Novel halogenated prostacyclins, process for the production thereof, and pharmaceutical use thereof

Claim 2

A halogenated prostacyclin selected from the group consisting of halogenated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions indicates that a single, double or triple bond exists between the 13- and 14-positions; R represents a C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted phenyl(C 1 -C 2 )alkyl group, or one equivalent of a cation whose salt is pharmaceutically acceptable; R 2 and R 3 represent a hydrogen or halogen atom, provided that R 2 and R 3 are not hydrogen atoms at the same time; R 4 represents a hydrogen atom, a methyl group, an ethynyl group or a protected ethynyl group; R 5 represents an unsubstituted C 5 -C 8 alkyl group, a substituted C 1 -C 5 alkyl group substituted by a substituent selected from phenyl, phenoxy, C 1 -C 6 alkox y and C 5 -C 6 cycloalkyl, which substituent may be substituted, or a substituted or unsubstituted alicyclic group; and R 6 and R 7 are identical or different and each represents a hydrogen atom, a C 2 -C 7 acyl group,, a tri-(C 1 -C 7 )hydrocarbon-silyl group or a group forming an acetal linkage with the oxygen atom of the hydroxyl group, and halogenated PGI 2 of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, provided that when R 2 is a hydrogen or fluorine atom, R 3 is not a hydrogen atom.

Claim 3

The halogenated prostacyclin of claim 1 which is selected from the halogenated PGI 1 of formula (A I ) in which R 2 and R 3 represent a hydrogen or fluorine atom.

Claim 4

The halogenated prostacyclin of claim 1 which is selected from the halogenated PGI 2 of formula (A 2 ) in which R 2 and R 3 represent a hydrogen or fluorine atom.

Claim 5

The halogenated prostacyclin of claim 1 which is selected from the halogenated PGI 1 of formula (A I ) in which R 2 and R 3 represent a hydrogen, chlorine, bromine or iodine atom.

Claim 6

The halogenated prostacyclin of claim 1 which is selected from the halogenated PGI 2 of formula (A 2 ) in which R 2 and R 3 represent a hydrogen, chlorine, bromine or iodine atom.

Claim 7

. The halogenated prostacyclin of any one of claims 1 to 5 wherein R 1 represents a hydrogen atom, a C 1 -C 10 alkyl group, or one equivalent of a cation whose salt is pharmaceutically acceptable.

Claim 8

The halogenated prostacyclin of any one of claims 1 to 5 wherein R 4 represents a hydrogen atom or a methyl group.

Claim 9

The halogenated prostacyclin of any one of claims 1 to 5 wherein R 5 represents an n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl or cyclohexyl group.

Claim 10

The halogenated prostacyclin of any one of claims 1 to 5 wherein R 6 and R 7 are identical or different and each represents a hydrogen atom, a tri(C l -C 4 )alkylsilyl group, a diphenyl(C l -C 4 )alkylsilyl group, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group, a 2-ethoxy-2-propyl group, a (2-methoxyethoxy)-methyl group, a 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl. group, an acetyl group or a benzoyl group.-10. The halogenated prostacyclin of any one of claims 1, 3 and 5 wherein in formula (A 2 ), the bond between the carbon atom at the 5-position of the double bond between the 5- and 6-positions and the carbon atom at the 4-position is cis to the bond between the carbon atom at the 6-position of the double bond and the oxygen atom.

Claim 11

The halogenated prostacyclin of any one of claims 1 to 10 wherein the bond between the 13- and 14-positions is a trans-double bond or a triple bond.

Claim 12

The halogenated prostacyclin of claim 1 which is selected from the group consisting of wherein the symbol between the 13- and 14- positions indicates that a single, double or triple bond exists between the 13- and 14- positions; R 11 represents a hydrogen atom, a C 1 -C 10 alkyl group, or one equivalent of a cation whose salt is pharmaceutically acceptable; R 21 and R 31 represent a hydrogen, fluorine or chlorine atom, provided that R 21 and R 31 are not hydrogen atoms at the same time; R 41 represents a hydrogen atom or a methyl group; R 51 represents an n-pentyl, n-hexyl, 2-methyl-l-hexyl, 2-methyl-2-hexyl or cyclohexyl group; and R 61 and R 71 represent hydrogen atom or an acetyl group, and halogenated PGI 2 of the formula wherein the symbol between the 13- and 14- positions, R 11 , R 21 , R 31 , R 41 , R 51 , R 61 and R 71 are as defined above, provided that when R 2 1 is a hydrogen or fluorine atom, R 31 is not a hydrogen atom.

