. (A) Experimental scheme for determining the activity of HO-1 inhibitors. (B) ELISA-based bilirubin quantification produced by hemin-treated PANC- 1 cells after incubation with selected compounds of formula (I) . Data are mean ± SD of 2 independent experiments. *p<0.05, **p<0.01. Figure 2: (A) HO-1 inhibition assay performed in saturation condition of purified HO-1, by adding a single concentration of the tested inhibitors and compound #A (40 pM) . Residual activity of the HO-1 enzyme in the tested conditions is shown. (B) ELISA-based bilirubin quantification produced by HeLa cells after treatment with the inhibitors #28 and #A derived from formula (I) , in comparison with the standard inhibitor OB24 and the heme oxygenase inducer hemin. The table shows the fold change of HO-1 activity upon 24h treatment with respect to untreated control.