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Патент USA US3036138

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United States Patent 0
1
3,036,129
ICC
Patented May 22, 1962
1
TABLE
3,036,129
PREPARATION OF 7-HALO-6-DEOXY
TETRACYCLINES
7-Bromo-6- 7-Bromo-6-
Organism
Joseph John I-llavka, Valley Cottage, N.Y., and James
Howard Boothe, Montvale, N.J., assignors to American
7-I0d0
Tetra- Deoxytetra- dernethyl-6~ 6~dcoxy~
cycline cycline deoxytctra- tetra
cycline
cycline
Cyanamid Company, New York, N.Y., a corporation
of Maine
10
This invention relates to the preparation of 7-halo-6
deoxytetracyclines which may be represented by the fol
lowing general formula’
N(CHs)2
—OH
~CONH2
(at
E ii
011
1
ATOC 607 _____________ __
1
0. 5
l
0.25
0. 25
4
8
Staphylococcus aureus 209P.
2
1
1
2
Sarciua luteo 1001 _________ __
2
1
0.5
2
Bacillus subtilis A’I‘CO 6633Streptococcus pyogeues C203.
Streptococcus 'y N o. 11..-__
Staphylococcus albus N o. 69.
0. 5
0. 5
250
>250
250
0. 25
0. 25
4
8
0. 25
0. 5
4
8
0. 5
2
4
15
4
2
4
Streptococcus B N o. 80- ___-
15
112.1 H R2 R3
Mycobacterium rauae _____ __
lllycobacteriurn smeumatis
No Drawing. Filed Oct. 9, 1959, Ser. No. 845,304
11 Claims. (Cl. 260-559)
Staphylococcus aureus NY
104
2
1
1
_ __
0. 25
0.25
0. 5
2
Pseudomouas acruginosa____
15
250
31
>250
Proteus vulaaris 8427______ -_
15
8
2
31
Escherichia coli ATCC 9637-
15
250
31
>250
Salmonella gallinarum .... __
Escherichia coli No. 22 ____ __
8
4
250
15
31
8
>250
62
Bacillus cereus N o.
2
The 7-iododeoxytetracycline and 7-bromodeoxytetra
cycline are particularly useful as diagnostic agents in the
detection of cancer. The 7-iododeoxytetracycline and 7
bromodeoxytetracycline appear to concentrate in rapidly
25 proliferating tissue such as found in tumor growths. These
compounds may be rendered radioactive by incorporation
wherein R1 is Br, C1 or I and R2 is H or CH3 when R, is -
of iodine 131 or bromine 82 in the 7-position of the ring
H, and R2 is CH3 when R3 is OH.
nucleus. These radioelabeled compounds by virtue of
their gamma rays and beta particle emissions allow the
The halodeoxytetracyclines of this invention may be
prepared by dissolving asuitable 6~deoxytetracycline, i.e.
6-deoxytetracycline itself, 6-demethyl-?-deoxytetracycline
30
or 5-hydroxy~o-deoxytetracycline, in a suitable solvent,v
detection, localization and diagnosis ‘of neoplastic tissue.
‘ The chemical methods for preparing these radio-labeled
compounds are similar to those preparative methods al
ready described for the preparation of non-radioactive
compounds with the obvious exception that the radioiso
as an N-haloamide, i.e., N-bromosuccinimide, N-bromo 35 tope of the appropriate halogens are used.
such as concentrated mineral acid, i.e., hydrochloric acid,
sulfuric acid, etc. and adding a‘halogenating agent such
The invention will be described in greater detail in
acetamide, N-bromophthalimide, N-chlorosuccinimide, N
conjunction with the following speci?c examples.
iodosuccinimide, etc. The reaction with the haloamide is
preferably carried out at temperatures of from about 0° C.
Example 1
to about 20° C. until the reaction is complete. Alterna
tively, the bromination may be carried out with bromine in 40 PREPARATION OF 7-BROMO-G-DEOXYTETRACYCLINE
a strong mineral acid, i.e., HBr and in a suitable organic
To ‘a solution of 0.2 gram of 6-deoxytetracycline
solvent such as a lower alkanoic acid, i.e. acetic acid, pro
[J.A.C.S. 80, 5324 (1958)] in 10 milliliters of concen
pionic acid, etc, at temperatures of from about 10° C. to
trated sulfuric acid at 0° C. is added 76 milligrams of
about 50° C. The halodeoxytetracycline so-formed is
N-bromosuccinimide. The reaction mixture is kept at 0°
isolated from the reaction mixture by any convenient 45 C. for 30 minutes, and then added slowly drop-wise to
method as, for example, by precipitation with ethyl ether
200 milliliters of cold ether. A solid precipitates which
or the like, and the product may be puri?ed by recrystal~
lization from an alcohol-acetone-ether solution in a stand
ard manner.
is ?ltered and dried. The product. weighs 160 milligrams.
