Note: Descriptions are shown in the official language in which they were submitted.
-~ 'i)9V
~082~77
Back~round Of the Invention
This invention relates to 10,11-dihydro-3-carboxy-
cyproheptadine (l-methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo-
,~cyclohepten-5-ylidene)piperidine) as an appetite stimulant
and as an antihistaminic agent; also contemplated within ~h~
scope of the present invention are the pharmaceutically ~:-
`` acceptable salt, ester, amide, and N-oxide derivatives of such
compound. Further, this invention relates to proCesses for
the preparation of such compounds; to pharmaceutical compo-
sitions comprising such compounds; and to methods of treatment
I comprising administering such compounds and compositions when
j an appetite stimulant and/or antihistamine effect is indicated.
The free acid form of the 10,11-dihydro-3-carboxycyproheptadine
of the present invention has the following structural formula ~ ;
OOH : ~
, ~NJ -
CH3 I .. ~. .
- 1 -
.. : . ~ . .. .
. . . ... . . .
15709Y
1~8'~17'7
Unexpectedly, it has been discovered that the 10,11-
dihydro-3-carboxycyproheptadines of the present invention are
appetite stimulants and antihistaminics substantially devoid
of other pharmacological effects such as anticholinergic
activity, which latter activity is so characteristic of
compounds structurally related to cyproheptadine, including
dihydro derivatives thereof. Accordingly, it is an object of
the present invention to provide 10,11-dihydro-3-carboxy-
cyproheptadine and its pharmaceutically acceptable salt,
10 ester, amide, and N-oxide derivatives as appetite stimulants
and antihistaminic agents. It is a further object of this
invention to provide processes for the preparation of such
compounds, pharmaceutical compositions comprising such
compounds, and methods of treatment comprising administering
such compounds and compositions when an appetite stimulant
and/or antihistaminic effect is indicated.
Detailed Description of the Invention
The 10,11-dihydro-3-carboxycyproheptadines of
the present invention may conveniently be prepared from
20 3-bromo-10,11-dihydro-5H-dibenzo~,~7cyclohepten-5-one
(see, for example, U.S. Patents 3,306,934 and 3,014,911)
by reaction with 1-methyl-4-piperidylmagnesium halide in
a suitable solvent such as tetrahydrofuran and the like
at 0C. to room temperature to provide l-methyl-4-(3-
bromo-10,11-dihydro-5-hydroxy-5H-dibenzo~,~7cyclohepten-
5-yl)piperidine, which is dehydrated on treatment with a
suitable dehydrating agent such as a mineral acid,
carboxylic acid, chloride or anhydride and the like either
.
.
~ ,
.' '' ' ' ' ~ , ' ' ~ .'
.. . .
15709Y
108~17~
1 alone or in a solvent such as chloroform or glacial acetic
2 acid to provide 1-methyl-4-(3-bromo-10,11-dihydro-5~I-
3 dibenzo[a,d]cyclohepten-5-ylidene)piperidine, which on con-
4 version to the 3-cyano species by treatment with cuprous
cyanide in a solvent such as dimethyl formamide or hexa-
6 methylene phosphoramide at 50-200C. for 2-12 hours,
7 followed by hydrolysis with a strong mineral acid at reflux
8 temperature for 1-24 hours yields the desired l-methyl-
9 4-(3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
ylidene)piperidine-(lo~ll-dihydro-3-carboxycyproheptadine)
11 Of the present invention. Alternatively, the Grignard
12 reaction may follow the reaction with cuprous cyanide on
13 the ketone; thus the next following treatment with mineral
14 acid not only dehydrates but also converts the 3-cyano
substituent into the desired 3-carboxyl function.
16 The resulting 10,11-dihydro-3-carboxycypro-
17 heptadine may then be oxidized to the desired N-oxide of
18 the present invention. Preferably, however, the oxidation
19 is conducted upon a suitable lower alkyl ester of the in-
termediate free acid which is prepared by conventional
21 techniques. For example,the ethyl ester may conveniently
22 be prepared by reacting the free acid in ethanol in the
23 presence of BF3(CH3CH2)2O. Hydrogen peroxide is a suitable
24 oxidizing agent, and the reaction may be conducted in any
suitably inert protic solvent such as aqueous methanol,
26 aqueous ethanol, or the like, at a temperature of from 0
27 to reflux for from 1 to 72 hours. Compound I may also
28 conveniently be prepared by reduction of 3-carboxycypro-
29 heptadine, Compound X, with hydrogen at 1.5-7 kg/cm2 and
~ ' ' ' .: '
15709Y
10~1'7~
1 room temperature in the presence of a noble metal catalyst
2 such as palladium especially 5% palladium on carbon in a
3 dilute mineral acid solvent such as 0.1 N hydrochloric acid.
