Guanidine derivatives

The invention concerns novel guanidine derivatives of the general formula (I) ##STR1## or pharmaceutically acceptable acid addition salts thereof, where.circle.Nrepresents ##STR2## wherein R.sup.1 and R.sup.2 each represent hydrogen, lower alkyl, trifluoromethyl or halogen and R.sup.11 and R.sup.12 each represent hydrogen, lower alkyl, trifluoromethyl or halogen with the proviso that when one or both R.sup.11 or R.sup.12 groups represent halogen then R.sup.1 and R.sup.2 each represent lower alkyl, trifluoromethyl or halogen, R.sup.9 and R.sup.10 each represent hydrogen, lower alkyl or trifluoromethyl and R.sup.13 and R.sup.14 each represent hydrogen, lower alkyl, trifuoromethyl or halogen with the proviso that when one or both R.sup.13 and R.sup.14 groups represent halogen then R.sup.9 and R.sup.10 each represent lower alkyl or trifluoromethyl and R.sup.7 and R.sup.8 each represent hydrogen or lower alkyl and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 each represent hydrogen or lower alkyl or R.sup.4 and R.sup.6 are each hydrogen and R.sup.3 and R.sup.5 together represent dimethylene or trimethylene. The guanidine derivatives lower blood pressure in warm-blooded animals.

This invention relates to novel guanidine derivatives, to processes for 
their preparation and to pharmaceutical compositions containing them. 
The novel compounds of the present invention are guanidine derivatives of 
the general formula (I) 
##STR3## 
or pharmaceutically acceptable acid addition salts thereof, where 
##STR4## 
wherein R.sup.1 and R.sup.2 which may be the same or different each 
represent hydrogen, lower alkyl, the trifluoromethyl or halogen and 
R.sup.11 and R.sup.12 which may be the same or different each represent 
hydrogen, lower alkyl trifluoromethyl or halogen with the proviso that 
when one or both R.sup.11 or R.sup.12 groups represent halogen then 
R.sup.1 and R.sup.2 each represent lower alkyl, trifluoromethyl or 
halogen, R.sup.9 and R.sup.10 which may be the same or different each 
represents hydrogen, lower alkyl or trifluoromethyl and R.sup.13 and 
R.sup.14 which may be the same or different each represents hydrogen, 
lower alkyl, trifluoromethyl or halogen with the proviso that when one or 
both R.sup.13 and R.sup.14 groups represent halogen then R.sup.9 and 
R.sup.10 each represent lower alkyl or trifluoromethyl and R.sup.7 and 
R.sup.8 are the same or different and each represent hydrogen or lower 
alkyl and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are the same or different 
and each represent hydrogen or lower alkyl or R.sup.4 and R.sup.6 are each 
hydrogen and R.sup.3 and R.sup.5 together represent dimethylene or 
trimethylene such that 
##STR5## 
The term "lower" as used herein means that the radical referred to contains 
1 to 6 carbon atoms. Preferably the radical contains 1 to 4 carbon atoms. 
The compounds of the invention in which 
##STR6## 
has the meaning (a) are pyrrole derivatives. Thus in one aspect the 
present invention provides pyrrole derivatives of general formula (II) 
##STR7## 
and pharmaceutically acceptable acid addition salts, thereof, wherein 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, 
R.sup.11 and R.sup.12 the meanings given above. In connection with formula 
(II), R.sup.1 and R.sup.2 can be hydrogen, lower alkyl (eg. methyl ethyl, 
propyl or butyl), trifluoromethyl or halogen (e.g. chlorine or bromine). 
Preferably R.sup.1 and R.sup.2 are both the same; for example they may be 
both methyl. R.sup.11 and R.sup.12 can be hydrogen, lower alkyl (e.g. 
methyl, ethyl, propyl or butyl) or trifluoromethyl. R.sup.11 and R.sup.12 
can also be halogen (eg. chlorine or bromine) when neither R.sup.1 and 
R.sup.2 is hydrogen. Preferably both R.sup.11 and R.sup.12 are hydrogen. 
