Organic compounds and their use as pharmaceuticals

This invention relates to organic compounds, their preparation and use as 
pharmaceuticals. 
The compounds of the invention are of the formula 
##STR2## 
in which R.sup.1 is --CHO, --CH.sub.2 OH, --CH.sub.2 OC.sub.1-4 alkyl, 
--COC.sub.1-3 alkyl, --CH(OH)C.sub.1-3 alkyl or --COOH, R.sup.2 is 
C.sub.1-4 alkyl, --CHO, --CH.sub.2 OH, --CH.sub.2 OC.sub.1-4 alkyl, 
--COC.sub.1-3 alkyl, --CH(OH)C.sub.1-3 alkyl or --COOH, R.sup.3 is 
C.sub.1-4 alkyl and X is pyrrolidinyl or pyrrolidinylmethyl; and salts and 
esters thereof. 
The compounds of the invention and their pharmaceutically-acceptable salts 
and esters have useful effects on the central nervous system and the 
invention comprises a compound of formula (I) for use as a pharmaceutical 
and, more particularly, a compound of formula (I) in 
pharmaceutically-acceptable form. 
When X is pyrrolidinyl it is preferably an N-substituted group of the 
formula 
##STR3## 
where R.sup.4 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl or optionally 
substituted C.sub.6 H.sub.5 CH.sub.2 --. When X is pyrrolidinylmethyl, it 
is preferably an N-substituted group of the formula 
##STR4## 
where R.sup.4 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl or optionally 
substituted C.sub.6 H.sub.5 CH.sub.2 --. R.sup.4 is preferably C.sub.1-4 
alkyl and especially ethyl. 
When reference is made to C.sub.1-4 alkyl this includes, for example, 
methyl, ethyl, propyl, isopropyl and butyl. A C.sub.2-4 alkenyl group is 
preferably vinyl or propenyl. An optionally substituted phenyl is 
preferably phenyl or a phenyl nucleus substituted with one or more, 
preferably one to three, substituents selected, for example, from halogen, 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitro, cyano, amino, carboxy 
and carboxamido. 
A preferred group of compounds is of the formula 
##STR5## 
in which R.sup.1 is --CHO, --CH.sub.2 OH or --COOH, R.sup.2 is methyl, 
--CHO, --CH.sub.2 OH or --COOH, R.sup.3 is C.sub.1-4 alkyl and R.sup.4 is 
ethyl; and salts and esters thereof. 
The novel compounds of the invention are useful both as the free compound 
or as salts, for example the pharmaceutically-acceptable acid addition 
salts such as salts derived from non-toxic inorganic acids, for example, 
hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, 
hydrobromic acid, hydriodic acid and phosphorous acid, as well as salts 
derived from non-toxic organic acids such as aliphatic mono and 
dicarboxylic acids, especially fumaric acid, phenyl-substituted alkanoic 
acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, 
aliphatic and aromatic sulphonic acids. In addition to 
pharmaceutically-acceptable salts, other salts are included such as for 
example, those with picric or oxalic acids; they may serve as 
intermediates in the purification of the compounds or in the preparation 
of other, for example pharmaceutically-acceptable, acid addition salts, or 
are useful for identification, characterisation or purification of the 
bases. 
Acid groups, such as --COOH on the thiophene nucleus, allow the formation 
of salts with bases. Examples of such salts are those derived from 
ammonium hydroxide and alkali and alkaline earth metal hydroxides, 
carbonates and bicarbonates, as well as salts derived from aliphatic and 
aromatic amines, aliphatic diamines and hydroxy alkylamines. Bases 
especially useful in the preparation of such salts include ammonium 
hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, 
methylamine, diethylamine, ethylene diamine, cyclohexylamine and 
ethanolamine. The potassium and sodium salt forms are particularly 
preferred. It is preferred that the salt is pharmaceutically-acceptable 
but, as explained above, other salts are also included in the invention. 
