Note: Descriptions are shown in the official language in which they were submitted.
~05503~;
The present invention concerns new aminopyrrole derivatives of
the following general formula:
R3 \ / R4
N CON
2 ~ ~ R5
'/ ~ 6
the pharmaceutically acceptable acid addition salts thereof, and the process
for their preparation. In the above formula I the substituents R through
R6 have the following meanings: R is selected from hydrogen, (Cl 4) alkyl,
benzyl and halo-substituted benzyl; Rl represents hydrogen, (Cl 4) alkyl,
phenyl or phenyl substituted with 1 to 3 radicals independently selected
from (Cl 4) alkyl, (Cl 4) alkoxy, benzyloxy, fluoro, chloro, bromo and
hydroxy; R2 is a member of the class consisting of hydrogen, (Cl 4) alkyl,
formyl, (C2 4) aliphatic acyl, benzoyl, carbamyl, phenylcarbamyl, (Cl 4)
alkylsulfonyl, ben7enesulfonyl, toluenesulfonyl and phenacylsulfonyl; R3
is selected from hydrogen and (Cl 4) alkyl; R4 and R5 independently represent
hydrogen, (C2 4) alkyl and substituted phenyl, though not simultaneously
hydrogen, or taken together with the adjacent nitrogen atom they can also
represent dimethylamino or a 5-6 membered heterocyclic ring which may contain
a further oxygen or nitrogen atom and be optionally substituted by one to
three (Cl 4) alkyl radicals or by a phenyl group; R6 represents a (Cl 4)
alkyl group; R2 and R3 taken together represent (C2 4) alkylidene, benzyl-
idene or halo-substituted benzylideneO
In the specification and claims the term "(Cl 4) alkyl" refers to
an alkyl radical containing 1 to 4 carbon atoms such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl and tertbutyl; the term "(C2 4) alkyl" identifies
the same radicals excluding methyl, the term "halo-substituted benzyl" essen-
tially identifies a benzyl radical substituted in the aromatic ring with
105S03~;
fluoro, chloro or bromo such as, for instance, p-chlorobenzyl, o-chlorobenzyl,
p-fluorobenzyl, o-bromobenzyl and m-bromobenzyl; the term "substituted
phenyl" designates phenyl radicals substituted with 1 to 3 groups independently
selected from (Cl 4) alkyl, ~Cl 4) alkoxy, fluoro, chloro, bromo, hydroxy,
nitro, amino, (C2 4) aliphatic acylamino, carbo (Cl 4) alkoxy, carboxy,
carbamyl and trifluoromethyl; the term "(C2 4) aliphatic acyl" refers to
an aliphatic acyl radical containing 2 to 4 carbon atom such as acetyl,
propionyl, butyryl and isobutyryl; "(Cl 4) alkoxy" identifies alkoxy groups
containing 1 to 4 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy,
butoxy, tert-butoxy; a "(C2 4) alkylidene" radical is essentially identified
by ethylidene, propylidene, isopropylidene, butylidene and isobutylidene;
the term "halo-substituted benzylidene" designates a benzylidene radical
substituted in the aromatic ring with chloro, fluoro or bromo such as, for
instance, o-chlorobenzylidene, m-chlorobenzylidene, p-chlorobenzylidene,
p-fluorobenzylidene, o-fluoro~enzylidene, m-bromobenzylidene.
A preferred group of compounds comprises those of formula I wherein
R represents hydrogen, benzyl or halo substituted benzyl, Rl is phenyl9 Rz
is selected from hydrogen, tCl 4) alkyl, (C2 4) aliphatic acyl and toluene-
sulfonyl, R3 may be hydrogen or (Cl 4) alkyl, R4 and R5 independently
represent hydrogen, (C2 4) alkyl, phenyl substituted by (Cl 4) alkyl, (C
aliphatic acyl, (Cl 4) alkoxy, halo, carboxy, carbo (Cl 4) alkoxy and
trifluoromethyl, though not simultaneously hydrogen or, taken together with
the adjacent nitrogen atom, they can also represent dimethylamino, piperidino,
morpholino, ~Cl 4) alkyl-piperazino and phenylpiperazino, and R6 is as above
defined, and salts therewith of pharmaceutically acceptable acids.
