CA1221105A - Omega halogenated fatty acids - Google Patents
Omega halogenated fatty acidsInfo
- Publication number
- CA1221105A CA1221105A CA000436822A CA436822A CA1221105A CA 1221105 A CA1221105 A CA 1221105A CA 000436822 A CA000436822 A CA 000436822A CA 436822 A CA436822 A CA 436822A CA 1221105 A CA1221105 A CA 1221105A
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- Prior art keywords
- methyl
- enolide
- group
- oxo
- cis
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
- C07C59/21—Saturated compounds having only one carboxyl group and containing keto groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/305—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups
- C07C59/315—Saturated compounds containing more than one carboxyl group containing ether groups, groups, groups, or groups containing halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyrane Compounds (AREA)
Abstract
OMEGA HALOGENATED FATTY ACIDS
Abstract of the Disclosure A novel process of preparing known and novel pharmaceutically useful omega substituted radioactive isomers of fatty acids from industrially available macrocyclic musk lactones, lactones and dilactones is disclosed. The process involves saponifying a lactone or dilactone, treating the resulting omega substituted hydroxy fatty acid to render the omega position recep-tive to the substitution of a radioactive isomer of a suitable substituent radical, and substituting a radio-active imaging isomer of a suitable substituent radical in the fatty acid at the omega position. The process provides an inexpensive and secure source of 16-iodo-hexadecanoic acid and 17-iodo-heptadecanoic acid which are valuable known radioactive imaging compounds. The novel process also provides a ready and inexpensive access to a large number of novel omega substituted radioactive isomers of fatty acids including novel omega halogenated fatty acid analogs.
Abstract of the Disclosure A novel process of preparing known and novel pharmaceutically useful omega substituted radioactive isomers of fatty acids from industrially available macrocyclic musk lactones, lactones and dilactones is disclosed. The process involves saponifying a lactone or dilactone, treating the resulting omega substituted hydroxy fatty acid to render the omega position recep-tive to the substitution of a radioactive isomer of a suitable substituent radical, and substituting a radio-active imaging isomer of a suitable substituent radical in the fatty acid at the omega position. The process provides an inexpensive and secure source of 16-iodo-hexadecanoic acid and 17-iodo-heptadecanoic acid which are valuable known radioactive imaging compounds. The novel process also provides a ready and inexpensive access to a large number of novel omega substituted radioactive isomers of fatty acids including novel omega halogenated fatty acid analogs.
Description
OMEGA ~ALOGENATED FATTY ACIDS
Field of the Invention This invention 15 directed to known and novel pharmaceutically useful omega substituted radioactive isomers of fatty acids including omega halogenated fatty acids and to a novel process for preparing such fatty acids. These omega substituted radioactive isomers of fatty acids are useful as analogs of natural fatty acids in enabling images of the human myocardium to be obtained for clinical diagnostic analysis.
ack~round of the Invention ` Fatty acids labelled at the omega position with a radioactive halogen, for example, iodine-131 or iodine-123, and injected into the human body have found considerable use as analogs oE natural fatty acids for imaging the human myocardium. Original axperiments conducted with 16-iodo-9-hexadecenoic acid have drawn attention to the usefulness of an omega halogenated atty acid in this field. It has been found that the uptake and gross metabolism of this compound in a human myocardium proceeds with the same kinetics as are associated with natural fatty acids. Successful results have also been obtained with 16-iodo-hexadecanoic acid and 17-iodo-heptadecanoic acid. Characteristic meta-bolic kinetics are measured when an omega halogenated fatty acid is supplied to normal or ischemic myocardium.
Considerable research has been devoted to interpreting the kinetics of omega halogenated fatty acids ernployed in this manner and to exploit the meta-bolism for clinical analysis. A significant development in this field has been the discovery of the utility of the pharmaceutical, p-iod~-phenylpentadecanoic acid, which has been found to afford reduced blood levels o~
Iodine-123 generated by metabolism. There is a pressing social medical need to develop further fatty omega halogenated acid analogs for use in this ~ield. To date, the fatty acid analogs that have been developed and utilized in this field have been expensive and in relatively short supply. A constant problem has heen to discover a simple, inexpensive process for preparing potentially useful omega halogenated fatty acids.
Macrocyclic musk lactones are well-known in~ustrial chemicals used in per~umery. The natuYal available macrocyclic musks civet, musk, anyelica and ambrette have played an essential role in commerciai perfumery for over one millennium and the present industrial supply of such known musks is ahun~1~nt and
Field of the Invention This invention 15 directed to known and novel pharmaceutically useful omega substituted radioactive isomers of fatty acids including omega halogenated fatty acids and to a novel process for preparing such fatty acids. These omega substituted radioactive isomers of fatty acids are useful as analogs of natural fatty acids in enabling images of the human myocardium to be obtained for clinical diagnostic analysis.
ack~round of the Invention ` Fatty acids labelled at the omega position with a radioactive halogen, for example, iodine-131 or iodine-123, and injected into the human body have found considerable use as analogs oE natural fatty acids for imaging the human myocardium. Original axperiments conducted with 16-iodo-9-hexadecenoic acid have drawn attention to the usefulness of an omega halogenated atty acid in this field. It has been found that the uptake and gross metabolism of this compound in a human myocardium proceeds with the same kinetics as are associated with natural fatty acids. Successful results have also been obtained with 16-iodo-hexadecanoic acid and 17-iodo-heptadecanoic acid. Characteristic meta-bolic kinetics are measured when an omega halogenated fatty acid is supplied to normal or ischemic myocardium.
Considerable research has been devoted to interpreting the kinetics of omega halogenated fatty acids ernployed in this manner and to exploit the meta-bolism for clinical analysis. A significant development in this field has been the discovery of the utility of the pharmaceutical, p-iod~-phenylpentadecanoic acid, which has been found to afford reduced blood levels o~
Iodine-123 generated by metabolism. There is a pressing social medical need to develop further fatty omega halogenated acid analogs for use in this ~ield. To date, the fatty acid analogs that have been developed and utilized in this field have been expensive and in relatively short supply. A constant problem has heen to discover a simple, inexpensive process for preparing potentially useful omega halogenated fatty acids.
Macrocyclic musk lactones are well-known in~ustrial chemicals used in per~umery. The natuYal available macrocyclic musks civet, musk, anyelica and ambrette have played an essential role in commerciai perfumery for over one millennium and the present industrial supply of such known musks is ahun~1~nt and
2~ secure. Meanwhile, newer synthetic macroçyclic musk lactones and strategies for their preparatiol) ~ynth~tic ally are being developed on a continuing basis. This a~ords an increasing supply of such lactones.
We have discovered that i~ is pro-luctive to consider the close relationship between omega halogena-ted fatty acids and corresponding macrocyclic musk lactones as a mean.s of identifying poten-tially useful inexpensive macrocyclic musk lactones, lactones starting blocks for the prepara-tion of useful omec3a substituted radioactive isomers of ~.2,~
fatty acids including omega halogenated ~atty acid endproducts with properties that are ideally suited ~o myocardial imaging. There are well over one hundred known individual macrocyclic musks. The literature discloses numerous general strategies ~or synthesis oE
t~ese substances. As one example, t'he preparation of - heptadecanolide and forty~four closely related analogs o t~at substance hav2 ~een descrlbed in a single disclosure.
~hile macrocyclic musk lactones promise to be of primary concern to the objectives of this invention, it is a act that ~he macrocyclic musk ketones have been standards of - reference in the ~ragrance field, and'such musk ketones have repeatedly ~letermined the direction of reseaxch with macrocyclic musk lactones. By working with cive~one and muscone (the active ingredients of civet and musk), it has been demonstrated in the art that macrocyclic structures, namely, 9-cycloheptadecenone and
We have discovered that i~ is pro-luctive to consider the close relationship between omega halogena-ted fatty acids and corresponding macrocyclic musk lactones as a mean.s of identifying poten-tially useful inexpensive macrocyclic musk lactones, lactones starting blocks for the prepara-tion of useful omec3a substituted radioactive isomers of ~.2,~
fatty acids including omega halogenated ~atty acid endproducts with properties that are ideally suited ~o myocardial imaging. There are well over one hundred known individual macrocyclic musks. The literature discloses numerous general strategies ~or synthesis oE
t~ese substances. As one example, t'he preparation of - heptadecanolide and forty~four closely related analogs o t~at substance hav2 ~een descrlbed in a single disclosure.