With regard to esters, these may be formed at the carboxyl group by 
conventional alcohols. Examples of such alcohols include alkanols of 
formula R.sup.4 OH where R.sup.4 is alkyl, preferably C.sub.1-8 alkyl and 
especially methanol and ethanol. Thus the most preferred ester derivatives 
are the methyl and ethyl esters of the compounds of formula (I). 
It will be appreciated that the compounds of the invention can contain one 
or more assymetric carbon atom which gives rise to isomers. The compounds 
are normally prepared as racemic mixtures and can conveniently be used as 
such but individual isomers can be isolated by conventional techniques if 
so desired. Such racemic mixtures and individual optical isomers form part 
of the present invention and it is preferred to use an enantiomerically 
pure form. Such pure forms can be separated from the racemic mixture, or, 
alternatively, the enantiomers can be prepared by utilising optically 
active amines in the preparation of the compounds. The preferred 
enantiomer is the laevorotatory (-) form. 
The invention also includes a process for producing a compound according to 
formula (I) above, which comprises 
(a) oxidizing a compound of formula (I) in which R.sup.1 or R.sup.2 is 
C.sub.1-4 alkyl, --CHO or --CH.sub.2 OH, 
(b) reducing a compound of formula (I) in which R.sup.1 or R.sup.2 is --CHO 
or --COC.sub.1-3 alkyl, 
(c) reacting a compound of formula (I) in which one or more of R.sup.1 and 
R.sup.2 is --CH.sub.2 OH, with an alkylating agent, or 
(d) reacting a compound of the formula 
##STR6## 
in which R.sup.1, R.sup.2 and R.sup.3 have the values defined in formula 
(I), a --COOH being suitably protected by an ester group, and Z is halo, 
--OH or --OR where R is a leaving group such as C.sub.1-4 alkyl, with an 
amine of the formula 
EQU XNH.sub.2 (III) 
in which X has the values defined in formula (I), optionally followed by 
the removal of an ester group. 
The oxidising step (a), referred to above, is preferably carried out in a 
suitable solvent such as for example aqueous sulphuric acid and at a 
temperature of from -20.degree. C. to 60.degree. C., more preferably from 
0.degree. C. to 25.degree. C. Examples of oxidising agents that can be 
employed include Ce.sup.IV oxidising agents such as for example cerium 
ammonium nitrate and cerium sulphate. The reaction can be monitored by 
means of chromatography in order to detect the formation of the desired 
product. For instance it may be desired to obtain a product in which one 
or other of the groups R.sup.1 and R.sup.2 is not fully oxidised, and to 
isolate, for example, a compound with R.sup.1 or R.sup.2 as --CHO. 
With regard to the reducing step (b), this is preferably carried out in a 
suitable solvent such as for example ethanol, and at a temperature of from 
-20.degree. C. to 60.degree. C., more preferably from 0.degree. C. to 
25.degree. C. Examples of suitable reducing agents for this reaction 
include sodium borohydride or lithium aluminium hydride. As in the case of 
the oxidising reaction it may be necessary to monitor progress of the 
reaction to determine when the desired product is obtained. For example it 
may be desired to prepare a compound in which only one of the R.sup.1 and 
R.sup.2 groups is fully reduced. This can be achieved by carefully 
adjusting the quantity of reducing agent. 
The alkylation reaction (c), referred to above, is a conventional step 
carried out under the usual reaction conditions. For example the reaction 
is preferably carried out at a temperature of from 0.degree. C. to 
100.degree. C. using as alkylating agent an alkyl iodide, and in the 
presence of a base such as for example sodium hydroxide. Alternatively a 
trialkyloxonium tetrafluoroborate has been found useful. 
With regard to reaction (d) above, it is preferably carried out at a 
temperature of from 0.degree. C. to 200.degree. C. in an inert organic 
solvent such as, for example a haloalkane, for example, dichloromethane. 
When Z is --OH a coupling agent is preferably employed such as a coupling 
agent commonly used in peptide synthesis, for example carbonyldiimidazole. 
When Z is OR, it is often desirable to carry out the reaction at a higher 
temperature, for example from 100.degree. C. to 200.degree. C. The 
preferred reactions are those in which the reactant is one of formula (II) 
in which Z is halo or --OH. 
