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Unformatted text preview: United States Patent  [1 1] 4,001,270
Alexander et al.  Jan. 4, 1977
 9-BENZOYL-I,2,3,4-TETRAHYDROCAR-  Int. Cl.2 ...................................... C07D 209/86
BAZOLE  Field of Search .................................... 260/315
 Inventors: Ernest John Alexander, East .
Greenbush; Aram Mooradian,  References and
Schodack, both of NY. UNITED STATES PATENTS
 Assignee: Sterling Drug Inc., New York, NY. 3,868,387 2/1975 Berger et a1. ...................... 260/315
 ﬁled: Dec. 12’ 1975 Primary Exaininer-Henry R. Jiles
 APPL NOJ 640,249 Assistant Examiner—R. W. Ramsuer
Attorney, Agent, or Firm—Frederik W. Stonner; B.
Related US. Application Data Woodrow Wyatt '
 Continuation-impart ot‘ Ser. No. 514,767, Oct. 15,
I974, Pat. No. 3,948,939, which is a  ABSTRACT
continuation-in-part of Ser. No. 314,099, Dec. 11, 9-Benzoyl-3-hydroxymethyl-l,2,3,4-tetrahydrocar—
1972.’ Pat: NC?‘ 3’905’998’ Wh'Ch ‘5 a bazole and 9-benzoy1-3-(N—phenylcarbamoyloxyme-
contmuation-m-part of Ser. No. 200,205, Nov. 18, - -
1971 P . . thyl)-1,2,3,4-tetrahydrocarbazole, havmg respectively
, at. No. 3,758,496, which IS a .. . . . . . .
continuation-in-part of Ser. No. 42 620 June 2 1970 antimﬂammatory and antibacterial activmes, and their
Pat. No. 3,687,969. ' ' ’ ’ preparation are described.
 US. Cl. ............................ 260/315; 260/340.9; 424/274 1 Claim, No Drawings 4,001,270 1 9—BENZOYL-1,2,3,4-TETRAHYDROCARBAZOLE CROSS-REFERENCES TO RELATED
APPLICATIONS This application is a continuation~in-part of copend—
ing application Ser. No. 514,767, ﬁled Oct. 15, 1974,
now US. Pat. No. 3,948,939, issued Apr. 6, 1976, in
turn a continuation-in-part of application Ser. No.
314,099, ﬁled Dec. 11, 1972, now US. Pat. No.
3,905,998, issued Sept. 16, 1975, in turn a continua—
tion—in-part of Ser. No. 200,205, ﬁled Nov. 18, 1971,
now U.S. Pat. No. 3,758,496, issued Sept. 11, 1973, in
turn a continuation—in—part of Ser. No. 42,620, ﬁled
June 2, 1970, now US. Pat. No. 3,687,969, issued Aug.
29, 1972. BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to 9ubenzoyl-3-(CH20Y)-
1 ,2,3 ,4-tetrahydrocarbazoles. 2. Description of the Prior Art 9-Benzoy1-1,2,3,4,—tetrahydrocarbazoles, having an—
tiphlogistic, analgesic, antifebric and sedative proper-
ties, are described in British Patent Specification No.
1,183,093, published Mar. 4, 1970. 4—Hydroxymethyl—
9-methy1—1,2,3,4—tetrahydrocarbazole, an intermediate for corresponding 4-aminomethyl compounds, is de-
scribed in US. Pat. No. 3,752,823, issued Aug. 14,
1973. SUMMARY OF THE INVENTION The invention provides a composition of matter de-
ﬁned as a 9-benzoyl-3-(CH20Y)-1,2,3,4-tetrahy-
drocarbazole of the formula CH20Y
CI , l.
C =0 wherein Y is hydrogen or N—phenylcarbamoyl. ' The compound of the invention having formula 1
wherein Y is hydrogen was found to be useful as an
antiinﬂammatory agent when tested in pharmacologi-
cal test procedures described hereinbelow. The compound of the invention having formula I
wherein Y is N-phenylcarbamoyl was found to be use-
ful as an antibacterial agent when tested as described
hereinbelow. DETAILED DESCRIPTION OF THE INVENTION The molecular structures of the compounds of the
invention were assigned on the basis of the method of
their synthesis and study of their infrared Spectra, and
conﬁrmed by the correspondence between calculated
and found values for the elementary analysis. The compounds of the invention were prepared as
follows: 10 15 20 25 30 35 4O 45 50 55 60 65 2 EXAMPLE 1 9-Benzoy1-3-hydroxymethyl— l ,2,3,4-tetrahydrocar-
bazole (formula 1, Y=hydrogen) l-Benzoyl- 1 -pheny1hydrazine hydrochloride (23.8
g.) and 18 g. of 4—hydroxymethylcyclohexanone ethyl-
ene ketal in 450 ml. of absolute ethyl alcohol was
heated under reflux for four hours. The chilled mixture
was ﬁltered, the ﬁltrate was evaporated to dryness
under reduced pressure and the resulting residue was
dissolved in ether. The ether solution was washed with
water, dilute hydrochloric acid. water, dilute sodium
bicarbonate, and water, dried and evaporated to dry-
ness to give, after recrystallization from ethyl acetate—
hexane, 9.6 g. of 9—benzoyl—34hydroxymethyl-l,2,3,4-
tetrahydrocarbazole; m.p. 105°—1()7° C. Preparation of 4-Hydroxymethylcyclohexanone
ethylene ketal Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml.
ethylene glycol and 21 g. of p-toluenesulfonic acid in
5.5 liters of benzene were heated at reﬂux with stirring
for 24 hours while water was separated by means of a
water trap. The mixture was cooled and poured into 4
liters of ice water. The benzene layer was separated.
washed with 1 liter of 5% sodium bicarbonate, 1 liter of
water and 1 liter of saturated sodium chloride solution.
dried and evaporated to dryness to give, after distilla-
tion, 245.6 g. of ethyl cyclohexanone-4-carboxylate
ethylene ketal; b.p. 95°—99.5° C. (0.07 mm.); n25 D
1.4620. A solution of 35 g. of the ketal~ester in 50 ml.
of dry tetrahydrofuran was added dropwise to 5.7 g. of
lithium aluminum hydride in 250 ml. of dry tetrahydro-
furan, and the mixture was heated at reﬂux for ﬁve
hours and cooled to room temperature. A saturated
sodium chloride solution (11.4 ml.) was added drop—
wise and heating at reﬂux was continued for one hour.