~hile macrocyclic musk lactones promise to be of primary concern to the objectives of this invention, it is a act that ~he macrocyclic musk ketones have been standards of - reference in the ~ragrance field, and'such musk ketones have repeatedly ~letermined the direction of reseaxch with macrocyclic musk lactones. By working with cive~one and muscone (the active ingredients of civet and musk), it has been demonstrated in the art that macrocyclic structures, namely, 9-cycloheptadecenone and
3-methyl-cyclopentadecanone respectively, are present.
It ~s also been revealed that the ve~etable musks possess macrocyclic lactone structures: am~rettolide (from Hibiscus abelmosc'nus Linn.) is 7-he~adecenolide and exaltolide (rom An~elica archangelica Linn.) is pentadecanolide. It has'become evident that many macrocyclic compounds h~ve a musk odor provided that a carbonyl group is present and 14-17 carbon atoms are present in the riny. (Thus, i~ i5 apparent that the size range of use~ul macrocyclic musks overlaps the size ran~e of fatty acids whch can be extracted efficientl~I
from the blood into the myoc~rdium). As a result of these discoveries, numerous synthetic musk lactones have been created.
Summary of the Invention .
~e have cliscovered that macrocyclic musk lac-ton~s, lactones which are in a : reasonably large family and are relatively inexpensive and in abundant supply, c~n be useful starting blocks Eor the preparation of omega substituted fatty acids.
We hav~ ~ound that such lactones need only be saponi-fied, treated to make the resulting product receptive to substitution, and then substituted in order to produce pharmaceutically use~ul omega substituted fatty acids.
A process o preparing an omega substi-tuted radioactive isomer of a ~atty acid o the foxmula~
~;o .
~ OH
wherein A is a radioactive Br and I and M may be:
(A) 13 12 Rl ~C~T~tCH)q~(CH2)n~X~(C112)m~(CH)p-CH2-wherein ~ may be a meth~lene group; an ether oxygen; a ca~bonyl group; or a dioxa dimethylene group;
Rl, R2, R3 each may be hydrogen, a ..
methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to lG;
`~
n is O to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 2~; or ~B) -R7-~H)p-(CH2)n~~6~(c~l2)m R5 ~C~)5 wherein R~ is hydrogen or a methyl group;
R5 may be a dimethylene group; or an : unsaturated dime~hylene group;
~6 may be a dimethylene group or an unsa-turated dimethylene group or an oxygen;
R7 may be a met'nylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is O or l;
m is 0, 2 or 3;
n is O to 4; and the sum of carbons and oxygens in-series in the M group is in the range 12 to 22; comprising:
~ ~a) ti~ When M is (A) above, saponiEying a macrocyclic saturated lactone of the formula:.
~, ' . '' ' .
S
CEI~ I _ 0~ - CH-R3 (Rl-C~)p (IH-R2)q . (C 2)m (fH2)n X
whe.rein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
Rl, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
- q is 0 or 1;
.
m -;s 1 to 16;
n is 0 to 10;
and the sum of carbons and oxy~ens in the ring group is in the range 14 to 24; or (ii) When M is (B) above, saponi~yi~g a macrocyclic unsaturated lactone of the formula:
O
( Cf~2 ~ 5 c - o ~
R5 (HC-R~)p (CEI2)m - (CH2)n - . . -- R6. - I ' ~ herein R4 is hyclrogen or a methyl group;
. Rs may be a dimethylene group; or an - unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene gxoup; or an unsaturated d~methylene group;
p i5 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24; to yield the corresponding omega substituted hydroxy fatty acid;
(b) treating the omega substituted hydroxy fatty acid to render the omega position receptive to the substitut-on of a radioactive isomer of a suitable substituent radical; and (c) substituting a radioactive imaging isomer or a nuclear magnetic resonance imaging isomer of a suitable D;
D~ a ~-~r~
substituent radical in place of the tosylate or other leaving group at the omega position.
Drawin~s In the drawing:
~'IGURE l'represents a scintigraphic study o a prone rabbit from the posterior view.
Detailed Description oE the Invention The commercial rnacrocyclic musk lactones, lactones and dilactones all into several categories, with over one hundred specie~ in all. The cater~ories range from simple, unsaturated and methyl lactones (48 known species), ketone lactones (24 species), lS - and ether lactones (6 species). The ' inventors have taken representa~ives of these major classes ` ~ and have converted them to the correspondiny omega halogenated fatty acids according to the process of the invention.
The examples which follow at the end oE this discussion demonstrate the preparation of various omega halo~Jenated ~atty acids Erom corresponding macrocyclic musk lactones, used as starting reagents accord ing to the process o~ this invention. The inventors have ~S worked specifically with hexadecanolide, pentadecano-lider 12-keto-pentadecanolide, 12-oxa-hexadecarlolide, and 7-hexadecenolide, which can be graphically depicted as fol~ows:
.
' 30 ,~ .
PJ~ 3s o 1. Hexadecanolide ~ ~O-I
~ (C~12)4 ~ ~ CH~
2. Pentadecanolide ~ ~ O~
1 1 :
~ /~
3. 12-Keto-Pentadecanolide . rrL~\
'~,,J
It ~s also been revealed that the ve~etable musks possess macrocyclic lactone structures: am~rettolide (from Hibiscus abelmosc'nus Linn.) is 7-he~adecenolide and exaltolide (rom An~elica archangelica Linn.) is pentadecanolide. It has'become evident that many macrocyclic compounds h~ve a musk odor provided that a carbonyl group is present and 14-17 carbon atoms are present in the riny. (Thus, i~ i5 apparent that the size range of use~ul macrocyclic musks overlaps the size ran~e of fatty acids whch can be extracted efficientl~I
from the blood into the myoc~rdium). As a result of these discoveries, numerous synthetic musk lactones have been created.
Summary of the Invention .
~e have cliscovered that macrocyclic musk lac-ton~s, lactones which are in a : reasonably large family and are relatively inexpensive and in abundant supply, c~n be useful starting blocks Eor the preparation of omega substituted fatty acids.
We hav~ ~ound that such lactones need only be saponi-fied, treated to make the resulting product receptive to substitution, and then substituted in order to produce pharmaceutically use~ul omega substituted fatty acids.
A process o preparing an omega substi-tuted radioactive isomer of a ~atty acid o the foxmula~
~;o .
~ OH
wherein A is a radioactive Br and I and M may be:
(A) 13 12 Rl ~C~T~tCH)q~(CH2)n~X~(C112)m~(CH)p-CH2-wherein ~ may be a meth~lene group; an ether oxygen; a ca~bonyl group; or a dioxa dimethylene group;
Rl, R2, R3 each may be hydrogen, a ..
methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to lG;
`~
n is O to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 2~; or ~B) -R7-~H)p-(CH2)n~~6~(c~l2)m R5 ~C~)5 wherein R~ is hydrogen or a methyl group;
R5 may be a dimethylene group; or an : unsaturated dime~hylene group;
~6 may be a dimethylene group or an unsa-turated dimethylene group or an oxygen;
R7 may be a met'nylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is O or l;
m is 0, 2 or 3;
n is O to 4; and the sum of carbons and oxygens in-series in the M group is in the range 12 to 22; comprising:
~ ~a) ti~ When M is (A) above, saponiEying a macrocyclic saturated lactone of the formula:.
~, ' . '' ' .
