Sapphyrins, derivatives and syntheses

• US 5,159,065 A
• Filed: 12/21/1989
• Issued: 10/27/1992
• Est. Priority Date: 12/21/1989
• Status: Expired due to Term

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Cyr, Michael J.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): WARD, EDWARD C
• Application Number:
  US07/454,298
• Time in Patent Office: 1,041 Days
• Field of Search: 540/465, 540/467, 540/470, 534/15
• US Class Current: 534/15
• CPC Class Codes: A61K 41/0076 PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61K 47/558 the modifying agent being a chemiluminescent acceptor
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 15/26 Acyclic or carbocyclic radicals, substituted by hetero rings
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/101 by chromatography, e.g. electrophoresis, ion-exchange, reverse phase

Abstract

The present invention involves, in addition to many unique substituted sapphyrins, a novel method for synthesizing sapphyrins with good efficiency and high yield. An improved 9-step synthesis of substituted sapphyrins, e.g., the two C₂ symmetric sapphyrins, compounds 2 and 4 of FIG. 1C, is described herein. This synthesis involves as an important step the condensation between a tripyrrane diacid and a diformyl bipyrrole. The key tripyrrane component is prepared in three high-yield steps from readily available pyrrolic precursors and the bipyrrole portion is prepared in four steps from ethyl 3-methyl-4-methylpyrrole-2-carboxylate in roughly 33% yield overall.

Claims

1. A sapphyrin compound of the formula:

##STR1## wherein at least one of D_a, D_b, D_c, D_d, D_e, and D_f is an alkyl and at least one is an alkyl with an amino, hydroxyl, carboxyl, cyanate, isocyanate, thiocyanate, sulfhydryl, nitrile, iodide, or sulfonic substituent.

2. A sapphyrin compound of the formula:

##STR2## wherein at least one of D_a, D_b, D_c, D_d, D_e, and D_f is an alkyl and at least one is an alkyl with a hydroxyl substituent.

3. A sapphyrin compound of the formula:

##STR3## wherein at least one of D_a, D_b, D_c, D_d, D_e, and D_f is an alkyl and at least one is an alkyl with an amino substituent.

4. A sapphyrin compound of the formula:

##STR4## wherein at least one of D_a, D_b, D_c, D_d, D_e, and D_f is an alkyl and at least one is an alkyl with a carboxyl substituent.

5. A sapphyrin compound of the formula:

##STR5## wherein at least one of D_a, D_b, D_c, D_d, D_e, and D_f is an alkyl and at least one is an alkyl with an alkenyl, aryl, alkynyl, cycloalkyl, fluoride, chloride or bromide substituent.

6. A sapphyrin compound of the formula:

##STR6## where D_a, D_e and D_f are ethyl;

D_b and D_c aremethyl; and

D_d is CH₂ CO₂ ET.

7. A sapphyrin compound of the formula:

##STR7## wher D_a, D_e and D_f are ethyl;

D_b and D_c are methyl; and

D_d is CH₂ CO₂ H.

8. A sapphyrin compond of the formula:

##STR8## where D_a, D_e and D_f are ethyl;

D_b and D_c are methyl;

one D_d is CH₂ CO₂ H and one is CH₂ CO₂ Et.

9. 9,18-Di(carboxymethyl)-4,13,14,23-tetraethyl -3,8,19,24-tetramethyl-25,26,27,28,29-pentazahexacyclo {20.2.1.1²,5.1⁷,10.1¹²,15.1¹⁷,20 }nonacosa-2,4,6,8,10(28),11,13,15,17(26), 18,20,22,24-tridecaene.

10. 9-Carboxymethyl-18-ethoxycarbonylmethyl-4,13,14,23-tetraethyl-3,8,19,24-tetramethyl-25,26,27,28,29-pentazahexacyclo{20 2.1.1²,5.1⁷,10.1¹²,15.1¹⁷,20 }nonacosa-2,4,6,8,10(28),11,13,15,17(26),18,20,22,24-tridecaene.

11. 9,18-Di(ethoxycarbonylmethyl)-4,13,14,23-tetraethyl -3,8,19,24-tetramethyl-25,26,27,28,29-pentazahexacyclo{20.2.1.1²,5.1.sup.7,10.1¹²,15.1¹⁷,20 }nonacosa-2,4,6,8,10(28),11,13,15,17(26), 18,20,22,24-tridecaene.

12. 8,12,13,17-Tetraethyl-7,18-dimethyldioxosapphyrin.

13. Gadolinium pentavalently coordinated to 8,12,13,17-tetraethyl-7,18-dimethyldioxosapphyrin.

14. 8,17-diethoxycarbonylmethyl-12,13-diethyl-7,18-dimethyldioxosapphyrin.

15. Gadolinium pentavalently coordinated to 8,17-diethoxycarbonylmethyl-12,13-diethyl -7,18-dimethyldioxosapphyrin.