WO1997032885B1

WO1997032885B1 - Synthesis of isoimide of chlorins and bacteriochlorins and their use for diagnosis and treatment of cancer

Info

Publication number: WO1997032885B1
Application number: PCT/US1997/003891
Authority: WO
Filing date: 1997-03-07
Publication date: 1997-11-06
Anticipated expiration: 1998-09-08

Abstract

Compounds having utility as light absorbing compounds, especially in the area of photodynamic therapy. Such compounds have formula (I), where z is = 0 or NR14; R14 is alkyl or substituted alkyl, R1 is an amino acid group, a polyamine group, a polyether group or OR13 where R13 is alkyl; R4 through R11 are -H, -OH, alkyl, alkylene, -OR16 where R16 is H, alkyl or aryl, or a carbonyl containing group, provided that: R4 may be taken together with R5 to form =O; R6 may be taken together with R7 to form =O; R8 may be taken together with R9 to form =O; R10 may be taken together with R11 to form =O; and R4 and R7 may together form a chemical bond and R8 and R11 may together form a chemical bond; and R12 is hydrogen or lower alkyl; provided that if one z is 0, the other z is -NR14.

Claims

AMENDED CLAIMS

[received by the International Bureau on 9 September 1997 (09 09.97), original claims 1 , 2, 9, 1 1 , 17 and 19 amended; original claims 12, 15, 16, 18, 22, 23 and 25 cancelled, remaimng claims unchanged (6 pages) |

1. A method for the manufacture of an imide derivative of purpurin comprising: reacting hexylamine with a chlorin or bacteriochlorin having a macrocycle with a six membered anhydride ring fused thereto, said macrocycle containing a and b rings which may be saturated or unsaturated at R^ to R-_j^ positions of the rings and which R₄ and R-±ι positions may contain at least one group selected from the group consisting of hydrogen, hydroxy, formyl, substituted and unsubstituted alkyl, alkoxy, alkenyl, aryl and aryloxy wherein carbon containing groups may be substituted with a substituent selected from carboxyl, hydroxy, phosphoro, carboxy, halo, sulfo, amino and ether, to obtain a purpurin derivative; and reacting the purpurin derivative with a carbodiimide to obtain the imide derivative of purpurin.

2. The method of Claim 1, wherein the carbodiimide is dicyclohexylcarbodiimide.

3. The method of Claim 1, wherein the imide derivative is further reacted with an alkali metal hydroxide to obtain a purpurin imide of the formula:

where R is selected from the group consisting of OMe and Asp-di¬ methyl ester and R- is selected from the group consisting of n- hexyl and tert-butyl Gly.

4. The method of Claim 1, wherein the imide derivative is further reacted with an alkali metal hydroxide to obtain a cyclic imide.

5. An imide of purpurin manufactured in accordance with the method of Claim 1.

6. An imide of purpurin manufactured in accordance with the method of Claim 2.

7. A reaction product comprising an imide of purpurin manufactured in accordance with the method of Claim 3.

8. A reaction product comprising an imide of purpurin manufactured in accordance with the method of Claim 4.

9. A compound of the formula:

40 where z is = 0 or = NR₁₄; R- is an amino acid group, a polyamine group, a polyether group or 0R₁₃ where R₁₃ is alkyl; R₁₄ is alkyl, substituted alkyl, a polyamine group, or an amino acid group; R₄ through R_{l λ} are -H, -OH, alkyl, alkoxy, alkenyl, alkylene, aryl, or aryloxy, or a carbonyl containing group, wherein carbon containing groups may be substituted with carbonyl, hydroxy, phosphoro, carboxy, halo, sulfo, amino and ether substituents, provided that; R₄ may be taken together with R₅ to form =0; R₆ may be taken together with R₇ to form =0; R₈ may be taken together with R₉ to form =0; R,_Q may be taken together with R-_j^ to form =0; and R₄ and R₇ may together form a chemical bond and Rg and R_1;L may together form a chemical bond; and R₁₂ i^s hydrogen or lower alkyl; provided that if one z is = 0, the other z is = NR₁₄.

10. The compound of Claim 9 wherein R_j^ and R₁₂ are -CH₃.

11. The compound of Claim 9 wherein Rg is -COCHo .

13. The compound of Claim 9 having the formula:

where R is normal alkyl of 2 through 12 carbon atoms .

41 14 . The compound of Claim 9 having the formula ;

C0₂Pr

where R is normal alkyl of 2 through 12 carbon atoms.

17. The compound of Claim 9 wherein R-^ is H₃C0₂C-.

19. A method for the manufacture of an isoimide derivati- purpurin comprising reacting a purpurin of the formula:

wherein z is =0 or NR₁₄; R-_j^ is an amino acid group, a polyamine group, a polyether group or 0R₁₃ where R₁₃ is alkyl; R₁₄ is alkyl, or substituted alkyl, a polyamine group, or an amino acid group; R₄ through R-^ are -H, -OH, alkyl, alkoxy, alkenyl, alkylene, aryl, or aryloxy, or a carbonyl containing group, wherein carbon containing groups may be substituted with carbonyl, hydroxy, phosphoro, carboxy, halo, sulfo, amino and ether substituents provided that; R₄ may be taken together with R₅ to form =0; R₆ may be taken together with R₇ to form =0; R_g may be taken together with Rg to form =0; R₁₀ may be taken together with R_1;L to form =0; and R₄ and R₇ may together form a chemical bond and Rg and R-^ may together form a chemical bond; and R₁₂ is hydrogen or lower alkyl; provided that if one z is =0, the other z is =NR₁₄, with 1-hexylamine to open the anhydride ring followed by reaction with a carbodiimide to obtain the isoimide derivative of purpurin.

20. A method for the manufacture of purpurin imide comprising reacting the compound of Claim 9 with alkali metal hydroxide.

21. A method for the manufacture of purpurin imide comprising reacting the compound of Claim 10 with an alkali metal hydroxide.

24. A method for the manufacture of purpurin imide comprising reacting the compound of Claim 17 with an alkali metal hydroxide.

26. A method for the manufacture of purpurin imide comprising reacting the purpurin derivative from Claim 19 with alkali metal hydroxide.

27. A method for the manufacture of purpurin imide comprising reacting the purpurin derivative from Claim 19 with alkali metal hydroxide.

43 28. A method for the manufacture of an imide derivative of purpurin comprising: reacting hexylamine with a chlorin or bacteriochlorin having a macrocycle with a six membered anhydrid ring fused thereto, said macrocycle containing a and b rings which may be saturated or unsaturated at R₄ to R-^ positions and which R₄ to R-,-^ positions may contain at least one group selected from the group consisting of hydrogen, hydroxy, formal, substituted and unsubstituted alkyl, alkoxy, alkenyl, aryl and aryloxy, wherein carbon containing groups may be substituted with a substituent selected from carbonyl, hydroxy, phosphoro, carboxy, halo, sulfo, amino and ether, to obtain a purpurin derivative; and reacting the obtained purpurin derivative with a carbodiimide to obtain the imide derivative of purpurin.

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