The compounds of the invention in which 
##STR8## 
has meaning (b) and (c) are respectively 2,5-dihydro-1H-pyrrol-1-yl and 
pyrrolidinyl-1-yl derivatives. Thus in a further aspect the invention 
provides 2,5-dihydro-1H-pyrrol-1-yl derivatives of general formula (III) 
below and pyrrolidinyl-1-yl derivatives of general formula (IV) below and 
their pharmaceutically acceptable acid addition salts: 
##STR9## 
In formulae (III) and (IV) R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, 
R.sup.8, R.sup.9, R.sup.10 and R.sup.13 and R.sup.14 have the meanings 
given above. Thus R.sup.9 and R.sup.10 are hydrogen, trifluoromethyl or 
lower alkyl (eg methyl), ethyl, propyl or butyl). Preferably R.sup.9 and 
R.sup.10 are both the same; for example they may be both methyl. R.sup.13 
and R.sup.14 can be hydrogen, lower alkyl (eg. methyl, ethyl, propyl or 
butyl) or trifluoromethyl. R.sup.13 and R.sup.14 can also be halogen (eg. 
chlorine or bromine) when neither R.sup.9 nor R.sup.10 is hydrogen. 
Preferably both R.sup.13 and R.sup.14 are hydrogen. 
In general formula (I), (II), (III) and (IV) when any of R.sup.3, R.sup.4, 
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are lower alkyl they can be, for 
example, methyl, ethyl, propyl or butyl. Preferably each group R.sup.3, 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 is hydrogen. 
Although the compounds of the invention have been shown in general formulae 
(I), (II) and (IV) as existing in the acylimino form it is possible that 
the compounds exist in other tautomeric forms or mixtures of such forms. 
For example, possible structures of the compounds in which R.sup.3, 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are all hydrogen include 
the acylamino structure (Ia) 
##STR10## 
and the enol forms (Ib), (Ic) or (Id) 
##STR11## 
Where in this specification there is used a name or formula implying any 
particular tautomeric form it is to be understood that the name or formula 
includes any of the other alternatives forms or a mixture of such forms. 
The compounds of the invention may contain one or more asymmetric carbon 
atoms and hence can exist in more than one isomeric form. Such forms can 
be obtained or separated by standard procedures. For example, the 
compounds of general formula (III) and (IV) in which R.sup.9 and R.sup.10 
are both trifluoromethyl or identical lower alkyl groups can exist in cis 
or trans forms. Either the cis or the trans form can be obtained by 
suitable choice of starting material in the processes hereinafter 
described. The trans form will normally be obtained as a racemate of the 
d- and l- enantiomorphs which can be separated by standard methods of 
resolution if desired. The compounds of general formula (III) and (IV) in 
which R.sup.13 and R.sup.14 are both hydrogen and R.sup.9 and R.sup.10 are 
different lower alkyl groups or one is trifluoromethyl and the other lower 
alkyl contain two asymmetric carbon atoms and hence can exist in four 
optically active forms. Normally the compounds are prepared in the form of 
racemates which can, if desired, be resolved by standard methods. 
Compounds of general formula (III) and (IV) in which R.sup.13 and R.sup.14 
are both hydrogen and in which one of R.sup.9 and R.sup.10 is lower alkyl 
and the other is hydrogen contain one asymmetric carbon atom and hence 
such compounds may be in the form of the optically active enantiomers or 
as mixtures of enantiomers, e.g. racemates. If desired, the racemates may 
be resolved by standard methods described in the literature. A further 
asymmetric carbon atom occurs in compounds of formula (IV) in which 
R.sup.13 or R.sup.14 is other than hydrogen. 
The compounds of the invention can be prepared by a process in which a 
reactive derivative of an acid of general formula (V) 
##STR12## 
(where 
##STR13## 
R.sup.7 and R.sup.8 have the meanings given above) or an acid addition 
salt thereof is reacted with a guanidine of the formula 
##STR14## 
(where R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each hydrogen or lower 
alkyl) or with 2-amino-imidazoline or 
2-amino-1,4,5,6-tetrahydropyrimidine. 
A possible reactive derivative of the acid of general formula (V) is the 
acid chloride but a preferred reactive derivative is an ester, in 
particular an ester of general formula (Va), 
##STR15## 
(wherein 
##STR16## 
R.sup.7 and R.sup.8 are as defined above and R is a lower alkyl, e.g. 
methyl or ethyl), or an acid addition salt thereof. 
