Note: Descriptions are shown in the official language in which they were submitted.
~3~
- The pres~nt invention relates to certain
novel pyrrole-l-carboxylic acid compounds and to a process
for the production thereof.
More particularly, this invention relates to
novel 1,~-dihydro-3H-pyrrolo[1,2-a]pyrrole l-carboxylic acids
substituted at the C-5 position by a 2-furoyl, 2-thenoyl, 3-
furoyl or 3-thenoyl group, represented by ~he formulas
~,
~ coo~ [~C~O~
(A) ~B)
- 15 and the individual (l~-acid isomers and the (d~-acid isomers
thereof and ~he pharmaceutically acceptable, non-toxic esters
and salts thereof, wherein X is oxygen or sulphur; R is
hydrogen or a lower alkyl group having from 1 to 4 car-
bo~ ato~s a~d Rl is hydrogen, methyl, chloro ox bromo, the
~1 substitution in the compounds of Formula (A) bein~ a~ the
3, 4 or 5 positions of the furan or thiophene ring, and to
the m~tho~ f or the production thereof.
The compounds o the present invention as
described above~ and more fully below, exclusive of the (d)-
acid isomers anddexivatives thereof, exhibit anti-infl~ma-
tory, analgesic and anti-pyretic activities and thus are
us~ful ~n the treatment of infla~mation, pain and/or pyrexia
in mammals, as described hereinafter in detail. They are
also smooth mu~cle relaxants.
The term "pharmaceutically acceptable, non-
~ ~ .
- 2 -
0~
toxic esters and salts" as used herein r~fers to "alkyl
esters" d~rived from hydrocarbons of branched or strai~ht
chain having from onc to twelve carbon atoms and salts
derived ~rom pharmaceutically accept.able non-toxic in~rganic
and orqanic base~, respectivcly.
Typical alkyl ester ~roups are methyl, ethyl,
propyi, isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl,
hexyl, octyl, nonyl, isodecyl, 6-methyldecyl and dodecyl
esters.
Salts derived from inorganic bases include
sodium, potassium, lithium, ammonium, calcium, magnesium,
ferrous, zinc, copper, manganous~ a7uminum, ferric, manganic
~alis ana ~he li~e. ~articularly pre~erred are the ammonium,
potassium, sodium, calcium and magneSium salts. Salts deriv-
ed from pharmaceutically acceptable organic non-toxic bases
include salts of primaryl secondary, and tertiary amines,
substituted amines including naturally occuring substituted
amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, die hylamine, triethylamine,
tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-di-
ethylaminoethanol, tromethamine, lysine, arginine, histidine,
¢affeine, procains, hydrabamine, choline, betaine, ethylene~
diamine, glucosamine, methylglucamine, theobromine, purine~,
piperazine, piperidine, N-ethylpiperidine, polyamine resins
and the like . Par~icularly pre~erred organic non-toxic bases
are isopropylamine, diethylamine, ethanolaminel piperidine,
tromethamine, choline and caf ~eine .
The novel compolmds o~ Formulas (A) and
(B~, and Formulas (XI) and (XII) depicted below exist as pairs
of optical isomers (or enan~iomo~phs), i.e., a (dl) mixture.
.
: - 3 -
However, each optical isomer as well as the (dl) mi~ure~
thereo~ are included within the present invention.
When the novel compounds of this inve~tion
; are to be used to elicit a physiological respo~se (e.g.,
anti-inflammatory, a~algesic or anti-pyretic activity),
i.e., they are to be used as medicinals, a pre~erxed sub-
grouping is that of the compounds o~ Formulas (A) and ~B),
and the (l)-acid isomers thereof ~nd the esters and phaxma-
ceutically acceptable salts thereof.
A still -further sub-gxouping, ~or compounds
to be used as medicinals are the compounds of Formula (A)
and the (l)-acid isomPr of Formula (A) and the esters and
pharmaceutically acceptable salt~ thereof, and this sub-
grouping may be divided into two further sub-groupings made
up of (a) ~he compound of Formula (A), i.e., the (dl)-com-
pound wherein R and Rl are both hydxogen and X is sulfur and
: (bi the (l)~acid isomer of Formula ~B) wherein R and Rl are
both hydrogen and X is sulfur and the esters and pharmaceuti-
. cally acceptable salts thereo~. ;
The (d)-a~id i~omer of Formulas (A)~nd ~B)
: ~ and the esters and pharmaceutically acceptable sal~s thereo~
are useful as intermedia 2S for the preparation of the (dl)-
acid of Formulas (A) and (~), as described more fully below.
: The novel (dl) compounds of the present
invention can be prepared by a process illustrated by the
~llowi~g reaction sequence:
`~
`: :
`;
`' ' -
:: :
- 4
.
3~
2 COOC}J3 COOC1~3
C~32 ~COOCH3 ~ CCOOCH3
(I) (I~)~c~2
n , COOC~3 ~, COOCH3
`~ ~ ~r--I ~
~ ,~COOCH 3 ~ ~ ~COOC~ 3
1 j2 , \, ~I2C--C~I
1~2 ~V) \ ~ t ~
oSo2cH3
.
~I.~T~COOCH3 ~ ~t~COOCH3
- - ! N CC(~CR 3 ~ ~ ~coo~ll3
Ç132 , .
(VI ) ~Vï X
~, .... ,,, , . ' ' . ~
. ,COOE~ OOH
~N ~ ; ~ ~ CooE~
X~ . . . tVIIX )
. .
' 1 :' ' ~_
I~OOR2
n; ~COOR
tXI I:) ~
R~3~
~ Coo:l
.. O , ,~
-- 5 .--
(x)
C ~ CG~
~XII) ~ I ~COOH
. ~B)
wherein X, R and Rl have the above-indicated meaning and
~2 is a lower alkyl group of 1 to 4 carbon atoms, e~g.,
methyl, ethyl, isopropy1 or n-butyL.
In practicing the process outlined above, or the pre-
paration of the compound of Formula (IV) wherein R is hydrogen,
.equimolecul~r amounts of ethanolamine ~I) and dimethyl l,3-
acetonedicarboxylate (II) are reacted at a temperature of
from about 0 to about room ~emperature, to readily form
a solution of the vinylamine.. o~ Formula (III), which is
- then treated, preferably in situ, in a suitable .inert organic
solvent, under anhydrous conditions, with 2-b-omoacetaldehyde
o.r 2-chloroacetaldenyde, at from about 40~ to about 100C
for a period of tlme of from a~out 30 minutes to about lG
hours. Suitable solvents for this reaction are the aprotic
solvents such as acetonitrile, tetrahvdrofuran, dimethoxy-
ethane, chloroform, dichloromethalle and the like. In the
preferred embodimen~s, .he reac~on is conducted in aceto-
nitrile solution, a~ reflux temperature ~or about 1 hour.
The 2-bromo-(chloro)-acetaldehyde reagents are ]snown com-
pounds, or can be obtainea by pyrolysis of ~he corres2on-
. --6~
.
ding diethyl ace~als in the presence of oxalic acid dihy-
drate.
To prepare the compounds o~ Formula (IV) wherein R
is a lower alkyl group, pref~rably straight chain, hav-
ing 1 to 4 carbon a~oms, an aqueous mixture of e~hanolamine
(I~ and dimethyl 1,3-acetonedicarboxylate (II) is treated
with a compound of the Lormula R3-~-C~2X, wherein X is
bromo or chloro and R3 is a lower alkyl group, prefera~ly
straight chain, of from 1 to 4 carbon atoms, and most pre-
ferably l-bromoace~.one, 1-bromo-2-butanone, 1-bromo-2-pen-
tanone, and l~bromo-2-hexanone, at from about 40 to a~out
100C or a period of time from about 30 minutes to about
16 hours. In the preferred embodiment the reaction is con-
ducted at a temperature of from about -10C to about room
temperature for from about 1 hour to about 6 hours. The
3 ~
R - -CH2X reagents are known compounds.
Esteri~ication o~ compound ~IV) with methane-
sulfonyl chloride in the presence of a tertiary amine, i.e.,
triethylamine, pyxidine and the like, optionally in the pres-
~o ence of a cosolvent such as dichloromethane, at a temperature
of from about -10C to about room temperature, for about 10
minutes to about 2 hours produces the corresponding mesylate
of Formula (V), which is converted into ~he corresponding
N~(2-iodoethyl3pyrrole of Formula (VI) by reaction with
sodium iodide in acetonitrile solution, at reflux temperature
for from about one to about ten hours.
Upon reaction o~ the io~oe~hyl compounds of
Formula (VI) with ~odium hydri.de in a suitable inert organic
solvent such as dimethylformamide there are obtained dimethyl-
1,2-dihydro 3H-pyrrolo[1,2-a]pyxrole-1,7-dicarboxylate and
the 6-aI~yl substituted deriva~ives thereof (VII). This
cyclization is conducted under an inert atmosphere, i.e.,
under argon or nitrogen atmosphere, at temperatures of the
order o~ from about 15 to about 40C, for a period of time
S of from about 15 minutes to about 4 hours. Best results are
obtained conductin~ the reaction at room temperature, for
about 30 minutes when R is hydrogen.
Alternatively, the compounds of ~ormula ~VII)
~` can be prepared by direct cyclization of the mesylate (V),
1~ with sodium hydride in dimethylformamide solution ~ at from
about -10C to about room temperature, ~or ~rom about 30
minutes to about 2 hours.
Basic hydroLysis of a compound of Formula
~VII) with an alkali metal hydroxide or alkali metal carbon-
`~ 15 ate, e.g., sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate and the like in an aqueous
lower aliphatic alcohol, e.g., methanol or ethanol, at a
temperature of between room temperature and reflux, for from
about 4 to about 24 hours, a~fords the corresponding free
diacid of Formula (VIII~, i.e., 1,2-dihydro-3E-pyrrolo~1,2-a~-
pyrrole-1,7-dicarboxylic acid and the 6-alkyl derivatives
t~ereof. q~ne ny~rolysis is pre~erably carried out using
a~ueous methan~lic potassium hydroxide, at reflux temperature
for abou~ lOhours.
The carboxylic acid group at the C-1 posi~
t~on in compound ~VIII) is then selectively esterified by
treatment with a lower aliphatic alcohol, e.g., methanol,
- ethanol, isopropanol, n butanol and the like in the presence
o~ hydrogen chloride, to produce the corresponding alkyl 1,2-
~` 30 dihydro~3~-pyrrolo~1,2-a]pyrrole-1-carboxylate-7 carboxylic
,
_ ~ _
acid of ~'ormuia ~l~j. Tne reaction is conducted at a temper-
ature of from about 0 to about 50C., for about 1 to about
4 hours.
Décarboxylation of the monoestérified com-
pounds (IX) to the corresponding compounds of Formula (X),
the key intermediates in the process for obtaining the com-
pounds of the present invention, is achieved by heating (IX)
at an elevated temperature, of the order of from about 230
to about 280C, for a period of time sufficient to complete
the reaction. The course of the reaction can be followed by
the xate of carbon dioxide evolution and t.l.c. analysis, de
carboxylation being generally completed within from about 45
to about 90 minutes. The reac~ion produc~, ~amely, alkyl
1,2-dihydro-3H-pyrrolo~1,2-a~pyrrole-1-carboxylate and the
6-alkyl derivatives thereo~ ~X) can be purified ~y chromato-
graphic techniques. Alternatively, and particularly for the
decarboxylation of small batches of compound (IX), the reac-
tion product (X~ can be distilled directly from the reaction
vessel.
Condensation of a compound (X) with an amide
o~ the formulas 1 ~ CON(CH3) ~ ON(CH3)2
wherei.n X and R have the above indicated meaning, affords
the corresponding alkyl 5-substituted-1,2-dihydro-3H-pyrrolo-
- 25 ~1,2-a]pyrrole-l~carboxylates of Formulas (XI) or (XII~
- respect~vely.
This reaction i5 co~ducted in an inert
organic aprotic solvent and in the presence of phosphorous
o~ychloride, at reflux temperature for from about 1 to about
72 ~ours, under an inert atmosphere, followed by further
.:
:' ' . ~, '
u~
reflux in the presence of sodium acetate, ~or ~rom about 2 to
about lO hours. Alternatively, instead of phosphorous oxy-
chloride other acid chlorides such as phosgene or oxalyl
chloride may be used.
In the preferred embodiments, this condensa-
tion is carried out by adding a solution of compound (X) in a
suitable solvent to a previously refluxed mixture of 1.1 to
2 molar equivalents of both the desired amide and pnosphorous
oxychloride in the same solvent, refluxing the reaction mix-
ture thus obtained for from about 2 to about 30 hours under
an argon atmosphere and thereafter adding thereto from about
3 to about lO molar equivalents of sodium acetate, followed
by an additional reflux period for from about 4 to about 6
hours.
Adequate solvents for this reaction are the
halogenated hydrocarbons such as dichloromethane, 1,2-dichloro-
ethane, chloroform, carbon tetrachlcride and the like, di-
~; methoxyethane and tetrahydrofuran. The preferred solvent i~
1,2-dichloroethane.
