Tricarbonyl complexes of transition metals with benzo-heterocyclic derivatives of the cyclopentadienyl anion

11845,763

17/040117

March 22, 2019

Complex compounds of transition metals according to formula (1) wherein the M(CO)3+ tricarbonyl-metal core forms a complex with the cyclopentadienyl anion linked to heterocyclic moieties of the benzothiazole, benzimidazole and benzoxazole families. The compounds exhibit high blood-brain barrier permeability and can be used in the diagnosis and/or treatment of diseases of the Central Nervous System. [chemical expression included]

National Centre For Scientific Research “Demokritos” (Agia Paraskevi, GR); Pelecanou Zampara, Maria (Athens, GR); Sagnou, Marina (Athens, GR); Papadopoulos, Minas (Attiki, GR); Pirmettis, Ioannis (Athens, GR)

NATIONAL CENTRE FOR SCIENTIFIC RESEARCH “DEMOKRITOS” (Agia Paraskevi, GR)

1. A compound according to formula 1 or a pharmaceutically acceptable salt thereof [chemical expression included] wherein M is Tc X is S or O A is C—R A , B is C—R B , C is C—R C , D is C—R D , wherein R A , R C , R D are the same or different and are selected from the group consisting of hydrogen, halogen, nitro-, alkyl-, haloalkyl- with 0 to 3 halogen atoms on each carbon atom, aminoalkyl-, alkylamino-, hydroxyl, alkyloxy-, benzyloxy-, aryloxy-, —SO 2 —C(═O)NR 4 R 5 , —C(═S)NR 4 R 5 , —SO 2 NR 4 R 5 , and —NC(═O)R 4 , wherein R B is selected from the group consisting of halogen, alkyl-, haloalkyl- with 0 to 3 halogen atoms on each carbon atom, aminoalkyl-, alkylamino-, hydroxyl, alkyloxy-, benzyloxy-, aryloxy-, —SO 2 —C(═O)NR 4 R 5 , —C(═S)NR 4 R 5 , —SO 2 NR 4 R 5 , and —NC(═O)R 4 , wherein R 4 , R 5 are the same or different and are hydrogen or C 1 -C 6 alkyl- R 1 is absent R 2 , R 3 are the same or different and are selected from hydrogen, —NR 4 R 5 , —NC(═O)R 4 wherein R 4 , R 5 are the same or different and are hydrogen or C 1 -C 6 alkyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and/or R 3 is hydrogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein M is Tc, A is C—H, C is C—H, D is C—H, R 2 is H, R 3 is H, and X is S or O.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Tc is 99m Tc.

5. A method of diagnosing and/or treating a CNS disease in a subject in need thereof, the method comprising; administering to the subject a compound according to formula 1 or a pharmaceutically acceptable salt thereof [chemical expression included] wherein M is Re, Tc, or other transition metal capable of forming a tricarbonyl cyclopentadienyl entity of the type CpM(CO) 3 + X is S, N, or O A is C—R A , B is C—R B , C is C-Rc, D is C—R D , wherein R A , R B , R C , R D are the same or different and are selected from the group consisting of hydrogen, halogen, nitro-, alkyl-, haloalkyl- with 0 to 3 halogen atoms on each carbon atom, aminoalkyl-, alkylamino-, hydroxyl, alkyloxy-, benzyloxy-, aryloxy-, —SO 2 —C(═O)NR 4 R 5 , —C(═S)NR 4 R 5 , —SO 2 NR 4 R 5 , and —NC(═O)R 4 , wherein R 4 , R 5 are the same or different and are hydrogen or C 1 -C 6 alkyl- when X is N, R 1 is hydrogen, alkyl-, alkenyl-, haloalkyl- with 0 to 3 halogen atoms on each carbon atom, alkoxyalkyl-, cycloalkyl-, or arylalkyl-, whereas when X is S or —O, R 1 does not exist when M is Re and X is N, Rc is selected from the group consisting of halogen, alkyl-, haloalkyl- with 0 to 3 halogen atoms on each carbon atom, aminoalkyl-, alkylamino-, hydroxyl, alkyloxy-, benzyloxy-, aryloxy-, —SO 2 —C(═O)NR 4 R 5 , —C(═S)NR 4 R 5 , —SO 2 NR 4 R 5 , and —NC(═O)R 4 R 2 , R 3 are the same or different and are selected from hydrogen, —NR 4 R 5 , —NC(═O)R 4 wherein R 4 , R 5 are the same or different and are hydrogen or C 1 -C 6 alkyl group, wherein the CNS disease is Alzheimer's disease or CNS cancer.

6. The method according to claim 5 , wherein M is Re or Tc.

7. The method according to claim 6 , wherein M is Tc.

8. The method according to claim 5 , wherein M is Re or Tc, A is C—H, B is C—H, C is C—H, D is C—H, R 2 is H, R 3 is H, X is S, O, N and when X is N, R 1 is H or CH 3 .

9. The method according to claim 8 , wherein Tc is 99m Tc.

10. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The method according to claim 5 , wherein the compound according to formula 1 or the pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

12. The method according to claim 5 , wherein the compound according to formula 1 or the pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

13. The compound according to claim 1 , wherein R 4 , R 5 are the same or different and are hydrogen or C 1 -C 2 alkyl.

WO-03086476 October 2003

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