Claim 13

The halogenated prostacyclin of claim 12 wherein in fbrmula (A 2 )-1, the bond between the carbon atom at the 5-position of the double bond between the 5- and 6-positions and the carbon atom at the 4-position is cis to the bond between the carbon atom at the 6-position of the double bond and the oxygen atom.

Claim 14

The halogenated prostacyclin of claim 12 wherein the bond between the 13- and 14-positions is a trans-double bond or a triple bond.

Claim 15

A process for producing a halogenated prostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions indicates that a double bond exists between the 5- and 6-positions or between the 6- and 7-positions; the symbol between the 13- and 14-positions, R 1 , R 4 , R 5 , R 6 and R 7 are as defined with regard to formula (A 1 ) in .claim 1; R 32 represents a hydrogen, chlorine, bromine or iodine atom; and X represents a chlorine, bromine or iodine atom; provided that when R 32 is a hydrogen atom, the bond between the 6- and 7- positions is a double bond, and when R 32 is other than hydrogen, the bond between the 5- and 6- positions is a double bond, which comprises halogenating a PGI2 of the following formula wherein the symbol between the 13- and 14- positions and R 5 are as defined above; R 12 represents a C 1 -C 10 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alicyclic group or a substituted or unsubstituted phenyl(C 1 -C 2 )alkyl group; R 42 represents a hydrogen atom, a methyl group or a protected ethynyl group; and R62 and R 72 are identical or different, and each represents a C 2 -C 7 acyl group, a tri(C 1 -C 7 )hydrocarbon-silyl group or a group forming an acetal linkage with the oxygen atom of the hydroxyl group, with an electrophilic halogenating agent of the following formula wherein X is as defined, and Q is a nucleophilic residue, in an inert organic solvent, if required in the presence of a basic compound, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 16

The process of claim 15 wherein the electrophilic halogenating agent is chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, N-bromophthalimide, N-chlorophthalimide, dioxane dibromide, dichlorohydantoin, dibromodimethyl hydantoin, trichloroisocyanuric acid, t-butyl hypochlorite, t-butyl hypobromite, or pyridinium hydrobromide perbromide.

Claim 17

The process of claim 15 or 16 wherein the halogenation is carried out in the presence of a basic compound.

Claim 18

A process for producing a halogenated PGI Z of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R 6 and R 7 are as defined with regard to formula (A 1 ) in claim 1, X' represents a chlorine, bromine or iodine atom, and X represents a chlorine, bromine or iodine atom, which comprises halogenating a halogenated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions, R 5 and X' are as defined above, and R12, R42, R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15, with an electrophilic halogenating agent of the following formula wherein X is as defined above, and Q is a nucleophilic residue, in an inert organic solvent, if required in the presence of a basic compound, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 19

A process for producing a halogenated PGI Z of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R , R 6 and R are as defined with regard to formula (A 2 ) in claim 1 and X' is - as defined with regard to formula (A 1 )-a 1 in claim 18, which comprises (a) treating the halogenated PGI 1 of formula (A 1 )-a in claim 18 with a catalytic amount of a protic acid or a pyridinium salt of an organic sulfonic acid in an inert aprotic solvent while, if required, causing a dehydrating agent to be present either subsequently or simultaneously, or (b) treating said halogenated PGI 1 with a catalytic amount of a protic acid in a protic solvent and then heating the treated product in an aprotic solvent, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 20

A process for producing a halogenated prostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R 6 , R and X are as defined with regard to formula (A)-l in claim 15, and R22 represents a hydrogen, chlorine, bromine or iodine atom, provided that when R 22 is a hydrogen atom, a double bond exists between the 5- and 6- positions and when R 22 is other than hydrogen, a double bond exists between the 6- and 7-positions, which comprises halogenating a PGI 1 of the following formula wherein the symbol between the 13- and 14- positions, R 12 , R 42 , R 5 , R 62 and R 72 are as de - fined with regard to formula (B 2 ) in claim 15, with the electrophilic halogenating agent of formula (C) given in claim 15 in an inert organic solvent, if required in the presence of a basic compound, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 21

The process of claim 20 wherein the electrophilic halogenating agent is chlorine, bromine, iodine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, N-bromo- phthalimide, N-chlorophthalimide, dioxane dibromide, dichlorohydantoin, dibromodimethyl hydantoin, trichloroisocyanuric acid, t-butyl hypochlorite, t-butyl hypobromite or pyridinium hydrobromide perbromide.

