U.S. patent number 3,728,351 [Application Number 05/733,248] was granted by the patent office on 1973-04-17 for radioiodinated quinoline derivatives.
This patent grant is currently assigned to The Regents of the University of Michigan. Invention is credited to Raymond E. Counsell, Persis Pocha Mehta.
United States Patent |
3,728,351 |
Counsell , et al. |
April 17, 1973 |
RADIOIODINATED QUINOLINE DERIVATIVES
Abstract
Radioiodinated analogs of 4-substituted-7-iodoquinolines when
administered parenterally or orally are selectively concentrated in
animal tissues containing melanin and may be used for the detection
and location of melanotic tumors as well as other abnormal growths.
The preferred quinoline compounds are
4-(dialkylaminoalkylamino)-7-iodoquinolines, such as for example
4-(3-dimethylaminopropylamino)-7-iodoquinoline. The radioiodinated
compounds are prepared by isotope exchange between the natural
iodinated compounds and radioactive alkali metal iodides.
Inventors: |
Counsell; Raymond E. (Ann
Arbor, MI), Mehta; Persis Pocha (Ann Arbor, MI) |
Assignee: |
The Regents of the University of
Michigan (Ann Arbor, MI)
|
Family
ID: |
24946829 |
Appl.
No.: |
05/733,248 |
Filed: |
May 31, 1968 |
Current U.S.
Class: |
546/163;
546/159 |
Current CPC
Class: |
C07D
215/42 (20130101); C07D 215/233 (20130101); C07D
215/46 (20130101) |
Current International
Class: |
C07D
215/42 (20060101); C07D 215/00 (20060101); C07D
215/233 (20060101); C07D 215/46 (20060101); C07d
033/54 () |
Field of
Search: |
;260/288,288A,694
;424/1 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
counsell et al., Jour. Pharm. Sci., Vol. 56, p. 1,042-4
(1967).
|
Primary Examiner: Daus; Donald G.
Claims
What is claimed is:
1. A compound having the formula: ##SPC5##
enriched in an iodine isotope selected from the group consisting of
iodine-123, iodine-125, iodine-131 and iodine 132;
R.sub.1 is selected from the group consisting of H and alkyl having
1 to 6 carbons;
R.sub.2 is selected from the group consisting of alkyl having 1 to
6 carbons and dialkylamino-substituted alkyl having 1 to 6 carbons
in each of the alkyls of the dialkyl group and 2 to 5 carbons in
the other alkyl group, and the pharmaceutically acceptable acid
addition salts thereof.
2. A compound having the formula: ##SPC6##
where n is a number from 1 to 5, and I is an iodine isotope
selected from the group consisting of iodine-123, iodine-125,
iodine-131 and iodine-132, and the pharmaceutically acceptable acid
addition salts thereof.
3. A compound according to claim 2 in which n is 3.
4. A compound according to claim 1 in which R.sub.1 is hydrogen and
R.sub.2 is the radical 4-methylpentyl.
5. A compound according to claim 1 in which both R.sub.1 and
R.sub.2 are methyl radicals.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates broadly to the field of radioactive
compositions and move particularly to radioiodinated analogs of
7-iodoquinolines and to methods of preparing and using such
analogs.
2. Description of the Prior Art
The use of various compounds labeled with radioactive elements for
diagnosis and radiotherapy of various pathological conditions,
including malignant tumors, is well known. Compounds of this kind
which could be used for the early detection and treatment of
melanotic tumors have not heretofore been known, and the use of
certain radioiodinated compounds for this purpose was first
suggested by the present applicant in the Journal of Pharmaceutical
Sciences, Volume 56, No. 8, pages 1042-1044, Aug., 1967.
It has previously been noted that a number of quinoline, acridine,
phenothiazine and other polycyclic drugs and dyes are rapidly
absorbed by melanin whereas monocyclic compounds such as pyridine
and hydroquinone as well as aliphatic compounds have no such
affinity for the biopolymer.
It has also been noted that certain drugs such as chloroquine and
chloropromazine have a marked affinity for pigmented tissue
containing melanin.