The mixture was cooled and ﬁltered, and the ﬁltrate
was dried and evaporated to dryness to give 26.9 g. of
4—hydroxymethylcyclohexanone ethylene ketal as a
clear, colorless oil which was used without further puri-
ﬁcation. EXAMPLE 2 9-Benzoyl-3-( N-phenylcarbamoyloxymethyl)- 1 ,2,3,4—
tetrahydrocarbazole (formula I, Y =
N-phenylcarbamoyl) 9-Benzoyl—3-hydroxymethyl— 1 ,2 ,3 ,4—tetrahydrocar—
bazole (9.8 g.) and phenylisocyanate (4.2 g.) were
combined and heated on a steam bath for one and
one-half hours. The mixture was cooled and triturated
in ether and the resulting solid was collected by ﬁltra-
tion and washed with ether to give 7.1 g. of the title
compound; m.p. 140°—143° C. The antiinﬂammatory activity of 9-benzoyl-3-
hydroxymethyl— 1 ,2,3,4—tetrahydr0carbazole was deter-
mined by its ability to inhibit in rats carrageenin-
induced foot edema and adjuvant-induced arthritis. A
brief description of the pharmacological test proce-
dures employed follows. Inhibition of Carrageenin-Induced Foot Edema in Rats Young male rats weighing 100—1 10 g. are used. Food
is withdrawn approximately 18 hours prior to medica-
tion but the animals are permitted free access to drink-
ing water up to the time of medication. Drugs to be
tested are suspended by triturating in 1% gum traga- 4,001,270 3 canth using ground glass homogenizers and adminis-
tered by gavage in a volume of l ml/100 g body weight.
Control animals receive the gum tragacanth only. One
hour after medication, 0.05 ml of 1% suspension of
carrageenin in 0.9% saline is injected into the plantar
tissue of the left hind paw. Three hours after injection of the carrageenin, edema formation, i.e., increase in
foot volume (difference between left hind paw and the uninjected right hind paw) is measured plethysmo-
graphically in the unanesthetized rat. inhibition Adjuvant—lnduced Arthritis in Rats Adult male rats weighing 200—230 grams are used.
Adjuvant (M. butyricum), 0.1 ml of a 0.6% suspension
in heavy mineral oil, is injected into the plantar tissue
of the left hind paw. A negative control group is in-
jected with mineral oil only. Beginning on the ninth day
after adjuvant injection (polyarthritis does not appear
until approximately the tenth day after ad juvant admin-
istration), the animals receive 6 daily medications of
test compound suspended by triturating in 1% gum
tragacanth using a ground glass homogenizer and ad-
ministered by gavage in a volume of 1 ml/100 g body
weight. Both the negative control and adjuvant injected
control animals receive the vehicle only. Food and 5 10 15 20 25 water are permitted ad libitum. Twenty-four hours ' after the last medication, the animals are weighed, the
degree of arthritic involvement, i.e., increase in foot
volume and plasma inﬂammation units are determined.
Foot volume is measured plethysmographically in the
unanesthetized rat. 30 35 40 45 50 55 60 65 4 9-Benzoy1-3-hydroxymethy1-1,2,3,4-tetrahydrocar-
bazole was found to be active when tested in rats at 100
mg./kg. of body weight in the Inhibition of Carragee-
nin-Induced Foot Edema and Adjuvant-lnduced Ar-
thritis Test Procedures described above and is indi-
cated for use as an antiinﬂammatory agent. This com-
pound can be prepared for use by following conven~
tional pharmaceutical procedures; that is, it can be
incorporated in unit dosage form in tablets or capsules
for oral administration either alone or in combination
with suitable adjuvants such as calcium carbonate,
starch, lactose, talc, magnesium stearate, gum acacia,
and the like; or as an aqueous or oil suspension or
solution in a pharmaceutically acceptable vehicle such
as aqueous alcohol, glycol, oil solution or oil water
emulsion for oral or parenteral administration. 9-Benzoyl-3—( N-phenylcarbamoyloxymethyl )-
1,2,3,4-tetrahydrocarbazole, when tested in the Auto-
titer method described by Goss et al., Applied Microbi—
ology 16 (No. 9), 1414—1416(1968), was found to be
antibacterially effective against Pseudomonas aerugin-
am at a concentration of 125 meg/m1. thus indicating
the utility of this compound as an antibacterial agent
against Pseudomonas aeruginosa. This compound may
be formulated for use by conventional procedures, e.g.,
for application to inanimate surfaces; it can be formu—
lated as a dilute solution in an aqueous medium or in a
solution containing a surfactant and is applied to the
surface to be disinfected by conventional means such
as spraying, swabbing, immersion and the like. We claim: 1 . 9-Benzoyl-3—( N~phenylcarbamoyloxymethyl )~ 1 ,2,3 .4—tetrahydrocarbazole.
* >I= * =1t * ...
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