One starting point for synthesis of the compounds of the invention are 
compounds of formula (I) in which both of the R.sup.1 and R.sup.2 groups 
are C.sub.1-4 alkyl. Such compounds can be prepared by a route similar to 
the condensation reaction described in (d) above, from known amines and 
2-carboxylthiophenes synthesised by conventional methods. 
Alternatively, intermediates of formula (II) can be synthesised according 
to literature methods such as described in Ber. 43 901-906 and Ber. 45 
2413-2418. 
As mentioned above, the compounds of the invention in free base and 
pharmaceutically-acceptable salt and ester form have useful central 
nervous system activity. They are also of low toxicity. Their activity has 
been demonstrated by testing in animal models using well-established 
procedures. More specifically, the compounds have been shown to block 
apomorphine induced climbing in mice according to the method of Costall, 
Naylor and Nohria (European J. Pharmacol. 50, 39; 1978), and/or to block a 
conditioned avoidance response in rats according to the method of Jacobsen 
and Sonne (Acta Pharmacol. et Toxacol. 11, 35; 1955), at doses below 50 
mg/kg when administered intraperitoneally. 
These tests show that the compounds of the invention block post-synaptic 
dopamine receptors and are accordingly indicated for the treatment of 
emesis, depression, anxiety and psychotic conditions such as schizophrenia 
and acute mania. 
The compounds are effective over a wide dosage range, the actual dose 
administered being dependent on such factors as the particular compound 
being used, the condition being treated and the type and size of mammal 
being treated. However, the dosage required will normally fall within the 
range of 0.05 to 10 mg/kg per day, for example in the treatment of adult 
humans dosages of from 0.2 to 5 mg/kg may be used. 
The compounds and pharmaceutically-acceptable salts and esters of the 
invention will normally be administered orally or by injection and, for 
this purpose, said compounds will usually be utilised in the form of a 
pharmaceutical composition. Such compositions are prepared in a manner 
well known in the pharmaceutical art and normally comprise at least one 
active compound or pharmaceutically-acceptable salt associated with a 
pharmaceutically-acceptable diluent or carrier therefor. Such compositions 
form part of the present invention. In making such compositions, the 
active ingredient will usually be mixed with a carrier or diluent. 
Additionally or alternatively it may be enclosed within a carrier which 
may be in the form of a capsule, sachet, paper or other container. When 
the carrier serves as a diluent, it may be a solid, semi-solid or liquid 
material which acts as a vehicle, excipient or medium for the active 
ingredient. Some examples of suitable carriers are lactose, dextrose, 
sucrose, sorbitol, mannitol, stargesh, gum acacia, calcium phosphate, 
alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl and 
propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The 
compositions of the invention may, as is well-known in the art, be 
formulated so as to provide quick, sustained or delayed release of the 
active ingredient after administration to the patient. 
Depending on the route of administration, the foregoing compositions may be 
formulated as tablets, capsules or suspensions for oral use or injectable 
solutions for parenteral use. Preferably the compositions are formulated 
in a dosage unit form, each dosage containing from 1 to 200 mg more 
usually 5 to 100 mg, of the active ingredient.

The invention is illustrated by the following Preparations and Examples. 
PREATION 1 
Methyl 4,5-dimethyl-3-hydroxythiophene-2-carboxylate 
Dry hydrogen chloride gas was bubbled through a mixture of ethyl 
2-methyl-3-oxobutanoate (7.6 g, 50 mmol) and methyl 2-mercaptoacetate 
(11.2 g, 100 mmol) at -10.degree. C. until saturated. The oil was allowed 
to stand for 3 hours at room temperature, diluted with dichloromethane and 
washed with brine. After drying with sodium sulphate and evaporation of 
solvent the oil was dissolved in methanol (10 ml) and added dropwise to 
methanolic potassium hydroxide (2N; 75 ml), stirring at room temperature 
for 1 hour. The solution was diluted with iced water (125 ml) and 
acidified with 3N hydrochloric acid at -3.degree. to 0.degree. C. to pH1. 