The reactive derivatives of the acid of general formula (V) may be prepared 
in a manner known for preparing analogous compounds. For example the 
pyrrole derivatives of general formula (V) [ 
##STR17## 
has meaning (a)] can be prepared by the method disclosed in German 
Offenlengunsscrift No. 2,312,006. The pyrrole derivatives can also be 
prepared by an alternative method in which a dicarbonyl compound of 
general formula 
##STR18## 
(where R.sup.1 and R.sup.2 are each hydrogen, trifluoromethyl or lower 
alkyl and R.sup.11 and R.sup.12 are each hydrogen, trifluoromethyl or 
lower alkyl) or a functional derivative thereof is reacted with a lower 
alkyl ester of an amino acid of formula NH.sub.2 CR.sup.7 R.sup.8 COOH, 
e.g. a lower alkyl ester of glycine or alanine. When R.sup.1 and R.sup.2 
are both hydrogen the functional derivative of the compound of general 
formula (IV) may be a 2,5-dialkoxytetrahydrofuran of general formula 
##STR19## 
In order to prepare a pyrrole derivative of general formula (Va) in which 
at least one of the R.sup.1, R.sup.2, R.sup.11 and R.sup.13 groups is 
halogen the corresponding compound in which the group is hydrogen may be 
halogenated. For example the compound can be halogenated with sulphuryl 
chloride. By suitable choice of, and proportions of, reactants it is 
possible to halogenate in the 2 and/or 5-position and also in the 3 and/or 
4-position. If the starting material contains trifluoromethyl or lower 
alkyl substituents in the 2 and 5-position then halogenation will occur in 
the 3 and/or 4-positions. 
The 2,5-dihydro-1H-pyrrol-1-yl derivatives [ 
##STR20## 
has meaning (b)] of general formula (Va) can be prepared, for example, by 
alkylating a dihydropyrrole of general formula 
##STR21## 
(where R.sup.9, R.sup.10, R.sup.13 and R.sup.14 have the meanings given 
above with a haloacid of general formula 
EQU X CR.sup.7 R.sup.8 COOR 
(where R, R.sup.7 and R.sup.8 are as defined above and X is halo, 
preferably bromo or chloro). The starting materials of general formula 
(IX) are known compounds or may be prepared in a manner known for 
preparing analogous compounds, for example, by reduction (eg. with zinc 
and hydrochloric acid of a corresponding pyrrole of general formula (X) 
##STR22## 
(where R.sup.1, R.sup.2, R.sup.11 and R.sup.12 are as defined above). 
The pyrrolidinyl-1-yl derivatives [ 
##STR23## 
has meaning (c)] of general formula (Va) may be prepared, for example, 
from the corresponding 2,5-dihydro-1H-pyrrol-1-yl derivatives, e.g. by 
catalytic hydrogenation. Alternatively a 2,5-dihydro-1H-pyrrol-1-yl 
derivative of general formula (Va) in which R.sup.13 and R.sup.14 are both 
hydrogen may be treated with halogen or a hydrogen halide to give a 
pyrrolidinyl-1-yl derivative of formula (Va) in which R.sup.13 and/or 
R.sup.14 is halogen. 
Once an ester of the acid of general formula (V) or its acid addition salt 
has been prepared this may be converted into other reactive derivatives of 
the acid by standard procedures. For example, the ester of formula (Va) 
may be hydrolysed to the acid which, in turn may be reacted with thionyl 
chloride to give the acid chloride. 
The compounds of general formula (I) in which R.sup.3, R.sup.4, R.sup.5 and 
R.sup.6 are each hydrogen or lower alkyl and R.sup.7 and R.sup.8 are both 
hydrogen may be prepared by an alternative procedure which comprises 
hydrolysing a compound of general formula 
##STR24## 
where 
##STR25## 
has the meaning defined in claim 1 and R.sup.3, R.sup.4, R.sup.5 and 
R.sup.6 are each hydrogen or lower alkyl and, if desired, converting a 
resulting base of general formula (I) into a pharmaceutically acceptable 
salt thereof. 
The compounds of general formula (XIV) may be prepared by formylation (eg. 