S
CEI~ I _ 0~ - CH-R3 (Rl-C~)p (IH-R2)q . (C 2)m (fH2)n X
whe.rein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
Rl, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
- q is 0 or 1;
.
m -;s 1 to 16;
n is 0 to 10;
and the sum of carbons and oxy~ens in the ring group is in the range 14 to 24; or (ii) When M is (B) above, saponi~yi~g a macrocyclic unsaturated lactone of the formula:
O
( Cf~2 ~ 5 c - o ~
R5 (HC-R~)p (CEI2)m - (CH2)n - . . -- R6. - I ' ~ herein R4 is hyclrogen or a methyl group;
. Rs may be a dimethylene group; or an - unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene gxoup; or an unsaturated d~methylene group;
p i5 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24; to yield the corresponding omega substituted hydroxy fatty acid;
(b) treating the omega substituted hydroxy fatty acid to render the omega position receptive to the substitut-on of a radioactive isomer of a suitable substituent radical; and (c) substituting a radioactive imaging isomer or a nuclear magnetic resonance imaging isomer of a suitable D;
D~ a ~-~r~
substituent radical in place of the tosylate or other leaving group at the omega position.
Drawin~s In the drawing:
~'IGURE l'represents a scintigraphic study o a prone rabbit from the posterior view.
Detailed Description oE the Invention The commercial rnacrocyclic musk lactones, lactones and dilactones all into several categories, with over one hundred specie~ in all. The cater~ories range from simple, unsaturated and methyl lactones (48 known species), ketone lactones (24 species), lS - and ether lactones (6 species). The ' inventors have taken representa~ives of these major classes ` ~ and have converted them to the correspondiny omega halogenated fatty acids according to the process of the invention.
The examples which follow at the end oE this discussion demonstrate the preparation of various omega halo~Jenated ~atty acids Erom corresponding macrocyclic musk lactones, used as starting reagents accord ing to the process o~ this invention. The inventors have ~S worked specifically with hexadecanolide, pentadecano-lider 12-keto-pentadecanolide, 12-oxa-hexadecarlolide, and 7-hexadecenolide, which can be graphically depicted as fol~ows:
.
' 30 ,~ .
PJ~ 3s o 1. Hexadecanolide ~ ~O-I
~ (C~12)4 ~ ~ CH~
2. Pentadecanolide ~ ~ O~
1 1 :
~ /~
3. 12-Keto-Pentadecanolide . rrL~\
'~,,J
4. 12-Oxa-Hexadecanolide ~o~
. ~ O (C,H2)4
. ~ O (C,H2)4
5. 7-Hexadecenolide O
rn~~ ' `. 15 .~ .
.~ .
2~
The starting lactones in each case were saponi~ied, the resultiny hydroxy fatty acids were tosylated, and the radioactive iodine isomer was ~inally introduced into the fatty acids by substitution. By this process, 16-iodo-hexadecanoic acid, 15-iodo-pentadecanoic acid, 15-iodo-12-keto-pentadecanoic acid, 16-iodo-12-oxa hexadecanoic acid, and 16-iodo-7-hexadecenoic acid, respectively, were produced. The latter four of the resulting omega halogenated fatty acids prepared are novel and have not been previously _ 9 ~
~.2~;:~CD5~
used in nuclear medicine. However, 16-iodo-hexadecanoic acid is a well known standard. Tests ~ere conducted and excellent TLC resolutions were obtained o~ iodo and tosyl fatty acids. Carrier-~ree preparations appear feasible.
~or purposes of this invention, the following methyl and saturated lactones are useful startin~
reagents for the preparation of the correspondng omega halogenated fatty acids: 7-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl~15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pen-tadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-12-enolide, cis-15~methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-enolide, trans-16-methyl~16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis 17-heptadec-ll-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide r trans-17-heptadec-12-enolidel cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl~17-heptadec-12-enolide, cis-17-methyl-17-hep-tadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, and trans-17-methyl-17-heptadec-12-enolide.
The following ketolactones are useful starting reagents ~or the preparation of the corresponding omega halogenated fatty acids according to the process of this invention: ll-oxo-tridecanolide, ll-oxo-13-methyl-tridecanolide, ll-oxo-tetradecanolide, ll-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, ll-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15~methyl-pentadecanolide, 12-oxo-1~,15-dimethyl pentadecanoIide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl-hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolide, 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, and 15-oxo-: octadecanolide.
The following ether lactones are useful starting reagents for the process of this invention:
12-oxa-tetradecanolide, 12-oxa-pentadecanolide, '~.2 ~
12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa-14-pentadecenolide, 13-oxa-15-hexadecenolide.
It is important .hat the radioactive isomer be substituted at the omega position on the fatty acid I
~2~
molecule. Substitution at an interior position on the chain has been found to render a substance whi~h does not provide satisfactory imaging properties~ Preferred halogen isomer substituents are Iodine 122, Iodine 123, Iodine 131, Bromine 75, Bromine 77. Iodine 131 has a half-life of about 8 days. Iodine 123 is attractive because it has favourable gamma ray energies for scintigraphic imaging and a relatively short half-life of 13.3 hours, thus running a lower risk of generating radioactive damage in the patient. Likewise, Iodine 122, Bromine 75 and Bromine 77 have short half-lives and gamma rays which are compatible with nuclear medicine technology. Fatty acid analogs are attractive for purposes of this invention because it has been ~ound that fatty acid analogs are well assimilated by the heart and hence when substituted with a radioactive agent are useful in imaging the heart area.
The myocardial analysis may be extended to several other human organs because fatty acids are assimilated and metabolized by numerous organs, particularly the liver and kidneys. Halogenated fatty acids have recently been reported to delineate tumors in the liver. A second class of application is possible because fatty acid glycerides make up the bulk of cell membranes. Non-metabolized label might be introduced into the membranes, for example, living white blood cells might be labelled in the membrane by means of suitable halogenated fatty acids. The white cells might then be introduced back into the patient's body where they would see~ out the sites of actlve immune response.
An image could then be obtained showing these same sites.
To illustrate the performance and utility of the invention, a number of specific iodine substituted tosylate fatty acids were prepared. The methods of conversion of the hydroxy fatty acids starting reagents to the corresponding tosylate fatty acids were derived from disclosures in Argentini, M., et al., "Comparison of Several Methods for the Synthesis of Omega~iodine-123-heptadecanoic Acid", J. Radioanalytical Chemistry, 65 (1981) 131-138. As may be seen in Figure 1, the myocardium is evident in the scintigraphic study of a prone rabbit from the posterior view utilizing one o~
the omega halogenated ~atty acids of the invention.
16-Iodine-131-7-hexadecenoic Acid Example la 16-Hydroxy-7-hexadecenoic Acid 5 gr. of 7-hexadecenolide (generic name Ambre-ttolide) (obtained ~rom Pfaltz and ~auer #A16740) was mixed with ~50 ml lN KOH and boiled ~or one hour with vigorous stirringO During this time the oily macrolide layer disappeared. The solution was cooled to 50C and 19.8 mls of concentrated HCl (11.6M) was then added to bring the pH to approximately 4. A heavy white precipitate appeared. The mixture was refrigerated overnight. The next day the precipitate was filtered, washed with water, and dried. Finally, the product was suspended in chloroform, recrystallized from ~2~ S
chloroform/petroleum ether and dried. The yield was 3.8 9 (70%) fine white crystals m.p. 69.0~70.5C~
Example lb 16-Tosylate-7-hexadecenoic Acid 776 mg p-toluenesulfonyl chloride was dissolved in 7.4 mls dry pyridine and then 1 g 16-hydroxy-7 hexadecenoic acid prepared according to Example la was added. The reaction mixture was held at 0C for 20 hours. It was then mixed with 50 mls of water whereupon the mixture took on a uniform white appearance. The mixture was extracted four times with 50 mls of chloroform. The chloroform phase was washed twice with 50 ml portions of 0.1 N sulfuric acid and twice with 50 ml portions of water. Finally, the chloro~orm phase was dried overnight in the presence of CaSO4 and was then evaporated. The residue, a clear light yellow liquid, was washed with petroleum ether and dried under a nitrogen stream. The yield was 1.3 g (83~) of white viscous oily liquid m.p. 10 20C. A mass 2U spectrosocopy analysis was performed at the University of British Columbia Department of Chemistry Mass ~pectroscopy Laboratory~ A mass spectrum m/e 424 was identified (theoretical 424).