The precipitate was filtered and washed with water (5.5 g, m.p. 
50.degree.-51.degree. C., methanol). 
PREATION 2 
Methyl 4,5-dimethyl-3-methoxythiophene-2-carboxylate 
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate 
(Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added 
anhydrous potassium carbonte (24.5 g, 178 mmol) and the mixture stirred 
for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was 
added and the mixture stirred under reflux for 2.5 hours. The solvent was 
evaporated under reduced pressure and the residue partitioned between 
water and ethyl acetate. The organic phase was washed with brine, dried 
with sodium sulphate and evaporated to give crude product which was used 
in the following preparation. 
PREATION 3 
3-Methoxy-4,5-dimethylthiophene-2-carboxylic acid 
Methyl 4,5-dimethyl-3-methoxythiophene-2-carboxylate (34 g) was heated 
under reflux in 1M sodium hydroxide solution (500 ml) for 1 hour. After 
cooling the mixture was acidified with concentrated hydrochloric acid to 
pH4. The solid was filtered, washed with water and dried, m.p. 
142.degree.-143.degree. C. 
PREATION 4 
Resolution of (.+-.)2-aminomethyl-1-ethylpyrrolidine 
(+)2-aminomethyl-1-ethylpyrrolidine 
To a solution of L(+) tartaric acid (80 g) in water (150 ml) was added, 
dropwise (.+-.)2-aminomethyl-1-ethyl-pyrrolidine keeping the temperature 
below 20.degree. C. The solution was stirred at room temperature for 1 
hour, diluted with ethanol (150 ml) then cooled at 5.degree. C. overnight. 
The salt was filtered and suspended three times in boiling methanol and 
filtered whilst warm to give the (+) tartrate (29 g), m.p. 161-162. 
(.alpha.).sub.589.sup.25 =+38.8.degree. (5% water). 
To the above tartrate (29 g) in water (45 ml) was added 30% sodium 
hydroxide solution (24 ml) and sodium hydroxide pellets (4.5 g), keeping 
the temperature below 20.degree. C. The solution was extracted with 
3.times.50 ml chloroform. Drying and evaporation of the solvent gave an 
oil which was distilled b.sub.15 .about.60.degree. (6.4 g) 
(.alpha.).sup.25.sub.589 =+90.degree. (5% chloroform). 
(-)2-Aminomethyl-1-ethylpyrrolidine was similarly prepared using D(-) 
tartaric acid as resolving agent. b.sub.15 .about.62.degree. (9.4 g) 
(.alpha.).sub.589.sup.25 =-151.degree. (50% chloroform). 
PREATION 5 
(.+-.) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-3-methoxy-4,5-dimethylthiophene-2-carbo 
xamide, fumarate 
To a solution of 3-methoxy-4,5-dimethylthiophene-2-carboxylic acid (18.6 g, 
0.1 mol) in dry dichloromethane (250 ml) under nitrogen was added 
1,1'-carbonyldiimidazole (16.2 g), 0.1 mol). After stirring for 1 hour 
(.+-.)2-aminomethyl-1-ethylpyrrolidine (12.8 g, 0.1 mol) was added and the 
solution stirred at room temperature for 24 hours. The reaction mixture 
was washed successively with 3.times.40 ml 3M hydrochloric acid, saturated 
sodium bicarbonate solution and brine. After drying (sodium sulphate) and 
evaporation of the solvent the residual oil was dissolved in hot ethyl 
acetate (750 ml), and fumaric acid (9.3 g) added. The fumarate salt was 
crystallised from the cooled solution and was filtered, m.p. 
123.degree.-125.degree. C. 