by reaction with ethyl formate) of a nitrile of general formula (XI) 
##STR26## 
(where 
##STR27## 
is as defined above) followed by condensation of the resulting 
.alpha.-formyl compound with a guanidine of formula (VI). The nitriles of 
formula (XI) may be prepared by reaction of an alkali metal salt (eg. the 
potassium salt) of the pyrrole, dihydropyrrole or pyrrolidine of general 
formula 
##STR28## 
(where 
##STR29## 
is as defined above) with chloracetonitrile. An alternative method of 
preparing the nitriles of general formula (XI) comprises halogenating (eg 
with sulphuryl chloride) a nitrile of formula (XI) in which 
##STR30## 
represents 
##STR31## 
to give the corresponding 2,5-dihalo-nitrile compound. Alternatively the 
corresponding 2,5-di(lower)alkyl or di(trifluoromethyl) nitrile compound 
can be halogenated in the 3 and 4-positions. The nitrile compound of 
formula (XI) in which 
##STR32## 
represents 
##STR33## 
(where R.sup.9 and R.sup.10 are as defined above and R.sup.13 and R.sup.14 
are halogen can be prepared by reduction (eg. with zinc and hydrochloric 
acid) of the corresponding pyrrole derivatives. The nitrile compound of 
formula (XI) in which 
##STR34## 
represents 
##STR35## 
(in which R.sup.9 and R.sup.10 are as defined above and R.sup.13 and 
R.sup.14 are halogen) can be prepared by halogenation of the nitrile 
compound in which 
##STR36## 
represents 
##STR37## 
The compounds of the invention in which R.sup.3 is hydrogen and R.sup.4, 
R.sup.5 and R.sup.6 are each hydrogen or lower alkyl may be prepared by a 
further method which comprises reacting an isothiourea derivative of 
general formula (VII) 
##STR38## 
(where 
##STR39## 
R.sup.7 and R.sup.8 are as defined in claim 1, R.sup.4 is hydrogen or 
lower alkyl and R.sup.15 is lower alkyl preferably methyl) with ammonia or 
an amine of formula 
EQU NHR.sup.5 R.sup.6 (XII) 
(where R.sup.5 and R.sup.6 are each hydrogen or lower alkyl), and, if 
desired, converting a resulting base into a pharmaceutically acceptable 
salt thereof. 
The isothioureas of general formula (VII) may be prepared by reacting an 
acyl chloride of general formula 
##STR40## 
(where 
##STR41## 
R.sup.7 and R.sup.8 are as defined above) with a 
S-(lower)alkylisothiourea, particularly S-methylisothiourea. 
The compounds of the invention in which R.sup.3 and R.sup.4 are both 
hydrogen and R.sup.5 and R.sup.6 are each hydrogen or or lower alkyl can 
be prepared by a still further method which comprises reacting an 
acylcyanamide of general formula (VIII) 
##STR42## 
(where 
##STR43## 
R.sup.7 and R.sup.8 are as defined above) with ammonia or amine of general 
formula (XII) above and, if desired, converting a resulting base into a 
pharmaceutically acceptable acid addition salt thereof. The acylcyanamides 
of general formula (VIII) may be prepared by condensing an acyl chloride 
of formula (XIII) above with an alkaline metal or alkaline earth metal 
salt of cyanamide, eg. sodium or calcium cyanamide. 
Compounds of the invention in which 
##STR44## 
represents 
##STR45## 
and in which R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are hydrogen may be 
prepared by a still further method which comprises condensing a 
dihydropyrrole or pyrrolidine of general formula 
##STR46## 
where 
##STR47## 
represents 
##STR48## 
(where R.sup.9, R.sup.10, R.sup.13 and R.sup.14 are as defined above with 
a haloacetylguanidine of general formula 
##STR49## 
(where R.sup.7 and R.sup.8 are as defined above and Hal is chlorine or 
bromine) and, if desired, converting a resulting base of general formula 
(I) into a pharmaceutically acceptable acid addition salt thereof. 
The compounds of the invention in which 
##STR50## 
represents 
##STR51## 
can be prepared by a still further process which comprises catalytically 
hydrogenating the compounds of the invention in which 
##STR52## 
represents 
##STR53## 
If in any of the processes described above the compound of the invention is 
obtained as an acid addition salt, the free base can be obtained by 
basifying a solution of the acid addition salt. Conversely if the compound 
of the invention is obtained as a free base in any of the above processes 
a pharmaceutically acceptable acid addition salt may be obtained by 
dissolving the free base in a suitable organic solvent and treating the 
solution with an acid, in accordance with conventional procedures for 
preparing acid addition salts from base compounds. Examples of acid 
addition salts include those formed from inorganic and organic acids such 
as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, 
maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic 
acids. The compounds of the invention lower blood pressure as indicated by 
standard hypotensive or antihypertensive pharmacological procedures. For 
example, N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide, a 
representative compound of the invention, when administered to 
normotensive anaesthetised rats produced a fall of diastolic blood 
pressure of at least 30 mm Hg at 15 minutes after administration at 
dosages of less than 2 mg/kg in duplicate experiments. The compound also 
lowered the blood pressure of hypertensive rats when administered at 5 
mg/kg per os. The compounds of the invention also possess hyperglycaemic 
activity as determined by a procedure in which the compounds are 
administered to normal male rats and blood samples are analysed for blood 
sugar prior to administration of the compound and at hourly intervals 
after administration. Hyperglycaemic agents can be of use for 
administration to patients who have too low a blood sugar concentration 
following, for example, administration of too large a dose of a 
hypoglycaemic agent such as insulin. Hyperglycaemic agents can also be 
used to produce hyperglycaemic animals which can be used in screening for 
hypoglycaemic compounds in pharmacological procedures. 
