Amino-and mercurio-substituted 4′,5'-dihydropsoralens and therapeutical uses thereof

A process for preparing a 5′-substituted-4′,5′-dihydropsoralen substituted at the 3, 4, 5, 8, or 4′ position of formula (8):

• wherein T is Br or I, or HgR4 wherein R4 is OC(O)(C1-C6 alkyl), OC(O)(C1-C6 fluoroalkyl), or a halogen;
• the process comprising the step of contacting a 6-allyl-7-hydroxycoumarin substituted at the 3, 4, 5, or 8 position of the formula:
• with a cyclization reagent under conditions to form said 5′-substituted-4′,5′-dihydropsoralen substituted at the 3, 4, 5, 8, or 4′ position;
• when T is Br, the cyclization reagent is selected from N-bromosuccinimide;
• when T is I, the cyclization reagent is selected from N-iodosuccinimide, I2, ICl, and IBr;
• or
• when T is HgR4, the cyclization reagent is Hg(R4)2 wherein R4 is as defined above.

A process for preparing a 5′-substituted 4,8-dimethyl-4′,5′-dihydropsoralen of formula (5):

• wherein R is hydrogen, a halogen, NO2, or CN and T is BR or I, or HgR4 wherein R4 is OC(O)(C1-C6 alkyl), OC(O)(C1-C6 fluoroalkyl), or a halogen;
• comprising the step of contacting a 4,8-dimethyl-6-allyl-7-hydroxycoumarin of the formula:
• with a cyclization reagent under conditions to form said 5′-substituted 4,8-dimethyl-4′,5′-dihydropsoralen, wherein:
• R is as defined above;
• and
• when T is Br, the cyclization reagent is selected from N-bromosuccinimide;
• when T is I, the cyclization reagent is selected from N-iodosuccinimide, I2, ICl, and IBr;
• or
• when T is HgR4, where R4 is R4 is OC(O)(C1-C6 alkyl), OC(O)(C1-C6 fluoroalkyl), or a halogen, the cyclization reagent is Hg(R4)2.

A process for preparing a 3-R-4,8-dimethyl-4′,5′-dihydro-5′-bromomethylpsoralen (5) having the formula:

• wherein R is hydrogen, a halogen, NO2, or CN;
• and T is Br;
• comprising the steps of brominating a compound of formula (3)
• where R′ is acetyl to form 4,8-dimethyl-6-(2,3-dibromopropyl)-7-acetoxycoumarin (4)
• and cyclizing the resulting 3-R-4,8-dimethyl-6-(2,3-dibromopropyl)-7-hydroxycoumarin to yield the compound (5), wherein the cyclizing step comprises contacting the 3-R-4,8-dimethyl-6-(2,3-dibromopropyl)-7-hydroxycoumarin with anhydrous K2CO3 in dry acetone.

A process for preparing a 3-R-4,8-dimethyl-4′,5′-dihydro-5′-iodomercurimethylpsoralen (5) having the formula:

• wherein R is hydrogen, a halogen, NO2, or CN;
• and T is HgI;
• comprising the steps of:
• contacting a 4,8-dimethyl-6-allyl-7-hydroxycoumarin of the formula:
• with a cyclization reagent under conditions to form said 3-R-4,8-dimethyl-4′,5′-dihydro-5′-iodomercurimethylpsoralen, wherein:
• R is hydrogen, a halogen, NO2, or CN;
• T is HgR4;
• R4 is OC(O)(C1-C6 alkyl), OC(O)(C1-C6 fluoroalkyl), or a halogen, and the cyclization reagent is Hg(R4)2 and
• contacting the resulting 3-R-4,8-dimethyl-4′,5′-dihydro-5′-R4mercurimethylpsoralen of formula (5) with I− under anion exchange conditions to convert the group HgR4 to HgI.

A process for preparing 5-N-aminomethyl substituted 4,8-dimethyl-4′,5′-dihydropsoralen of the formula (5):

• wherein
• R is hydrogen, a halogen, NO2, or CN;
• T is NR1R2 or (N+R1R2R3)X−;
• R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X−, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or a 6-member heterocyclic aromatic ring;
• R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring;
• X− is bromo or iodo;
• comprising the steps of:
• contacting a 4,8-dimethyl-6-allyl-7-hydroxycoumarin of the formula:
• with a cyclization reagent under conditions to form a compound of formula (5) where T is Br or I, and wherein:
• when T is Br, the cyclization reagent is selected from N-bromosuccinimide;
• when T is I, the cyclization reagent is selected from N-iodosuccinimide, I2, ICl, and IBr;
• and contacting the compound of formula (5) where T is Br or I with an amine of the formula of HNR1R2 or NR1R2R3.

A process for preparing 5-N-aminomethyl substituted 4,8-dimethyl-4′,5′-dihydropsoralen of the formula (5):

• wherein
• R is hydrogen, a halogen, NO2, or CN;
• T is NR1R2 or (N+R1R2R3)X−;
• R1 and R2 are independently a C1-C6 alkyl, or R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring, or when T is (N+R1R2R3)X−, R1 and R2 together with the nitrogen form a 5-8 member heterocyclic ring or a 6-member heterocyclic aromatic ring;
• R3 is hydrogen, a C1-C12 alkyl, or, when R1 and R2 together with the nitrogen form a heterocyclic aromatic ring, R3 is a double bond within the heterocyclic aromatic ring;
• X− is bromo or iodo;
• comprising the steps of:
• brominating a compound of formula (3)
• where R′ is acetyl to form 4,8-dimethyl-6-(2,3-dibromopropyl)-7-acetoxycoumarin (4)
• and cyclizing the resulting 3-R-4,8-dimethyl-6-(2,3-dibromopropyl)-7-hydroxycoumarin to yield the compound (5);
• and
• contacting the compound of formula (5) where T is Br or I with an amine of the formula of HNR1R2 or NR1R2R3, wherein the cyclizing step comprises contacting the 3-R-4,8-dimethyl-6-(2,3-dibromopropyl)-7-hydroxycoumarin with anhydrous K2CO3 in dry acetone.

A process for preparing 5-N-aminomethyl substituted 4,8-dimethyl-4′,5′-dihydropsoralen of claim 16, wherein

• R is hydrogen, F, Br, I, NO2, or CN;
• R1 and R2 are independently methyl, ethyl, hydroxyethyl, or propyl, or R1 and R2 together with the nitrogen form a heterocyclic ring selected from N-pyrrolidinyl, N-2-pyrrolidinonyl, N-pyrrolinyl, N-pyrazolidinyl, N-pyrazolinyl, N-pyrazolyl, N-imidazolidinyl, N-imidazolinyl, N-imidazolyl, N-oxazolidinonyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, N-pyridinyl, N-4-(C1-C4 alkyl)pyridinyl, N-hexamethyleneiminyl, N-heptamethyleneiminyl, N-quinolinyl or N-isoquinolyl;
• and
• R3 is hydrogen, methyl, ethyl, dodecyl, or a double bond within a heterocyclic aromatic ring defined by N, R1, and R2.