Representative of the N,N-dimethyl amides
which ~an be used are: N,N-dimethylthiOphene-2-carboxamide,
: NIN-dimethyl~uran-~-carboxamide,
N,N-dimethyl-3-methylthiophene-2-carboxamide,
N,N-dimethyl-4-methylthiophene-2-Carboxamide,
N,N-dimethyl-S-m~thylthiophene-2-carboxamide,
N,N-dimethyl-4-chlorothiophene-2-carboxamide,
N,N-dimethyl-5-chlorothiophene-2-carboxamide,
N,N-dimethyl-3-bromothiophene-2-carboxamide,
N,N-dimethyl 5-bromothiophene-2-carboxamide,
N,N-dimethyl-3-methylfuran-2-carboxamide,
-- 10 --
N,N-dimethyl-4-methyl~uran-Z-carboxamide,
~,N-dimethyl-4~chlorofuran-2-carboxamide,
N,N-dimethyl-5-chloro~uran-2-carboxamide,
N,N-dimethyl-4-bromofuran-2-carboxamide,
N,N-dimethyl-5-bromofuran-2-carboxamide,
N,N-dimethylthiophene-3-carboxamide and
N,N-dimethyl~uran-3-carboxamide.
Thece amides can be prepared in a conven-
tional manner from the ccrresponding thiophene- or furan-2-
~3)-carboxylic acids i.e., by conversion into the acid
chlorides ~ollowed by trcatment wi~h dimethylamine.
Upon alkaline hydrolysis of the alkyl ester
group in a compound o~ Pormulas (XI) or (XII) there are ob-
tained the corresponding free acids of Formulas (A) or ~B),
respectively. The hydrolysis is effected in a conventional
- manner, with an alkali metal hydroxide or alkali metal carbon-
ate, e.g., sodium hydroxide, potassium hydroxide, sodium
carbonate~ potassium carbonate and the like, in an aqueous
- lower aliphatic alcohol, e.g., methanol, ethanol and the like,
at a temperature o~ ~rom about room temperature to reflux,
for from about 30 minutes to about 4 hours, under an inert
a~mosphere. In~the preferred emkodiments, this hydrolysis is
e~ected with aqueous methanolic potassium hydroxide, at
reflux temperature for about 2 hours~
~ The aompounds o~ Fo m ula~ (A) and (B) can be
resolved, according to method~ known in the art, to obtain ~he
; correæponding individual isomers thereo~. Thuq, ~or example,
the compound of Formula (A) wherein R and Rl are both hydrogen
and X i~ sulfur can be suhjected to ~urther trea~ment in
: .
:. - . , , , ", .': ', . :
accordance with the following flow diagram:
~ ~ COOH
~ ~ _ l
. .
resolution
~ , ' .
~ \
A~-tl)-acid isomer-(d)-amphetamine
¦ salt .
A ~ acid isomer .
` .
Mixture of ~ A ~(d)-acid isomer~(d) amphetamine salt
( A~ acid isomer-(d)-amphetamine salt ~
A more detailed~description of this procedure is set
~orth in ~x~mple 10 B-l b~low.
~ Alternatively, the (l)-acid isomers and (d1-acid
isomers o~ the compounds of Formulas (A) and (B~ can be
obtained by applying the known technique of high pressure
:~ liquid~chromotography (~PLC) ~o the ~-phenethyl dia~ereo-
i omeric es~ers of the compounds of Formulas (A) and (B),
`' ' .
- 12 -
:` ~
~ollowed by acid cleavage. Thus, for example, the compounds
of Formula tA) whersin R and Rl are both hydrogen and x is
suflur can be subjected to ~urther treatment in accordance
with the following flow diagram:
~Cool~ ~
10(Al)
several
steps
C (A~ acid isomer-(l)-a-phenethyl ester
15~ixture ~ ~ 1
( (A )-(d)~acid isomer-(l)-a-phenethyl ester~
separate
using
~PLC
~ \
(Alj-tl)-acid isomer-tl)-phenethyl este
. \~
~ 25 (A )-(d)-acid isomer (l)-phene~,hyl ester
~ / ' ' I
(A~ .)-a~id isomer (Al)-(d)-acid isomer _
~ more de~ailed description of this procedure is set
orth in Example 10 B-2 below.
- 13 -
~ he free acids o~ Formulas (A) and (B~ can be con-
verted into o~her alkyl es~ers having ~rom 1 to 12 carhon
atoms by conventional methods, e.g., by treatment with (a)
the alcohol corresponding to the desired ester in the pre-
sence of a strong mineral acid, (b) an etheral diazoalkane
or (c) the desired alkyl iodide in the presence of lithium
carbonate. The (l)-acid isomers can ~e converted into their
alkyl esters by the methods of (b) and (c) above.
The salt derivative~ of the compounds of Formulas
(~) and ~B) a~d the (l)-acid isomers thereof are prepared
by treating these free acids with an appropriate amount of
a pharmaceutically ~cceptable base. Representative pharma-
ceutically acceptable bases ~re sodium hydroxide, potassium
hydroxide, lithium hydroxide, ammonium hydroxide, calcium
hydroxide, magnesium hydroxide, ferrou~ hydroxide, zinc
hydroxide, copper hydroxide, manganous hydroxide, aluminum
hydroxide, ferric hydroxide, manganic hydroxide, isopropyl-
amine, trimethylamine, diethylamine, triethylamine, tripropyl-
amine, ethanolamine, 2-dimethylaminoe~hanol, 2-diethylamino-
ethanol, tromethamine,~lysine, arginine, histidine, caffeine,
procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosami~e, methylglucamine, theobromune, purines, pipera-
zine, piperidine, N-ethylpiperidine, pol~amine resins and
the like. The reaction is conduc~ed in water, alone or in
combination with an inert, water-misible organic solvent~
a~ a temperature of from about 0C. to about lOO~C, pre-
ferably at room tempera~ure. Typical inert, water-miscible
organic solvents include methanol, ethanol, isopropanol,
butanol, ac2tone, dioxane or ~e~rahydrofuran. The molar
ratio o~ compound3 of Formula~ (A) or (B) or the (1)~ acid
isomer~ thereof to base used are chosen to provide the ratio
- 14 -
~ `
desired forany particular salt. For preparing, for example,
the calcium salts or magnesium salts of th0 compounds of
Formula (A) or (B) or the (1)- acid isomers khereof~ the
free acid starting material can be treated with at least
one-half molar equivalent o~ pharmaceutically acceptable
base to yield a neutral saltO When the aluminum salts of
the compounds of Formulas (A) or (B) or the (1)- acid is~mers
thereof are prepared at least one-third molar equivalent of
the pharmaceutically acceptable base are employed if a neutral
salt product is desired.
In the preferred proceaure, the calcium salts
and magnesium salts of the compounds of ~ormulas (A) and
(B) and (l)-acid~isomers thereof can be prepared by treating
the corresponding sodium or potassium salts thereof with at
leas~t one-half molar equivalent of calcium chloride or mag-
nesium chloride, respectively, in an aqueous solution, alone
or in combination with an inert water-miscible organic sol-
vent, at a temperature of ~rom about 20C to about 100C. .
Preferably, the aluminum salts of the compounds hereof, can
. be prepared by treating the corresponding free acids with
at least one-third molar equivalent of an aluminum alkoxide,
such as aluminum triethoxide, aluminum tripropoxide and the
like, in a hydrocarbon solvent, such as ben~ene, xylene,
cyclohexane and the like, at a temperature of from about
20C to about 115C. SLmilar procedures can be used to
prepare salts of lnorganic bases which are not su~ficiently
: soluble for easy reaction.
It is to be understood that isolation of
the compounds described herein can be effected, if desired,
by any suitable separation or purification procedure, such as,
: - 15 -
,
for example, extraction, ~iltration, evaporation, distilla-
tion, crystallization, thin-layer chromatography or column
chromatography, high pressure liquid chromotography (HP~C)
or a combination of the~e procedures. Illustrations of
suitable separation and isola~ion procedures can be had by
reference to the Examples herein below. However, other
equivalent separation or isolation procedures could, of
course, also be used.
While the (d)-acid isomers are not used as
medicinal agent~ per se, they can, i~ desired, be converted
to their pharmaceutically acceptable, non-toxic esters and
salts thereof according to the methods described for the
conversion of the ~l)-acid isomexs to their pharmaceutically
acc~p~able, non-toxic es~ers and salts thereof.
The compounds of Formulas (A) and (B) and
the (l)-acid isomers thereof and the pharmaceutioally accept-
able non-toxic esters and salts thereof, are useful as a~ti-
inflammatory agents, analgetic agents, platelet aggregation
inhibitors, fibrinolytic agents, and as smooth muscle relax-
ants. These compounds can be used both prophylactically
and therapeu~ically.
The compositions containing these compounds
are thus useful in the treatment and elimination of inflam-
mation such as inflammatory conditions of the muscular skel-
etal system, skeletal joints and oth~r tissues, ~or example~
; in the t~eatment of inflammatory conditions such as rheuma-
tism, concussion, laceration, arthritis, bone ~ractures,
post-traumatic conditions, and gout. In those cases in which
the above conditions include pain and pyrexia coupled with
inflammation, the instant compounds are useful for the relief
- 16 -
of these conditions as well as the inflammation.
Aaministratlon o~ the active compounds o~
Formulas (A) or (B) or the (l)-acid isomers thereof and the
pharmaceutically acceptable, non-toxic esters a~d salts
thereof, in an appropriate pharmaceutical composition can
be via any o~ the accepted modes of administration o~ ayents
~or the treatment of inflammation, pain or pyrexia, or the
prophylaxis thereo~. Thus, administration can be for xample,
orally, parenterally or topically, in ~he form of solid,
seml-solid or liquid dosage forms, such as, for example,
tablets, suppositories, pills, capsules, powders, solutions,
suspensions, emulsions, creams, lotions, ointments or the
like, preferably in unit dosage ~orms suitable ~or simple
administration of precise dosages. The compositions will
include a co~ventional pharmaceutical carrier or excipien~
and a~ active compound of Formulas (A) or (B) or the (l)-acid
isomers thereof and the pharmaceutically acceptable non-toxic
esters and sal~s the~eof, and, in addition, may include.other
medicin~l agents, pharmaceutical agents, carriers, adjuva~
etc.
The preferred manner of administration, for
the conditions detailed above, is oral using a convenient
daily dosage regimen which can be adjusted according to the
de~ree of affliction. Generally, a daily dose of from 25 mg.
to 500 mg. of the active compound of Formulas (A) or (B) or
the (l)-acid lsomers thereof and the pharmaceu~ically accept-
~ able, non-koxic esters and salts thereo~ is used. Most con-
.~ ditions respond to treatmen~ comprising a dosaye level of the
- order of 0.5 mg. ~o 6 mg. per kilogram of body weight per day.
For such oral administration, a pharmaceutically acceptable,
~: `
- 17 -
non-toxic composition is formed by the incorporation o~ any
of the normally employed excipients, such as, for example,
pharmaceutical grade~ of mannitol, lactose, starch, magnesi-
um stearate, sodium saccarine, talcum, cellulose, glucose,
gelatin, sucrose, magnesium carbonate, and the like. such
compositions take the form of solutions, suspensions, tablets,
pills, capsules, powdexs, qustained release formulations and
the like.
The active compounds of Fo~mulas (A) or tB)
or the (l)-acid isomers thereo~ and the pharmaceutically
acceptable, non-toxic esters and salts ~hereo~, may be formu-
lated into a suppository using, for example, polyalkylene
glycols r or example, polypropylene glycol, as the carrier.
Liquid phaxmaceutically administerable compositions can, for
example, be prepared by dissolving, dispersing, etc. an
active compound ! as described above, and optional pharmaceu-
; tical adjuvants in a carrier, such as, ~or example, water,
saline, aqueous dextro~e, glycerol, ethanol and the like, to
thereby folm a solution or suspension. If desired, the phar-
maceutical composition to be administered may al~o contain
mlnor amounts of non-toxic auxiliary substances such as
wetting or emulsifying agents, pH bufering agents and the
like,:such as ~or example, sadium acetate, sorbitan monolau-
rate, triethanolamine oleate, etc.
~ Actual methods of preparing such dosage
: forms are ~nown, or will be apparent, to those skilled in
. this art; ~or example, see Remington's Pharmaceutlcal Sciences,
Mack Publishing Company, Easton, Pennsylvania, 14th. Edition,
1970. The composition to be administered will, in any event,
- 18 -
.
contain a quanti~y o~ ~he active compound(s~ in a pharma-
ceutlcally effective amount or relief of the particular con-
dition being treated in accordance with the teachings of this
invention.
Th~ co~pounds o~ Formulas (~) and tB) and
the (l)-acid isomers thereo~ and the non-toxlc, pharmaceuti-
cally acceptable esters and qalts thereof, described above,
are also uterine smooth muscle relaxants and thus are useful
as agents ~or maintaining the pr~gnanc~ of pregnant mammals~
for the benefit of the mother and/or fetus, until tenmination
of ~he pregnancy is considered, from a medical poin~ of view,
to be favorable, or more f~vorable, for the mother and~or
the fetus. It should be understood, howe~er, that in certain
in~tances, for e~ample where parturition has already begun
(i.e., the mother is expexie~cing uterine contractions,
especially near full term), that administration of the com-
pounds herein described may not maintain the pregnant state
for an indefinite period of time. Rather, in such instances,
the pregnancy will, most probably, be slightly "prolonged",
a ~actor which may be advantageous to either the mother and/or
tAe fetu~.
particular, the compounds of Formulas (A)
and (B) and the (l)-acid isomers thereo~ and the phaxmaceuti-
cally acceptable, non-toxic es~ers and salt~ thereo~, are
used as agents ~or delaying the o~set of, or for postponing,
~arturition. As used in this application, the phrase "to
delay the on~et o parturition" is intended to cover that
delay i~ parturition caused by the administration o~ the com-
pounds o~ Foxmulas (~) or (B) or the (l)-acid isomers thereof
and ~he pharmaceutically acceptable, non-toxic esters and sal~s
~ -- 19 --
thereof, at any time before uterine muscle contractions have
begun. Thus, it is intended that the aforemenkioned phrase
couer abortion prevention early in pregnancy (i.e., before
the fetus i9 "viable") as well as delaying premature parturi-
tion, a term which sometimes is used with reference to that
premature labor experienced later in the pregnancy when the
fetus is considered to be "viable". In either case, the
agents are administered as prophylactic agents in that such
administratio~ tends to prevent the onset of parturition.