Some of the compounds of the invention are also anti-ulcer agents which 
possess anti-secretory activity in the test of H. Shay, D. Sun and H. 
Greenstein, Gastroenterology, 1954, 26, 903-13. Compounds which possess 
anti-secretory activity are exemplified by 
N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide, 
N-diaminomethylene-(2,5-dichloro-1H-pyrrol-1-yl)acetamide and 
N-diaminomethylene-(trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetamid 
e. For example, 
N-diaminomethylene-(trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetamid 
e, shows potent antisecretory activity in the test of Shay et al at dosages 
as low as at least 5 mg/kg intraduodenally as indicated by the following 
results: 
______________________________________ 
% decrease 
Dose volume of conc. amount 
mg/kg gastric of of free 
total 
Compound (i-duod.) 
contents acid acid acid 
______________________________________ 
N-diamino- 
methylene-(trans- 
2,5-dihydro-2, 
5-dimethyl-1H- 
pyrrol-1-yl) 
acetamide 5 72 39 79 72 
______________________________________ 
The invention includes a pharmaceutical composition comprising a compound 
of general formula (I) or a pharmaceutically acceptable salt thereof in 
association with a pharmaceutically acceptable carrier. Any suitable 
carrier known in the art can be used to prepare the pharmaceutical 
compositions. In such a composition, the carrier may be a solid, liquid or 
mixture of a solid and a liquid. Solid form compositions include powders, 
tablets and capsules. A solid carrier can be one or more substances which 
may also act as flavouring agents, lubricants, solubilisers, suspending 
agents, binders, or tablet-disintegrating agents; it can also be an 
encapsulating material. In powders the carrier is a finely divided solid 
which is in admixture with the finely divided active ingredient. In 
tablets the active ingredient is mixed with a carrier having the necessary 
binding properties in suitable proportions and compacted in the shape and 
size desired. The powders and tablets preferably contain from 5 to 99, 
preferably 10-80% of the active ingredient. Suitable solid carriers are 
magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, 
dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium 
carboxymethyl cellulose, a low melting wax, and cocoa butter. The term 
"composition" is intended to include the formulation of an active 
ingredient with encapsulating material as carrier to give a capsule in 
which the active ingredient (with or without other carriers) is surrounded 
by the carrier, which is thus in association with it. Similarly cachets 
are included. 
Sterile liquid form compositions include sterile solutions, suspensions, 
emulsions, syrups and elixirs. The active ingredient can be dissolved or 
suspended in a pharmaceutically acceptable sterile liquid carrier, such as 
sterile water, sterile organic solvent or a mixture of both. Preferably a 
liquid carrier is one suitable for parenteral injection. Where the active 
ingredient is sufficiently soluble it can be dissolved in normal saline as 
a carrier; if it is too insoluble for this it can often be dissolved in a 
suitable organic solvent, for instance aqueous propylene glycol or 
polyethylene glycol solutions. Aqueous propylene glycol containing from 10 
to 75% of the glycol by weight is generally suitable. In other instances 
compositions can be made by dispersing the finely-divided active 
ingredient in aqueous starch or sodium carboxymethyl cellulose solution, 
or in a suitable oil, for instance arachis oil. Liquid pharmaceutical 
compositions which are sterile solutions or suspensions can be utilized by 
intramuscular, intraperitoneal or subcutaneous injection. In many 
instances a compound is orally active and can be administered orally 
either in liquid or solid composition form. 
Preferably the pharmaceutical composition is in unit dosage form, e.g. as 
tablets or capsules. In such form, the composition is sub-divided in unit 
doses containing appropriate quantities of the active ingredient; the unit 
dosage form can be a packaged compositions, the package containing 
specific quantities of compositions, for example packeted powders or vials 
or ampoules. The unit dosage form can be a capsule, cachet or tablet 
itself, or it can be the appropriate number of any of these in package 
form. The quantity of active ingredient in a unit dose of composition may 
be varied or adjusted from 5mg. or less to 500 or more, according to the 
particular need and the activity of the active ingredient. The invention 
also includes the compounds in the absence of carrier where the compounds 
are in unit dosage form. 
Pharmaceutical compositions containing compounds of the invention 
possessing antisecretory activity may be administered as anti-ulcer 
compositions. Those compositions may be administered orally in liquid or 
solid composition form and such compositions may include one or more 
antacid ingredients, e.g. aluminium hydroxide, magnesium hydroxide, 
bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium 
trisilicate, sodium bicarbonate or the alumina gel described in U.K. 