Claim 22

The process of claim 20 or 21 wherein the halogenation is carried out in the presence of a basic compound.

Claim 23

A process for producing a halogenated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R5, R 6 , R 7 , X and Y' are as defined with regard to formula (A 2 )-a l in claim 18, which comprises halogenating a halogenated PGI 2 of the following formula wherein the symbol between the 13- and 14- positions, R 12 , R 42 , R , R 62 , R and X' are as defined with regard to formula (A l )-a in claim 18, with the electrophilic halogenating agent of formula (C) given in claim 15 in an inert organic solvent, if required in the presence of a basic compound, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 24

A process for producing a halogenated PGI 1 of the .following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R 6 , R 7 and X' are as defined with regard to formula (A 2 )-a 2 in claim 19, which comprises (a) treating the halogenated PGI 2 of formula (A 2 )-a given in claim 23 with a catalytic amount of a protic acid or a pyridinium salt of an organic sulfonic acid in an inert aprotic solvent while, if required, causing a dehydrating agent to be present subsequently or simultaneously, or (b) treating said halogenated PGI 2 with a catalytic amount of a protic acid in a protic solvent and then heating the treated product in an aprotic solvent, and thereafter, as required, subjecting the reaction product of (a) or (b) to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 25

A process for producing a halogenated prostacyclin of the following formula wherein R , R 4 , R , R 6 and R are as defined with regard to formula (A 1 ) in claim 1, and R 23 and R 33 represent a hydrogen or fluorine atom, provided that R 23 and R 33 are not hydrogen atoms or fluorine atoms at the same time, and when R 23 is a fluorine atom, a double bond exists between the 6- and 7-positions and when R 33 is fluorine atom, a double bond exists between the 5- and 6-positions, which comprises fluorinating the halogenated PGI 1 of formula (A l )-a in claim 18 or the halogenated PGI 2 of formula (A 2 )-a in claim 23 with a fluorinating agent in an aprotic inert organic solvent, and thereafter, if required, subjecting the reaction product to a reaction of removing'the protective group and/or a salt-forming reaction.

Claim 26

The process of claim 25 wherein the fluorinating agent is silver fluoride, cesium fluoride, potassium fluoride, sodium fluoride, mercury fluoride, silver borofluoride, or tetrabutyl ammonium fluoride.

Claim 27

A process for producing a halogenated prostacyclin of formula (A)-a 1 given in claim 25, which comprises fluorinating an oxyprostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions, and R 5 are as defined with regard to formula (A)-l in claim 15; R 12 , R 42 , R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15; and Z 1 and Z 2 represent a hydrogen atom, a mesyloxy group, a trifluoromesyloxy group or a tosyloxy group, provided that either one of Z 1 and Z 2 is a hydrogen atom, and when Z 1 is a hydrogen atom, a double bond exists between the 5- and 6-positions, and when Z 2 is a hydrogen atom, a double bond exists between the 6- and 7- positions, with a fluorinating agent in an aprotic inert organic solvent, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 28

The process of claim 27 wherein said fluorinating agent is silver fluoride, cesium fluoride, potassium fluoride, sodium fluoride, mercury fluoride, silver borofluoride or tetrabutyl ammonium fluoride.

Claim 29

A process for producing a halogenated prostacyclin of formula (A)-a 1 given in claim 25, which comprises fluorinating a hydroxyprostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions, and R 5 are as defined with regard to formula (A)-l in claim 15; R 12 , R 42 , R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15; and Z 3 and Z 4 are different from each other and represent a hydrogen atom or a hydroxyl group, provided that when Z 3 is a hydrogen atom, a double bond exists between the 5- and 6- positions, and when Z 4 is a hydrogen atom, a double bond exists between the 6- and 7-positions, with a di(C 1 -C 5 )alkylamino-SF 3 , a bis[di(C 1 -C 5 )alkylamino]-SF 2 , morpholino-SF 3 or CF 3 CHFCF 2 N(C 2 H 5 ) 2 in an aprotic inert organic solvent, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 30

A process for producing a halogenated PGI 2 of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R , R 6 and R 7 are as defined with regard to formula (A l ) in claim 1, and X is a chlorine, bromine or iodine atom, which comprises halogenating a fluorinated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions and R 5 are as defined with regard to formula (A 1 ) in claim 1 and R 12 , R 42 , R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15, with the electrophilic halogenating agent of formula (C) given in claim 15 in an inert organic solvent, if required in the presence of a basic compound, and thereafter if required, subjecting the resulting product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 31