This product is crystallized from ethanol-acetone-ether
solution to give 120 milligrams of puri?ed product. This
The halodeoxytetracyclines are biologically active and 50 product is 1.2—1.5 times as active biologically as tetra~
cycline.
have the broad-spectrum antibacterial activity of the
Example 2
previously known tetracyclines. The antibacterial spec
trum of certain of these compounds, representing the
PREPARATION OF 7-BROMO-‘6~DEMETHYL-6-DEOXY
amount required to inhibit the growth of various typical
TETRACYCLINE
bacteria, was determined in a standard manner by the 55
A solution of 200 milligrams (0.045 m mole) of 6
agar dilution streak technique which is commonly used
in testing new antibiotics. The minimal inhibitory con
centrations, expressed in gamrnas per milliliter, of 7
demethyl-6-deoxytetracycline hydrochloride [J.A.C.S. 80,
For comparison purposes the antibacterial activity of
tetracycline against the same organisms is also included.
A portion (25 milligrams) of this material is recrystal
lized from ethanol/ether yielding 19 milligrams of pure
51324 (1958)] and 80 milligrams (0.45 m mole) of N
bromosuccinimide in 5.0 milliliters of concentrated sul
furic acid is stored at ice-bath temperature for 30 minutes.
tetracycline and 7-iodo - 6 - deoxy-tetracycline against 60
The reaction mixture is slowly added to 250 milliliters of
various test organisms are reported in the table below.
cold ether and the solid that separates weighs 0.2 gram.
bromo-o-demethyl-6-deoxytetracycline, 7dbromo~6-deoxy
3,036,129
4
3
into 250 milliliters of cold ether. The solid that sepa
rates weighs 0.157 gram. A portion (50 milligrams) of
this material is crystallized from methyl cellosolve/
7-brorno~6-demethyl-6-deoxytetracycline which is 2.2 to
2.5 times as active as tetracycline.
Example 3
PREPARATION OF 7-CHLORO~6~DEOXYTETRACYCLINE
chloroform; yield, 20 milligrams.
5
The procedure of Example 1 is followed except that
N-chlorosuccinirnide is used as the halogenating agent.
This application is a continuation-in-part of our co
pending application Serial No. 795,609, ?led February
26, 1959, now abandoned.
We claim:
1. The method of preparing 7-halo-6-deoxytetra
The product is isolated as in Example 1 and 7-chloro-6
deoxyltetracycline is obtained.
cyclines of the formula:
Example 4
PREPARATION OF 7-CHLORO-6-DEMETHYL-6-DEOXY
TETRACYCLINE
I'M H Ra Ra
N(CHs)2
The procedure of Example 2 is followed except that
N-chlorosuccinimide is used as the halogenating agent. 15
The product is isolated as in Example 2 and 7-chloro-6
OH
demethyl-6-deoxytetracycline is obtained.
Example 5
PREPARATION OF 7-BROM0-6~DEOXYTETRACYCLINE
—CONH2
l
OH O
20
‘
OH
H
O
OH
85.6 milligrams of 6-deoxytetracycline is dissolved in
3.9 ‘milliliters of acetic acid and 1 milliliter of 30% HBr
acetic acid is added. With stirring, 0.22 milliliter of 1
wherein R1 is a member of the group consisting of
molar bromine in acetic acid is added (10% excess of 1
bromine, chlorine and iodine and R2 is a member of the
equivalent). After standing about 65 hours at room 25 group consisting of hydrogen and methyl when R3 is hy
temperature, 10 milliliters of ether are added and a yel
drogen and R2 is methyl when R3 is hydroxy which com
low crystalline solid slowly deposits. After 6 hours the
prises treating a compound of the group consisting of
solid is ?ltered off and dried; weight, 68.4 milligrams.
6-deoxytetracycline, 6~demethyl-6-deoxytetracycline and
Example 6
30 5-hydroxy-6-deoxytetracycline with an N-haloamide of
the group consisting of N-bromosuccinimide, N-bromo
PREPARATION OF 7-BROMO-5~HYDROXY-6-DEOXY‘
TETRACYCLINE
A solution of 200 milligrams (0.42 m mole) of S-hy
droxy-6-deoxytetracycline hydrochloride [J.A.C.S. 80,
5324 (1958)] and 75 milligrams (0.42 m mole) of N
bromosuccinimide in 5.0 milliliters of concentrated sul~
acetamide, N-bromophthalirnide, N-chlorosuccinimide,
and N-iodosuccinimide in the presence of a concentrated
mineral acid at a temperature of from about 0° C. to
35 about 20° C.
2. The method of preparing 7-bromo-6-deoxytetra—
cycline which comprises treating 6-deoxytetracyc1ine with
furic acid is stirred at ice-bath temperature for 10 min~
N-bromosuccinimide in the presence of a concentrated
utes. The reaction solution is slowly poured into 250
mineral acid at a temperature of from about 0° C. to
milliliters of cold ether. The solid is ?ltered and dried; 40 about 20° C.
yield 1.8 grams. This material is converted to the free
3. The method of preparing 7-bromo-6-demethyl-6-de
base by dissolving in water, adjusting the pH of the solu
oxytetracycline which comprises treating 6-demethyl-6
tion to 6.5 with 1 N sodium carbonate and extraction
deoxytetracycline with N-bromosuccinimide in the pres
with n-butanol; yield 75 milligrams.