Patent Specification No. 1,284,394. 
The following Examples illustrate the invention and the preparation of 
intermediate compounds:

EXAMPLE 1 
Methyl (2,5-dimethyl-1H-pyrrol-1-yl)acetate 
A solution of hexan-2,5-dione (23 g.), glycine methyl ester hydrochloride 
(25 g.), and sodium acetate (16 g.) in acetic acid (100 cm.sup.3) was 
heated under reflux for 1 hour. The mixture was then poured into water, 
extracted with ether, and the ethereal phase washed with sodium carbonate 
solution, dried, and evaporated to yield a brown oil. The product was then 
distilled under vacuum to give methyl (2,5-dimethyl-1H-pyrrol-1-yl)acetate 
as a colourless oil which crystallised on standing. (22.1 g.) b.p. 
123.degree.-129.degree. C./15 mm, m.p. 44.degree.-46.degree. C. 
EXAMPLE 2 
N-Diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl)acetamide 
A solution of guanidine hydrochloride (5.7 g.) and sodium ethoxide (1.15 g. 
of sodium) in dry ethanol (60 cm.sup.3) was stirred at room temperature 
for 1 hour. The precipitated sodium chloride was removed by filtration and 
washed with ethanol (10 ml.). Methyl (2,5-dimethyl-1H-pyrrol-1-yl) acetate 
(8.4 g.) was added to the combined filtrate and washing obtained above and 
the solution stoppered and stirred for 3.5 h., then cooled in ice and the 
precipitated solid collected by filtration. Crystallisation from ethanol, 
with filtration to remove insoluble impurities, gave 
N-diaminomethylene-(2,5-dimethyl-1H-pyrrol-1-yl) acetamide as straw 
coloured plates (6 g.) m.p. 198.5.degree.-200.degree. C. The hydrochloride 
(m.p. 228.degree.-230.degree. C.) was precipitated from warm ethanol on 
treatment with ethanolic hydrogen chloride. 
EXAMPLE 3 
N-Diaminomethylene-1H-pyrrole-1-yl acetamide 
A solution of guanidine hydrochloride (2.85 g.) and sodium ethoxide (from 
0.6 g. of sodium) in dry ethanol (30 cm.sup.3) was stirred at room 
temperature for 1 hour. The precipitated sodium chloride was removed by 
filtration and washed with ethanol (5 cm.sup.3). Methyl 
1H-pyrrol-1-ylacetate (3.5 g.) was added to the combined filtrate and 
washings obtained above and the solution stoppered and stirred for 3.5 
hours, then cooled in ice and the precipitated product collected by 
filtration. Crystallization from methanol gave the title compound as white 
needles (1.8 g.) m.p. 213.5.degree.-214.degree. C. The hydrochloride m.p. 
200.degree.-201.degree. C., was precipitated from a solution of the base 
in ethanol by addition of ethanolic hydrogen chloride. 
EXAMPLE 4 
Methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate 
A solution of sulphuryl chloride (10.8 g.) in dry ether (20 cm.sup.3) was 
added dropwise to a stirred solution of methyl 1H-pyrrol-1ylacetate (5.6 
g.) in dry ether (20 cm.sup.3) maintained below 0.degree. C. After 
addition was complete the reaction was stirred for a further 0.5 hour, 
without external cooling. Water and ether were then added, the ethereal 
phase was separated, washed with sodium carbonate solution, dried and 
evaporated. The residual oil was then distilled under vacuum to give 
methyl(2,5-dichloro-1H-pyrrol-1-yl)acetate as a light yellow oil (5.2 g.) 
b.p. 120.degree.-121.degree. C./15 mm. 
EXAMPLE 5 
N-Diaminomethylene-(2,5-dichloro-1H-pyrrol-1-yl)acetamide 
A solution of guanidine hydrochloride (2.85 g) and sodium ethoxide (from 
0.6 g. of sodium) in dry ethanol (30 cm.sup.3) was stirred at room 
temperature for 1 hour. The precipitated sodium chloride was removed by 
filtration and washed with ethanol (5 cm.sup.3). Methyl 
(2,5-dichloro-1H-pyrrol-2-yl)acetate (5.2 g) was added to the combined 
filtrate and washings obtained above and the solution stoppered and 
stirred for 3.5 hours, then cooled in ice and the precipitated title 
compound collected by filtration (2.3 g) m.p. 223.degree.-225.degree. C. 