PREATION 6 
(.+-.) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-3-methoxy-4,5-dimethylthiophene-2-carbo 
xamide, fumarate 
To a suspension of 3-methoxy-4,5-dimethylthiophene-2-carboxylic acid (1.86 
g, 0.010 mol) in dry toluene (30 ml) and two drops of dimethylformamide, 
thionyl chloride (1.2 g), 0.010 mol) was added drop-wise. The solution was 
stirred for 15 minutes, the solvent evaporated under vacuum, and a solid 
was obtained. To a solution of this solid in dry dichloromethane (50 ml) 
under a nitrogen atmosphere (.+-.) 2-aminomethyl-1-ethylpyrrolidine (1.28 
g, 0.010 mol) was added. The solution was stirred for 3 hours, the mixture 
was partitioned between diluted hydrochloric acid and dichloromethane. 
The organic layer was washed with sodium bicarbonate solution and brine, 
dried with sodium sulphate and evaporated. The residue was dissolved in 
boiling ethylacetate and fumaric acid (0.088 mol) added. After 
crystallisation, the solid was filtered, m.p. 121.degree.-123.degree. C. 
EXAMPLE 1 
(.+-.) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2- 
carboxamide 
To a solution of (.+-.) 
N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-methoxy-4,5-dimethylthiophene-2-carbo 
xamide, fumarate (3 g) in dilute sulphuric acid (100 ml concentrated 
sulphuric acid in 500 ml water) was added ammonium cerium nitrate (17.56 
g) in one portion. After stirring at room temperature for 0.5 hours and 
then cooling to 0.degree. C., 0.88 ammonia solution (235 ml) was added 
dropwise to give a neutral solution. This was extracted several times with 
dichloromethane, the organic extracts combined and washed with water, 
dried over magnesium sulphate and the solvent removed in vacuo to give a 
light brown oil. Column chromatography on silica eluting with 10% methanol 
in dichloromethane gave the pure free base of the title compound, fumarate 
salt, m.p. 122.degree.-123.degree. C. (ex ethyl acetate-ethanol as 
recrystallising solvent). 
EXAMPLE 2 
(.+-.) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-5-hydroxymethyl-3-methoxy-4-methylthiop 
hene-2-carboxamide 
To a solution of (.+-.) 
N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2- 
carboxamide (1.15 g) in ethanol (30 ml) was added sodium borohydride (0.154 
g) in one portion. The solution was stirred at room temperature for 2 
hours and then water (50 ml) added. After extraction with ethyl acetate, 
washing the organic extracts with water, drying over magnesium sulphate 
and filtering, the solvent was removed in vacuo to give the title compound 
as a golden oil, fumarate salt, m.p. 118.degree.-119.degree. C. (ex 
ethylacetate-ethanol ether as recrystallising solvent). 
EXAMPLE 3 
(-) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2- 
carboxamide 
The above compound was synthesised from (-) 4,5-dimethyl 
N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-methoxy thiophene-2-carboxamide in a 
similar manner outlined in Example 1. 
EXAMPLE 4 
(-) 
N-[(1-Ethyl-2-pyrrolidinyl)methyl]-5-hydroxymethyl-3-methoxy-4-methylthiop 
hene-2-carboxamide 
The above compound was synthesised from (-) 
N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-formyl-3-methoxy-4-methylthiophene-2- 
carboxamide in a similar manner outlined in Example 2. 
PREATION 7 
Dimethyl 3-hydroxy-4-methyl-2,5-thiophene dicarboxylate 
To a solution of sodium methoxide from sodium (5.4 g) in methanol (100 ml) 
was added a solution of methyl pyruvate (24 g) and dimethyl thiodiacetate 
(41.83 g) in methanol (50 ml). The reaction was stirred at room 
temperature for 2 days, and then added to ice water (500 ml). After 
neutralization with 5N HCl and extraction with chloroform, the organics 
were washed with brine, dried over anhydrous magnesium sulphate, filtered 
and the solvent evaporated to give a solid, m.p 95.degree.-97.degree. ex 
methanol. 
PREATION 8 
Trimethyl 3-hydroxy-2,4,5-thiophene tricarboxylate 
The above compound was prepared as in Preparation 7 from dimethyl 
ketomalonate and dimethyl thiodiacetate. 