While many chloroquinolines have been prepared and tested as
antimalarial drugs, few iodinated compounds of this kind have been
described. A. R. Surrey and H. F. Hammer (J. Am. Chem. Soc., 68
113(1946)) reported the preparation of
4-(4-diethylamino-1-methylbutylamino)-7-iodoquinoline, but did not
prepare this compound labeled with radioactive iodine or suggest
any utility for such a compound.
SUMMARY OF THE INVENTION
Among the several objects of this invention may be noted the
provision of radioactive iodoquinoline compounds useful for the
detection of melanomas and other malignant tumors; the provision of
novel derivatives of 7-iodoquinoline useful as intermediates for
preparing the said radioactive compounds; and the provision of
compositions and methods for detecting melanomas in animals using
radioiodinated substances having an affinity for melanin.
The present invention relates to iodinated quinoline derivatives
corresponding to the formula: ##SPC1##
Enriched in an iodine isotope
I is an iodine isotope selected from iodine- 123, iodine-125,
iodine-131 or iodine-132; and R is selected from alkylamino,
dialkylamino, dialkylaminoalkylamino, alkoxy, hydroxyalkoxy, or
dialkylaminoalkoxy groups and the acid addition salts thereof.
More particularly, the invention relates to compounds corresponding
to the formulas: ##SPC2##
in which
I is an iodine isotope selected from iodine-123, iodine-125,
iodine-131 or iodine-132;
R.sub.1 is H or alkyl;
R.sub.2 is alkyl or dialkylamino-substituted alkyl;
R.sub.3 is alkyl, hydroxyalkyl or dialkylaminoalkyl and the acid
addition salts thereof.
A preferred series of compounds falling within the scope of the
invention have the structure: ##SPC3##
where n is a number from 0 to 5, and I is an iodine isotope
selected from the group consisting of iodine-123, iodine-125,
iodine-131 and iodine-132 and the acid addition salts thereof.
The invention also comprises methods of preparing iodine-containing
compounds of the kind described above which methods comprise
reacting 4-chloro-7-iodoquinoline, in which the iodine is
preferably the stable non-radioactive isotope iodine-127, with a
compound having the formula RH where R is a radical as defined
above. This reaction is preferably carried out by heating the
compounds at a temperature sufficient to effect replacement of the
chlorine atom by the radical R-. The resulting
4-substituted-7-iodoquinoline is isolated and, if desired, it can
be purified and stored for later use in preparing pharmaceutically
useful radioactive compounds. To prepare such radioactive
compounds, the 4-substituted-7-iodoquinoline is interacted with a
radioactive alkali metal iodide to effect isotope exchange and so
introduce a diagnostically useful proportion of radioactive iodine
in the said quinoline compound. The isotope exchange may, for
example, be carried out by dissolving the
4-substituted-7-iodoquinoline compound and the radioactive metal
iodide in a suitable solvent and heating the solution at an
elevated temperature for a length of time sufficient to effect
substantial interchange of iodine between the iodoquinoline
compound and the radioactive iodide.
The invention further relates to pharmaceutical compositions
comprising a compound of the kind described above in which the
iodine is a radioactive isotope, and said compound being dissolved
in a pharmaceutically acceptable solvent. The iodine radioisotope
is preferably one having a gamma-radiation energy of not more than
500 kev.
The invention also relates to a method for detecting and locating
melanotic tumors in living animals which comprises parenterally or
orally administering a detectable dose of a radioactive compound of
the kind described above and then subsequently scanning the animal
by means of a conventional radiation scanning device to determine
the loci and intensity of radiation emitted by the radioisotopic
iodine. More broadly, such methods for detecting and locating
melanotic tumors in living animals comprise administering to the
animal a detectable dose of a compound having quinoline as its
nucleus to which is attached a radioisotope of iodine, the said
radioisotope preferably having a gamma-radiation energy of not more
than 500 kev., allowing sufficient time for the said compound to be
concentrated in any melanotic tumors present in said animal, and
then scanning the animal by means of a conventional radiation
scanning device for radioactive loci within the animal.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Among the preferred compounds of this invention are those in which
the organic radical R in the first formula shown above is an
alkylamino or substituted-alkylamino group. As examples of such
compounds may be mentioned: 7-iodoquinoline compounds in which the
substituent at the 4 -position is an alkylamino group such as
dimethylamino, diethylamino, dipropylamino, hexylamino,
4-methylpentylamino, pentylamino, 4-methylbutylamino, butylamino,
propylamino, 3-methylpropylamino, etc. Likewise the substituent at
the 4-position may be a substituted-alkylamino group such as a
dialkylamino-substituted alkylamino group. Examples of such
substituents are 2-dimethylaminoethylamino,
3-dimethylaminopropylamino, 3-diethylaminopropylamino,
3-dipropylaminopropylamino, 4-dimethylaminobutylamino,
5-dimethylaminopentylamino, and the like. Such compounds may be
prepared, for example, by reacting 4-chloro-7-iodoquinoline with an
appropriate amine.