Example lc 16-Iodine-131-7-hexadecenoic Acid 2 microl. of 16-tosylate-7-hexadecenoic acid, prepared according to Example lb, 6 micro Ci I-131 in 2 micro 1 water, and 150 micro g NaI were added to 1 ml of methylethyl ketone. The mixture was sealed in a 5 ml borosilicate glass vial having a rubber septum and aluminum seal~ and autoclaved for 30 min at 125C to prepare 16-iodine 131-7~hexadecenoic acid.
Example ld The extent of I-131 incorporation into the fatty acid was measured by thin layer chromatography on cellulose TLC sheets (Eastman 13255TM~ using as a solvent, petroleum ether/diethyl ether/acetic acid in the volumetric ratio 266/133/1. Rf(iodide) - Q.0 Rf (fatty acid) = 1Ø It was found tha~ 97~ of the original I-131 was incorporated into the fatty acid.
16-Iodine-131-hexadecanoic Acid 16-Hydroxy-hexadecanoic acid was prepared from 5 g of hexadecanolide (obtained from Haarmann & Reimer) according to the procedure outlined in Example la~ The yield was 1.8 g (34%3 of fine white needles m.p.
95-97C. 16-Tosylate-hexadecanoic acid was prepared from 1 9 of the 16-hydroxy-hexadecanoic acid according to the procedure set out in Example lb. The yield was 1.38 g (88~) of fine white needles m.p. 62-65C. A mass spectrum m/e 426 was identified (theoretical 426).
16-Iodine-131-hexadecanoic acid was prepared from the tosylate fatty acid 16-tosylate-hexadecanoic acid according to the procedure outlined in Example lc.
It was found that 89~ of the original I-131 was incorporated into the iodo fatt~ acid.
16-Iodine-131-12-oxa-hexadecanoic Acid _ 16-Hydroxy-12-oxa-hexadecanoic acid was prepared from 5 g of 12-oxa-hexadecanolide (obtained from ~laarmann ~ Reimer) as specified in the process of Example la, Yield: 4.92 g (92%) fine white needles m.p. 5~.0~59.5C. The 16-tosylate-12-oxa-hexadecanoic acid was prepared from 1 g of the hydroxy fatty acid according to the process provided in Example lb. The yield was 1.07 g (68%) of white amorphous solid, m.p.
40-50C. 16-Iodine-131-12-oxa-hexadecanoic acid was prepared ~rom the tosylate fatty acid according to the procedure in Example lc. It was found that 59% of the original I-131 was incorporated into the iodo fatty acid.
15-Iodine~131~entadecanoic Acid 15-Hydroxy-pentadecanoic acid was prepared from 1.65 g of pentadecanolide (obtained form Haarmann &
Reimer) according to the method discussed in Example la.
The yield was 1.1 g (62%) of fine white needles m.p.
82-~4C. 15~Tosylate-pentadecanoic acid was prepared from 500 mg of the hydroxy fatty acid as in the procedure o~ Example lb. Yield: 0.~41 g (80%) of fine white needles, m.p. 64-66.5C. Mass spectrum: m/e 412 wa~ identified (calculated 412). 15-Iodine-131-pentadecanoic acid was prepared from -the tosylate fatty acid pursuant to the process of Example lc. It was found that 79% of the original I-131 was incorporated into the iodo fatty acid.
15-Iodine-131-12-keto-pentadecanoic Acid 15-hydroxy-12-keto-pentadecanoic acid was prepared from 5 g of 12-keto-pentadecanolide according to the ~rocedure in Example la. The yield was 4.8 g ~88%) in the form of fine white needles m.p. 76-78C.
15-Tosylate-12-keto-pentadecanoic acid was prepared from 1 g of the hydroxy fatty acid according to the method in Example lb. The yield was ~86 mg (31%) of hard white amorphous solid mOp. 72-76C. 15-Iodine 131~12~keto-pentadecanoic acid was prepared from the tosylate fatty acid according to the process in Example lc. It was found that 52% of the original I-131 was incorporated into the iodo fatty acid.
Test 1 Gamma Camera Scan of Heart of New Zealand Rabbit 16-Iodine-131-7-hexadecenoic acid was prepared by mixing the 0.2 ml water, 5 mCi I-131 in 0.33 ml water, 5 ml ascorbic acid, and 5 micro 1 16-tosylate-7-hexadecenoic acid in a 5 ml borosilicate vial and autoclaving 30 min at 125C. Subsequently, the aqueous phase was set aside while the lipid droplets were solubilized in 2.3 mls TweenTM/D5W/Propylene glycol. 1.44 mCi I-131 was recovered and it was found that 97% of the I-131 was tagged to fatty acid. Later, 0.6 mCi of the preparation was injected into a vein in the ear of a New Zealand rabbit and the rabbit was observed using a gamma camera (see Figure 1). It can be seen that the scan indicates the heart very clear]y in comparison to other preliminary studies with rabbits in which alternative known iodine-131-fatty acids had been used.
;J5 A systematic evaluation of the iodinated fatty acids has been carried out S~udies have been completed in mice with four of the fatty acids. The iodo-fatty acids were labelled with I-131 as in Example lc. The methylethyl ketone was evaporated, inorganic iodine removed in water, and the fatty acids suspended in TweenTM/D5W/Propylene glycol as above. Ali~uots of 1 micro Ci were iniected into the tail veins of mala white mice. ~ice were sacrificed 30sec, lm, 2m, 4m, 6m, lOm, 15m, 30m, 40m, and 120m post injection. The I-131 activity was then determined in the blood, heart, lung, liver, spleen~ and kidneys. For each fatty acid 85 mice were thus sacrificed. The results most important for heart imaging are given in Table 1. It can be seen that the results for all the fatty acids are roughly of the same magnitude as determined for the control, 16-iodo-hexadecanoic acid, which is already known to be useful clinically. Two of the fatty acids (15-iodo-pentadecanoic acid and 16-iodo-12-oxa-hexadecanoic acid) 0 gave better results than the control.
Table 1 Maximum I-131 Fatty Acid Uptake Heart Heart/
Fatty Acid~ dose/gm Heart/Lung Blood 16-iodo-7-hexadecenoic16.3+6.75 0.991~0.461 1.02+0.71 16-iodo-hexadecanoic15.6+3.29 1.42+0.369 1.42~0.290 16-iodo-12-oxa hexadecanoic14.5~3.82 2.33+0.523 1.24+0.314 15-iodo-pentadecanoic29.1+16.8 2.35+0.789 2.45+1.43 As will be apparent to those skill.ed in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
rn~~ ' `. 15 .~ .
.~ .
2~
The starting lactones in each case were saponi~ied, the resultiny hydroxy fatty acids were tosylated, and the radioactive iodine isomer was ~inally introduced into the fatty acids by substitution. By this process, 16-iodo-hexadecanoic acid, 15-iodo-pentadecanoic acid, 15-iodo-12-keto-pentadecanoic acid, 16-iodo-12-oxa hexadecanoic acid, and 16-iodo-7-hexadecenoic acid, respectively, were produced. The latter four of the resulting omega halogenated fatty acids prepared are novel and have not been previously _ 9 ~
~.2~;:~CD5~
used in nuclear medicine. However, 16-iodo-hexadecanoic acid is a well known standard. Tests ~ere conducted and excellent TLC resolutions were obtained o~ iodo and tosyl fatty acids. Carrier-~ree preparations appear feasible.
~or purposes of this invention, the following methyl and saturated lactones are useful startin~
reagents for the preparation of the correspondng omega halogenated fatty acids: 7-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl~15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pen-tadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-12-enolide, cis-15~methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-enolide, trans-16-methyl~16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis 17-heptadec-ll-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide r trans-17-heptadec-12-enolidel cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl~17-heptadec-12-enolide, cis-17-methyl-17-hep-tadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, and trans-17-methyl-17-heptadec-12-enolide.