The filtrate was evaporated and the residue crystallised from a mixture of 
ethanol (5 cm.sup.3) and water (5 cm.sup.3) to give further title product 
(1 g.) m.p. 223.5.degree.-225.degree. C. The hydrochloride of the title 
compound m.p. 204.degree.-205.degree. C., was precipitated from a solution 
of the base in ethanol by addition of ethanolic hydrogen chloride. 
EXAMPLE 6 
Methyl (trans-2,5-dihydro-2,5-dimethyl-1 H-pyrrol-1-yl)acetate 
Methyl bromoacetate (16.8 g, 0.11 mol) was added, dropwise, to a stirred 
mixture of 2,5-dimethyl-3-pyrroline (10 g, 0.1 mol), potassium carbonate 
(13.8 g, 0.1 mol), and dimethylformamide (25 cm.sup.3) maintained below 
30.degree. C. by ice cooling. After addition was complete the mixture was 
cooled in ice for a further 1 h, then stirred at room temperature 
overnight. The reaction mixture was then diluted with water (50 cm.sup.3) 
and the product extracted into ether. The ether extract was dried and 
evaporated to yield an oil* which was distilled under vacuum to give 
methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (7 g) b.p. 
89.degree.-92.degree. C./15 mm. 
FNT * G.l.c. shows this to contain a mixture of the cis and trans isomers in 
the ratio 1:3. The cis isomer could not be obtained pure from this 
distillation, but a sample was isolated by preparative g.l.c. 
EXAMPLE 7 
N-Diaminomethylene-(trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetamide 
A solution of guanidine hydrochloride (2.3 g, 0.024 mol) and sodium 
ethoxide (from 0.55 g, 0.024 mol of sodium) in absolute ethanol (24 
cm.sup.3) was stirred at room temperature for 1 h. The precipitated sodium 
chloride was removed by filtration and washed with ethanol (4 cm.sup.3). 
Methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (3.4 g, 0.02 
mol from Example 6) was added to the combined filtrate and washings 
obtained above and the solution stoppered and stirred for 18 h. The 
reaction mixture was then evaporated and the residue crystallised from 
ethanol to give the product (1.25 g). The base was suspended in ethanol 
and acidified the ethanolic hydrogen chloride, the clear solution thus 
obtained was diluted with ethyl acetate and concentrated by evaporation to 
precipitate the title compound as the dihydrochloride (1.6 g.), m.p. 
210.degree.-211.degree. C.(d). 
EXAMPLE 8 
2,5-Dichloro-N-(2-imidazolidinylidene)-1H-pyrrole-1-acetamide 
Methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate (2.08 g.) was added to a 
solution of 2-aminoimidazoline hydroiodide (3.2 g.) and sodium ethoxide 
(from 0.35 g. of sodium) in ethanol (10 cm.sup.3). The solution was 
stirred at room temperature for 3 hr. and the precipitated title product 
collected by filtration (1.9 g.) m.p. 225.degree.-227.degree. C. The base 
was suspended in ethanol (25 cm.sup.3) and acidified with ethanolic 
hydrogen chloride to give the hydrochloride of the title compound (1.9 g.) 
m.p. 225.degree. C.(d). 
EXAMPLE 9 
Ethyl 2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propionate 
Ethyl 2-bromopropionate (9.8 g.) was added, dropwise, to a stirred mixture 
of trans-2,5-dimethyl-3-pyrroline (5 g.), potassium carbonate (6.9 g.), 
and dimethylformamide (12.5 cm.sup.3) maintained below 30.degree. C. by 
external cooling. After addition was complete the mixture was stirred at 
room temperature overnight. The mixture was then diluted with water (25 
cm.sup.3) and the product extracted into ether. The ether extract was 
dried and evaporated to give an oil which was distilled under vacuum to 
give ethyl 2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propionate 
(2.5 g.) b.p. 90.degree.-97.degree. C./15 mm. 
EXAMPLE 10 
N-Diaminomethylene-2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propion 
amide 
A solution of guanidine hydrochloride (2.0 g.) and sodium ethoxide (from 
0.46 g. of sodium) in ethanol (12.5 cm.sup.3) was stirred at room 
temperature for 1 h. The precipitated sodium chloride was removed by 
filtration and washed with ethanol (5 cm.sup.3). Ethyl 
2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl) propionate (2.5 g.) was 
added to the combined filtrate and washings obtained above and the 
solution allowed to stand overnight. The reaction mixture was then 
evaporated and the residue partitioned between water (5 cm.sup.3) and 
ether (10 cm.sup.3). On cooling the crystalline title product separated, 
was collected by filtration, and washed with water and ether. The product 
was suspended in isopropyl alcohol and acidified with ethanolic hydrogen 
chloride to give the title compound as the dihydrochloride (0.5 g.) m.p. 