The 4-substituent may also be an alkoxy or substituted alkoxy
group. Examples of such groups are ethoxy, hydroxyethoxy, propoxy,
3-dimethylpropxy, pentyloxy, 4-dimethylaminopentyloxy,
4-diethylaminopentyloxy, and the like. Such 4-alkoxy-substituted
compounds of the invention may be prepared, for example, by
reacting 4-chloro-7-iodoquinoline with an appropriate alcohol or
alkali metal alkoxide.
For diagnostic purposes radionuclides with a gramma-radiation
energy of less than 500 kev. are preferred. Examples of such
isotopes are iodine-125 which has a half-life of 60 days and a
radiation energy of 35 kev. and iodine-131 which has a half-life of
8 days and a radiation energy of 360 kev. While the synthesis and
storage of compounds containing iodine-125 is simpler, for some
purposes the higher radiation energy of iodine-131 may be necessary
or desirable. Other known radioisotopes of iodine, such as
iodine-123 and iodine-132, are also useful and may even be
advantageous for certain purposes.
The compounds of the present invention are preferably used in the
form of one of their water-soluble acid addition salts. Methods for
preparing such salts are well known to those skilled in the art. In
practice, salts with hydrochloric acid have been found to be very
satisfactory and are usually preferred, but the acid addition salts
of other strong mineral acids such as hydrobromic acid, nitric
acid, sulfuric acid, or strong organic acids such as glacial acetic
acid are also useful.
The following examples illustrate the invention.
EXAMPLE 1
Preparation of 4-(3-Dimethylaminopropylamino)-7-iodoquinoline
A solution of 4-chloro-7-iodoquinoline (2.5 g.) in
3-dimethyaminopropylamine (10 ml.) was heated at the reflux
temperature for up to 23 hrs. The excess amine was removed by
distillation under reduced pressure and the residual oil dissolved
in a minimum of acetone. NH.sub.4 OH was added and the resulting
yellow precipitate was collected by filtration and washed with
water. Several recrystallizations from acetone afforded pale yellow
needles (2 g., 65 percent) of the desired product, mp
101.degree.-103.degree., nmr peaks at 7.64 (NCH.sub.3), 7.43
(--CH.sub.2 N--), (triplet, J = 6 cps.) and 6.67 ppm (--CH.sub.2
NH--, multiplet). The latter became a triplet upon deuteration (J =
6 cps.) The IR spectra was as expected. Anal. (C.sub.14 H.sub.18
IN.sub.3) calcd. C 43.21, H 4.14; found C 43.34, H 4.11. Acute
toxicity tests in mice gave an LD.sub.50 value of 58 mg./kg. with
confidence limits of 49.6 to 67.9 mg./kg.
EXAMPLE 2
Preparation of 4-(4-Methylpentylamino)-7-iodoquinoline
A solution of 4-chloro-7-iodoquinoline (2 g.) in
4-methylpentylamine (4 ml.) was heated under reflux for 23 hrs. and
the excess of solvent evaporated under reduced pressure. Addition
of acetone to the residue gave a solid hydrochloride (1.75 g.), mp
168.degree.-173.degree. and V.sub.max 2,700 cm.sup.-.sup.1 (N.sup.+
H). Recrystallization from EtOH-Me.sub.2 CO gave an analytical
sample, mp 183.degree.-4.degree.. The motor liquors afforded a
second fraction (0.35 g.), mp 130.degree.-135.degree., which upon
recystallization from ethyl alcohol-water gave the desired base in
pure form, mp 144.degree.-5.degree.. Treatment of an ethyl alcohol
solution of the HCl salt gave the same free base. Anal. (C.sub.15
H.sub.19 IN.sub.2) Calc. C 50.88, H 5.41; found C 50.74, H 5.32.