This administration is particularly useful in the treatment
o women having a history o~ spontaneous abortion, miscarri-
age or premature delivery (i.e., delivery prior to ~ull term).
Such administration is also useful where there are clinical
indications that the preynancy might be t0rminated prior to
that time and i5 considered favorable to the mother and/or
~etus.
With respect to animals, this treatment can
~` also be utilized to synchronize the deliveries ~rom a group
-- of pregnant animals to happen at or about the same time, or
to happen at or about a desired time and/o~ place, when the
births can be handled with greater facil~ty.
As used in this application, the phrase
"postponing parturition" is intended to covex that delay in
parturitian caused by the administration of the c~mpounds o~
Form~la3 (A) or (B) or the (l)-acld isomers thereof and the
~- ph~rmacoutically acceptable, non-toxic esters and salts
- thereo~ a~ter uterine muscle contractions have begun. The
condition o~ the patient, including the time within khe ge~ta-
tion period when the contractions have begun, the severity
of the contractions and how long the contractions have taken
',
~- - 20 -
.
- , .
place ~ill afrect the resul~s achieved with the administra-
tion of the compounds hereof. For Example, the e~ect can
be to reduce the intensity and/or the duration of the con-
tractions (the actual act of parturition being "prolonged"),
or to stop ~he contractions altogether. In either case,
the e~fect will be ~o prolong the gestation period although,
depending upon the co~ditions of the patient as descri~ed
above, the effect may ei~her by slight or, under appropriate
- circumstances, omewhat greater. Such administrati~n may
be to prevent spontaneous abortion, to cause the delivery
to be more easily accomplished and/or less pain~ul to the
- mother~ or to occur at a more appropriate time and/or place.
In all cases, administration of the com-
pounds of Formulas (A) or (B) or the (1) acid isomers thereo~
and the pharmaceutically acceptable, non-toxic esters and
salts thereof, for the purposes set forth herein should be
consistent with best and/or accepted medical (or veterinary)
practices so as to maximize the benefits to the mother and
the fetus. For example, administration should not be con-
tinued so long past ~ull term that the fetus dies in utero.
In the practice of the methods of the pre-
sent invention, a therapeutically effective amount of a com-
pound o~ Formulas ~) or (B) or the (l)-acid isomers thereof
and the pharmaceutically acceptable, non-toxic esters and
salts thereo, or a pharmaceutical composition containing
same, is administered to the pregnant mammal via any of the
usual nd acceptable methods known in the art. The compound
can be admi~istered ei~her singly or in combina~ion with
; another compound or compounds, as de~ined above, or other
pharmaceutical agent~, carrierQ, adjuvants, etc. Such
- 21 -
`'`' : ' "'''' ' '' `' ' ` ' '
4~
compound(s) or compositions can be admini~tered orally,
parenterally, either in the form of solid, semi-solid, or
liquid dosage forms. Typically, administration is by a
pharmaceutical composi~ion containing the pharmaceutically
active compound and one or more pharmaceutical carriers or
adjuvants.
The administera~le pharmaceutical composi-
tion may take the form o~ oral tablets, vaginal or uterine
tablets or suppositories, pills, capsules, liquid solutions~
suspensions, or the like, preferably in unit dosage forms
suitable ~or simple administration of precise dosages.
Conventional non-toxic solid carriers include, for example,
pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium sacsharin, talcum, cellulose, ylucose, gelatin,
sucrose, magnesium carbonate, and the like. The active com~
pound as de~ined above may be formulated as suppo-citories
using, for example, polyalkylene glycols, for example,
polypropylene gl~col, as the carrier. Liquid Pharmaceutically
administerable compositions can, for example, be prepared by
dissolving, dispersing, etc. an active compound as defined
above a~d optional pharmaceutical adjuvants in a carrier,
~uch as, for example, water, saline, aqueous dextrose,
glycerol, ethanol, and the like, to thereby form a solution
or suspension. I de~ired, the pharmaceutical composition
to be admin:istered may al=o contain minor amounts of non-
toxic auxlIiary substances such as wetting or emulsifying
age~ts, pH buffering agents and the like, or example,sodium
acetate, ~orbitan monolaurate, triethanolamine oleate, etc.
Actual methods o~ preparing such dosage ~orms are known, or
will be apparent, to those skilled in this art; ~or example,
- 22 -
~ee Remington's Pharmaceutical sciences, Ma~k Publishing
Company, Easton, Pennsylvania, 14th Edition, 1970. The com-
posi~ion or formulation to be administered will, in any event,
contain a quantity of the active compound(s) in an amount
effective to delay the onset of parturitio~ or to postpone
partu-ition i~ uterine contractions have already begun.
Generally a daily dose o~ from O.S mg. to about 25 mg. of
the active compound per kilogram of body weight will be
administered, with administra~ion being a single daily dose
or up to three or four smaller dosages regularly given
throughout the day. The amount of active compound adminis~
tered will, of course, depend on its relative activity.
The following Preparation and Examples il-
lustrate the invention but are not intended to limit its
scope. The abhreviation t.l.c. refers to thin-layer chroma-
tography and all mixture ratios used with regard to liquids
refer to volume ratios. Also where necessary, examples are
repeated to prepare additional material ~or subsequent
examples; and u~less otherwise specified the reac~ions are
carried out at room temperature (20C to 30C).
PREPA~ATION
A mixture of 23 g. o~ 4-chlorothiophene-2-
carboxylic acid ~J. Iriarte et al., J. ~eterocyclic Chem. 13,
393) and 80 ml. of thionyl chlorids is heated to reflux, un-
der anhydrous con~itions for 4 hours. The excess thionyl
chloride is eliminated and the residue distilled under re-
duced pressure (60C/Z mm), to afford 18 g. of 4-chlorothio-
phe~e-~-carboxylic acid chloride.
A solution of 10.5 g. o~ 4 chlorothiophene-
- 23 -
2-carboxylic acid chloride in 500 ml~. of anhydrous benzene is
cooled in an ice water bath and dimethylamine is slowly bubbl-
ed through the solution for 30 minutes. The ice water bath
is removed, maintaining the stream of dimethylamine or 15
~dditional minutes. The reaction mixture is then diluted
with lOO ml. o~ lO~ sodium chloride ~olution and stirred for
; S minutes at room temperature, the organic phase is separat-
ed, wa hed with lO~ hydrochloric acid, saturated sodium bi-
carbonate solution and saturated sodium chloride solution,
dried over sodium sulfate and evaporated to dryness under
xeduced pressure, to produce N,N-dimethyl-4-chlorothiophene-
2-car~oxamide.
In a similar manner the thiophene and furan-
2-carboxylic acids listed below under I are converted into
the N,N-dimethyl amides listed undar II:
~ I II
Thiophene-2-carboxylic acid N,N-dimethylthiophene-~-car-
boxamide
furan-2-carboxylic acid N,N-dimethylfuran-2-carboxa-
mide
3-methylthiophene-2-carboxylic N,N-dimethyl-3~methylthio-
acid phene-2-carboxamlde
4-methylthiophene-2-carboxylic N,N-dimethyl-4-methylthio
acid phene~2-carboxamide
5-methylthiophene-2-carboxylic N,N-dimethyl 5-methylthiophe-
acid ne-2-carboxamide
S-chlorothiophene~2-ca~oxylic N,N-dimethyl-5-chlorothio-
acid phene-2-carboxamide
3-bromothiophene-2~carboxylic N,~-aimetnyl-3-bromothiophene-
acid 2-carboxamide
4-bromothiophene~2-carbo~ylic N,N-dimethyl-4-bromothiophene-
acid 2-carboxamide
5-bromothiophene-2-carboxylic N,N~dimethyl-5-bromothiophene-
acid 2 carboxamide
- 24 -
3-methylfuran-2-carboxylic N,N-dimethyl-3-methylfuran-2-
acid carboxamide
4-m thylfuran~2-carboxylic N,N-dimethyl 4-methyl~uran-2-
acid carboxamide
5-methylfuran-2-carboxylic N,N-dimethyl-5-methylfuran-2-
acid carboxamide
.~ .
3-chlorofuran-2-carboxylic N,N-dimethyl-3-chlorofuran-
acid 2-carboxamide
4-chlorofura~-2-carboxylic N,N-dime~hyl-4 chloro~uran-
acid 2-carboxamide
5-chlorofuran-2-carboxylic N,N-dimethyl-5-chlorouran-
acid 2-carboxamide
4-bromofuran-2-carboxylic N,N-dimethyl-4-bromofuran-
acld 2-carboxamide
5-bromofuran-2-carboxylic N,N-dimethyl-5-bromofu~an-
acid 2-carboxamide
thiophene-3 carboxylic N,N-dimethylthiophene-3-
acid carboxamide
~uran-3-carboxylic acid N,N-dimethylfuran-3-carb~
oxamide
~X~MPLE 1
A 250 ml. 3-necked round bottomed flask con~
taining a magnetic stirring bar and fitted with a calcium
- chloride filled drying tube is connected directly (via one of
the outer necks) by means of a receiver adapter and short
(3") water condenser to the acetal pyrolysis apparatus. This
~atter apparatus consistq of a 100 ml. round bottomed flask
[previou~ly ch~rged with 15.6 g~ o~ oxalic acid dihydrate and
11. 82 g. o~ bromoacetaldehyde diethyl acetal, prepared from
vinyl acetate, as de~cribed by P.Z. Bedoukian, J. ~m. Chem.
Soc. 66, 651 (1944)], topped with a 6" Vigreux column, bear-
ing a thenmometer, connected to the above mentioned condenser.
- 2~ ~
The 3-necked flas~ is charged with 3.36 g.
of ethanolamine cooled in an ioe ba~h at 0-10C and treated
dropwise, with stirring, with 8.7 g. of dimethyl 1,3-acetone-
dicarboxylate. Methyl 3-carbomethoxymethyl-3(2'-hydroxy-
ethyl)amino acrylate (III) forms immediately. When the ad-
dition is completed, the ice bath is removed and 100 ~1. of
dry acetonitrile is added. ~he pyrolysis part of the ap-
paratus is placed in an oil bath and the temperature thereof
is raised to 150-160C. The bromoacetaldehyde solution which
forms is distilled (b.p. 80-83C/580 mm) directly into the
magnetically stirred solution of the vinylamine (III). When
the distillation temperature drops below 80C, the pyrolysis
apparatus is disconnected and replaced by a re~lux condenser
fitted with a drying tube containing calcium chloride. The
solution is heated at reflux temperature for 1 hour, the
solvent is removed under reduced pressure and then 200 ml. of
methanol and 20 g. of silica gel are added to the residue.
This mixture is evaporated to dryness in vacuum and placed on
top of a column o~ 200 g. of silica gel packed in hexane.
The column is then eluted with hexane:ethyl acetate ~80:20;
500 ml.~ and hexane:ethyl acetate (1:1; 9 x 500 ml.). Frac-
tions 2 and 3 contain less polar impurities and dimethyl 1,3-
acetonedicarboxylate; fractions 4-8 a~ord 4.1 g. o~ methyl
N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R=H),
which upon recrystallization ~rom ether-hexane has a meltin~
point o 52-54C.
EXAMPLE 2
To a stirred solution o~ 4.1 g. o~ methyl
- 26 -
.
N-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate in 35 ml.
of dry dichloromethane cooled to -10C, are added 2.65 ml.
of triethylamine and thereafter, in a dropwise fashion,
1.46 ml. of me~hanesulfonyl chloride, maintaining the temper-
ature o~ the reaction mixture at -10 to -5~C. The course
o the reaction is followed by t.l.c. analysis using chloro-
form:acetone (90:10). When the reac~ion appears to be com-
plete ~about 30 minutes after t~e addition of the methane-
sulfonyl chloride is terminated) there is added slowly 10 ml.
of water. The organic phase is separated, washed with water
~3 x ~0 ml.), dried over sodium sulfate and evaporated under
reduced pressure. Crystallization of the,residue from di-
chloromethane-hexane affords 4.75 g. (77.7%) of methyl N-(2- -
mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate (V, R = H),
m.p. 99-lOl~C.
~XAMPLE 3
A solution of 785 mg. of methyl N-(2-mesyl~
oxyethyl)-3-~arbomethoxypyrrole-2-acetate and 1.83 g. of
sodium iodide in 10 ml. of acetonitrile is refluxed for 1
hour. The coole~ reaction mix~ure is evaporated to dryness
under reduced pressure and the residue is triturated with
watex. The i~soluble material is separated by filtration
and alr dried, thus obtaining 840 mg. (97~) of methyl N-(2-
iodoeth~ 3-carbomethoxypyrrole-2-acetate ~VI, R - H), m.p.
137-138C.