A second preferred group of compounds comprises those of formula
I wherein R is hydrogen, Rl is phenyl, R2 is selected from hydrogen, (Cl 4)
alkyl, (C2 4~ aliphatic acyl and toluenesulfonyl, R3 may be hydrogsn or (Cl 4)
alkyl, R4 and R5 independently represent hydrogen, (C2 4) alkyl, phenyl sub-
lOSS~36
stituted by ~Cl 4~ alkyl9 (C2 4) aliphatic acyl, ~Cl_4) alkoxy, halo, carboxy,
carbo ~Cl 4) alkoxy and trifluoromethyl, though not simultaneously hydrogen,
or, taken together with the adjacent nitrogen atom, they can also represent
dimethylamino, piperîdino, morpholino, (Cl 4) alkylpiperazino and phenyl-
piperazino, and R6 is as above defined and salts therewith of pharmaceutically
acceptable acids.
A further preferred group of compounds comprises those of formula
I wherein R, R2 and R3 stand fOr hydrogen, Rl is phenyl, R4 and R5 indepen-
dently represent hydrogen, tC2 4~alkyl, phenyl, substituted by (~1 4)alkyl
(C2_4) aliphatic acyl, (Cl 4) alkoxy, halo, carboxy, carbo (Cl 4) alkoxy
and trifluormethyl, though not simultaneously hydrogen, or taken together
with the adjacent nitrogen atom, they can also represen~ dimethylamino,
piperidino, morpholino, (Cl 4) alkylpiperazino and phenylpiperazino, and
R6 is methyl, and salts therewith of pharmaceutically acceptable acids.
The compounds of the invention are prepared starting from a 3-
amino-4-carboxy-pyrrole derivative of formula
H2N COOH
~ II
or an acid addition salt thereof, wherein R, Rl and R6 have the meanings
given above, which is reacted with carbonyl chloride to form an intermediate
compound of formula
o
C o
H _ N
~CcO
Rl ¦ R6 III
iOS~3~;
wherein R, Rl and R6 are as above defined. This compound is in turn reacted
with a molsr excess over the starting compound of formula II of an amine
of formula HN / 4 in which R4 and R5 are as above defined, whereby compounds
of formula I are obtained in which R2 and R3 are hydrogen and Rl, R4, R5
and R6 have the aforesaid meanings. If compounds of formula I are desired
in which R2 and /or R3 are different from hyd~ogen, they are obtained by
means of conventional procedures as hereinbelow described.
According to a preferred mode of carrying out the process of the
inYention, a molar proportion of the starting compound of formula II is
dissolved in an anhydrous inert organic solvent, preferably dioxane or
tetrahydrofuran though many other solvents as, for instance, halogenated
hydrocarbons, of 1 to 4 carbon atoms can suitably be employed. The resulting
solution is heated at abou~ 40-70C, the phosgene is allowed to bubble into
this solution for about 1-3 hours. The unreacted phosgene is preferably
removed from the reaction ambient by a current of dry nitrogen.
The obtained intermediate of formula III which can be regarded as
the anhydride of a 3-(N-carboxamino)-4-pyrrolecarboxylic acid and formally
is a 4H,6H-pyrrole [3,4-d] (1,3) oxazine-2(IH), 4-dione derivative, can be
isolated and characterized if desired) but can also be employed as a crude
product for the subsequent condensation step with the selected amin~ of
/ ~4
formula HN \
This step is performed by dissolving the anhydride of formula III
in a suitable organic Solvent, which is preferably selected from halogenated
hydrocarbons containing from 1 to 4 carbon atoms. The resulting solution
is added to the solution containing the amine, or to the amine itself if it
is a liquid substance. The amine is employed in a molar proportion corre-
sponding to about three-ten times the molar amount of ~he starting material
of formula II; suitable solvents of the amine are again halogenatet hydro-
carbons containing from 1 to 4 carbon atoms. The addition occurs at room
temperature, but the obtained reaction mixture is preferably heated for
105503~
about one to about three hours to 30~40C or, if necessary, even to the
boiling temperature to speed up the formation of the desired end products
of formula I.
Compounds of formula I are obtained, wherein R2 and R3 represent
hydrogen. They are recovered from the reaction mixture following ~echniques
which are entirely familiar to a skilled chemist. These techniques comprise
removing the solvent from the reaction mixture by evaporation, taking up
the residue with a solvent5 evaporating again the solvent and purifying
the obtained solid, liquid or oily substance by column chromatography, recryst-
allization, fractional distillation, or distillation under reduced pressure.If a crystalline solid directly results from the reaction, this is recovered
simply by filtration, and, if necessary, purified by recrystallization.