The IR and nmr spectra were as expected.
EXAMPLE 3
Preparation of 4-(3-Dimethylaminopropoxy)-7-iodoquinoline
A mixture of 3-dimethylamino-1-propanol (1.45 g., 0.014M) and
sodamide (0.67 g., 0.017M) in dry toluene 15 ml.) was heated under
reflux until the evolution of ammonia ceased (about 3 hrs.). The
grey suspension was cooled and a solution of
4-chloro-7-iodoquinoline (1 g., 0.0034M) in toluene (5 ml.) added
dropwise with stirring. The reaction mixture was heated under
reflux for 18 hrs. On cooling, water was added to dissolve the
solid material, and the toluene phase was separated, dried over
sodium sulfate, and evaporated to leave a pale brown oil which
solidified upon addition of petroleum ether (bp,
30.degree.-40.degree.). The white solid (0.7 g., 57 percent) mp
85.degree.-90.degree., was recrystallized from acetone to give an
analytical sample, mp 93.degree.-4.degree., V.sub.max 1180
cm.sup.-.sup.1 (C--O--C), and nmr peaks at 2.29 (NMe.sub.2), 2.50
(triplet, J = 6 cps., --NCH.sub.2), and 4.23 ppm (triplet, J -- 6
cps., --OCH.sub.2). Anal. (C.sub.14 H.sub.17 IN.sub.2 O) Calcd. C
47.22, H 4.81; found C 47.37, H 4.80.
EXAMPLE 4
Preparation of 4-(4-Methylpentyloxy)-7-iodoquinoline
A solution of 4-chloro-7-iodoquinoline (3.1 g.) in toluene (5 ml.)
was added dropwise with stirring to a previously heated mixture of
4-methyl-1-pentanol (4.4 g.) and sodamide (2.1 g.) in toluene (10
ml). The reaction was carried out as in Example 3 and afforded a
white solid (2.45 g.), mp 85.degree.-88.degree.. Recrystallization
from hexane gave the desired compound in pure form, mp
97.degree.-9.degree., V.sub.max at 1,115 cm.sup.-.sup.1 (C--O--C)
and nmr peaks at 9.94 [doublet, J = 6 cps, C--(CH.sub.3).sub.2 ]
and 4.15 ppm. (triplet, J -- 6.5 cps, --OCH.sub.2). Anal. (C.sub.15
H.sub.18 INO) Calcd. C 50.72, H 5.11; found C 50.80, H 4.98.
EXAMPLE 5
Preparation of 4-Dimethylamino-7-iodoquinoline
Dimethylamine gas was bubbled through an ice-cooled solution of
4-chloro-7-iodoquinoline (2 g.) in toluene (20 ml.) and methylethyl
ketone (10 ml.) for 3 hours in a pressure bottle. The bottle was
tightly stoppered and placed in an oven at 50.degree.C. for 10
days. The mixture was cooled and washed with water. The organic
phase was dried over sodium sulfate and the solvent removed in
vacuo. Recrystallization of the solid residue gave the desired
compound in pure form (1.1 g.), mp 107.degree.-8.degree., and an
nmr peak at 2.99 ppm. (NCH.sub.3). Anal. (C.sub.11 H.sub.11
IN.sub.2) Calcd. C 44.32, H 3.72; found C 44.42, H 3.59.
EXAMPLE 6
Preparation of 4-Hydroxyethoxy-7-iodoquinoline
A solution of the compound described in Example 5 (100 mg.) in
ethylene glycol (1.5 ml.) was heated in an oil bath at 185.degree.
for 16 hours, cooled, and diluted with water. The precipitate (70
mg.), mp 153.degree.-5.degree., was recrystallized from
acetone-water to give the desired product in pure form, mp
154.degree.-5.degree.. The IR and nmr spectra were as expected.