206.degree.-206.5.degree. C. 
EXAMPLE 11 
Methyl (2,3,4,5-tetrachloro-1H-pyrrol-1-yl)acetate 
A solution of sulphuryl chloride (5.4 g.) in dichloromethane (5 cm.sup.3) 
was added, dropwise, to a stirred solution of methyl 
(1H-pyrrol-1-yl)acetate (1.39 g.) in dichloromethane (5 cm.sup.3) 
maintained below 5.degree. C. by an ice/salt bath. After addition was 
complete the cooling bath was removed and the solution stirred for a 
further 0.5 h. Aqueous sodium carbonate solution was then added and the 
organic phase separated, dried and evaporated to give a crystalline solid. 
The product was introduced onto a short column of alumina and eluted with 
cyclohexane to give methyl (2,3,4,5-tetrachloro-1H-pyrrolyl)acetate as 
white prisms (1.4 g.) m.p. 115.degree. C. 
EXAMPLE 12 
N-Diaminomethylene-(2,3,4,5-tetrachloro-1H-pyrrol-1yl) acetamide 
A solution of guanidine hydrochloride (2.3, 0.024 mol) and sodium ethoxide 
(from 0.55 g. of sodium) in ethanol (20 cm.sup.3) was stirred at room 
temperature for 1 h. The precipitated sodium chloride was removed by 
filtration and washed with ethanol (5 cm.sup.3). Methyl 
(2,3,4,5-tetrachloro-1H-pyrrol-1-yl)acetate (4.8 g.) was added to the 
combined filtrate and washings obtained above and the solution stirred for 
3 h., then cooled in ice and the precipitated title product collected by 
filtration (1.5 g.). A further 0.3 g. of product was obtained by 
evaporation of the mother liquors. The two crops were combined, 
crystallised from isopropyl alcohol and then treated with ethanolic 
hydrogen chloride to give 1.5 g. of pure hydrochloride of the title 
compound, m.p. 215.degree.-217.degree. C. 
EXAMPLE 3 
2,5-Dichloro-N-(2-hexahydropyrimidinylidene)-1H-pyrrol-1-acetamide 
By a procedure analogous to Example 8, 2-amino-1,4,5,6-tetrahydropyrimidine 
is reacted with methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate to give the 
title compound. 
EXAMPLE 14 
N-Diaminomethylene-(2,3,5-trimethyl-1H-pyrrol-1-yl)-acetamide 
By a procedure analogous to Example 1, 3-methylhexan-2,5-dione (J. Amer. 
Chem. Soc., 1929, 51, 3514) is reacted with glycine methyl ester to give 
methyl(2,3,5-trimethyl-1H-pyrrol-1-yl)acetate. 
By a procedure analogous to Example 2, guanidine is reacted with methyl 
(2,3,5-trimethyl-1H-pyrrol-1-yl) acetate to give the title compound. 
EXAMPLE 15 
N-Diaminomethylene-(2,5-ditrifluoromethyl-1H-pyrrol-1-yl)-acetamide 
By the general procedures described in Arch. Pharm., 1959, 292, 508, for 
conversion of .beta.-keto esters nitro .gamma.-diketones, ethyl 
4,4,4-trifluoroacetate is converted to 
1,1,1,6,6,6-hexafluorohexan-2,5-dione. 
By a procedure analogous to Example 1, 
1,1,1,6,6,6-hexafluorohexan-2,5-dione is reacted with glycine methyl ester 
to give methyl (2,5-ditrifluoromethyl-1H-pyrrol-1-yl)acetate. 
By a procedure analogous to Example 2, guanidine is reacted with methyl 
(2,5-ditrifluoromethyl-1H-pyrrol-2-yl)acetate to give the title compound. 
EXAMPLE 16 
N-Diaminomethylene-(trans-2,5-dimethylpyrrolidin-1-yl)-acetamide 
By a procedure analogous to Example 6, methyl bromoacetate is reacted with 
trans-2,5-dimethylpyrrolidine (J. Amer. Chem. Soc. 1951, 73, 5230) to give 
methyl (trans-2,5-dimethylpyrrolidin-1-yl)acetate. 
By a procedure analogous to Example 7, guanidine is reacted with methyl 
(trans-2,5-dimethyl-pyrrolidin-1-yl)acetate to yield the title compound.