A process for producing a halogenated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R 6 , R 7 and X are as defined with regard to formula (A 2 )-a 4 in claim 30, which comprises halogenating a fluorinated PGI 2 of the following formula wherein the symbol between the 13- and 14- positions, R 12 , R42, R 5 , R 62 and R 72 are as defined with regard to formula (A 1 )-a 3 in claim 30, with the electrophilic halogenating agent of formula (C) given in claim 15 in an inert organic solvent, if required in the presence of a basic compound, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 32

A process for producing a fluorinated prostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R 6 and R 7 are as defined with regard to formula (A 1 ) in claim 1, which comprises fluorinating a halogenated prostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions and R 5 are as defined with regard to formula (A 1 ) in claim 1, R 12 , R 42 , R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15; and Y and Y' are identical or different and and each represents a fluorine, chlorine, bromine or iodine atom, provided that Y and Y' are not fluorine atoms at the same time, and when Y is a fluorine atom, a double bond exists between the 5- and 6-positions and when Y' is a fluorine atom, a double bond exists between the 6- and 7- positions, with a fluorinating agent in an-aprotic inert organic sol- vent, and thereafter, if required, subjecting the reaction product to a reaction of removing the protective group and/or a salt-forming'reaction.

Claim 33

A process for producing a fluorinated PGI 1 of the following formula wherein the symbol between the 13- and 14- positions, R 1 , R 4 , R 5 , R and R are as defined with regard to formula (A 1 ) in claim 1, which comprises (a) treating the fluorinated PGI 2 of formula (A 2 )-a 3 given in claim 31 with a catalytic amount of a protic acid or a pyridinium salt of an organic sulfonic acid in an inert aprotic solvent while, if required, causing a dehydrating agent to be present subsequently or simultaneously, or (b) treating said fluorinated PGI 2 with a catalytic amount of a protic acid in a protic solvent and thereafter heating the treated product in an aprotic solvent, and thereafter, if required, subjecting the reaction product of (a) or (b) to a reaction of removing the protective group and/or a salt-forming reaction.

Claim 34

A pharmaceutical composition for controlling vascular actions, said composition comprising a halogenated prostacyclin selected from the group consisting of the halogenated PGI1 of formula (A 1 )-1 in claim 12 and the halogenated PGI 2 of formula (A 2 )-1 in claim 12 as an active ingredient together with a pharmaceutically acceptable carrier.

Claim 35

The pharmaceutical composition of claim 34 which is for vasodilation, blood pressure lowering or antithrombosis.

Claim 36

The pharmaceutical composition of claim 34 or'35 which is for controlling arteriosclerosis, angina pectoris, myocardial infarction, endotoxin shock, pulmonary hypertension, cerebral apoplexy, transient ischemic attack, thrombocytopenic purpura, deep vein thrombosis or peripheral vascular diseases.

Claim 37

The pharmaceutical composition of claim 34 which is for inhibiting metastasis of a malignant tumor.

Claim 38

The pharmaceutical composition of claim 34 which is for use in organ transplantation, vascular surgery or extracorporeal circulation.

Claim 39

A medicament in unit dosage form comprising the pharmaceutical composition of any one of claims 34 to 38.

Claim 40

A method for controlling vascular actions of. a warm-blooded animal, which comprises administering a pharmaceutically effective amount of the halogenated prostacyclin of claim 12, or the pharmaceutical composition of any one of claims 34 to 38, or the medicament of claim 39 to said animal which requires such control.

Claim 41

The method of claim 40 wherein the warm-blooded animal is a human.

Claim 42

The method of claim 41 wherein the pharmaceutically effective amount is about 0.02 µg to about 2 mg/kg of body weight/day.

Claim 43

A hydroxyprostacyclin of the following formula wherein the symbol between the 5-, 6- and 7- positions, the symbol between the 13- and 14- positions, and R 5 are as defined with regard to formula (A)-l in claim 15; R 12 , R 42 , R 62 and R 72 are as defined with regard to formula (B 2 ) in claim 15; and Z 3 and Z 4 are different from each other and represent a hydrogen atom or a, hydroxyl group, provided that when Z 3 is a hydrogen atom, a double bond exists between the 5- and 6- positions, and when Z 4 is a hydrogen atom, a double bond exists between the 6- and 7-positions.