The following ketolactones are useful starting reagents ~or the preparation of the corresponding omega halogenated fatty acids according to the process of this invention: ll-oxo-tridecanolide, ll-oxo-13-methyl-tridecanolide, ll-oxo-tetradecanolide, ll-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, ll-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15~methyl-pentadecanolide, 12-oxo-1~,15-dimethyl pentadecanoIide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl-hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolide, 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, and 15-oxo-: octadecanolide.
The following ether lactones are useful starting reagents for the process of this invention:
12-oxa-tetradecanolide, 12-oxa-pentadecanolide, '~.2 ~
12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa-14-pentadecenolide, 13-oxa-15-hexadecenolide.
It is important .hat the radioactive isomer be substituted at the omega position on the fatty acid I
~2~
molecule. Substitution at an interior position on the chain has been found to render a substance whi~h does not provide satisfactory imaging properties~ Preferred halogen isomer substituents are Iodine 122, Iodine 123, Iodine 131, Bromine 75, Bromine 77. Iodine 131 has a half-life of about 8 days. Iodine 123 is attractive because it has favourable gamma ray energies for scintigraphic imaging and a relatively short half-life of 13.3 hours, thus running a lower risk of generating radioactive damage in the patient. Likewise, Iodine 122, Bromine 75 and Bromine 77 have short half-lives and gamma rays which are compatible with nuclear medicine technology. Fatty acid analogs are attractive for purposes of this invention because it has been ~ound that fatty acid analogs are well assimilated by the heart and hence when substituted with a radioactive agent are useful in imaging the heart area.
The myocardial analysis may be extended to several other human organs because fatty acids are assimilated and metabolized by numerous organs, particularly the liver and kidneys. Halogenated fatty acids have recently been reported to delineate tumors in the liver. A second class of application is possible because fatty acid glycerides make up the bulk of cell membranes. Non-metabolized label might be introduced into the membranes, for example, living white blood cells might be labelled in the membrane by means of suitable halogenated fatty acids. The white cells might then be introduced back into the patient's body where they would see~ out the sites of actlve immune response.
An image could then be obtained showing these same sites.
To illustrate the performance and utility of the invention, a number of specific iodine substituted tosylate fatty acids were prepared. The methods of conversion of the hydroxy fatty acids starting reagents to the corresponding tosylate fatty acids were derived from disclosures in Argentini, M., et al., "Comparison of Several Methods for the Synthesis of Omega~iodine-123-heptadecanoic Acid", J. Radioanalytical Chemistry, 65 (1981) 131-138. As may be seen in Figure 1, the myocardium is evident in the scintigraphic study of a prone rabbit from the posterior view utilizing one o~
the omega halogenated ~atty acids of the invention.
16-Iodine-131-7-hexadecenoic Acid Example la 16-Hydroxy-7-hexadecenoic Acid 5 gr. of 7-hexadecenolide (generic name Ambre-ttolide) (obtained ~rom Pfaltz and ~auer #A16740) was mixed with ~50 ml lN KOH and boiled ~or one hour with vigorous stirringO During this time the oily macrolide layer disappeared. The solution was cooled to 50C and 19.8 mls of concentrated HCl (11.6M) was then added to bring the pH to approximately 4. A heavy white precipitate appeared. The mixture was refrigerated overnight. The next day the precipitate was filtered, washed with water, and dried. Finally, the product was suspended in chloroform, recrystallized from ~2~ S
chloroform/petroleum ether and dried. The yield was 3.8 9 (70%) fine white crystals m.p. 69.0~70.5C~
Example lb 16-Tosylate-7-hexadecenoic Acid 776 mg p-toluenesulfonyl chloride was dissolved in 7.4 mls dry pyridine and then 1 g 16-hydroxy-7 hexadecenoic acid prepared according to Example la was added. The reaction mixture was held at 0C for 20 hours. It was then mixed with 50 mls of water whereupon the mixture took on a uniform white appearance. The mixture was extracted four times with 50 mls of chloroform. The chloroform phase was washed twice with 50 ml portions of 0.1 N sulfuric acid and twice with 50 ml portions of water. Finally, the chloro~orm phase was dried overnight in the presence of CaSO4 and was then evaporated. The residue, a clear light yellow liquid, was washed with petroleum ether and dried under a nitrogen stream. The yield was 1.3 g (83~) of white viscous oily liquid m.p. 10 20C. A mass 2U spectrosocopy analysis was performed at the University of British Columbia Department of Chemistry Mass ~pectroscopy Laboratory~ A mass spectrum m/e 424 was identified (theoretical 424).
Example lc 16-Iodine-131-7-hexadecenoic Acid 2 microl. of 16-tosylate-7-hexadecenoic acid, prepared according to Example lb, 6 micro Ci I-131 in 2 micro 1 water, and 150 micro g NaI were added to 1 ml of methylethyl ketone. The mixture was sealed in a 5 ml borosilicate glass vial having a rubber septum and aluminum seal~ and autoclaved for 30 min at 125C to prepare 16-iodine 131-7~hexadecenoic acid.
Example ld The extent of I-131 incorporation into the fatty acid was measured by thin layer chromatography on cellulose TLC sheets (Eastman 13255TM~ using as a solvent, petroleum ether/diethyl ether/acetic acid in the volumetric ratio 266/133/1. Rf(iodide) - Q.0 Rf (fatty acid) = 1Ø It was found tha~ 97~ of the original I-131 was incorporated into the fatty acid.
16-Iodine-131-hexadecanoic Acid 16-Hydroxy-hexadecanoic acid was prepared from 5 g of hexadecanolide (obtained from Haarmann & Reimer) according to the procedure outlined in Example la~ The yield was 1.8 g (34%3 of fine white needles m.p.
95-97C. 16-Tosylate-hexadecanoic acid was prepared from 1 9 of the 16-hydroxy-hexadecanoic acid according to the procedure set out in Example lb. The yield was 1.38 g (88~) of fine white needles m.p. 62-65C. A mass spectrum m/e 426 was identified (theoretical 426).
16-Iodine-131-hexadecanoic acid was prepared from the tosylate fatty acid 16-tosylate-hexadecanoic acid according to the procedure outlined in Example lc.
It was found that 89~ of the original I-131 was incorporated into the iodo fatt~ acid.
16-Iodine-131-12-oxa-hexadecanoic Acid _ 16-Hydroxy-12-oxa-hexadecanoic acid was prepared from 5 g of 12-oxa-hexadecanolide (obtained from ~laarmann ~ Reimer) as specified in the process of Example la, Yield: 4.92 g (92%) fine white needles m.p. 5~.0~59.5C. The 16-tosylate-12-oxa-hexadecanoic acid was prepared from 1 g of the hydroxy fatty acid according to the process provided in Example lb. The yield was 1.07 g (68%) of white amorphous solid, m.p.
40-50C. 16-Iodine-131-12-oxa-hexadecanoic acid was prepared ~rom the tosylate fatty acid according to the procedure in Example lc. It was found that 59% of the original I-131 was incorporated into the iodo fatty acid.
15-Iodine~131~entadecanoic Acid 15-Hydroxy-pentadecanoic acid was prepared from 1.65 g of pentadecanolide (obtained form Haarmann &
Reimer) according to the method discussed in Example la.
The yield was 1.1 g (62%) of fine white needles m.p.
82-~4C. 15~Tosylate-pentadecanoic acid was prepared from 500 mg of the hydroxy fatty acid as in the procedure o~ Example lb. Yield: 0.~41 g (80%) of fine white needles, m.p. 64-66.5C. Mass spectrum: m/e 412 wa~ identified (calculated 412). 15-Iodine-131-pentadecanoic acid was prepared from -the tosylate fatty acid pursuant to the process of Example lc. It was found that 79% of the original I-131 was incorporated into the iodo fatty acid.
15-Iodine-131-12-keto-pentadecanoic Acid 15-hydroxy-12-keto-pentadecanoic acid was prepared from 5 g of 12-keto-pentadecanolide according to the ~rocedure in Example la. The yield was 4.8 g ~88%) in the form of fine white needles m.p. 76-78C.