EX~MPLE 4
A solution o~ 1 g. o~ methyl N-(2-iodoethyl)_
3-carbomethoxypyrrole-2-acetate in 5 ml. of dry dimethyl-
- 27 -
formamide is stirred, under an atmosphere of argon, with
137 mg. of 50% sodium hydride in mineral oil. The reaction
mixture is maintained for 30 minutes at room tempera~ure and
then quenched with 100 mlO of water. The product is extract~
S ed with ethyl acetate (3 x 50 ml.), the combined extracts
are washed with water, dried over magnesium sulfate and
evaporated to dryness. Chromatography o~ the residue on
silica yel (20 g.) usiny hexane~ethyl ace~ate (4:1) as eluant
a~fords 500 mg. (80~) of dimethyl 1,2-dihydro-3H-pyrrolo
[1,2-a]pyrrole-1,7-dicarboxylate ~VII, R = H) m.p. 70-71C.
A solution of 1.80 g. of dimethyl 1,2-di-
hydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate in 20 ml. of
methanol is ~rea~ed with a solu~ion of 4.48 g. of potassium
- hydroxide in 20 ml. of water, and the reaction mixture is
lS re~luxed for 6 hours. I'he cooled solution is evaporated to
dryness and the residue is treated with 50 ml. of satu~ated
sodium chloride solution. The resultant solution is
acidified with 6N hydrochloric acid and extracted with ethyl
acetate (3 x 50 ml.). The combined extrac~s are dried over
2~ magnesium sulfate and evaporated to dryness under reduced
pressure, to yield 1.51 g. (95~) of 1,Z-dihydro-3H-pyrrolo-
~1,2-a]pyrrole-1,7-dicarbo~ylic acid (VIII, R = H), m.p.
220C, with decomposition.
EXA~PLE 5
A solution of 1.34 g. o~ l,Z-dihydro 3H-
pyrrolo[L,2-a]pyrrole-1,7-dicarboxylic acid in 50 ml. o~ iso-
propanol, cooled in an ice bath is saturated with gaseous
hydrogen chloride, malntaining the temperature of the reac-
; 30 tion mixture below 50C. The ice bath is then removed and
- 28 -
''
the reaction mixture is stirred for 1.5 ~ours at room temp~r-
a~ure, and evaporated to dryness under reduced pressure;
10 ml. of ~enzene is added to the residue and th~ solution
is evaporated under vacuum once again, repeating this process
a total of three times to completely remove the excess
-- hydrogen chloride, thus obtaining 1.58 g. (96%) of isopropyl
1~2-dihydro-3H-pyrroloC1~2-a]pyrr~le-l-carboxylate-7-carboxy-
lic acid (IX, R = H, ~ ~ iC3~7), which upon crystallization
from methanol-e-thyl acetate has a melting point of 144-145C.
In a similar manner but substituting methan-
ol, ethanol, propanol, and n-butanol for isopropanol in the
above procedure there are respectively ob~ained:
methyl 1,2 dihydro-3H-pyrrolo[1,2-a~pyrrole-1-
carboxylate-7-carboxylic acid,
ethyl 1,2 dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxyl-
ate-7-carboxylic acid,
propyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-
carboxylate 7-caxboxylic acid, and
butyl 1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxyi-
ate-7~carboxylic acid.
EXAMPLE 6
1.054 G. of i~opropyl 1,2-dihydro-~H-pyrrolo-
~1,2-a]pyrrole-1-carbo.Yylate-7-carboxylic acid is heated to
240-250C~in a dry 10 mlO round bottomed flask, distilling
direc~ly the reaction product from the reaction vessel. Xn
this manner there is obtained 745 mg. (87%) o~ isopropyl
lt2-dihydro-3H-pyrrolo[1,2-a]pyrrol~ carboxylate (X, R = H,
R2 = iC3H7), a pale yellow oil , having the ~ollowing
MeOH '
physical constants: U.V.: A max ;~15 nm (~ 6020); I .R.:
CHC13 -1 CDC13
v max 1725 cm ; N.M.R.: ~TMS 1.22 (d, J = 7 Hz, 6H),
-- 29 --
L4131
.
2.40-2.90 ~m, 2H), 3.60-4.20 (m, 2~), 4.65-5.2 ~m, lH),
5.73-5.92 (m, lH), 6.10 (t, J = 3 Hz, lH), 6.43-6.53 (m, lH).
EXAMPLE 7
A 100 ml. 3-necked round bottomed ~lask
equipped with a condenser, ~itrogen inlet tube and a gas
bub~ler is charged with 5.0 g. of isopropyl 1,2-dihydro-3H-
pyrrolo[l,2-a~pyrrole-1-carboxylate-7-carboxylic acid. The
apparatus is thoroughly flushed with nitrogen and then the
nitrogen flow is stopped. The apparatus is immersed in an
oil bath heated at 270C and the reaction is ollowed by the
rate of carbon dioxide evolution (gas bubbler) and by t.l.c.
on silica gel, u ing benzene:dioxan:acetic acid t90:10:1~ as
developing solvent. After 45 minutes the reac~ion is almost
complete. A~ter one hour, the vessel is removed from the oil
; bath and the contents of the reaction flask are transferred
to a round bottomed flask with 500 ml. of acetone. The
solvent is removed under reduced pressure, and the residue
is~purified by column chromatography on 100 g. of sîlica gel.
The fractions eluted with hexane:benzene (70:30) and bexane:
benzene~(SO:S0) afford 2.77 g. (68%) of isopropyl 1,2-di-
~hydro-3H-pyrrolo[1,2-a]pyrrole l-carboxylate (X, R - H,
R a-~ iC3~7), an oil, whose physical constants are identical
` to those obtained in Example 6
EXAMPLE 8
710 Mg. of a 50% suspension o~ sodium
hydride in mineral oil i5 washed with anhydrous h0xane under
an atmosphere of nitrogen, and then suspended in 50 ml. of
dimethylformamide. The suspension is cooled to -5C and
- 30 -
4.5 g. of methyl N-(2-mesyloxyme~hyl)-3~carbomethoxypyrrole-
2-acetate are added, stirring the reaction mixture a~ -5
to O~C for 1 hour. It is then poured into iced sodium
chlcride solution and extracted several times with benzene.
The combined extracts are washed with water, dried and
evaporated to dryness under xeduced pressure. The solid
residue is crystallized from ether, thus obtaining dimethyl
1,2-dihydro-3~-pyrrolotl,2-a]pyrrole-1,7-dicarboxylate
(VII, R = H) identical to the produc~ obtained in Example 4;
EXAMPLE 9
A solution o~ 232.5 mg. of N,N dimethylthio-
phene-2-carboxamide and 0.15 ml. of phosphorous oxychloride
in 2 ml. of 1,2-dichloroethane is re~luxed for 30 minutes.
To this solution is add~d a solution of 181 mg. of isopropyl
1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carhoxylate in 2 ml.
of 1,2-dichloroethane. The reaction mixture is refluxed
under an argo~ atmosphere ~or 8 hours, treated with 450 mg.
of sodium acetate and refluxed for a further 5 hours. The
resultant mixtuxe is then evaporated to dryness and the
residue is chromatogr~phed on 12 g. of silica gel, eluting
wi~h hexane:ethyl acetate (3:1), thus obtaining isopropyl
5-(2-~henoyl)-1~2-dihydro 3~-pyrrolo[1,2-a]pyrrole=~1-carboxyl-
ate (XI, R and Rl = H, R = iC3H7, X = S).
; EX~MP~E 10 A
: :~ A solution of 300 mg. of isopropyl 5-(2-
the~oyl) 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate
.~
in 30 ml. of 50~ aqueou9 methanol containing 1% of potassium
hydroxide is refluxed under an atmosphere o~ nitrogen ~or 2
hours~ The methanol is then removed under redused pressure
- 31 -
' " ' ' . " ~
and t~e basic solution which remains is diluted with water
and extracted with chloroform to remove any unsaponifiable
product. The aqueous alkaline phase is acidified with 20~
hydrochloric acid and extractad three times with e-thyl ace-
tate. The com~ined extracts are dxied over sodium sul~ate
and evaporated to dryness under reduced pressure, thus ob-
taining 250 mg. of crude 5-(2-thenoyl)--1,2-dihydro-3H-pyrrolo-
~1,2-a]pyrrole-1-carboxylic acid, [(A), R and Rl = ~, X - S~,
having a melting point of 145-148C, which upon recrystalliza-
tion from ethyl acetate melts at 152-153C, with decomposi-
tion.
EXAMæLE 10 B-l -
410 Mg. o~ 5-(2-thenoyl)-1,2-dihydro-3~-
pyrrolo-[1,2-a]pyrrol0-l-carboxylic acid and 212.3 mg. of (d)-
; amphetamine are dissolved in 15 ml. of absolute methanol and
heated at reflux for 15 minutes, followed by removal of the
me~hanol u~der vacuum. The resulting diastereoisomeric-(d)-
amphetamine salt mixture (612.3 mg.) is dissolved in a mini-
mum volume of hot (55C) acetone, cooled ko room temperature,
filtered and washed with 2 ml. of cold (-10C) acetone. ThiC
recrystallization procedure was repeated three additional
times to yield 247 mg. of (1)-5-(2-thenoyl)-1,2-dihydxo-3H
pyrrolo-[1,2-a]pyrrole-1-carboxylic acid-(d)-amphetamine salt
having an ~ HC13 -181.3 and a melting point of 168 170C.
The (l)-acid isomer~(d)-amphetami~e salt,
ob ained immediately above, is added ~o 30 ml. of methylene
chloride and shaken three times with 1~ ml. of O.lN a~ueous
hydrochloric acid. The methylene chloride solution is washed
` 30 three times with 15 ml. of saturated sodium chloride/waker
; - 32 -
` " ` ~. `
(2:1/V:V) and dried over anhydrous sodium sulfate. Fil-
tration and r~noval of the organic solvent under vacuum
yields 90 mg. of (1)-5-2-(thenoyl)-1,2-dihydro-3H-pyrrolo-
[1,2-a]pyrrole-1-carboxylic acid, which has an ~ HC13 -1i7
and a melting point of 134-135.5C.
The acetone mother liquors resulting
from the resolution (i.e., the multiple crystallizations) of
the diastereoisomeric-(d)-amphet~nine salt mixture, descxibed
1o above, are combined and converted, using the hydrochloric
acid cleavage procedure as described above, to yield 245 mg.
of a mixture enriched in ~d)-5-(2-thenoyl)-1,2-dihydro-3H-
pyrrolo-~1,2-a]pyrrole-1-carboxylic acid and con~aini~g (1)-
5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-car-
is boxylic acid. This mixture is racemized (recycled) back to
~ a 1:1 mixture of the (d)-and (l)-isomers of 5-(2-thenoyl)-
- - 1,2-dihydro-3~-pyrrolo-~1,2-a]pyrrole-1-car~oxylic acid as
follows: The 245 mg. of the mixture enriched in the (d)-
isomer and containing the (l)-isomer J described above, is
dissolved in 15 ml. of methanol. 1.5 Ml. of me~hanol and
350 mg. of sodi~n hydroxide are added and the solution is
heated at re~lux, under nitrogen, for one hour. The metha-
nol is removed under vacuum, 2.5 ml. of water is added and
the solution acidified to pH 2 with 10~ aqueous hydrochloric
acid. ~he mixture is extracted with three 10 ml. portions
; of methylene chloride and the methylene chloride extrac~s
are combined and back-washed to neu~rality (pH 7~, dried
ov~r anhydrous ~odium sulfate and concentrated in vacuo to
~yield 230 mg. of a crude crystalline product, which upon
recry~alliza~ion from ethyl acetate-hexane yields 180 ms-
,: ~
. ~ .,
- 33 -
of 5-(2-thenoyl)~1,2-dihydro-3H~pyrrolo-~1,2-a]pyrrole-
l-carboxylic acid having an aDMeH 0 0 and a melting point
o~ 152~-154C.
In like man~er other (d)-optically
active bases may be substituted ~or (d)-amphe~amine in the
above process. Particularly ~uitable are:
(d)-p-bromo a-phenethylamine,
- (d)-a-phenethylamine,
(d~--l-naphthethylamine, and
(d)-a-2-naphthethylamine,
wi~h (d)-p-bromo-a-phenethylamine being mast preferred after
(d)-amphetamine.
Similarly, the (d)-acid isomers e.g.,
- (d)-5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-~1,2-a~pyrrole-1-
carboxylic acid, are obtained by substituting th~ (l)-opti-
cally active bases for the (d)-optically active bases~ e.g.,
the suhstitution of (l)-amphétamine for (d)-amphetamine.
- EXAMPLE 10 B-2
To a solution of 118 mg. of 5-~2-
thenoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxylic
acid in 8 ml. of dry benzene, 0.234 g. of trifluoroacetic
~nhydride is added. The mixture is stirred at room temper-
ature for 10 minutes and the resulting solution is cooled
to 0-5C and 0.55 g o~ dry triethylamine is added, ~ollowed
immediately by the addition of 0.2 g o (l)-~-phenyl ethyl
alcohol. The thus-obtained xeaction solution is stirred
at room temperature for 15 minutes and poured into 20 ml.
of watex containing 1 ml. of triethylamine, ~ollowed by
- 30 extraction with ethyl acetate. The ethyl acetate extract
is dried over sodium sulfate, ~ollowed by removal of the
i'
- 34
solvent and excess (l)-a-phPnyl ethyl alcohol under vacuum
to yield 0.166 g.of a mixture of (1)~5-12-thenoyl)-1,2-
dihydro-3H-pyrrolo-[l~2-a]pyrrole-l-carboxylic acid-(l)-a-
phenethyl ester and (d)-5 (2-thenoyl)-1,2-dihydro-3H-pyrrolo-
~1,2-a]pyrrole-l-carhoxylic acid-(l)-a-phenethyl ester which
is separated by high pressure liquid chromatography (using
4% EtOAc/hexane on a 11 mm. x 50 cm., 10~m. Lichrosorb
Sl-60 column) to give 68 mg. of a more polar ester (aMeH
-149.1) and 73 mg. ~f a les~ polar ester (aDIeOH +105.2).