Anal. (C.sub.11 H.sub.10 INO.sub.2) Calcd. C 41.94, H 3.20; found C
42.03, H 3.25. EXAMPLE 7
Preparation of Iodine-125 Analogs by Isotope Exchange
Radioiodinated analogs of the previously described quinoline
derivative are prepared as follows: A solution containing 1-3 mc.
of sodium iodide-125 was placed in a 10 ml. round-bottom flask and
evaporated to dryness at 100.degree.C. under a gentle stream of
nitrogen. The substituted 7-iodoquinoline (100 mg.), dissolved in
the appropriate solvent (2 ml.) (see Table 1), was added. A
condensor was then attached, and the bath temperature was raised.
The mixture was stirred under nitrogen for the specified time and
allowed to cool. In the case of the compounds described in Examples
1 and 3, water was added and the product collected by filtration
and washed well with water. For the compound described in Example
2, the solution was concentrated to approximately 0.5 ml. under
reduced pressure, treated with water and ammonium hydroxide, and
the precipitate collected as above. For the compound described in
Example 4, the solvent was removed in vacuo, the residue treated
with water containing a little acetone, and the precipitate
collected. In all cases, the products were purified by
recrystallization and the purity established by (a) TLC and a
radiochromatogram of the strip and b) admixture melting point with
authentic samples. Further details of the individual preparations
are given in Table 1. ##SPC4##
EXAMPLE 8
4 to 5-week-old male, black mice of the BL6J strain were injected
intraperitoneally with 10 microcuries of
4-(3-dimethylaminopropylamino)-7-iodoquinoline containing
iodine-125. The animals were sacrificed at 12, 24 and 48 hrs.
Control mice were injected via the same route with 10 microcuries
of sodium iodide-125 and sacrificed at the same time intervals.
Counting was done in a commercial well counter. This radioiodinated
quinoline compound showed the same marked affinity for melanin and
slow release from pigmented tissues that had earlier been observed
in rats and mice using chloroquine labeled with carbon-14.
Moreover, the low thyroid activity observed for the animals
receiving the radioiodinated quinoline compound versus those given
the sodium radioiodide, indicates that significant diodination did
not occur.
EXAMPLE 9
4-(3-Dimethylaminopropylamino)-7-iodoquinoline containing
iodine-125 was injected into Syrian hamsters with malignant
melanomas at a dosage of 100 microcuries per animal. Excellent
visualization of the melanotic tumor was obtained within 4 days.
The concentration of iodine-125 in the tumor was approximately 10
times its concentration in other tissues. Its concentration in the
melanoma remained constant or increased for about 5 days following
the injection while concentrations in all other tissues fell
rapidly during the first 3 days. There was no evidence of uptake by
the thyroid. Since a portion of the injected material is excreted
in the bile, the scans were also made several (3-5) days after the
injection to allow time for the material to be eliminated from the
bowels, spleen and liver.
EXAMPLE 10
When 1 millicurie of 4-(3-dimethylaminopropylamino)-7-iodoquinoline
containing iodine-125 was injected into a melanotic dog weighing
145 lbs., concentration of the radioactive compound in the melanoma
was similar to that observed in the Syrian hamsters described in
Example 9.
From the preceding it is evident that the usefulness of the
compounds of this invention resides in their selective
concentration in melanotic tissues. It should also be noted that
the utility of these compounds is not necessarily limited to the
detection of melanomas, for concentration of the compounds in other
kinds of malignant tissue, such as breast tumors in mice, has also
been observed.
Using the sensitive scanning devices now available only minute
amounts of the radioactive compound are necessary to produce
diagnostically useful scans. For example, using iodine-125, a
useful dose will ordinarily be about 1 millicurie. For a person of
average size, this is equivalent to approximately 5 microcuries/per
kilogram. The chemical dosage is therefore measured in micrograms
of the chemical compound, and so it is evident that chemical
dosages and toxicities in the ordinary sense are of minor
significance compared with radiation dosages and toxicity.
In view of the above, it will be seen that the several objects of
the invention are achieved and other advantageous results
attained.
As various changes could be made in the above methods and products
without departing from the scope of the invention, it is intended
that all matter contained in the above description or shown in the
accompanying drawings shall be interpreted as illustrative and not
in a limiting sense.
* * * * *