15-Tosylate-12-keto-pentadecanoic acid was prepared from 1 g of the hydroxy fatty acid according to the method in Example lb. The yield was ~86 mg (31%) of hard white amorphous solid mOp. 72-76C. 15-Iodine 131~12~keto-pentadecanoic acid was prepared from the tosylate fatty acid according to the process in Example lc. It was found that 52% of the original I-131 was incorporated into the iodo fatty acid.
Test 1 Gamma Camera Scan of Heart of New Zealand Rabbit 16-Iodine-131-7-hexadecenoic acid was prepared by mixing the 0.2 ml water, 5 mCi I-131 in 0.33 ml water, 5 ml ascorbic acid, and 5 micro 1 16-tosylate-7-hexadecenoic acid in a 5 ml borosilicate vial and autoclaving 30 min at 125C. Subsequently, the aqueous phase was set aside while the lipid droplets were solubilized in 2.3 mls TweenTM/D5W/Propylene glycol. 1.44 mCi I-131 was recovered and it was found that 97% of the I-131 was tagged to fatty acid. Later, 0.6 mCi of the preparation was injected into a vein in the ear of a New Zealand rabbit and the rabbit was observed using a gamma camera (see Figure 1). It can be seen that the scan indicates the heart very clear]y in comparison to other preliminary studies with rabbits in which alternative known iodine-131-fatty acids had been used.
;J5 A systematic evaluation of the iodinated fatty acids has been carried out S~udies have been completed in mice with four of the fatty acids. The iodo-fatty acids were labelled with I-131 as in Example lc. The methylethyl ketone was evaporated, inorganic iodine removed in water, and the fatty acids suspended in TweenTM/D5W/Propylene glycol as above. Ali~uots of 1 micro Ci were iniected into the tail veins of mala white mice. ~ice were sacrificed 30sec, lm, 2m, 4m, 6m, lOm, 15m, 30m, 40m, and 120m post injection. The I-131 activity was then determined in the blood, heart, lung, liver, spleen~ and kidneys. For each fatty acid 85 mice were thus sacrificed. The results most important for heart imaging are given in Table 1. It can be seen that the results for all the fatty acids are roughly of the same magnitude as determined for the control, 16-iodo-hexadecanoic acid, which is already known to be useful clinically. Two of the fatty acids (15-iodo-pentadecanoic acid and 16-iodo-12-oxa-hexadecanoic acid) 0 gave better results than the control.
Table 1 Maximum I-131 Fatty Acid Uptake Heart Heart/
Fatty Acid~ dose/gm Heart/Lung Blood 16-iodo-7-hexadecenoic16.3+6.75 0.991~0.461 1.02+0.71 16-iodo-hexadecanoic15.6+3.29 1.42+0.369 1.42~0.290 16-iodo-12-oxa hexadecanoic14.5~3.82 2.33+0.523 1.24+0.314 15-iodo-pentadecanoic29.1+16.8 2.35+0.789 2.45+1.43 As will be apparent to those skill.ed in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.
Claims (44)
1. A process of preparing an omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group or an unsaturated dimethylene group or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; comprising (a) (i) When M is (A) above, saponifying a macrocyclic saturated lactone of the formula:
wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10, and the sum of carbons and oxygens in the ring group is in the range 14 to 24; or (ii) When M is (B) above, saponifying a macrocyclic unsaturated lactone of the formula:
wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group, R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24; to yield the corresponding omega substituted hydroxy fatty acid;
(b) treating the omega substituted hydroxy fatty acid to render the omega position receptive to the substitution of a radioactive isomer of a suitable substituent radical; and (c) substituting a radioactive imaging isomer of a suitable substituent radical in place of the tosylate or other leaving group at the omega position.
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group or an unsaturated dimethylene group or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; comprising (a) (i) When M is (A) above, saponifying a macrocyclic saturated lactone of the formula:
wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10, and the sum of carbons and oxygens in the ring group is in the range 14 to 24; or (ii) When M is (B) above, saponifying a macrocyclic unsaturated lactone of the formula:
wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group, R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24; to yield the corresponding omega substituted hydroxy fatty acid;
(b) treating the omega substituted hydroxy fatty acid to render the omega position receptive to the substitution of a radioactive isomer of a suitable substituent radical; and (c) substituting a radioactive imaging isomer of a suitable substituent radical in place of the tosylate or other leaving group at the omega position.
2. A process according to Claim 1 wherein step (b) involves tosylating the omega-substituted hydroxy fatty acid produced in step (a) with a suitable tosylating agent to obtain the corresponding fatty acid tosylate.
3. A process according to Claim 1 wherein step (b) involves substituting a natural halogen at the omega position of the omega-substituted hydroxy fatty acid produced in step (a) and then replacing the natural halogen with the radioactive isomer.
4. A process according to Claim 1 wherein step (b) involves substituting a mesylate, triflate, or another suitable sulfonate ester leaving group at the omega position of the omega-substituted hydroxy fatty acid produced in step (a) and then replacing the mesylate, triflate, or other suitable sulfonate ester leaving group with the radioactive isomer.
5. A process according to Claim 1 wherein the radioactive isomer is a radioactive member of the Br or I family.
6. A process according to Claim 1 wherein the radioactive isomer is selected from the group consisting of Iodine 122, Iodine 123, Iodine 125, Iodine 131, Bromine 75, Bromine 77.
7. A process according to Claim 2 wherein the radioactive isomer is Iodine-123 or Iodine-131.
8. A process according to Claim 1 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 7-hexadecenolide, 7-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl-15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pentadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-l2-enolide, cis-15-methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-enolide, trans-16-methyl-16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis-17-heptadec-11-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide, trans-17-heptadec-12-enolide, cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl-17-heptadec-12-enolide, cis-17-methyl-17-heptadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, trans-17-methyl-17-heptadec-12-enolide, 12-oxa-tetradecanolide, 12-oxa-pentadecanolide, 12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa-14-pentadecenolide, 13-oxa-15-hexadecenolide, 11-oxo-tridecanolide, 11-oxo-13-methyl-tridecanolide, 11-oxo-tetradecanolide, 11-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, 11-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15-methyl-pentadecanolide, 12-oxo 14,15-dimethyl pentadecanolide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl-hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolide, 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, 15-oxo-octadecanolide.
9. A process according to Claim 2 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 7-hexadecenolide, 9-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl-15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pentadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-12-enolide, cis-15-methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-anolide, trans-16-methyl-16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis-17-heptadec-11-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide, trans-17-heptadec-12-enolide, cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl-17-heptadec-12-enolide, cis-17-methyl-17-heptadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, and trans-17-methyl-17-heptadec-12-enolide.
10. A process according to Claim 2 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 12-oxa-tetradecanolide, 12-oxa-pentadecanolide, 12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa 14-pentadecenolide, and 13-oxa-15-hexadecenolide.
11. A process according to Claim 2 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 11-oxo-tridecanolide, 11-oxo-13-methyl-tridecanolide, 11-oxo-tetradecanolide, 11-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, 11-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15-methyl-pentadecanolide, 12-oxo-14,15-dimethyl pentadecanolide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl-hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolide, 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, and 15-oxo-octadecanolide.
12. A process according to Claim 6 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 7-hexadecenolide, 9-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl-15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pentadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-12-enolide, cis-15-methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-enolide, trans-16-methyl-16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis-17-heptadec-11-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide, trans-17-heptadec-12-enolide, cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl-17-heptadec-12-enolide, cis-17-methyl-17-heptadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, and trans-17-methyl-17-heptadec-12-enolide.
13. A process according to Claim 6 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 12-oxa-tetradecanolide, 12-oxa-pentadecanolide, 12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa-14-pentadecenolide, and 13-oxa-15-hexadecenolide.
14. A process according to Claim 6 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 11-oxo-tridecanolide, 11-oxo-13-methyl-tridecanolide, 11-oxo-tetradecanolide, 11-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, 11-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15-methyl-pentadecanolide, 12-oxo-14,15-dimethyl pentadecanolide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolidet 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, and 15-oxo-octadecanolide.