PREATION 9 
Dimethyl 3-methoxy-4-methyl-2,5-thiophene dicarboxylate 
A solution of dimethyl 4-hydroxy-3-methyl-2,5-thiophene dicarboxylate (4.26 
g) in acetone (100 ml) containing anhydrous potassium carbonate (2.34 g) 
was stirred for 1 hour at room temperature. Dimethyl sulphate (1.62 ml) 
was added and the solution refluxed for 2 hours. The solvent was then 
removed under vacuum and, after treating the residue with water-ethyl 
acetate, was extracted several times with ethyl acetate; the organic 
extracts were collected, washed with water, dried over anhydrous magnesium 
sulphate, filtered and the solvent evaporated to give a solid, m.p. 
61.degree.-64.degree. ex methanol. 
PREATION 10 
Trimethyl 3-methoxy-2,4,5-thiophene tricarboxylate 
The above compound was prepared as in Preparation 9 from trimethyl 
3-hydroxy-2,4,5-thiophene tricarboxylate. 
EXAMPLE 5 
(.+-.) 
5-Carbomethoxy-N-[1-ethyl-2-pyrrolidinylmethyl]-3-methoxy-4-methylthiophen 
e-2-carboxamide 
The above compound was prepared by heating 
dimethyl-3-methoxy-4-methyl-2,5-thiophene dicarboxylate and 
(.+-.)2-(aminomethyl)-1-ethyl-pyrrolidine at 170.degree. under nitrogen 
atmosphere. After column chromatography, the title compound was obtained, 
as its fumarate salt, m.p. 155.degree.-156.degree. ex ethyl acetate. 
EXAMPLE 6 
(.+-.) 
4,5-Dicarbomethoxy-N-[1-ethyl-2-pyrrolidinylmethyl]-3-methoxythiophene-2-c 
arboxamide 
The above compound was prepared from trimethyl 3-methoxy-2,4,5-thiophene 
tricarboxylate and (.+-.) 2-(aminomethyl)-1-ethyl-pyrrolidine as in 
Example 5. 
EXAMPLE 7 
(-) 
5-Carbomethoxy-N-[1-ethyl-2-pyrrolidinylmethyl]-3-methoxy-4-methylthiophen 
e 
The above compound was prepared from dimethyl 
3-methoxy-4-methyl-2,5-thiophene dicarboxylate and (-) 
2-(aminomethyl)-1-ethyl-pyrrolidine as in Example 5. 
EXAMPLE 8 
(-) 
4,5-Dicarbomethoxy-N-[1-ethyl-2-pyrrolidinylmethyl]-3-methoxythiophene-2-c 
arboxamide 
The above compound was prepared from trimethyl 3-methoxy-2,4,5-thiophene 
carboxylate and (-) 2-(aminomethyl)-1-ethylpyrrolidine as in Example 5. 
The following Examples illustrate the preparation of typical formulations 
containing an active ingredient according to the invention. 
EXAMPLE 9 
Hard gelatin capsule 
Each capsule contains 
______________________________________ 
Active ingredient 10 mg 
PEG 4000 250 mg 
______________________________________ 
The PEG 4000 is melted and mixed with the active ingredient. Whilst still 
molten the mixture is filled into capsule shells and allowed to cool. 
EXAMPLE 10 
Tablet 
Each tablet contains 
______________________________________ 
Active ingredient 10 mg 
Calcium carbonate 300 mg 
Magnesium stearate 10 mg 
Starch 30 mg 
Hydroxypropylmethyl- 10 mg 
cellulose 
Iron Oxide 4 mg 
______________________________________ 
The active ingredient is granulated with calcium carbonate and starch. The 
dried granulate is blended with lubricant and disintegrant and compressed 
into tablets of the required dosage strength. The tablet may then be 
coated. 
EXAMPLE 11 
Injection 
______________________________________ 
Active ingredient 10 mg 
Water 1 mg 
______________________________________ 
The active ingredient is dissolved in water and distributed into vials, 
ampoules or pre-pack syringes using appropriate equipment. The product is 
sterilised.