62.1 Mg. o~ the more polar ester is
dissolved in 3 ml. of dry benzene. The solution is cooled
to 15-20C and 2.5 ml. of tri~luoroacetic acid is added and
the solution stirred at room temperature for 1 hour and 40
minutes. The reaction solution is poured into 6G ml. o~
dry benzene and the solvents are removed under vacuum and
at ambient temperature. Purification is effected by high
pressure liquid chromatography (using a column as that
described above, except that 35~ EtOAc/hexane in 1/2~ acetic
acid is substituted fox 4% EtOAc/hexane) to give 41 mg. (1)-
5-(2-thenoyl)-1,2 dihydro-3~-pyrroIo-[1,2 a]pyrrole-l-car-
boxylic acid having an aDeH -144, and a melting point of
130-132C.
Similarly, cleavage of the less polar
25~ estex t according to the method described above ~or, the
clea~age of the m'ore polar ester, yields (d)-S-(2-thenoyl)-
1,2-dihydro-3H-pyrrolo~1,2-a]p,yrrole~l-caxboxylic acid
ha~ing an aMeH ~142.4, and a meltiny point of 127-129C.
The thus-obtained (d)-acid isomer may, if desired,be racemized
~ .
~`
- 35 -
(and recycled), according to methods known in ~he art.
Similarly other (dl) compounds may be
converted to their respectlve (l)-isomers and (d)-isomers.
EXAMPLE 11
solution o 336 mg. of isopropyl 5-(2-
thenoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-carboxylate
in 10 ml. of methanol is treated with a solution of 690 mg.
o~ potassium carbonate in 5 ml. o~ water. The reaction mix~
ture is refluxed under nitrogen atmosphere for 2 hou~s,
cooled, and evaporated to dryness. The residue is taken up
in 10 ml. of 10~ aqueous hydrochloric acid and 50 ml. of
water and the resultant mixturè extracted with ethyl acetate
(2 x 50 ml.). The combined extracts are dried over magnesium
; sulfate and evaporated to dryness under reduced pressure.
; Crystallization of the residue from e~hyl acetate affords
5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbo~y-
lic aoid, identical to the product obtained in Example 10A~
- EXAMPLE 12
By following the methods of Examples 6 or 7,
the remaining compounds obtained in Example 5 are conver~ed
respectively into:
methyl 1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1- -
caxboxylate,
ethyl 1~2-dihydro-3H-pyrrolo[l~2-aJpyrrole
ca~boxylate,
propyl 1,2-dihydro-~H-pyrrolo[1,2-a]pyrrole-1
c~rboxylate and
- 36 -
butyl 1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-
carboxylate.
Upon condensation of these compounds with
N,N-dimethylthiophene-2-carboxamide, in accordance ~Jith
the method of Example 9 there are respectively obtained:
methyl 5-~2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylate,
ethyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
Me~H
pyrrole-l-carboxylate, ~max 265, 328 nm (~ 7580, 17780),
propyl 5-t2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylate and
butyl 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylate.
.
EXAMPLE 13
Following the procedure of Ex~mple 9,
using 1.1 to 2 molar equivalents of
~` ~ N,N-dimethylfuran-2-carboxamide,
N,N-~imethyl-3-methylthiophene-2-carboxamide,
N,N-dimethyl-4-methylthiophene-2-carboxamide,
N,N-dimethyl-5-methylthiophene-2-carboxamide,
N,N-dimethyl-4-chlorothiophene-2-carboxamide,
:
NjN-dimet~yl-5-chlorothiophene-2-carboxamide,
N,N-dimethyl-3-bromothiophene-2-carboxamide,
25~ ~ N~N-dimethyl-4-bromothiophene-2-carboxamide~
N,N~dimethyl-5-bromothiophene-2-carboxamide,
N,N-dimethyl-3-methylfuran-2-carboxamide,
N,N-dimethyl-4-methyl~uran-2-carboxamide,
N~,N-dimethyl-S-methylfuran-2-carboxamide,
3~ N,N-dimethyl-3-chlorofuran-2-carboxamide~
. ~ .
'
- - 37 -
N,N-dimethyl~~-chlorofuran-2-carboxamide,
N,N-dimethyl-5-chlorofuran-2-carboxamide,
N,N-dimethyl-4-bromofuran-2-carboxamide and
N,N-di~e-thyl-5-bromofuran-2-carboxamide,
in place of N,N-dimethylthiophene-2-carboxamide, and
- monitoring the course of the reaction by t.l.c., there
are obtainea respectively:
isopropyl 5-(2 ~uroyl)-1,2-dih~dro-3~-pyrrolo[1,2-a]-
pyrrole-l-carboxylate, an oil, having the following
physical constants: - -
MeOH
U.V~ ~max 27S, 332.5 nm (~ 8900, 17800);
CHCl
I.R. vmax 3 1735, 1685, 1605 cm
CDCl
N.M.R~ ~TMS 3 1.23 [d, 6H, J = 6 Hz; (CH3~2CH],
2.60-3.00 (m, 2H), 3.90 (dd, lH, JAX- 6 Hz;
JBX = 7 Hz; H-l), 4.10-4.67 (m, 2H),
4.95 [sept., lH, J = 6 HZ; (CH3)2CH],
6.00 (d, lH, J = 4 Hz; H-7), 6.40 (m, lH~,
7.10 (m, lH), 7.23 (d, lH, J s 4 Hz; H-6),
:: .
7.43 ppm (m, lH);
~.S. m/e 287-~M ),
.
isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-3~-
pyrrolo~l,2-a~pyrrole-1-carboxylate,
isopropyl 5-(4-methyl-2-thenoyl3-1,2-dihydro-3H-
pyrrolo[l,2-~Jpyrrole-l-carboxylate,
isopropyl 5-(5-methyl-2-thenoyl)-1,2-dihydro-3~-
pyrrolo[l,2-a~pyrrol~-1-carboxylate, having a melting
point o~ 82-82.5C,
isopropyl 5~(4~chloro-2-thenoyl-1,2-dihydro-3H
pyrrolo[l,2-a~pyrrole-1-carboxylate,
::
:', . . .
~ - 38 -
.~ .... .
- .. : .,, " , . . .
isopropyl 5-(5-chloro-2-thenoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylate,
isopropyl 5-t3-bromo-2-the~oyl)-1,2-dihydro-3~-
pyrrolo~1,2-a]pyrrole-1-carboxylate,
S isopropyl 5-~4~bromo-2-thenoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a~pyrrole-1-carboxylate,
isopropyl 5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-
pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl-5-(3-methyl-2-furoyl)-1,2-dihydro-3~-
pyrrolo~l,2-a]pyrrole-1-carboxylate,
isGpropyl-5-t4-methyl-2-furoyl)-1,2-dihydro-3H-
pyrrolo[l,2-aJpyrrole l-carboxylate,
isopropyl 5-(5-methyl-2-furoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylate,
isopropyl 5-(3-chloro-2-furoyl)-1,2-dihydro~3H-
pyrrolo[l,2-a]pyrrole-1-carboxylate,
- isopropyl 5-(4-chloro-2-furoyl)-1,2-dihydro~3H-
pyrrolo[l,2-a]pyrrole-1-carboxylate,
isopropyl 5-(5 chloro-2-furoyl)-1,2-dihydro-3H-
pyrrolo~l,2-a]pyrrole-1-carboxylate,
isopropyl 5-(4-bromo-2-furoyl)-1,2-dihydro-3H-
pyrxolo[l,2-a]pyrrole l-carboxyla~e and
isopropyl 5-(5~bromo-2-furoy~ 2-dihydro-3H
pyrrolo[l,2-a]pyrrole-1-carboxylate.
. ~ Upon hydrolysis of the isopropyl ester group,
i~ accordance with the methods of Examples lOA or 11, there
; are o~ai~ed the corresponding free acids, namely:
5-~2~furoyl)-1,2-dlhydro-3~-pyrrolo[1,2-a]pyrrole-1
carboxylic acid, having a melti~g point of 184-184.5C,
:, :
:
: - 39 -
.,, ~
5-(3-methyl-2-thenoyl) 1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrxole-l-carboxylic acid,
5-(4-methyl-2-thenoyl)-1,2.-dihydro-3H-pyrrolo[1,2-a]-
pyrrole 1-carboxylic acid,
5-(5-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyxrole l-car~oxylic acid~ havi~g a melting paint of 169~-170C,
5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid,
5-~5-chloro-2-thenoyl)-1,2-dihydro-3H-pyrro~o[1,2-a]-
` 10 pyrrole-l-carboxylic acid,
5-~3-bromo-2-thenoyl)~1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l~carboxylic acid,
5-(4-bromo-2-thenoyl)-1,2~dihydro-3~-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid,
5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-1-carboxylic acid,
5-(3wmethyl~2-furoyl)-l,Z-dihydro-3H-pyrrolo~1,2-aj-
pyrrole-l-carboxylic a d d,
5 (4-methyl-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l carboxylic acid,
5-(5~methyl-2-furoyl~-1,2-dihydro-3~-pyrrolo[1,2-a]-
pyrrole l-carboxylic acid,
5-(3-chloro-2-furoyl)-1,2~dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid,
5-(4-chloro-2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l carboxylic acid,
5-(5-chloro-2 ~uroyl)-1,2-dihydro~3~-pyrrolo~1,2-a]-
pyrrole-1-car~oxylic acid,
5-(4-bromo~2~furoyl)-1,2-dihydro-3~I-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid, and
- 40 -
5-(5-bromo-2-~uroyl)-1,2-dihydro-3H-pyrrolo~1,2-a]-
pyrrole-l-carboxylic acid.
,
EXAMPLE 14 A
A 250 ml. 3-necked round bottomed flask con-
taining a magnetic stirring bar and ~itted with a calcium
chloride filled drying tube, is charged with 3.36 g. of
ethanolamine, cooled in an ice bath at 0-10C and treated
dropwise, with stirring, wLth 8.7 g. of dimethyl 1,3-acetone-
dicar~o~yl~t~ ethyl 3-carbomethoxymethyl-3-(2'-hydroxyethyl)
amino acrylate (III) forms immediately. When the addition is
~`~ complete, the ice bath is removed a~d 80 ml. of dry aceto-
nitrile is added. The reac~ion mixture is then trcated drop-
wise with 6.75 g. of bromoacetaIdehyde in 20 ml. of aceto~
nitrile and thereafter heated at reflux temperature for 2
; h~urs. The solvent is then removed under reduced pressure
~ ~and Z00 ml. of methanol and 20 g. of silica gel are added to
,
t~e residue. This mixture is evaporatsd to dryness i~ vacuum
~` and placed on top of a column o~ 200 g. of silica gel packed
20 ~ ~ in hexane, eluting the column with hexane:ethyl acetate mix-
tur~s. The fractions eluted witX hexane:ethyl acetate (1:1)
a~ord methyl N-(2-hydroxyethyl)-3-Garbomethoxypyrrole-2-
acetate (IV, R = H) identical to the product obtained in
Example 1.
25~
EXAMP~E 14 B
To a ~olution o~ 6 ml. o~ e~hanolamine in
5 ml. o~ water there i~ added 1.74 g.o~ dimethyl 1,3-acet-
. ~
~- onedicarboxylate. The resultant mixture i~ rapidly cooled to
30 ~ ~ -10C and t~eated dropwise, over a lS minute period, with
: ::
:
- 41 -
:
.
.
stirring, with 1.67 ml. of l-bromoaceto~e, whilst maintain-
ing the reaction mi~ture at a temperature not higher than
40C. When the addition is completed the dark reaction mix-
ture is stirred for an additional hour at room temperature,
and then poured into a mixtura of hydrochloric acid-ice,
saturated with solid sodium chloride and extracted with
ethyl acetate (3 X lO0 ml.). The comhined organic extract
is washed with cold water to neutrality, dried with anhy-
drous sodium sulate and evaporated to dryness under re-
duced pressure. Chromatography of the residue on 30 g.
of silica gel, using hexane: ethyl acetate (70:30) as.eluant,
a~fords 890 mg. o~ crystalline methyl N-(2-hydroxyethyl)-3-
carbomethoxy-4-methylpyrrole-2-acetate which upon recrystal-
lization from methylene chlorlde-hexane melts at 78C and
has the following analysis:
calculated for C12Hl7N5 C, 56-45; H, 6-71
Found: C, 56.41; H, 6.73.
In a similar manner but using a stoichio-
metric egui~alent of l-bromo-2-butanone, 1-bromo-2-pentanone
and l-b~omo-2-hexa~one in place of l-bromoacetone there are
respectively obtained:
methyl N-(2-hydroxye.thyl)-3-carbomethoxy-4-ethyl-
pyrrole-2-acetate,
methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-propyl-
pyrrole-2-acetate and
methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-butyl-
pyrrole-2-acetate.