15. A process according to Claim 7 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 7-hexadecenolide, 9-hexadecenolide, hexadecanolide, pentadecanolide, 14-methyl-14-tetradecanolide, 15-methyl-15-pentadecanolide, 14-methyl-15-pentadecanolide, 15-hexadecanolide, 17-heptadecanolide, 16-methylhexadecanolide, 15-methyl-16-hexadecanolide, 17-methyl-17-heptadecanolide, 16-methyl-17-heptadecanolide, cis-15-pentadec-11-enolide, trans-15-pentadec-11-enolide, cis-15-pentadec-12-enolide, trans-15-pentadec-12-enolide, cis-14-methyl-15-pentadec-11-enolide, trans-14-methyl-15-pentadec-11-enolide, cis-15-methyl-15-pentadec-11-enolide, trans-15-methyl-15-pentadec-11-enolide, cis-14-methyl-15-pentadec-12-enolide, trans-14-methyl-15-pentadec-12-enolide, cis-15-methyl-15-pentadec-12-enolide, trans-15-methyl-15-pentadec-12-enolide, cis-16-hexadec-11-enolide, trans-16-hexadec-11-enolide, cis-16-hexadec-12-enolide, trans-16-hexadec-12-enolide, cis-15-methyl-16-hexadec-11-enolide, trans-15-methyl-16-hexadec-11-enolide, cis-15-methyl-16-hexadec-12-enolide, trans-15-methyl-16-hexadec-12-enolide, cis-16-methyl-16-hexadec-11-enolide, trans-16-methyl-16-hexadec-11-enolide, cis-16-methyl-16-hexadec-12-enolide, trans-16-methyl-16-hexadec-12-enolide, cis-17-heptadec-11-enolide, trans-17-heptadec-11-enolide, cis-17-heptadec-12-enolide, trans-17-heptadec-12-enolide, cis-16-methyl-17-heptadec-11-enolide, trans-16-methyl-17-heptadec-11-enolide, cis-16-methyl-17-heptadec-12-enolide, trans-16-methyl-17-heptadec-12-enoliae, cis-17-methyl-17-heptadec-11-enolide, trans-17-methyl-17-heptadec-11-enolide, cis-17-methyl-17-heptadec-12-enolide, and trans-17-methyl-17-heptadec-12-enolide.
16. A process according to Claim 7 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 12-oxa-tetradecanolide, 12-oxa-pentadecanolide, 12-oxa-hexadecanolide, 11,14 dioxa-hexadecanolide, 12-oxa-14-pentadecenolide, and 13-oxa-15-hexadecenolide.
17. A process according to Claim 7 wherein the starting macrocyclic musk lactone is selected from the group consisting of: 11-oxo-tridecanolide, 11-oxo-13-methyl-tridecanolide, 11-oxo tetradecanolide, 11-oxo-14-methyl-tetradecanolide, 11-oxo-13-methyl-tetradecanolide, 11-oxo-pentadecanolide, 12-oxo-tetradecanolide, 12-oxo-14-methyl-tetradecanolide, 12-oxo-pentadecanolide, 12-oxo-14-methyl-pentadecanolide, 12-oxo-15-methyl-pentadecanolide, 12-oxo-14,15-dimethyl pentadecanolide, 12-oxo-14-ethyl-pentadecanolide, 12-oxo-15-ethyl-pentadecanolide, 12-oxo-hexadecanolide, 12-oxo-14-methyl-hexadecanolide, 13-oxo-pentadecanolide, 13-oxo-hexadecanolide, 13-oxo-16-methyl-hexadecanolide, 13-oxo-15-methyl-hexadecanolide, 14-oxo-hexadecanolide, 14-oxo-hepta-decanolide, 15-oxo-heptadecanolide, and 15-oxo-octadecanolide.
18. A process of preparing 16-iodine-131-7-hexadecenoic acid which comprises saponifying 7-hexadecenolide, tosylating the resulting 16-hydroxy-7-hexadecenoic acid to produce 16-tosylate-7-hexadecenoic acid and substituting iodine-131 at the 16 position of the tosylate.
19. A process of preparing 16-iodine-131-hexadecanoic acid which comprises saponifying hexadecanolide, tosylating the resulting 16-hydroxy-hexadecanoic acid to produce 16-tosylate-hexadecanoic acid and substituting iodine-131 at the 16 position of the tosylate.
20. A process of preparing 16-iodine-131-12-oxa-hexadecanoic acid which comprises saponifying 12-oxa-hexadecanolide, tosylating the resulting 16-hydroxy-12-oxa-hexadecanoic acid to produce 16-tosylate-12-oxa-hexadecanoic acid and substituting iodine-131 at the 16-position of the tosylate.
21. A process of preparing 15-iodine-131-pentadecanoic acid which comprises saponifying pentadecanolide, tosylating the resulting 15-hydroxy-pentadecanoic acid to produce 15-tosylate-pentadecanoic acid and substituting iodine-131 at the 15-position of the tosylate.
22. A process of preparing 15-iodine-131-12-keto-pentadecanoic acid which comprises saponifying 12-keto-pentadecanolide, tosylating the resulting 15-hydroxy-12-keto-pentadecanoic acid to produce 15-tosylate-12-keto-pentadecanoic acid and substituting iodine-131 at khe 15 position of the tosylate.
23. A process of preparing 16-iodine-123-7-hexadecenoic acid which comprises saponifying 7-hexadecenolide, tosylating the resulting 16-hydroxy-7-hexadecenoic acid to produce 16-tosylate-7-hexadecenoic acid and substituting iodine-123 at the 16 position of the tosylate.
24. A process of preparing 16-iodine-123-hexadecanoic acid which comprises saponifying hexadecanolide, tosylating the resulting 16-hydroxy-hexadecanoic acid to produce 16-tosylate-hexadecanoic acid and substituting iodine-123 at the 16 position of the tosylate.
25. A process of preparing 16-iodine-123-12-oxa-hexadecanoic acid which comprises saponifying 12-oxa-hexadecanolide, tosylating the resulting 16-hydroxy-12-oxa-hexadecanoic acid to produce 16-tosylate-12-oxa-hexadecanoic acid and substituting iodine-123 at the 16-position of the tosylate.
26. A process of preparing 15-iodine-123-pentadecanoic acid which comprises saponifying pentadecanolide, tosylating the resulting 15-hydroxy-pentadecanoic acid to produce 15-tosylate-pentadecanoic acid and substituting iodine-123 at the 15-position of the tosylate.
27. A process of preparing 15-iodine-123-12-keto-pentadecanoic acid which comprises saponifying 12-keto-pentadecanolide, tosylating the resulting 15-hydroxy-12-keto-pentadecanoic acid to produce 15-tosylate-12-keto-pentadecanoic acid and substituting iodine-123 at the 15 position of the tosylate.
28. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br or I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or l;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may he a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group, p is 0 or 1, m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 1, 2 or 3.
wherein A is selected from the group consisting of radioactive Br or I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or l;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may he a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group, p is 0 or 1, m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 1, 2 or 3.
29. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or l;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 4, 5 or 6.
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or l;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 4, 5 or 6.
30. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group, an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 7, 8 or 9.
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group, an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 7, 8 or 9.
31. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A may be selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 10, 11 or 12.
wherein A may be selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 10, 11 or 12.
32. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or l;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 13, 14 or 15.
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or l;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 13, 14 or 15.
33. An omega substituted radioactive isomer of a fatty acid of the formula:
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group, R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4, and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 16 or 17.
wherein A is selected from the group consisting of radioactive Br and I and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10; and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group, R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4, and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; whenever prepared according to the process of Claim 16 or 17.
34. 16-Iodine-131-7-hexadecenoic acid whenever prepared according to the process of Claim 18.
35. 16-Iodine-131-hexadecanoic acid whenever prepared according to the process of Claim 19.
36. 16-Iodine-131-12-oxa-hexadecanoic acid whenever prepared according to the process of Claim 20.
37. 15-Iodine-131-pentadecanoic acid whenever prepared according to the process of Claim 21.
38. 15-Iodine-131-12-keto-pentadecanoic acid whenever prepared according to the process of Claim 22.
39. 16-Iodine-123-7-hexadecenoic acid whenever prepared according to the process of Claim 23.
40. 16-Iodine-123-hexadecanoic acid whenever prepared according to the process of Claim 24.
41. 16-Iodine-123-12-oxa-hexadecanoic acid whenever prepared according to the process of Claim 25.
42. 15-Iodine-123-pentadecanoic acid whenever prepared according to the process of Claim 26.
43. 15-Iodine-123-12-keto-pentadecanoic acid whenever prepared according to the process of Claim 27.
44. A process for preparing an imaging agent for human organs and cells from a macrocyclic lactone to produce the corresponding omega substituted halogenated radioactive fatty acid imaging agent of the formula:
wherein A is selected from the group consisting of radioactive Br and l, and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group or an unsaturated dimethylene group;
R6 may be a dimethylene group or an unsaturated dimethylene group or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M
group is in the range 12 to 22;
comprising:
(a)(i) When M is (A) above, selecting and saponi-fying a macrocyclic saturated lactone within the formula:
wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in the ring group is in the range 14 to 24 to yield the corresponding omega substituted hydroxy fatty acid;
(ii) When M is (B) above, selecting and saponi-fying a macrocyclic unsaturated lactone within the formula:
wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24 to yield the corresponding omega substituted by hydroxy fatty acid;
(b) reacting the corresponding omega substituted hydroxy fatty acid with a leaving group which is reactive with the said hydroxy group at the omega position so as to make the said fatty acid receptive to substitution of the leaving group by a radioactive form of Br or I; and (c) substituting a radioactive form of Br or I in place of the said leaving group at the omega position.
wherein A is selected from the group consisting of radioactive Br and l, and M may be:
(A) wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in series in the M group is in the range 12 to 22; or (B) wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group or an unsaturated dimethylene group;
R6 may be a dimethylene group or an unsaturated dimethylene group or an oxygen;
R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in series in the M
group is in the range 12 to 22;
comprising:
(a)(i) When M is (A) above, selecting and saponi-fying a macrocyclic saturated lactone within the formula:
wherein X may be a methylene group; an ether oxygen; a carbonyl group; or a dioxa dimethylene group;
R1, R2, R3 each may be hydrogen, a methyl group, or an ethyl group;
p is 0 or 1;
q is 0 or 1;
m is 1 to 16;
n is 0 to 10;
and the sum of carbons and oxygens in the ring group is in the range 14 to 24 to yield the corresponding omega substituted hydroxy fatty acid;
(ii) When M is (B) above, selecting and saponi-fying a macrocyclic unsaturated lactone within the formula:
wherein R4 is hydrogen or a methyl group;
R5 may be a dimethylene group; or an unsaturated dimethylene group;
R6 may be a dimethylene group; or an unsaturated dimethylene group; or an oxygen; and R7 may be a methylene group; a methyl substituted methylene group; a dimethylene group; or an unsaturated dimethylene group;
p is 0 or 1;
m is 0, 2 or 3;
n is 0 to 4; and the sum of carbons and oxygens in the ring is in the range 14 to 24 to yield the corresponding omega substituted by hydroxy fatty acid;
(b) reacting the corresponding omega substituted hydroxy fatty acid with a leaving group which is reactive with the said hydroxy group at the omega position so as to make the said fatty acid receptive to substitution of the leaving group by a radioactive form of Br or I; and (c) substituting a radioactive form of Br or I in place of the said leaving group at the omega position.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000436822A CA1221105A (en) | 1983-09-16 | 1983-09-16 | Omega halogenated fatty acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000436822A CA1221105A (en) | 1983-09-16 | 1983-09-16 | Omega halogenated fatty acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221105A true CA1221105A (en) | 1987-04-28 |
Family
ID=4126083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000436822A Expired CA1221105A (en) | 1983-09-16 | 1983-09-16 | Omega halogenated fatty acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1221105A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2726765A1 (en) * | 1994-11-14 | 1996-05-15 | Cis Bio Int | RADIOPHARMACEUTICAL COMPOSITIONS COMPRISING AN INCLUSION COMPLEX OF CYCLODEXTRIN AND RADIOHALOGEN FATTY ACID |
| EP0818452A2 (en) * | 1996-07-09 | 1998-01-14 | V. Mane Fils S.A. | Preparation of cis-isoambrettolides and their use as a fragrance |
| US5831101A (en) * | 1996-11-08 | 1998-11-03 | Quest International B.V. | 14-methyl-hexadecenolide and 14-methyl-hexadecanolide |
| AU748249B2 (en) * | 1997-10-09 | 2002-05-30 | Givaudan-Roure (International) Sa | Macrocycles |
| US7569535B2 (en) | 2004-04-30 | 2009-08-04 | Soda Aromatic Co., Ltd. | 11-methyl-13-tridecanolide, 12-methyl-14-tetradecanolide and 13-methyl-15-pentadecanolide, perfume compositions containing the same, and process for production of compounds including the same |
| JP2016175898A (en) * | 2015-03-20 | 2016-10-06 | 三洋化成工業株式会社 | Cyclic polyether-ester, lubricant composition including the same, and production method of cyclic polyether-ester |
| CN110819451A (en) * | 2012-09-14 | 2020-02-21 | 西姆莱斯股份公司 | Unsaturated lactones as odorants |
| US11549131B2 (en) | 2018-07-17 | 2023-01-10 | Conagen Inc. | Biosynthetic production of gamma-lactones |
-
1983
- 1983-09-16 CA CA000436822A patent/CA1221105A/en not_active Expired
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2726765A1 (en) * | 1994-11-14 | 1996-05-15 | Cis Bio Int | RADIOPHARMACEUTICAL COMPOSITIONS COMPRISING AN INCLUSION COMPLEX OF CYCLODEXTRIN AND RADIOHALOGEN FATTY ACID |
| WO1996014881A1 (en) * | 1994-11-14 | 1996-05-23 | Cis Bio International | Inclusion complex of a radiohalogenated fatty acid in a cyclodextrin |
| EP0818452A2 (en) * | 1996-07-09 | 1998-01-14 | V. Mane Fils S.A. | Preparation of cis-isoambrettolides and their use as a fragrance |
| US5726328A (en) * | 1996-07-09 | 1998-03-10 | V. Mane Fils S.A. | Preparation of cis-isoambrettolides and their use as a fragrance |
| EP0818452A3 (en) * | 1996-07-09 | 1998-03-11 | V. Mane Fils S.A. | Preparation of cis-isoambrettolides and their use as a fragrance |
| US5786321A (en) * | 1996-07-09 | 1998-07-28 | V. Mane Fils S.A. | Preparation of cis-isoambrettolidies and their use as a fragrance |
| US5831101A (en) * | 1996-11-08 | 1998-11-03 | Quest International B.V. | 14-methyl-hexadecenolide and 14-methyl-hexadecanolide |
| AU748249B2 (en) * | 1997-10-09 | 2002-05-30 | Givaudan-Roure (International) Sa | Macrocycles |
| EP0908455B1 (en) * | 1997-10-09 | 2002-07-10 | Givaudan SA | Macrocycles |
| US7569535B2 (en) | 2004-04-30 | 2009-08-04 | Soda Aromatic Co., Ltd. | 11-methyl-13-tridecanolide, 12-methyl-14-tetradecanolide and 13-methyl-15-pentadecanolide, perfume compositions containing the same, and process for production of compounds including the same |
| CN110819451A (en) * | 2012-09-14 | 2020-02-21 | 西姆莱斯股份公司 | Unsaturated lactones as odorants |
| JP2016175898A (en) * | 2015-03-20 | 2016-10-06 | 三洋化成工業株式会社 | Cyclic polyether-ester, lubricant composition including the same, and production method of cyclic polyether-ester |
| US11549131B2 (en) | 2018-07-17 | 2023-01-10 | Conagen Inc. | Biosynthetic production of gamma-lactones |
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