Recrystallization solvents are preferably selected from tCl 4)-
alkanols, diethylether, water or mixtures thereof.
When substituents R2 and R3 different ~rom hydrogen are desired
they are introduced through well known procedures by reacting the compounds
of formula I with appropriate reactants.
Thus9 for instance, the reaction with (Cl 4) alkyl halides or
(Cl 4) alkylsulfates gives compounds wherein R2 and/or R3 represent (Cl 4)
alkyl. Compounds where R2 is a (C2 4) aliphatic acyl radical or benzoyl
are obtained by reaction with halides or anhydrides of ~C2 4) aliphatic or
benzoic acids, whereas the benzenesulfonyl, toluenesulfonyl, (Cl 4) alkyl-
sulfonyl and phenacylsulfonyl groups are conveniently introduced by reaction
with benzenesulfonyl, toluenesulfonyl, (Cl 4) alkylsulfonyl or phenacylsulf-
onyl halides respectively.
The carbamyl and phenylcarbamyl groups are introduced by reacting
the aminopyrrole of formula I wherein R2 and R3 represent hydrogen, with an
alkali isocyanate or phenylisocyanate respectively.
The replacement of one of the hydrogen atoms of the amino group
at the 3-position by formyl is achieved by contacting a predetermined 3-
1055036
aminopyrrole with formic acid in substantially equimolecular ratios, whereassubstances where R2 and R3 taken together represent tC2 4) alkylideneJ
benzylidene or halo-substituted benzylidene are easily prepared according
to the known reactions for obtaining Schiff's bases from amines and carbonyl
compounds .
The sulfonylation of the amino group at the position 3 provides
also a useful route for preparing compounds of formula I wherein ~ is
hydrogen and R3 is a (Cl 4) alkyl group. Said route consists in tCl 4)
alkylating the amine nitrogen of a compound of formula I wherein R2 is
benzenesulfonyl, tCl 4) alkylsulfonyl, toluenesulfonyl or phenacylsulfonyl,
R3 is hydrogen, according to the usual procedures for alkylating amines.
The group ~ as above defined is removed by hydrolytic cleavage with acids
or according to the method described by J.B. Hendrickson and R. Bergeron,
Tetrahedron Letters, page 345, 1970 when R2 is a phe~acylsulfonyl group.
The co~pounds of formula I may be obtained either as free bases
or as the corresponding salts of pharmaceutically acceptable acids.
These salts are essentially represented by the hydrochloride,
hydrobromide, hydroiodide, sulfate, phosphate, benzoate, oxalate, acetate,
methanesulfonate, cyclohexylsulfonate and analogs. These salts possess the
same degree of pharmacological activity of ~he free bases and accordingly
are included within the scope of the invention. They are easily obtained by
treating a compound of formula I as the free base with a predetermined pharm-
aceu~ically acceptable acid. In turn, it is possible to restore the free
base from the corresponding acid salt by reaction wi~h at least one equi-
molecular amount of a basic agent.
The starting amines of formula HN \ 4 are commercially available
products or are prepared through obvious modifi5caticns of commercially avai-
lable products.
~ he starting compounds of formula II are prepared through a process
which involves as the first step the condensation bet~een an -aminonitrile
lOSS036
of formula
CN
",CH ~ V
or an acid salt thereof wherein Rl has the meaning given above tthe compounds
of formula V are prepared according to the method described by Steiger in
Organic Synthesis, ~ 13, 1942 and 22, 23, 1942) and a ~ ketoester of
formula
I 2 Coo-~cl-4) alky
CO~
R6 VI
wherein R6 has the meaning gi~en aboYe. The intermediate ~-aminopyrrole
which forms, of formula
2 ~ COO-(Cl 4) alkyl
Rl N R6 VII
is subjected to basic hydrolysis, by means of 10% of aqueous lithium hydroxide,
to obtain starting compounds of formula II wherein Rl and R6 are as above
defined and R stand for hydrogen. If starting materials of formula II are
desired, wherein R is ~Cl 4) alkyl, benzyl or halo-substituted benzyl, the
above aminester of formula VII is transformed by mea~s of a predetermined
carbonyl compounds according to common procedures into the corresponding
Schiff's base of formula
R7 = N COO-(Cl 4) alkyl
Rl N R6 VIII
wherein R7 is a diYalent radical deriving from the employed carbonyl compound
. such as, for instance, benzylidene, p-chlorobenzylidene, butylidene, iso-
propylidene ~th~lide~e.~nd analogs. This substance is subsequently reacted
~0~503~;
in an anhydrous medium at about 0-5C with sodium hydride and with a (Cl 4)
slkyl-,benzyl- or halo-substituted benzyl halide, thus obtaining a compound
of formula:
7 N ~ _ _ ~ COO-(Cl 4) alkyl
N IX
R
wherein Rl and R6 are as above defined and R stands for (Cl 4) alkyl, benzyl
or halo-substituted benzyl. The obtained product of formula IX, which, if
desired, may be isolatad and characterized, i5 subjected to acid hydrolysis
to the corresponding starting substances of formula II.