EXAMPLE 15
By following the method of Example 2, meth~l
. - 42 -
N~(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate
(IV, R = CH3) is converted into methyl N-t2-mesyloxyethyl)-
3-carbomethoxy-4-methylpyrrole 2-acetate and then cyclized
with sodium hydride in ~imethylformamide, in accordance with
the method of Example 8, to a~ord dimethyi 1,2-dihydro-6-
methyl-3H-pyrrolo~1,2-a]pyrrole-1,7-dicarboxyl~te.
Upon hydrolysis of the latter compound with
potassium hydroxide, in accordance with the method of Example
4 followed by selective esterification at C-l and decarboxy-
lation at C-7, in accordance with ~he methods of Examples 5
and 7, respectively, there are successively obtained 1,2-di-
: hydro 6-methyl-3H-pyrrolo~1,2-a]pyrrole~1,7-dicarboxylic
acid, isopropyl 1,2-dihydro-~-methyl-3H-pyrrolo~1,2-a]-
lS pyrrole l-carboxylate-7-car~oxylic acid and isopropyl 1,2-di
hyd.ro 6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (X,
R = C~3, R = iC3H7).
In a similar manner, subsli~ffl i~g ~ chy;
N-~2-hydroxyethyl)-3-carbomatho~y-4-ethylpyrrole-2-acetate,
methyl N-(2-hydroxyethyl~-3-carbomethoxy-4-pro~ylpyrrole-2-
acetate and methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-butyl-
pyrrole-2-acetate for methyl N-(2-hydroxyethyl)-3-carbo-
methoxy-4 methylpyrrole~2 acetate there are respectively
obtained as final products:
isopropyl 1,2-dihydro-6-ethyl-3H-pyrrolotl,2-a]-
pyrrole-l-carboxylate,
isGpropyl l~2-dihydro-~-propyl-;}I-pyrroio~l~2 &J-
pyrrole-l-carboxylate and
: isopropyl 1,2-dihydro-6-butyl-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylate.
~. :
- 43 -
EXA~LE 1 6
In accordance with the method of Example 9,
. ~ isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-
carboxylate is condensed with N,N-dimethylthiophene-2-car-
boxamide to produce isopropyl 5- (2-thenoyl) -1, 2-dihydro-6-
methyl-3H-pyrrolo~1,2-a]pyrrole-1-carbo~ylate (XI, ~ = CH3,
~- Rl = H, R = iC3~7, X - S), haviny a melting point of lOZ.5C.
In a similar manner but using the N,N-di-
methylthiophene- or ~uran-2-carboxamides listed in Example
13 in place of N,N-dimethylthiophene-2-carboxamide, there are
respectively obtained:
isopropyl 5-(2-furoyl)-1,2-dihydro-6-methyl-3H-
; pyrrolo~l,2 a]pyrrole l-carboxylate,
- isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-
3H~pyrrolo[1,2-a]pyrrole-1-carboxylate, .
isopropyl 5-(4-me~hyl-2-thenoyl)-1,2-dihydro-6-methyl-
3H-pyxrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(5-methyl-2-thenoyl)-1,2-dihydro-6-methyl~
: 3H-pyrrolo~1,2-a]pyrrole-1-caxboxylate,
2 isopropyl 5-(4-chloro-2-thenoyl)-1,2-dihydro 6-methyl-
3H-pyrrolo r 1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(5-chloro-2-thenoyl)-1,2-dihydro-6-methyl-
3H-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(3-bromo-2-thenoyl)-1,2-dihydro-6-methyl-
~H-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-~4-bromo-2-thenoyl)-1,2-dihydro-6-methyl-
~-- 3H-pyrrolo[1,2-a]pyrrole l-carboxylate,
isopropyl 5-~S-bromo-2-thenoyl~-1,2-dihydro-6-methyl-
3H-pyrrolo[1,2-a~pyrrole-1-carboxylate,
i~opropyl 5-(3-methyl-2-~uroyl)-1,2-dihydro-6-methyl-
' ~ .
- 44 -
3H-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(4-methyl-2-~uroyl)-1,2-dihydro-6-methyl-
3H-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(5-methyl-Z-furoyl)-1,2-dihydro-6-methyl-
3H=pyrrolo[1,2-a]pyrrole l-carboxylate,
isopropyl 5-(3-chloro-2-furoyl)-1,2-dihydro-6-methyl-
3~-pyrroloC1,2-a]pyrrole-1-carboxylate,
isopxopyl 5-(4~chloro-2-furoyl)-1;2-dihydro-6-methyl-
3~-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(5-chloro-2-furoyl)-1,2-dihydro-6 methyl-
3H-pyrrolo[1,2-a]pyrrole-1-carboxylate,
isopropyl 5-(4-bromo-2-furoyl)-1,2-dihydro-6-methyl-
3H-pyrrolo[1,2-a~pyrrole-1-carboxylate and
i~opropyl 5-~5-bromo-2-furoyl)-1,2-dihydro-6 me~hyl-
3~-pyrrolo~1,2-a~pyrrole-1-carboxylate.
Likewise, the remaining final compounds
obtained in Example 15 are converted into the corresponding
5-furoyl or thenoyl substituted derivativ~s. R~presentative
compounds thus obtained are:
isopropyl 5-(2-thenoyl)-1,2-dihydro-6-ethyl-3H
py~rolotl,2~a]pyrrole~1-carboxy:late,
isopropyl 5-(2-furoyl)-1,2-dihydro-6-propyl-3H-
pyrrolo~1,2-a]pyrrole-l-carboxylate,
isopropyl 5-(3-methyl-2-thenoyl)-1,2-dihydro-6-butyl~
3H-pyrrolo E 1,2 a]pyrxole-1-carboxylate,
isopropyl 5-~4-chloro-2-thenoyl)-1,2-dihydro-6-ethyl-
~H-pyrroloC1,2-a]pyrrol0-l-carboxylate,
isopropyl 5-~5-methyl-2-~uroyl)-1,2-dihydro~6-propyl-
3H-pyrrolo~1,2-a~pyrrole-l~carboxylate and
- 45 -
isopropyl 5-(3-chloro-2-~uroyl) 1,2~dihydro-6-butyl-
3~-pyrrolo[1,2-a]pyrrole-1-carboxylate.
EXAMPLE 17
A solution of SOO mg. of isopropyl 5-(2-
thenoyl)~l,2-dihydro-6-methyl-3H-pyrrolo[1,2-a~pyrrole-1-
carboxylate in 15 ml. o~ methanol is treated with a solution
of 1.05 g. of potassium carbonate in 8 ml. o~ water. The
reaction mixture is refluxed under nitrogen atmosphere for
3 hours, cooled, and evaporat~d to dryness. The residue is
taken up in lO ml. of lO~ aqueous hydrochloric acid and
:50 ml. of water and the resultant mixture extracted with
ethyl ac~tate (3 x 50 ml.). The combined extracts are dried
over mag~esium sulfate and evaporated to dryness undex
reduced pressure, to give 5-(2 thenoyl~-1,2-dihydro-5-methyl~
3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid [~A), R = CH3,
Rl = H, X = S], having a melting point of 166C.
In a similar manner, or alternatively by the
hydrolysis method of Example 10 A, the xemaining isopropyl
ester compounds obtained in Example 16 are converted into the
corresponding free acids, namely:
5-(2-furoyl)-1,2-dihydxo-~-methyl-3H-pyrxolo~1,2-a]-
pyrrole-l-carboxylic acid,
5 (3-methyl-2-thenoyl)-1,2-dihydro-6-methyl-3H-
: 25 pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5~(4-methyl-2~thenoyl)-1,2-dihydro-6-methyl-3H-
. pyrrolo~l,2~a]pyrrole-1-carboxylic acid,
5-~S methyl-2-thenoyl)~-1,2-dihydro-6 methyl-3H-
pyrrolo~l,2-a]pyrrole-1-car~oxylic acid,
; 30 5-~4-chloro-2-.thenoyl)-1,2-dihydro-6-methyl-3H-
.
- 46 -
pyrrolo~l,2-a]pyrrole-1-carboxylic acid,
5-(5-chloro-2-thenoyl)-1,2-dihydro-6-methyl-3H-
pyrrolo[1,2-a]pyrrole~ carboxylic acid,
5-(3-bromo-2-thenoyl)-1,2-dihydro-6-methyl-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(4-bromo-2-~henoyl)-1,2-dihydro-6-methyl-3~1-
: pyrrolo[l,2-a~pyrrole-1-carboxylic acid,
5-(5-bromo-2-thenoyl)-1,2-dihydro-6-methyl-3~-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(3-methyl-2-~uroyl)-1,2~dihydro-6~methyl-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(4-methyl-2-furoyl)-1,2-dihydro 6-methyl-3H-
pyrrolo[l,2-aJpyrrole-l-carboxylic acid,
5 t5-methyl-2-furoyl)-1,2-dihydro-5 methyl-3H-
pyrrolo[1,2-a]pyrrole-1-carboxylic acid,
5-(3-chloro-2-furoyl)-1,2-dihydro-6-methyl~3H-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(4-chloro-2-furoyl)~1,2-dihydro-6-methyl-3~-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(5-chloro-2-furoyl)-1,2-dihydrG-6-m~thyl-3H-
pyrrolo[l,2-a~pyrrole-l~carboxylic acid,
5-(4-bromo-2-furoyl)-1,2-dihydro-6-methyl-3H-
pyrxolotl,2-a]pyrrole-1-carboxylic acid,
: 5-(5-bromo-2-fuxoyl)-1,2-dihydro-6-methyl-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5--(2-thenoyl)-1,2 dihydro-6-ethyl-3H-pyrrolo~1,2-a]-
: pyrrole-l-carboxylic acid,
~:: 5-(2-~uroyl)-1,2-dihydro-6-propyl-3H-pyrrolo[1,2~a]-
pyrrole-l-carboxylic acid,
~ .
~ , .
- 47 -
~, . ..
- : ,
5-(3-methyl-2-thenoyl)-1,2-dihydro-6-butyl~3~-
pyrrolo~l,2-a]pyrrole-l~carboxylic acid,
5-(4-chloro-2-thenoyl)-1,2-dihydro-6-ethyl-3~-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid,
5-(S-methyl-2-furoyl)~1,2-dihydro-6-propyl~3H-
pyrrolo~l,2-a]pyrrole-1-carboxylic acid and
5-(3-chloro-2-~uroyl)~1,2~dihydro~6-hutyl-3H-
pyrrolo[l,2-a]pyrrole-1-carboxylic acid.
.,
BXAMPLE lt3
A solution of 232.5 mg. of N,N-dimethylthio-
phene-3-carboxamide and 0.15 ml. of phosphororus oxychloride
in 2 ml . o~ 1,2-dichloroethane is refluxed for 30 minutes.
To this solution is added a solution of 181 mg. of isopropyl
1,2-dihydro-3~-pyrrolol1,2-a]pyrrole-1-carboxylat~ in 2 ml.
of 1,2-dichloroethane~ The reaction mixture is refluxed
under an aryon atmosphere for 8 hours, treated with 450 mg.
of sodium aceta~e and refluxed for a further 5 hours. The
resultant mixture is then.evaporated to dryness and the
residue is chromatographed on 12 g. o~ silica gel, eluting
wi~h hexane:ethyl acetate (3:1), thus ob~aining isopropyl
5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1
carboxylate (XII, ~ = H, R2 = iC3H7, X = S).
In a ~imilar manner isopropyl 1,2-dihydro-
6-methyl-3H-pyrrolotl,2-a]pyrrole-1-carboxylate and isopropyl
1,2 dihydro-6-propyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate
are converted re~pectively into i~opropyl 5-(3-thenoyl)-1,2-
dihydro-6-methyl-3~-pyrrolo~1,2-a]pyrrole-1-carboxylate and
i~opropyl 5-(3-thenoyl)-1,2-dihydro-6-propyl-3H-pyrrolo-
30 . ~1,2-aipyrrole-1-carboxylate.
- 48 -
v
~ y the same me~hod, substitu~ing N,M-di-
methylfuran-3-carboxamide for N,N-dimethylthiophene-3-
carboxamide there are obtained the corresponding 5-(3-fur~yl)
derivatives, namely:
isopropyl 5-(3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-1-carboxylate, an oil, ha~lng the ~ollowing ~hysical
constants~
U.V. ~MaeH 222, 244-277 (shoulder), 314 nm
(~ 6750, 4250, 14800);
I.R~ Vm~aXC13 1730, 1610, 1560 cm 1;
N.M.R. ~CMDcl3 1.23 [d, 6H, J = 6 ~z; (CH3)2CH],
2.50-3.00 (m, 2H)~ 3.92 (dd, 2~, J~X = 6 Hz,
JBX = 7 ~7 H-l~, 4.10-4.60 (m, 2~), 4.95
[sept., 1~, J = 6 Hz; (C~3)2CH], 5-95 (d~ lH~
J = 4 ~æ; H-7), 6.78 (m, 1~), 6.83 (d, lH,
J = 4 Hz; ~-6), 7.30 (m, lH), 7.83 ppm (m, lH);
M.S. m/e 270 (M ),
~ isopropyl 5-(3-furoyl)-1,2-dihydro-6-methyl-3H-
: 2~ pyrrolo[1,2-a]pyrrole-l-carboxylate a~d
: isopropyl 5~(3-furoyl~-1,2-dihydro-6-propyl-3H-
py~rolo[1,2-a]pyrrole-l carboxylate.