Microbiological activity equals 45% of tetracycline
(activity of starting S-hydroxy-6-deoxytetracycline equals
30% of tetracycline).
Example 7
PREPARATION OF 7-IODO-6-DEOXYTETRACYCLINE
SULFATE
A solution of 200 milligrams (0.38 m mole) of 6-de
oxytetracycline sulfate and 85.5 milligrams (0.35 m mole)
ence of a concentrated mineral acid at a temperature of
45 from about 0° C. to ‘about 20° C.
4, The method of preparing 7-chloro-6-deoxytetra
cycline which comprises treating 6-deoxytetracycline with
N-chlorosuccinimide in the presence of a concentrated
mineral acid at a temperature of from about 0° C. to
50 about 20° C.
5. The method of preparing 7-chloro-6-demethyl-6-de
oxytetracycline which comprises treating 6-demethyl-6
deoxytetracycline with N-chlorosuccinimide in the pres
of N-iodosuccinimide in 5.0 milliliters of concentrated
ence of a concentrated mineral acid at a temperature of
sulfuric acid is stirred ‘at 0° C. for forty minutes. The 55 from about 0° C. to about 20° C.
mixture is added dropwise to 250 milliliters of cold ether.
‘6. The method of preparing 7-bromo-5-hydr0xy-6-de
The sOlid that separates Weighs 0.16 grams. A portion
oxytetracycline which comprises treating 5-hydroxy-6-de
(50 milligrams) of this material is recrystallized from
methyl cellosolve/chloroform; yield 22 milligrams.
Example 8
PREPARATION OF 7-IODO-5-HYDROXY-6-DEOXYTETRA
CYCLINE SULFATE
The procedure of the preceding example is following
except that 5-hydroxy-6-deoxytetracycline is used. 7
iodo-5-hydroxy-6-deoxytetracycline is obtained.
Example 9
oxytetracycline with N-bromosuccinirnide in the presence
of a concentrated mineral acid at a temperature of from
60 about 0° C. to about 20° C.
7. The method of preparing 7-iodo-6-deoxytetra
cycline which comprises treating 6-ideoxytetracycline with
N-iodosuccinimide in the presence of a concentrated
mineral acid at a temperature of from about 0° C. to
65 about 20° C.
8. The method of preparing 7-iodo-6-demethyl-6-de
oxytetracycline which comprises treating 6-demethy1-6
deoxytetracycline with N-iodosuccinimide in the presence
of a concentrated mineral acid at a temperature of from
7-10DO-6-DEMETHYL~6~DEOXY'I‘ETRACYCLINE SULFATE
70 about 0° C. to about 20° C.
9. The method of preparing 7-iodo-5-hydroxy-6-de
To a solution of 0.2 gram (0.39 m mole) of 6-de
methyl-6-deoxytetracycline sulfate in 5.0 milliliters of
cold (0° C.) concentrated sulfuric acid is added 88 milli
oxytetracycline which comprises treating 5-hydroxy-6-de
oxytetracycline with N-iodosuccinimide in the presence
of a concentrated mineral acid at a temperature of from
grams (0.39 m mole) of N-iodosuccinimide. The mix
ture is stored at 0° C. for forty minutes and slowly poured 75 about 0° C. to about 20° C.
5
,r 3,036,129
10. The method of preparing 7-bromo-6-deoxytetra
cyclines of the formula:
6
an organic solvent at a temperature of from about 10°
C. to about 50° C.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,736,725
Ritter _______________ .... Feb. 28, 1956
OTHER REFERENCES
Geschickter: J. Am. Med. Assoc., Feb. '1, 1930, pages
wherein R2 is a member of the group consisting of hy
‘ drogen and methyl when R3 is hydrogen and R2 is methyl
when R3 is hydroxy which comprises reacting a com
pound of the group consisting of 6-deoxytetracyc1ine, 6
demethyl-6-deoxytetracycline and S-hydroxy - 6 - deoxy
tetracycline with bromine in a strong mineral acid, and
326—328.
Fieser et 211.: Natural Products Related to Phenan
threne, pages 388-389, 458; 533-536. Reinhold Pub.
Co., New York (1949).
Abbott Laboratories, “Diagnostic Procedures With
Radioisotopes,” pages 23, 28 (January 1955).
Migrdichian: Organic Synthesis, vol. II, page 924,
in the presence of an organic solvent at a temperature of
from about 10° C. to about 50° C.
Reinhold Pub. Co., New York (1957).
Rall et al.: “Journ. US. National Institute of Cancer,”
11. The method of preparing 7~bromo-6-déoxytetra 20 pages 79-83 (July 1957).
cycline which comprises reacting 6-deoxytetracycline with
Stephens et al.: I. Am. Chem. Soc., vol. 80, pages
bromine in a strong mineral acid and in the presence of
5324-5 (October 1958).
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