A number of compounds of the invention, namely those where R, R2
and R3 represent hydrogen atoms, can advantageously be prepared through an
alternative process which comprises reacting the above ~ -aminonitrile of
formula V
CN
C~l
/ \ V
Rl NH2
or an acid salt thereof with a ~ -ketoamide of general formula
CH2-CON \ 4 X
R5
C--R
wherein R4, R5 and R6 h ~e the meanings previously reported.
The ~ -ketoamides of formula X are prepared through common procedures,
as for instance, those described by Williams and Krynitsky, Organic Synthesis,
21, 4, 1941 and by Kaslow and Cookp Jour. Am. Chem. Soc., 67, 1969, 1945,
starting from diketenes of formula
~OS'~03~;
R'6-CH-C-O=C XI
R'6--CHGC--O
in which R'6 is an alkyl from 1 to 3 carbon atoms, and amines of formula
HN ~ . The compounds of formula XI are known products and are reported
by Wa~ er and Zook in Synthetyc Organic Chemist~y, page 409, John Wiley and
Sons, Inc" New York, 1965.
The reaction between compounds V and X generally proceeds with
the formation of an intermediate open chain compound representable by the
following general formula XII or its tautomeric iminic form
CN CON
~ ~ \ R5
Rl N R6
which may be isolated, purified and characterized, but is generally used as
a crude material for the subsequent cyclization step.
The reactants V and X are contacted in substantially equimolecul-ar
amounts in the presence of an anhydrous organic solvent which is advantage-
ously selected from benzene, dioxane, tetrahydrofuran and analogs.
A small amount of p-toluenesulfonic acid or molecular sieves,
acting as the catalysts and waterblocking agents, is added to the reaction
mixture, which is kept for about 2-28 hours at a temperature varying from
room temperature to the reflux temperature.
The subsequent cycli~ation step is carried out in the presence of
basic agents selected from alkali carbonates, hydroxides, alkoxides, hydrides
or amides and in the presence of a solvent, which is preferably selected
from anhydrous lower alkanols with a maximum of four carbon atoms.
~05503~;
The cyclization may take place at room temperature, but sometimes
it is necessary to apply a gentle heating or to reflux the reaction mix~ure,
in order to speed up this step, which is completed within an interval of
time ranging from 1-30 hours.
The so obtained compounds of formula I, wherein R, R2 and R3 stand
for hydrogen, are recovered as free bases or as the above mentioned salts of
pharmaceutically acceptable acids through known methods as hereinbefore
described, and may undergo the previously outlined chemical transformations
for introducing the substituents R2 and/or R3, when one of them or both are
desired to be different from hydrogen. Accordingly, compounds of formula I
can be obtained wherein Rl, R4, R5 and R6 are as above defined, R represents
hydrogen atom and ~ and R3 are as above defined, as the free bases or as
the already mentioned salts of pharmaceutically acceptable acids.
The compounds of the invention display ~ery interesting pharma-
cological properties: more particularly, they are active as antiinflammatories,
antipyretics and as prostaglandin synthetase inhibitors. Furthermore, some
of them display also interesting C.N.S. depressant and anti-hypertensive
properties and possess a valuable degree of activity on the hydric balance
of warm blooded animals,
The antiinflammatory activity has been investigated through the
"carrageenin induced edema" test in rats, which was performed following sub-
stantially the operative scheme proposed by C.A. Winter et al. in Proc. Soc.
Expl. Biol. Med., 111, 544 1962.
Representative experiments have shown that the compounds of Examples
3, 4, 5 and 11 are particularly active in this test i.e., they cause a
percent decrease of the induced edema significantly higher than 30 when
tested at dose level very far from the lethal dose i.e., at about 1/5 of the
LD50 -
Said LD50 Yalues are very favorable in that they are generally
higher than 500 mg/kg p.o. in mice.
lOS5036
The following table gives a more detailed account of the foregoing
mentioned ant}~inflammatory activity:
Table
CompoundLD50 mgfkgDose mg/kg % Decrease of the
of Examplep.o. micep.o rats induced edema
..... _ _ _
3 1000 50 16.9
100 30.0
200 45.9
4 1000 50 26.1
100 30.4
200 35.2
~000 50 17.4
100 27.7
200 52.1
11 500 20 20.0
28.0
100 35.2
. _ . . .. _ . . _
The compounds of the invention may be administered by various routes.
While the preferred routes of administration are oral and rectal,
parenteral administration can also be employed.
For oral administration, the compounds are compounded into pharma-
ceutical dosage forms, such as, for instance, tablets, capsules9 elixirs,
solutions and the like. The dosage unit may contain the usual excipien~s,
e.g. starch, gums, fatty acids, alcohols, sugars, etc., For rectal administrat-
ion the compounds are administered in the form of suppositories, admixed with
conventional vehicles, such as, for instance, cocoa butter, wax, spermaceti
or polyoxyethyleneglycols and their derivatives.
The dosage range is from about 0.05 to about 2.00 g. per day,
preferably adminis$ered in divided dose.
Accordingly the present invention provides a therapeutic composition
comprising as the active ingredient a compound of the invention together with
a pharmaceutically acceptable carrier.
1055036
The following additional description and examples further describe
the invention and the manner and process of making and using it to enable
the art skilled to make and use the same and set forth the best mode con-
templated by the inventors of carrying out the inYention.
Example 1
3-Amino-4-diethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride
A) Phosgene (Carbonyl chloride) is bubbled for about two hours in
a solution of 12.0 g. (0.0556 mole) of 3-amino-4-carboxy-5-methyl-2-phenyl-
pyrrole in 600 ml. of anhydrous dioxane, keeping the reaction solution under
vigorous stirring at about 55C. The unreacted carbonyl chloride is removed
from the reaction ambient by means of a current of dry nitrogen, the reaction
solution is cooled to room temperature and the obtained solid is recovered
by filtration and washed with hexane. Yield 7.3 g. of the intermediate an-
hydride of formula III wherein R is hydrogen~ Rl is phenyl and R6 is methyl,
namely 5-methyl-7-phenyl-4H, 6H-pyrrolo [3,4-d] (1,3) oxazine- 2(IH), 4-diGne.
M.p. 247-49C.
B) A solution of 7.0 g. ~0.029 mole) of the compound obtained
under point A) in 100 ml. of chloroform is added dropwise to 30 ml. ~0.29
mole) of diethylamine at room temperature. After refluxing for about two
hours the reaction mixture is e~aporated to dryness and the obtained residue
is taken up with 40 ml. of diethylether. The ether solution is first washed
with water, then with aqueous sodium bicarbonate and is finally separated
from the aqueous phase.
The title compound is obtained by bubbling gaseous hydrogen chloride
in the ether solution. Yield 2.0 g. M.p. 212-14C tfrom ethanol/diethylether).
Example 2-18
The following compounds ha~e been prepared pursuant to the same
procedure of the foregoing example, starting from 3-amino-4-carboxy-5-methyl-
2-phenyl-pyrrole hydrochloride and a selected amine of formula HN < 4
2) 3-Amino-4-ethylcarbamyl-5-methyl-2-phenyl-pyrrole hydrochloride. 5
1~55 0 3 ~
Yield 35%. M.p. 261-63C (~rOm 4ThQnol /water).
3) 3-Amino-4-isopropylcarbamyl-5-methyl-2-phenyl-pyrrole. Yield 33%. M.p
197-98C (from methanol).
4) 3-A no-4-(p-chloro~ enylcarbamyl)-5-methyl-2-phenyl-pyrrole hydrochloride.
Yield 40%. M.p. 231-33C ~from methanol/water).
5) 3-Amino-5-methyl-2-phenyl-4-(p-tolylcarbamyl)-pyrrole hydrochloride.
_ . _ _ _ . _ .
Yield 52%. M.p. 250C (with decomposition).
6) 3-Amino-4-~p-anisylcarbamyl)-5-methyl-2-phenyl-pyrrole
.
Yield 43%. M.p. 190-92C (from ethanol).
7) 3-Amino-4-f~ carbethoxyphenylcarbamyl)-5-methyl-2-phenyl-pyrTole.
Yield 61%. M.p. 217-19C (from ethanol).
8) 3-Amino-4-(~-carboxyphenylcarbamyl)-5-methyl-2-phenyl-pyrrole.
Yield 37%. M.p. 200-10C (from methanol/water).
9) ~ dinocarbonyl-p-yrrole hydrochloride.
Yield 50%. M.p. 245-49C (from methanol/water).
10) 3-Amino-5-methyl-4-(4-methyl-l-Riperazinylcarbonyl)-2-phenyl-pyrrole.
Yield 46%. M.p. 104-106C (from ethanol)
11) 3-Amino-5-methyl-2-phenyl-4-(4-phenyl-1-piperazinylcarbonyl)-pyrrole
hydrochloride. Yield 44%. M.p. 220-22C (from ethanol/ water), The free
base melts at 154-56C (from methanol).
12) 3-Amino-4-(o-chlorophenylcarbamyl)-5-methyl-2-phenyl-pyrrole hydrochloride.
.
Yield 47%. M.p. 268-72C (from methanol/water)
13) 3-Amino-5-methyl-4-morpholinocarbonyl-2-phenyl-pyrrole hydrochloride
Yield 81%. M.p. 236-38C (from methanol/water).
14) 3-Amino-4-( -ethylphenylcarbamyl)-5-me ~ rochloride.
. ~ . ...
Yield 62%. M.p. 250-52C (from ethanol/ether).
15) ~ yrrole/
Yield 80%. M.p. 234-237C tfrom dimethylformamide).
A 16) 3-Amino-5-methyl-2-phenyl-4-(m-trifluoromethy~caTballlyl~-pyrrole~
30 Yield 46~. M.p. 150-51C. (from ethanol/water).
13
1055036
17) 3-AminO-5-m hyl-2-phenyl-4-~o-tolyl)-pyrrole.
Yield 33~ M.p. 218C (from ethanol/water).
18) 3-Amino-5-methyl-2-phenyl-4-(m-tolyl)-pyrrole,
Yield 31% M,p, 171-73C (from ethanol/water),
Example 19
. _
3-Amino-~p-chlorobenzyl)-5- ~ nyl-pyrrole
hydrochloride, from 3-amino-4-carboxy-1-(p-chlorobenzyl)-5-methyl-2-phenyl-
pyrrole hydrochloride and piperidine,according to the procedure of Example 1,
Yield 44%, M,p, 195-97C (from methanol/water), The corresponding intermediate
compound of formula III has not been isolated in this case,
Example 20
4-Ethylcarbamyl-5-methyl-2-~henyl-3-~p-toluenesulfonamido) _yrrole
A solution of 5,0 g. (0,018 mole) of the compound of Example 2,
3.4 g. (0,018 mole) of p-toluenesulfonylchloride and 1,8 g, of triethylamine
in 250 ml, of pyridine is stirred at room temperature for about 15 minutes
and is subsequently allowed to stand overnight at about 5C. The reaction
mixture is then poured into 250 ml, of aqueous hydrochloric acid and crushed
ice and the resulting solution is extracted with ethyl acetate.
The precipitate which forms upon chilling is recrystallized from
ethanol/water, Yield 2,0 g, of the title compound. M,p. 219-21C,
Example 21
3-Acetylam no-5-methyl-2-~henyl-4-piperidinocarbonyl-~yrrole hydrochloride
5,0 Grams ~0,016 mole) of the compound of Example 9 are dissolved in 250 ml,
of pyridine and the resulting mixture is added with 25 ml. of acetic anhydride,
After standing for about 90 minutes at room temperature, the whole is poured
into 250 ml, of 10% aqueous hydrochloric acid, The obtained solid is recovered
by filtration and recrystallization from ethanol.
Yield 2,5 g, of the title compound, M,p, 289-90C,
Example 22-25
The following compounds have been prepared pursuant to the same
14
lOS503~;
procedure of the foregoing Example.
22) 3-Acetylamino-4-t -ethylphenylcarbamyl)-5-methyl-2-phenyl-Ryrrole from
P
the compound of Example 14 and acetic anhydride. Yield 67%. M.p. 230
~decomposition); (from methanol/water).
23) 3~Acetylamino-4-isopropylcarbamyl-5-methyl-2-phenYl-pyrrole from the
compound of Example 3 and acetic anhydride. Yield 71%. M.p. 275C (from
methanol/water).
24) 3-Acetylamino-4-(o chlorophenylcarbamyl)-5-methyl-2-phenyl-pyrrole?
from the compound of Example 12 and acetic anhydride Yield 56~ M.p. 255-257C
(from ethanol).
25) 5-Methyl-2-phenyl-3-propionylamino-4-(o-tolycarbamyl)-pyrrole, from the
compound of Example 17 and propionic anhydride. Yield 60% M.p. 254C
(from acetone/water)
Exampie ?6
3-Dimeth~lamino-5-methyl-2-phenyl-4-piperidinocarbonyl-pyrrole
-
A solution of 5.0 g. (0.016 mole) of the compound of Example 9 in
70 ml. of methanol and 20 ml. of water is added with 5 ml. of dimethylsulfate
and 15.0 g. of potassium carbonate. The resulting mixture is refluxed for
about four hours, then is poured into water and the obtained solid is recovered
by filtration.
Yield 2,8 g. of the title compound. M.p.207-9 C. (from acetone).
Example 27
l-(p-Chlorobenzyl)--3-dimethylamino-5-methyl-2-phenyl-4-pi~eridinocarbonyl-
. . _
pyrrole from the compound of Example 19 and dimethylsulfate, according toths procedure of the foregoing Example. Yield 42%. M.p. 199-201C (from
ethanol/diethyl ether).
Typical compounds of formula I which can be prepared according to
the procedure described in the foregoing Examples are
lOSS03~
R3~ / R4
R / ~ CON \ R5
Rl I R6
Exam- ~ Rl R2 R3 R4 R5 R6
28 1~ _ H ~ CONH~ CH3
29 H ~ H I H H ~ NO2 CH3
H ~ H ¦ H H ~NH2 CH3
31 H ~3 H H H ~NHCOCH3 CH3
32 H~ OCH3 H H H C2H5 3
33 H~ OCH3 H H C2H5 C2H5 CH3
34 H~ OCH3 H H H CH~CHH3 CH3
H~ OCH3 H H H ~Cl CH3
36 H~ OCH3 H H ~Q2 CH2 ~ ~3 CH3
37 H~ CH3 H H C3H7 C3 7 C~H5
38 H- ~ C4Hg H H C2H5 ~ CH3
39 H~3 H H H ~CF3 l CH3
16
1(3SS~36
40 H ~3 H CF3
41~ H ~3 H H CH3 ~ CH3 CH3
42 H CH3 4 9 C3 7
43 H ~ H H CH ~CH3 3
44 I H ~3 H HCzH5 C2H5 C2H5
H OC2115 H ~ 2 OE 2 ~ C2H5
46 H C4Hg H H
47 H ~3 OE3 CH3C2H5Cl C2HS OEH3
48 H ~ [~ CH3 H ~ C2 5
49 CH3 ~ 4 9 2 H CH~CH3 C3H7
50 C2H5 1~3 NH2C HC2H5 C2H5 CH3
~ H H F ~ Cl C4Hg
17
~05503f~
C2HS H ~i C113
53 ~ ~ C2H5 C2H5 H C2H5 CH3
CH2 OC~3
54 Cl [~3 H C2H5C2H5 3
C4Hg C2H5 CH3CO CH3 H ~ C2H5
56 C4Hg ~ C2 5 H C2 5C2H5 ~ CH3
57 C4Hg ~ H H H C2H5 CH3
58 , ~ ` ~ H H C2H5 C2HS CH3
59 Cl 4~ 2 5
H ~ ~ H C2HS ~ H3
61 OH¦ CH3/CH H H 2HS CH3
1055036
62 ~ CH2 ~3 C2H5 CH3 CH3
63 H OCH3~ / ~ C2 5
64 CH3 ~ Cl CH3 H H ~3 CH3
H ~3 ~ C2 5 3
66 H ~3OCH3 CH3~C= H C2 5 CH3
67 H ~ Br~3CH= H C2 5 CH3
68 H ~3~ Cl ~ CH= H C2H5 CH3
69 H ~ CI~CH= H C2H5 CH
19
~05503t;
The compound of Example 1 can also be prepared according to the
alternative procedure described in the following Example.
Example 70
3-Amino-4-diethylcarb~nyl-5-methyl-2-phenyl-pyrrole hydrochloride.