, ~ .
EXAMPLE l9
A:.solution o~ 300 mg. o isopropyl 5~(3-
the~oyl)-1,2-dihydro-3H-p~rrolo~ -a]pyrrole-l-carboxylate
in 30 ml. o~ 50% agueous me hanol containing 1~ of potassium
hydroxide i9 re~luxed under an atmosphere of nitrogen for 2
~^ hours. The methanol is then removed under reduced pressur~
and the ~as~c solution which remains is diluted with water
~' .
- 49 -
:
and extracted with chloroform to remo~e any unsaponifiable
produ~t. The aqueous alkaline phase is acidiied with 20~
hydrochloric acid and extracted three times with ethyl ace-
tate. The combined extracts are dried over sodium sulfate
and evaporated to dryness under reduced pressure, thus ob-
taining 250 mg. of crude 5-~3-thenoyl)-1,2-dihydro-3H-
pyrrolo~l,2-a]pyrrole-1 carbo~ylic acid, [(B), R = H, X - S].
By the ~ame method, the remaining compounds
obtained in Example 18 are converted into the free acids,
namely:
5-(3-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]~
pyrrole-l-carboxylic acid,
5-(3-thenoyl3-1,2-dihydro-6-propyl-3H-pyrrolo[1,2-a~-
; pyrrole-l-carboxylic acid,
5-(~-~uroyl)-1,2-dihydro-3H-pyrroloEl,2-a]pyrrole-1
carboxylic acid, having a melting point of 156~C,
5-(3-furoyl)-1,2~dihydro-6-methyl-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid and
5-(3-furoyl)-1,2-dihydro-6-propyl-3H-pyrrolo~1,2-a]-
pyrrole l-carboxylic acid.
EXAMRLE 20
A solution of 200 mg. of 5-(2-furoyl~-1,2-
dihydro-3H-pyrrolo~1,2-a]pyrrole-l~carboxylic acid in 5 ml.
o~ dichloromethane is treated with an excess o~ ethereal di-
azomethane, and the reaction mixture is mai~tained at room
temperature for 30 minutes. The solvents and excess reayent
are eliminated under reduced pressu~e and the residue cry~-
tallized from ethyl acetate-methanol, to yield methyl 5-
~2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-~carbo~ylate.
- 50 -
.4~
Likewise but using diazoethane and diazo-
propane is place of diazomethane there are respectively
obtained ethyl 5-(2-furoyl)-1,2-dihydro-3H~pyrrolo~1,2~a]
pyrrole~ arboxylate and propyl 5-(2-~uroyl)-1,2~dihydro-3H~
pyrrolo~l,2-a]pyrrole-1 carboxylate.
In a similar manner, the remaining free
acids obtained in Ex2mples 10 A, 10 B-l (and 10 B~2), 13
and the acids of Examples 17 and 19 are converted into the
corresponding methyl, eth~l and propyl esters. Representa-
tive compounds thus-obtained are:
methyl 5-(2-thenoyl)-1~2-dihydro-3H-pyrrolo-[1,2-a]
pyrrole-l-carboxylate,
e~hyl 5-(2-thenoyl)-l,2-dihydro-3H-pyrrolo-tl~2-a]
; pyrrole-1-carboxylate,
. propyl 5-(2-~henoyl)-1,2-dihydro-3H-pyrrolo-[1,2~a]
pyrrole-l-carboxylate, and
the methyl ethyl and propyl Psters o~ 5-(Z-thenoyl)-1,2-
dihydro-3H~pyrrolo-~1,2-a]pyrrole~l-carboxylic acid.
~XAMP~E 21
A ~olution of 300 mg. of 5-(2-theno~1)-1,2-
dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml.
of isoamyl alcohol is saturated with hydrogen chloride.
After 24 hours, the excess alcohol is distilled off in vacuum
and the residue purified by chromatography on alumina to
yield isoamyl 5-(2-the~oyl)-1,2-dihydro-~H-pyrrololl,2-a]
pyrrole-l-carboxyl~e.
Likowise other esters, e.g., pentyl, hexyl,
: octyl, nonyl, dodecyl and the like, of 5-(2-thenoyl)-1,2-
:` :
- 51 -
. . . . . . .
dihydro-3~-pyrrolo[1,2-a]pyrrole~l-carboxylic acid ar~
obtained by substituting other alcohol~, e.g., pentyl, hexyl,
octyl~ nonyl, dodecyl alcohol and the like, for lsoamyl
alcohol.
: 5
By the same method the free acid compounds
obtained in Examples 10 B-l, 13, 17 and 19 æe esterified
with the appropriate alcohol to produce the corresponding
asters, e.g.,
isoamyl 5-(2-furoyl~-1,2-dihydro-3R-pyrrolo[1,2-al-
pyrrole~l-carboxyiate,
pentyl 5-(4-methyl-2-thenoyl~-1,2-dihydro-3H-pyrrolo-
- [1,2-a~pyrrole-1-carboxylate,
hexyl 5-(5-chloro~2~thenoyl)-1,2-dihydro-3H-pyrrolo-
~1,2-a]pyrrole-1-carboxylate,
isoamyl 5-(4-bromo-2-thenoyl)-1,2-dihydro-3H-pyrrolo-
tl~2-a]pyrrole-l-carboxylate~
ccty~ 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-car~oxylate,
. nonyl 5-(3-methyl-2-furoyl)-1,2-dihydro--~H-pyrrolo
a]pyrrole-l-carboxylate,
dodecyl 5-(3-chloro-2-furoyl)-1,2-dihydro-3H-pyrrolo-
[1,2-a~pyrrole-1-carboxylate,
hexyl 5 (4-chloro-2-thenoyl)-1,2-dihydro-6-methyl-3H-
:~ pyrrolo~lr2-a]pyrrole-1-carboxylate,
isoamyl 5-(2-thenoyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-
11,2-a]pyrrole-1-carboxylate and
octyl S-(3-f~royl)-1,2-dihydro-3H-pyrrolo~1,2-a~-
~ .
- 52 -
pyrrole-l-carboxy~ate.
EXAMPLE 22
To a solution of 300 mg. of 5-~2-thenoyl)-
1,2-dihydro-3H-pyrrolo[1,2-alpyrrole-1-car~oxylic acid in
S ml. o~ methanol is added 1 molar equivalent o~ sodium
hydroxide, in the form o~ a O.lN solu~ion. The solvent is
then evaporated under reduced pre~sure and the residue taken
; up in 2 ml. of methanol, followed by precipitation with ether,
to yield crude sodium 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-
Zl,2-a]pyrrola-1-carbo~late which can be crystalli~ed from
isopropanol~
Likewise other salts, e.g., ammonium and po
tassium,of 5-[2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2 a]-
pyrrole-l-carboxylic acid are prepared by substituting am-
monium hydroxide and pota~sium hydroxide for sodium hydroxyde.
In a similar manner, the 5-substituted 1,2-
dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid compounds
obtained in Examples 10 B-l (and 10 B-2) 13, 17 and 19 can be
converted into the correspo~di~g sodium, potassium a~d ammonium
salts.
Representative compound~ thus obtained are:
sodium ~ 5-~2-thenoyl)-1,2-dihydro-3H-pyrrolo-
[1,2-a]pyrrole--1-carboxylate,
sodium 5-~2-~uroyl)-1,2-dihydro-3H-pyrrolo[1,2-a]
pyrrole-1-carboxylate,
sodium 5-(4-methyl-2-thenoyl)~1,2-dihydro-3H-pyrrolo-
~1,2-a]pyrrole~l~carboxylate,
; potassium 5-(4-chloro-2-thenoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a~pyrrole-l~carboxylate,
,
~ 53 -
potassium 5-(5-bromo-2-thenoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a]pyrxole-1-carboxylate,
sodium 5-(3-methyl~2-furoyl)-1,2-dihydro-3H-pyrrolo-
~1, 2-a] pyrrole-l-carboxylate,
ammonium 5-(2-furoyl)-1,2-dihydro-3H-pyrrolo[1,2~a]-
pyrrole-l-carboxylate,
ammonium 5-~3-chloro-2-furoyl)-1,2-dihydxo 3H-
pyrrololl,2-a]pyrrole-1-carboxylate,
sodium 5-~4-mathyl-~-thenoyl)-1,2-dihydro-6-ethyl-3~-
pyrrolo[l,2-a]pyrrole-1-carboxylate,
potassium 5-~5-chloro;2-thenoyl)~1,2-dihydro-6-methyl-
3H-pyrrolo~1,2-a]pyrrole-1-carboxylate,
ammonium 5-~3~thenoyl)-1,2-dihydro 3~-pyrrolo~1,2-a]-
pyrrole-lrcarboxylate and
sodium 5-~3-furoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
~ pyrrole-l-car~oxylate.
,~;
EXAMPLE 23
To a solution of 237 mg. o 5-(2-thenoyl)-
~ 1,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid in
8~ml. of methanol is added 1 molar equivalent of potassium
hydroxide, in the form of a O.lN solution to yield a solu~
tion containing potassium 5-(2~thenoyl)-1,2-dihydro-3H-
pyrrolo~l,2-a]pyrrole-1-carboxyla e. A solution o~ 50 mg.
of~alciu~ carbon~te dissolved in the minimum amount o~ lN
hydrochlorLc acid necessary to eect solut~on o the
calcium carbonate, is bufered with lOO mg. of solid a~nonium
chloride, followed ~y the further addition of S ml. of water.
The thus o~tained bu~ered calcium solution is then added to
30; the 501ution 0~ potassium 5-~2-thenoyl)-1,2-dihydro-3H-
~::
~ : :
` ~ - 54 -
:
. ~ .. .
:: :
pyrrolo[l,2-a]pyrrole-1-carboxylate and the precipitate which
forms is collected by filtration, washed with water and air
dried, to yield calcium 5-~2-thenoyl)-1,2-dihydro-3~-pyrrolo~
[1,2-a~pyrrole~l-carboxylate.
~ 5 Likewise magnesium 5-(2-thenoyl)-1,2 dihydro-
`~ 3H-pyrrolo[1,2 a]pyrrole~l-carboxylat~ is prepared by subs-
tituting magnesium carbonate for calcium carbonate.
Similarly~ by substituting
5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-[1,2-aJp~rrole-
l-carboxylic acid,
5-(2-furoyl)-1,2-dihydro-3~-pyrrolo[1,2-a]pyrrole-1-
carboyxlic acid,
5-(4-chloro~2 thenoyl)-1,2-dihydro-3H-pyrrolo~1,2-a]-
pyrrole-l-carboxylic acid,
~` 5-(3-methyl-2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-
pyrrole-l-carboxylic acid,
` 5-(5-bromo-2-furoyl)-1,2-dihydro-6-methyl-3H-pyrrolo-
[1,2-a]pyrrole-1-carboxylic acid, and
5-(3 chloro-2-~uroyl)~1,2-dihydro-6-ethyl-3H-pyxrolo-
1,2 a]pyrrole-1-carbo~ylic acid, for 5-(2-thenoyl)-1,2-
dihydro-3~-pyrrolo~1,2-a]pyrrole-l~carboxylic acid there are
obtained ~he corresponding calcillm and magnesium salts~
.
EXAMPLE 24
To a solution of 237 mg. of 5-~2-thenoyl)
- I,2-dihydro-3H-pyrrolo~1,2-a]pyrrole-1-carboxylic acid in
8 ml. o methanol i added 1 molar equivalent o~ potassium
hydroxide, in the form of a O.lN solution. The solvent is
stripped and the residue i~ dissolved in 5 ml. o~ water. The
'
~hus obtained aqueous solution of po~assium 5-~2-thenoyl~-
1,2-dihydro 3~-pyrrolo[1,2-a]pyrrole l-carboxylate is added
to a solution o~ 110 mg. of cupric nitrate trihydrate in 5 ml.
of water. The formed precipitate is collected, washed with
water and air dried, thus obtaining copper 5-(2-thenoyl)-1,2-
dihydro-3H-pyrrolo~1,2-a]pyrrole-l~carboxylate.
In a similar manner the free acid compounds
obtained in ~xamples 10 B-l (and 10 B-2~, 13, 17 and 19 can
be converted into the corresponding copper salt-q.
EXAMPLE 25
A solution of 27 mg. of 5-(2-thenoyl)-l,Z-
dihydro-3H-pyrrolo[1,2~a]pyrrole-1-carboxylic acid in 15 ml.
of hot benzene is treated with 59 mg. of isopropylamine.
The solution is allowed to cool to room temperature and the
pxoduct filtered o~f, washed with ether and dried,to yield
the isopropylamine salt of 5-(2-thenoyl)-1,2-dihydro-3H-
pyrrolo[l,2-a]pyrrole-l~carboxylic acid.
Likewise other amine salts, e.g., diethyl-
amine, ethanolamine, piperidine, tromethamine, choline and
caffeine salts of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo-
- 11,2-aJpyrrole-l-carboxylic acid are prepared by su~s~itut- -
ing each of the respective amines for isopropylamine~
In similar manner the free acid compounds
obt~ined in Examples 10 B-l (or 10 ~-2), 13, 17 and l9 can be
converted into the corre~ponding isopropylamine, diethylamine,
ethanol~mine, pipqridine, tromethamine, choline and caffeine
; ~alts.