4 A further procedure for the preparation of Com-
pound I comprises forming a Grignard reagent from magnesium
6 and 3-bromo-10,11-dihydrocyproheptadine in a solvent
7 commonly employed for Grignard reactions, such as ether,
8 tetrahydrofuran, or the like, at about -5 to 20C.,
9 followed by treatment with dry carbon dioxide gas at the
same temperatures until reaction is complete.
11 Another process for the preparation of a compound
12 I or its ester comprises the alcoholysis of either Compound
13 V or VII with sulfuric acid in a lower alkanol, especially
14 methanol. If desired, the resulting ester may be de-
esterifiéd with acid or alkali by standard procedures.
16 The following diagrams illustrate these processes.
15709Y
1082177
SCHEME I
-
MgBr
'' (~) : ~
Br C~ 3
II
~3_ Br > ~)L Br 1 Ng
CH3 III CH3 I~tt
.t.
/CuCN
N ~ _ COOH
Hvdrolvsis
. H3 CII3 I :
oxidation> I -N-oxide ~ % Pd/C
~COOEI
,
CH HCl
X :
.: ,''. - ' '' , : ' . - ~ -
15709Y
108Z177
SCHEME II
~gC 1
3r ~
COOH< ~ CN ROH
Cl C~3 1 32S4
De-esterification VII
Est~rification ,~ ~ ~
> ~COCR <
R = loweralkyl
/ ~N J VIII
Oxidaticn / CH3
Ester hydrolysis
-COOR ) ~ COO~
~2CH ~2CH3
3 IX I-N-oxide
- . ~ ,
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108~77
1 Suitable pharmaceutical salt, ester and amide
2 forms of the 10,11-dihydro-3-carboxycyproheptadine and N-
3 oxide of the present invention may be prepared by conven-
4 tional means. Salt forms are the most preferred and in-
clude (relative to the nitrogen atom of the piperidyl
6 moiety): the hydrochloride, sulfate, phosphate, citrate,
7 tartrate, succinate and the like; with respect to salts
8 based upon the carboxy function, salts derived from the
9 alkali and alkaline earth metals such as sodium and po-
tassium are preferred. These salts are generally equivalent
11 in potency to the free acid form taking into consideration
12 the stoichiometric quantities employed.
13 In the method of treatment and pharmaceutical
14 composition aspects of the present invention it is noted
that the precise unit dosage form and dosage level
16 depend upon the case history of the individual being
17 treated and consequently are left to the discretion of
18 the therapist. In general, however, the compounds of the
19 present invention produce the desired effect of appetite
stimulation when given at from about 0.01 to about 10.0 mg.
21 per kg. body weight per day. The preferred form of delivery
22 of the instant compounds for appetite stimulation of
23 domestic animals is by solution in drinking water
24 or preformulated feedstuffs. For human and animal
administration, any of the usual pharmaceutical oral
26 forms may be employed such as tablets, elixirs and
27 aqueous suspensions comprising from about 0.01 to
28 about 10.0 mg. of the compounds of this invention per
-7-
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1082~7
1 kg. body weight given daily. Thus, for example, tablets
2 given 2-4 times per day comprising from about 0.5 to
3 about 50 mg. of the compounds of this invention
4 are suitable for human treatment. Sterile solutions
(representatively given for human treatment) for
6 injection comprising from about 0.1 to about 10.0 mg.
7 of the compounds of this invention given two to four
8 times daily are also suitable means of delivery. When
9 an antihistaminic effect is indicated, the above-
recited dosage forms and levels are also appropriate.
11 The following examples representatively
12 illustrate but do not limit the product, compositional
13 or method of treatment aspect of the present invention.
14
14 EXAMPLE 1
Preparation of l-methyl-4-(3-carboxy-10,11-dihydro-5H-
16 dibenzo[a,d]cyclohepten-5-ylidene)piperidine
17 Step A: l-Methyl-4-(3-bromo-10,11-dihydro-5~I-
18 dibenzo[a,d]cyclohepten-5-ylidene)-
19 piperidine
To an ice-cooled solution of 15.0 gm. (0.0523
21 mole) of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
22 5-one in 150 ml. of dry tetrahydrofuran is added dropwise
23 over 0.5 hr., 100 ml. of 0.53_ 1-methyl-4-piperidyl-
24 magnesium chloride in tetrahydrofuran. The solution is
stirred for one hour, and then the tetrahydrofuran is
26 removed on a rotary evaporator. The red-oily residue
27 that remains is dissolved in benzene and water is added
28 dropwise until a clear benzene supernatant and a
29 gelatinous aqueous phase is obtained. The benzene is
decanted and the gelatinous aqueous phase is extracted
-8-
15709 y
. 108~1~7
1 with two 100 ml. portions of hot benzene. The combined
2 benzene phases are washed with six 200 ml. portions of
3 water and then the benzene phase is evaporated on a
4 rotary evaporator. The residue that remains is
triturated with acetonitrile. The crystalline product
6 is removed by filtration, washed with additional
7 acetonitrile, collected and dried at 60C. The product
8 1-methyl-4-(3-bromo-10,11-dihydro-5-hydroxy-5H-dibenzo-
9 [a,d]cyclohepten-5-yl)piperidine, 9.66 gm. (65~), melts
at 203-207C.
11 A mixture of 9.66 gm. of 1-methyl-4-(3-bromo-
12 l0,11-dihydro-5-hydroxy-5H-dibenzo[a,d]cyclohepten-5-yl)
13 piperidine and 130 ml. of 6N hydrochloric acid is
14 stirred and refluxed for 0.5 hr. The bulk of the
hydrochloric acid is removed on a rotary evaporator
16 and the residue is partitioned between 5% aqueous sodium
17 hydroxide and ether. The ether phase is removed, washed
18 with water, dried over magnesium sulfate, filtered, and
19 the ether removed to give 9.17 gm. of 1-methyl-4-(3-
bromo-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5-ylidene)
21 piperidine.
22 Step B: l-Methyl-4-(3-cyano-10,11-dihydro-5H-
23 dibenzo[a,d]cyclohepten-5-ylidene)-
24 piperidine
A mixture of 9.17 gm. (0.0249 mol) of l-methyl-
26 4-(3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
27 ylidene)piperidine, 4.58 gm. (0.0498 mol) of cuprous
28 cyanide, and 30 ml. of dry dimethylformamide is stirred
29 and heated under reflux for 6.5 hr. To the cooled
solution ~25C.) is added 54 ml. of water, 27 ml. of
15709y
108'~77
1 a saturated aqueous solution of sodium cyanide, and
2 75 ml. of benzene. The mixture is stirred until a two
3 phase system is obtained. The benzene phase is removed
4 and the a~ueous phase is extracted with two 75 ml.
portions of benzene. The combined benzene phases are
6 washed with 100 ml. of aqueous O.lM sodium cyanide,
7 three 100 ml. portions of water, and dried over magnesium
8 sulfate. After filtering, evaporation of the benzene
9 gives 7.40 gm. of a crystalline residue. This material
is dissolved in the minimum volume of chloroform and
11 passed over an alumina column (15" x 1") packed in
12 chloroform. The column is eluted with chloroform.
13 Evaporation of the chloroform gives a crystalline product
14 that is recrystallized from isopropyl alcohol to give
pure 1-methyl-4-(3-cyano-10,11-dihydro-5H-dibenzo[a,d]-
16 cyclohepten-5-ylidene)piperidine, m.p. 152-154C.
17 Analysis Calc. for: C22H22N2:
18 Calc.: C, 84.04; H, 7.05; N, 8.91.
19 Found: C, 83.87; H, 7.41; N, 8.73.
Step C: l-Methyl-4-(3-carboxy-10,11-dihydro-
21 5H-dibenzo[a,d]cyclohepten-5-ylidene)-
22 piperidine hydrochloride
23 A mixture of 1.0 gm. (0.00318 mol) of l-methyl-
24 4-(3-cyano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
ylidene)piperidine and 20 ml. of 6_ hydrochloric acid
26 is stirred and refluxed for 18 hours. After cooling,
27 the mixture is filtered, and the collected solid is
28 washed with 6N hydrochloric acid and then with ethanol.
--10--
15709Y
1~:)8Z177
1 The dried material weighs 1.03 gm. (87~). Recrystalliza-
2 tion from absolute ethanol gives pure 1-methyl-4-(3-carboxy-
3 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene~piperi-
4 dine hydrochloride, m.p. 304-307C.
Analysis Calc- for: C22H23NO2.}~Cl:
6 Calc.: C, 71.43; H, 6.54; N,3.79; Cl, 9.59.
7 Found: C, 71.01; H, 6.87; N, 3.73; Cl, 9.44.
8 EXAMPLE 2
9 Preparation of l-Methyl-l-oxo-4-(3-carboxy-10,11-dihydro-
10 5EI-dibenzo[a,d]cyclohepten-5-ylidene)piperidine
.
11 A solution of 4.13 gm. tO.0177 mol) of 3-cyano-
12 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (prepared
13 from the 3-bromo ketone by reaction with CuCN according to
14 the procedure of Example 1, Step B, when the appropriate
substitution of reactants is made) in 40 ml. of tetrahydro-
16 furan is treated with 42 ml. of 0.43M l-methyl-4-piperidyl-
17 magnesium chloride. The solution is stirred for one hour,
18 and then the tetrahydrofuran is removed on a rotary evapora-
19 tor. The red-oily residue that remains is dissolved in
benzene and water is added dropwise until a clear benzene
21 supernatant and a gelatinous a~ueous phase is obtained.
22 The benzene is decanted and the gelatinous aqueous phase is
23 extracted with two 100 ml. portions of hot benzene. The
24 combined benzene phases are washed with six 200 ml. portions
of water and then the benzene phase is evaporated on a
26 rotary evaporator. The residue that remains is triturated
27 with acetonitrile. The crystalline product is removed by
28 filtration, washed with additional acetonitrile, collected
29 and dried at 60C. to give 2.88 g. (49~) of crystalline VII
--11--
15709Y
10~'~177
1 (Scheme II, chart supra) which is mixed with 60 ml. of 6N
2 hydrochloric acid and re~luxed 24 hours to give 2.80 gm.
3 of I (Scheme II, supra). A mixture of 2.80 gm. of I and
4 2 ml. of boron trifluoride-etherate in 200 ml. of absolute
ethanol is refluxed for 8 hours. The solution is evapor-
6 ated to dryness and the residue is partitioned between
7 ether and aqueous sodium carbonate solution. The ether
8 phase is removed, dried over magnesium sulfate, filtered
g and the ether is removed by evaporation. There is obtained
2-7 gm. of the ethyl ester VIII (Scheme II, supra) that is
11 dissolved in 100 ml. of methanol, 10 ml. of water, and
12 10 ml- of 30% hydrogen peroxide. After stirring for 48
13 hours at room temperature, a small scoop of 5% Pt/C is
14 added and the mixture is stirred an additional 2 hours to
decompose the excess hydrogen peroxide. The mixture is
16 filtered and the solvent is evaporat.ed to give chroma-
17 tographically pure ethyl ester -N-oxide IX (Scheme II,
18 supra). One gram of ethyl ester -N-oxide IX is dissolved
19 in 10 ml. of methanol containing 2 ml. of 2N potassium
hydroxidé. The solution is heated on the steam bath for
21 2 hours. The methanol is removed, 10 ml. of water is
22 added to the residue, and, while stirring, glacial acetic
23 acid is added dropwise until no further precipitate forms.
24 The white solid that forms is removed by filtration and
is washéd thoroughly with water. The product is collected
26 and dried to give I -N-oxide sesquihydrate; m.p. 208-209
21 (dec., foams); tlc homogenous.
28 Analysis calcd- for C22H23NO3.1 1/2 H2O:
29 Calc.: C, 70,19; H, 6.96; N, 3.72.
Found: C, 70.30; H, 6.77; N, 3.51.
-12-
. . .
- ,. :
,. ,
,
15709Y
108i~177
1 EXAMPLE 3
2 Pharmaceutical Compositions
3 A typical tablet containing 1 mg. 1-methyl-4-
4 (3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
ylidene)piperidine per tablet is prepared by mixing to-
6 gether with the active ingredient calcium phosphate, lactose
7 and starch in the amounts shown in the tables below. After
8 these ingredients are thoroughly mixed, the appropriate
9 amount of magnesium stearate is added and the dry mixture
blended for an additional three minutes. This mixture is
11 then compressed into tablets weighing approximately 124 mg.
12 each. Similarly prepared are tablets containing l-methyl-
13 4-(3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
14 ylidene)piperidine hydrochloride, or 1-methyl-1-oxo-4-
(3-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
16 ylidene)piperidine. `
17 TABLET FORMULA
18 Ingredient Mg. per tablet -
19 1-Methyl-4-(3-carboxy-10,11-
20 dihydro-5H-dibenzo[a,d]-
21 cyclohepten-5-ylidene)piperidine 1 mg.
22 Calcium phosphate 52 mg.
23 Lactose 60 mg.
24 Starch 10 mg.
25 Magnesium stearate 1 mg.
-13-
.
- ' -
` 15709Y
108~177
SUPPLEMENTARY DISCLOSURE
One of the following example is submitted to illus-
trate the steps of reducing the 3-carboxycyproheptadine,
Compound X, with hydrogen under pressure and room temperature
in the presence of a noble metal catalyst such as palladium,
especially 5~ palladium on carbon in a dilute mineral acid
solvent such as 0.1 N hydrochloric acid.
Another example is submitted to illustrate the
preparation of the desired compound by forming a Grignard
reagent from magnesium and 3-bromo-10,11-dihydrocyproheptadine
in a solvent at about -5 to 20C followed by treatment with
dry carbon dioxide gas until the reaction is complete.
EXAMPLE 4
l-Methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo ~, ~cyclo-
; hepten-5-ylidene)piperidine hydrochloride
~' .
0.1 N ~Cl ~
COOH 5% Pd/C ~ COOH
¦ HCl ¦ HCl
CH3 CH3
A solution of 0.43 g. (0.00162 mol) of 1-methyl-4-
(3-carboxy-5H-dibenzo ~, ~cyclohepten-5-ylidene)piperidine
hydrochloride in 25 ml. of 0.lN hydrochloric acid is hydrogen-
ated over 50 mg. of 5% palladium on charcoal at room tempera-
ture at an initial hydrogen pressure of 40 psi for 12 hours.
Water (15 ml.) is added and the mixture is filtered to remove
the catalyst. The filtrate is concentrated to dryness under
vacuum and the residue is recrystallized from 10 ml. of abso-
lute ethanol. The product is collected and dried at 100
- 14 - -
.~
. .
: ~
~ 15709Y
lOl~Z~77
under vacuum to give 0.16 g. of 1-methyl-4-(3-carboxy-10,11-
dihydro-5H-dibenzo ~, ~cyclohepten-5-ylidene)piperidine hydro-
chloride, m.p. 307-310.
EXAMPLE 5
l-Methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo ~, ~cyclo-
hepten-5-ylidene)piperidine hydrochloride
__
~Br 3 ) NC 1 ~COOH
l l HCl
CH3 C 3
Into a flame dried, nitrogen flushed flask equipped
with stirrer, condenser with a CaC12 drying tube, and dropping
~; 10 funnel is placed 0.68 g. (0.028 mol) of magnesium turnings and
2 ml. of dry tetrahydrofuran. The mixture is heated to reflux
and 0.81 g. of 1-methyl-4-chloropiperidine and a crystal of
iodine are added. The Grignard reaction starts promptly. A
solution of 5.0 g. (0.0136 mol) of 1-methyl-4-(3-bromo-10,11-
dihydro-5H-dibenzo ~, ~cyclohepten-5-ylidene)piperidine in 25
ml. of tetrahydrofuran is added dropwise to the gently reflux-
ing solution over one hour. After the addition is complete,
the mixture is refluxed for four hours, cooled to room temper-
ature, and then is poured onto an excess of crushed dry ice
- 20 (carbon dioxide). The mixture is stirred and allowed to warm
to room temperature. Ether (150 ml.) and 6 N hydrochloric
acid (150 ml.) are added, and the mixture is stirred until a
two phase system is obtained. The aqueous acid phase is
withdrawn and washed a second time with ether. The aqueous
acid phase is made basic by the addition of 40% sodium hydrox-
ide solution, after which the solution is filtered. The clear
- 15 -
~t
. ' ' ' ' '
15709Y
~08'~77
aqueous phase is extracted with 200 ml. of ether, and then is
made acidic by the addition of 6 N hydrochloric acid. The
solution is concentrated on a rotary evaporator at 60-70 to a
volume of about 100 ml. During this concentration, l-methyl-
4-(3-carboxy-10,11-dihydro-5H-dibenzo ~, ~cyclohepten-5-yl-
idene)piperidine hydrochloride crystallizes from the solution.
The liquid is decanted from the solid, and the crystalline
residue is slurried with 50 ml. of water. This water is
decanted and the residue is triturated with 50 ml. of absolute
ethanol. The product is collected by filtration, washed with
cold absolute ethanol, and dried to give 1.30 g. (26~) of 1-
methyl-4-(3-carboxy-10,11-dihydro-5H-dibenzo ~, ~cyclohepten-
5-ylidene)piperidine hydrochloride, m.p. 304-307; mixed
melting point with authentic material previously prepared,
304-307; the product is homogeneous on tlc in fluorescent
silica gel using _-butanol, acetic acid, water (5,2,3) and is
homogeneous on tlc when admixed with authentic material previ-
ously prepared.
- 16 -
'
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