_
A solution of 42.0 g. (0.318 mole) of 2-amino-2-phenyl acetonitrile9
50.0 g. t0.318 mole) of ~-ace~yl-N, N-diethylacetamide and 2.1 g. of p-
toluenesulfonic acid in 700 ml. of benzene is refluxed for seven hours
under nitrogen atmosphere and then is allowed to stand overnight at room
temperature. After distilling off the benzene at atmospheric pressure, the
obtained residue ls taken up with diethyl ether, the resulting solution is
filtered from any insoluble and is subsequently brought to dryness. 95.0
Grams of a residue are obtained, corresponding to the intermediate compound
of formula XII in which Rl is phenyl, R4 and R5 are ethyl, R6 is methyl.
It is used as such for the subsequent cyclization step.
B) 14.0 Grams of sodium are dissolved in 360 ml, of ethanol and the
resulting solution is added with a solution of 95.0 g. of the crude compound
prepared unter A) in 360 ml. of ethanol.
After stirring for S hours and standing overnight at room tem-
perature, the reaction mixture is concentrated to small volume by evaporat-
ing the ethanol an~ is subsequently added with 300 ml. of a mixture of
aqueous 10~ hydrochloric acid and diethyl ether. The obtained precipitate
is recovered by filtration and recrystallized from ethanol/diethyl ether.
Yleld 67.0 g. of the title compound. M.p. 212-14C.
The compounds of Examples 2-18, 28-46, and 63 can be prepared
substantially following the method described in the foregoing Example.
PREPARATION OF THE STARTING AMINO ACIDS OF FO~MULA II
,, .. ... . _
A) 3-Amino-4-carboxy-5-methyl-2-phenyl-pyrrole.
a) A solution of 6 g. (0.042 mole) of 2-amino-2-phenyl-acetonitrile
and 5 g. (0.042 mole) of ethylacetoacetate in 30 ml. of anhydrous benzene is
refluxed for four hours on an oil bath in the presence of 100 mg. of p-
~LI )S503~i
toluenesulfonic acid. Af~er cooling, the reaction mixture is filtered,
then the solvent is evaporated off to give an oily residue, which is distilled
under reduced pressure. B. p. 140C /0.05.
b) 0.80 Grams of sodium are dissolYed in 15 ml. of anhydrous ethanol,
then a solution of 5 g. of the above compound in 35 ml. of anhydrous ethanol
is added dropwise and the mixture is allowed to stand at room temperature
for ~ous hours.
After bubbling dry hydrogen chloride in the ethanol solu~ion, a
precipitate readily forms, which is filtered and recrystallized from a
~ixture of ethanol and diethyl ether. Yield 4 g. of 3-amino-4-carbethoxy-
5-methyl-2 phenyl-pyrrole hydrochloride. M.p. 249-252C (from ethanol/ethyl
ether).
A solution of 4 g. (0.0143 mole) of the compound prepared under
b) in 60 ml. of dimethylsulfoxide is added with a solution of 6 g. of
lithium hydroxide monohydride in 90 ml. of water and the resulting mix~ure
is heated at about 80-85C for 3-4 hours.
After chilling, pouring into 160 ml. of ice water and adjusting
the pH to 7, the solution is four time extracted each time with 60 ml. of
ethylacetate. The organic extracts are collected and dried over sodium
sulfate, then the solvent is evaporated off in vacuo. 2.58 Grams of an
oily residue are obtained, which are taken up with chloroform, from which
a solid crystallizes upon cooling. Yield 1.3 g. of the title compound.
M.p. 153-54C. The hydrochloride melts at 200-200.5C dec. (from water).
B) 3-Amino-4-carboxy-1-p-chlorobenzyl-5-methyl-2-phenyl-~yrrole
hydrochloride.3-Amino-4-carbemoxy-5-methyl-2-phenyl-pyrrole hydrochloride,
.
prepared as under point b) of the previous example is reacted with p-
chlorobenzaldehyde according to the known procedures for preparing Schiff's
bases from amine and carbonyl compounds. The so formed 4-carbethoxy-3-(p-
chlorobenzylîdenea~ino)-5-methyl-2-phenyl-pyrrole (M.p 180-82C, from
ethanol/water) is reacted in a strong alkaline medium with p-chlorobenzyl
21
~C)55036
chloride, according to the usual procedures for introducing a substituent
into the nitrogen atom of a pyrrole nucleus.
The obtained 4-carbethoxy-1-(p-chlorobenzyl)-3-(p-chlorobenzylid-
eneamino)-5-methyl-2-phenyl-pyrrole is not isolated and is hydrolyzed under
acidic conditions to give the title compound M.p. 170-171C tfrom methanol/
ethcr).
22