:
'
- 56 -
EXAMPLE 26
nqredientsQuantity_per tablet, mgs.
5-(2 thenoyl)-1,2-dihydro-
3~-pyrrolo-~1,2-a]pyrrole-
l-carboxylic acid25
cornstarch ~o
lactose, spray-dried 153
magnesium stearate 2
The above ingredients are thoroughly mixed
and pressed into single scored tablets.
.
EX~MPLE 27
IngredientsQuantity per tablet, mgs.
5-(2-thenoyl)-1,2 dihydro-
3H-pyrrolo-[1,2-a]pyrrole-
; l-carboxylic acid 200
cornstarch 50
lactose 145
; magnesium stearate 5
The abo~e ingredients are mixed intimately
and pressed into single scored tablets.
100 ~g. o~ -5~(2-thenoyl)-1,2-dihydro-3H-pyrr
olc~[l,2-a~pyrrole-1-carboxylic acid is substituted for the
200 mg- of the (dl) compound of the above composition.
_~
i
,
~ 30
; - 57 - -
4~
EXAMPLE: 2 8
In~redients Quantity per capsule, mgs.
potassitlm S- (2-thenoyl) -
1, 2-dihydro- 3H-pyrrolo-
11, 2-a] pyrrole l-car-
bc~xylal:e 108
lactose 15
cornstarch 25
- magnesium stearate 2
The above ingredients are mixed and intro-
duced into a hard-shell gelatin capsule.
~XAMPLE 29
Tn~rf~ nt~sQllantit~v per capsttJ.e, mgs~
calcium 5- ( 2-thenoyl) -
1, 2-dihydro-3X-pyrrolo-
[1,2-a]pyrrole-1-car-
boxyl Ite 115
lactose 93
cornstarch 4
magnesium s tearate 2
The above ingredients are mixed and intro-
deced into a hard-shell galatin capsule.
.._
~', /
. '
/~
/
~ .
~ ~ .
:`
~ 58 --
EXAMPLE 30
In~redientsQuanti_~ E~ let ! mgs.
isopropylammonium 5-(2-
thenoyl)-1,2-dihydro-3H-
pyrrolo-[1,2-a]pyxrole-
l-carboxylate 245
cornstarch 75
lactose 175
magnesium stearate 5
The above ingredients are.mixed intimately
- and pr ssed into single scored tablats~
EXAMPLE 31
Quantitv per ca~sule, mgs.
methyl 5-(2-thenoyl)-1,2-
dihydro-3~-pyrrolo-[1/2-a]
pyrrole l-carboxylate 25
lactose 125
The above ingredients are mixed and intro-
duced into a ~o. 1 hard-shell gelatin capsule.
EXAMPLE 32
Qua~tity per tablet, m~s.
5-(2-thenoyl)-1,2-dihydro-
3~-pyrrolo-[1,2-a]pyrrole-
l-carboxylic acid 300
sucrose 300
; The above ingredients are thoroughly mixed
and processed into single scored tablets, one tablet being
administer~d every three to four hours.
3~
`'
- 59 -
.. . .
.: , , ,, :
EX~MPLE 33
IngredientsQuant_~c~ tablet, m~s.
isoamyl 5-(2-thenoyl)-1,2-
dihydro-3~-pyrrolo-[1,2-a]
pyrrole-l-carboxyla~e 254
cornstarch 50
lactose 190
magnesium stearate Ç
The above ingredients are mixed intimately
and pressed into single scored tablets.
'10
EXAMPLE 34
IngredientsQuantity per capsule, mgis.
5-(2)-the~oyl-1,2-dihydro-
~-~ 3H-pyrrolo-~1,2-a]pyrrole-
1 l-c2rboxylic acid 100
lactose 148
- dextrose 2
~: The above ingredients aremixed and intxo-
duced into a hard-shell gelatin capsule.
50 Mg. of (1)-5-(2-thenoyl)-1,2-dinydro-
3~-pyrroloo~1,2-a]pyrrole-1-carboxylic acid is substituted
for the lOOmg. o~ the ~dl) compound of thie above composi-
tion.
: 25 .
~, /
~.
, ~ ,
, ~ .
: - 60 -
..
EXAMPLE 35
InqredientsQuantity per capsule, m~s.
- methyl 5-(2-thenoyl)-1,2-
dihydro-3H-pyrrolo~[1,2-a]
pyrrole-l-carboxylate158
: lactose 92
The above ingredients are mixed and intro-
duced into a hard-shell gelatin capsule.
EXAMPT~ 36
IngredientsQuantity_~er tablet, mgs
isoamyl 5-(2-thenoyl)-1,2-
dihydro-3H-pyrrolo-[1,2-a]
pyrrole-l carboxylate 127
lactose 91
corn~tarch 25
magnesium stearate. 2
gelatin 5
The above inyredients are mixed and pressed
into single ~cored tablets.
.
- 61-
.
~X~MPL~ 37
In~redientsQuantity per tablet, mys.
calcium 5-(2-thenoyl)-l,2-
dihydro-311-pyrrolo-[l,2~a]
pyrrole-l-carboxylate 230
cornstarch (paste)40
cornstarch 50
magnesium stearate2
lactose 178
The above ingredients are ~horol~ghly mixed
and pressed into single scored tablets.
EX~MPLE 38
InqredientsQuantit~_eer tablet, mgs
potassium 5-(2-thenoyl)-l,.2-
dihydro-3H-pyrrolo-~l,2-a]
pyrrole-l carboxylate 217
cornstarch 50
magnesium stearate 2
gelatin 226
lactose
Tn,e above ingredients a~e mixed intimately
and pressed into single scored tablets.
.. ..... ....
//
,: 25 , ~
- : /
~
~ 62 -
l4~
EXAMPLE 39
Ingredients Quantity per c~
isopropylammonium 5-(2-
thenoyl) -1, 2-dihydro-3H-
: pyrrolo-~1,2 a]pyrrole-
l-carboxylate 122
cornstarch 3 o
lactose 98
The above ingredients are mixed and
introduced into a hard-shell gelatin capsule.
1~
EXA~PLE 40
?ngredientsQuantity per capsule, mqs.
isoamyl 5- ( 2-thenoyl) -1, 2-
dihydro-3EI-pyrrolo- ~1, 2-a]
pyrrole-l carboxylate32
lactose 101
cornstarch 15
mag~esium stearate 2
.
The above ingredients are mixed and intro-
duced into a hard-shell gela~in capsule.
`---~
, / .
~' ' /
~ : ~ 25
.~ ~
' /
: `: :
~. 30
.
~ - 63 -
o~
EXAMPLE 41
An injectable preparation buffered to a
- p~ of 7 is prepaxed having the followirlg composition:
5-(2-thenoyl)-1,2-dihydro-
3~-pyrrolo-[1,2-a3pyrrole-
l-carboxylic acid 0.2 g
K2ElPO4 bu~fer (0.4 M
solution) 2 ml.
KOH (lN) q.s. to p~7
water (distilled sterile) q.s. to 20 m}.
0.1 G. of (1)-5-(2-thenoyl)-1,2-dihydro-
3H-pyrralo-[1,2-a~pyrrole~l-carboxylic acid is ubstituted
for the 0.2g. of the (dl) compound of the above composi-
tion.
EX~MPLE 42
A suppo~itory totaling 2.8 grams is pre-
pared having the ~ollowing composition:
5-(2-~henoyL)-1,2-di~ydro-
3H-pyrxolo-[1,2-a]pyrrole-
l~carboxylic acid 25 mg.
Witsps~l ~-15
(triglycerides of satu-
rated vegetable ~atty
acids; a product of
Richeq-Nelso~, Inc.,
New York, N.Y.) balance
~ 12.5 ~g. of (1)-5-(2-thenoyl)-1,2-dihydro-
3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid is substituted
for the 25 mg. of the (dl) cornpound of the above compo-
sition.
~X~PLE 43
An oral su~pensio~ for pediatric use is
prepared having the following composition.
- 64 -
5-(2-thenoyl)-1,2-
dihydro~3H-pyrrolo-
[1,2-a]pyrrole-1-car-
boxylic acid O~l g~
~- fumaric acid 0.5 g~
sodium chloride 2.0 g.
methyl paraben 0.1 g~
granulated sugar 25.5 g.
sorbitol ~70% solution) 12.85 g.
.- Veegum K (Vanderbilt Co.) 1.0 g.
fla~orins 0.035 ml.
colorings 0.5 mg.
distilled water ~.s. to 100 ml.
0.05 G. o (1)-5-(2-thenoyl)-1,2-dihydro-
3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid i5 sub~tituted
for the 0.1 g. of the (dl) compound of ~he above compo-
~; sition.
. ~ :
:
EX~PLES 44-45
Powdered top dressings for veterinary uie
are prepared having the ~ollowing compositions:
~. i
Ex. 44 Ex. 45
5-(2-thenoyl)-1,2-dihydro-
3~-pyrrolo-[1,2-a]pyrrole-
l-carboxylic ac-d 0.1 g. 1,2 g.
` :25 suc~ose 5.7 g. 3.7 gO
polyvinyl pyrrolidone 0.3 g. 0.3 g.
0.05 G. o~ 5-(2-thenoyl)-1,2-dihydro-
3H-pyrrolo-~1,2-a]pyrrole-1-carboxylic acid i~ substituted
~or the 0.1 g. of the (dl) compound of the compo~ition of
Example 44.
0.6 G. of (1) 5-~2-thenoyl)-1,2-dihydro-
::
~ ~5 -
-
~ [l 2-alpyrrole- = acid ~s sub tltUt d
.- .
. .
EXA~PLE 46
BIODATA
A. Mouse Analgesic (Anti-writhing) Assay
Protocol: The test material is administered orally
S by gavage in an a~ueous vehicle at time 0 to 18 20 gram male
Swiss~Nebster mice. Twenty minutes later 0.25 ml. o~ a
0.02% solution of phenylquinone i9 injected intraperitoneallyO
This solution induces writhing. The animals are then observed
during the next 10 minutes for writhing.~
End point: The total number o~ mice that writhe and
the average number of writhes per mouse.
Using The above protocol i.t is determin~d tha-~ 5-(2-
thenoyl~-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic
acid has approximately 350 times the analgetic activity of
aspirin; and
~ 5-(2-thenoyl)-1,2-dihydro-3~-pyrrol~[1,2-a]
pyrrole-l-carboxylic acid has 670 times the analgetic acti-
vity o~ aspixin.
B. Test ~or A~i-Infl = atory Activity Utilizing Carra-
. . .
~geenin Indu~ed Paw Inflammation in the Rat
Protocol: Simonsen ~emale rats weighing 80-90 grams
:
are used. The test materials are given at hour 0 orally by
gavage in l ml.~ of aqueous vehicle. At hour 1, 0.05 ml. of
a l~;soIution (in 0.9~ NaCl) of carrageenin is injected into
the right hind pawO This injection causes an inflammation
o~ the paw. The~ rats are sacrificed at hour 4, at which time
both hind paws are removed and weighed separately.
End point: % increase in paw size calculated as
follows:
~ ~30 Wt O~ Le~tpPaw-Wt. o~ Left Paw X l00
; -6~-
;
; Using ~he above protocol it is determined that 5-
(2-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-car-
boxylic acid has 48 (95~ confidence limits:32-72) times the
anti~inflammatory activity of phenylbutazone.
- 5 C. Test for Anti-Pyretic Activity
Protocol: Simonsen ~emale rats weighing 90-100 grams
- are used. The "normal" rectal ~emperature of the rats i5
recorded at hour 0, followed by the injection of 2 ml. of a
- yeast suspension subcutaneously (1 ml. dorsally, 1 ml. ven-
trally). The injectio~ sites are massaged to spread the
suspenion beneath the skin. The yeast injec~ion induces
elevated body temperature (pyresis). At hour 17 the rats
-; are massaged again to stimulate a further increase in body
temperature. At hour 18 the second rectal temperature is
recorded, after which the test material is administered
- orally by gavage in 1 ml. aqueous ~ehicle. The third rectal
temperature is obtained 2 hours after administration of the
test material.
End point: The reduction in temperature (F) from
~ the second to the third temperature readings.
Using ~he above protocol it is determi~ed that 5-
(~2-thenoyl)-1,2~dihydro-3H-pyrrolo[1,2-aJpyrrole-l-carbox-
- ylic acid has 17 times the anti-pyretic activity of aspirin.
D. ~ouse Acute Oral Toxicity (LD50)
Pxotocol: The test material is suspended in 2%
agueous starch. Concentration~ are adjusted so t~at doses
can be given in volumes of 0.1 ml./10 g. body weight. Six
groups (comprising six Swiss-Webster ~emale mice in each
group) of rnice are used. A single oral dose, by stomach
tube, per kilogram of body weight, of either 50 mg., 100 mg.,
-66B-
200 mg., 400 mg., 800 mg., or 16Q0 mg. of 5-(2-thenoyl)-1,2-
dihydxo-3~-pyrrolo[1,2-a~pyr~ole-1-c æboxylic acid is ad-
ministered to the mice. A~ter adminictration the mice are
- observed 4Or a two week period.
Using ~he above prot w ol, the acute oral LD50 of 5-
~2-thenoyl)~1,2-dihydro-3~-pyrrolo~1,2-a~pyrrole-1-carboxylic
acid is esti~ated to be 631 mg./kg. with a 95% confidence
e~ of~4~0~,4~,!tu;99~
,
- : , : , .,, :
- . ~ . . ...
:'.
:
