Compounds of the formula ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, X, m, n, p, and q are as set forth in the specification, as well as pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids, which are useful in the control or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological or cardiovascular disorders or for the treatment of asthma, AIDS or diabetic complications or for the stimulation of hair growth are described.

BRIEF SUMMARY OF THE INVENTION 
The present invention relates to substituted pyrroles of the formula 
##STR2## 
wherein R.sup.1 and R.sup.3 together form a bond and R.sup.2 is hydrogen 
or R.sup.1 and R.sup.2 together form a bond and R.sup.3 is hydrogen; 
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently are hydrogen, 
halogen, alkyl, haloalkyl, alkoxy, nitro, amino, alkanoylamino, 
aroylamino, alkylthio or alkylsulfonyl; R.sup.8 is hydrogen, alkyl or 
aralkyl; X is --N(R.sup.9)-- or --CHN(R.sup.10,R.sup.11)-- in which 
R.sup.9, R.sup.10 and R.sup.11 each are hydrogen, alkyl, aralkyl or 
alkanoyl; m is 0-2 and n is 1-3, with the proviso that the sum of m and n 
is 1-3; p is 0-4 and q is 0-4, with the proviso that the sum of p and q is 
2-4 when X is --N(R.sup.9)--, that the sum of p and q is 1-5 when X is 
--CHN(R.sup.10,R.sup.11)-- and R.sup.1 and R.sup. 2 together form a bond, 
that the sum of p and q is 0-4 when X is --CHN(R.sup.10,R.sup.11)-- and 
R.sup.1 and R.sup.3 together form a bond, and that p is 1-4 when X is 
--N(R.sup.9)--, R.sup.1 and R.sup.3 together represent a bond and m is 0, 
as well as pharmaceutically acceptable salts of acidic compounds of 
formula I with bases and of basic compounds of formula I with acids. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to substituted pyrroles of the formula 
##STR3## 
wherein R.sup.1 and R.sup.3 together form a bond and R.sup.2 is hydrogen 
or R.sup.1 and R.sup.2 together form a bond and R.sup.3 is hydrogen; 
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each independently are hydrogen, 
halogen, alkyl, haloalkyl, alkoxy, nitro, amino, alkanoylamino, 
aroylamino, alkylthio or alkylsulfonyl; R.sup.8 is hydrogen, alkyl or 
aralkyl; X is --N(R.sup.9)-- or --CHN(R.sup.10,R.sup.11)-- in which 
R.sup.9, R.sup.10 and R.sup.11 each are hydrogen, alkyl, aralkyl or 
alkanoyl; m is 0-2 and n is 1-3, with the proviso that the sum of m and n 
is 1-3; p is 0-4 and q is 0-4, with the proviso that the sum of p and q is 
2-4 when X is --N(R.sup.9)--, that the sum of p and q is 1-5 when X is 
--CHN(R.sup.10,R.sup.11)-- and R.sup.1 and R.sup. 2 together form a bond, 
that the sum of p and q is 0-4 when X is --CHN(R.sup.10,R.sup.11)-- and 
R.sup.1 and R.sup.3 together form a bond, and that p is 1-4 when X is 
--N(R.sup.9)--, R.sup.1 and R.sup.3 together represent a bond and m is 0, 
as well as pharmaceutically acceptable salts of acidic compounds of 
formula I with bases and of basic compounds of formula I with acids. 
Objects of the present invention are the compounds of formula I and their 
pharmaceutically acceptable salts; a process for making these compounds 
and salts; novel intermediates useful in the process; medicaments 
containing the compounds and salts; and the use of the compounds and salts 
in the control or prevention of illnesses, especially in the control or 
prevention of inflammatory, immunological, oncological, bronchopulmonary, 
dermatological and cardiovascular disorders, in the treatment of asthma, 
AIDS or diabetic complications or for the stimulation of hair growth. 
As used herein, the term "alkyl", alone or in combination, denotes a 
straight-chain or branched-chain alkyl group containing a maximum of 7, 
preferably a maximum of 4, carbon atoms such as, for example, methyl, 
ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl and the 
like. The term "alkoxy", alone or in combination, denotes an alkyl group 
as defined earlier which is attached via an oxygen atom, examples of 
alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, 
tert.butoxy and the like. A haloalkyl group can carry one or more halogen 
atoms, with examples of such groups being chloromethyl, trifluoromethyl 
and the like. The term "alkanoyl", alone or in combination, denotes an 
alkanoyl group derived from an alkanoic acid containing a maximum of 7, 
preferably a maximum of 4, carbon atoms, for example, formyl, acetyl, 
propionyl, butyryl and the like. The term "aralkyl" means an alkyl group 
as defined earlier in which one of the hydrogen atoms is replaced by a 
phenyl group or a phenyl group carrying one or more substituents selected 
from, for example, halogen, alkyl, haloalkyl and hydroxy; such as, for 
example, benzyl, p-chlorobenzyl, p-tolyl, 2-phenylethyl and the like. The 
aroyl moiety of an aroylamino group is derived from an aromatic carboxylic 
acid which can be unsubstituted or substituted with alkyl, alkoxy, halogen 
and the like, such as, for example, benzoyl, p-toluoyl, p-methoxybenzoyl, 
o- or p-chlorobenzoyl, 1- or 2-naphthoyl and the like. The term "halogen" 
denotes fluorine, chlorine, bromine or iodine. 
When the compounds of formula I contain a chiral carbon atom they can be 
present in racemic or optically active form. The present invention 
includes within its scope not only the racemic compounds, but also the 
optically active isomers. 
One preferred class of compounds of formula I comprises those in which 
R.sup.1 and R.sup.3 together form a bond and R.sup.2 is hydrogen, X is 
--N(R.sup.9)-- and m, n, p and q each are 1. Another preferred class of 
compounds of formula I comprises those in which R.sup.1 and R.sup.2 
together form a bond and R.sup.3 is hydrogen, X is --N(R.sup.9)--, m, n 
and q each are 1 and p is 2. R.sup.4, R.sup.5, R.sup.6, and R.sup.7 each 
preferably are hydrogen. R.sup.8 is alkyl, especially methyl. R.sup.9 is 
preferably hydrogen or alkyl, especially preferred is hydrogen or methyl. 
Preferably, R.sup.10 and R.sup.11 each represent hydrogen or each 
represent alkyl, especially methyl. 
Other classes of compounds of formula I comprise those in which: 
(i) R.sup.1 and R.sup.3 together form a bond and R.sup.2 is hydrogen, Y is 
--N(R.sup.9)-- and m, n and q are 1 and p is 3; 
(ii) R.sup.1 and R.sup.3 together form a bond and R.sup.2 is hydrogen, Y is 
--CHN(R.sup.10,R.sup.11)-- and m and n each are 1 and p and q each are 0 
or m and q each are 0, n is 2 and p is 3; 
(iii) R.sup.1 and R.sup.2 together form a bond and R.sup.3 is hydrogen, X 
is --N(R.sup.9)-- and m, n and q are 1 and p is 3; and 
(iv) R.sup.1 and R.sup.2 together form a bond and R.sup.3 is hydrogen, X is 
--CHN(R.sup.10,R.sup.11)-- and m and q each are 0, n is 2 and p is 1 or m 
and n each are 1, p is 3 and q is 0 or m, n and p each are 1 and q is 0. 
Especially preferred compounds of formula I are: 
3-[6,7,8,9-Tetrahydrospiro[pyrido[1,2-a]indole-8,3'-pyrrolidin]-10-yl]-4-(1 
-methyl-3-indolyl)-1H-pyrrole-2,5-dione, 
cis-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2-a 
]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione and 
trans-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2 
-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione. 
According to the process of the present invention, the compounds of formula 
I, as well as pharmaceutically acceptable salts of acidic compounds of 
formula I with bases and of basic compounds of formula I with acids, are 
prepared by 
(a) reacting a compound of the formula 
##STR4## 
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, m, n, p and q are described above and X' is --N(R.sup.9')-- or 
--CHN(R.sup.10',R.sup.11')-- in which R.sup.9', R.sup.10' and R.sup.11' 
each are hydrogen, alkyl, aralkyl, alkanoyl, alkoxycarbonyl or 
aryloxycarbonyl, with ammonia under pressure or with hexamethyldisilazane 
and methanol and, where required, cleaving off any alkoxycarbonyl or 
aralkoxycarbonyl group(s) present in the reaction product, or 
(b) for the preparation of a compound of formula I in which R.sup.8 is 
hydrogen, debenzylating a compound of formula I in which R.sup.8 is 
benzyl, and 
(c) if desired, converting an acidic compound of formula I into a 
pharmaceutically acceptable salt with a base or converting a basic 
compound of formula I into a pharmaceutically acceptable salt with an 
acid. 
The alkoxycarbonyl or araloxycarbonyl group which can be present as 
R.sup.9', R.sup.10' or R.sup.11' in the starting material of formula II is 
preferably the tert.butyloxycarbonyl or benzyloxycarbonyl group, 
respectively. 
The reaction of a compound of formula II with ammonia under pressure in 
accordance with embodiment (a) of the process is conveniently carried out 
using aqueous ammonia, preferably 33% aqueous ammonia, and in the presence 
of a water-miscible inert organic solvent such as DMF (dimethylformamide). 
The reaction is preferably carried out at an elevated temperature, for 
example, at a temperature in the range of from about 100.degree. C. to 
about 150.degree. C. 
The reaction of a compound of formula II with hexamethyldisilazane and 
methanol, also in accordance with embodiment (a) of the process, is 
preferably carried out in DMF at about room temperature or in acetonitrile 
at from about room temperature to about 82.degree. C. However, it can also 
be carried out in a halogenated hydrocarbon, for example, chloroform, 
carbon tetrachloride or chlorobenzene, or an aromatic hydrocarbon, for 
example, benzene, toluene or xylene, and at an elevated temperature, for 
example, from about 40.degree. C. to 110.degree. C. 
The cleavage of any alkoxycarbonyl or aralkoxycarbonyl group(s) which may 
be present in the reaction product can be carried out in a known manner. 
For example, the cleavage can be carried out using a mineral acid such as 
hydrochloric acid in an inert organic solvent such as an ether, for 
example, THF (tetrahydrofuran) or dioxan; an alkanol, for example, 
methanol or ethanol, or a halogenated, especially chlorinated, 
hydrocarbon, for example, methylene chloride, and the like or using 
trifluoroacetic acid. The cleavage is suitably carried out at a 
temperature between about 0.degree. C. and room temperature. 
The debenzylation of a compound of formula I in which R.sup.8 is benzyl, in 
accordance with embodiment (b) of the process, to give a compound of 
formula I in which R.sup.8 is hydrogen can be carried out in a known 
manner. Thus, the debenzylation can be carried out using hydrogen in the 
presence of a suitable catalyst, for example, a palladium catalyst which 
may be supported on a carrier material such as palladium/charcoal, and in 
an inert organic solvent, for example, an alkanol, such as, methanol or 
ethanol, conveniently at ambient temperature and under atmospheric 
pressure. 
The conversion of an acidic compound of formula I into a pharmaceutically 
acceptable salt in accordance with embodiment (c) of the process can be 
carried out by treatment with a suitable base in a known manner. Suitable 
salts are those derived not only from inorganic bases, for example, sodium 
salts, potassium salts, calcium salts and the like, but also from organic 
bases, for example ethylenediamine, monoethanolamine, diethanolamine and 
like salts. The conversion of a basic compound of formula I into a 
pharmaceutically acceptable salt, also in accordance with embodiment (c) 
of the process, can be carried out by treatment with a suitable acid in a 
known manner. Suitable salts are those derived not only from inorganic 
acids, for example, hydrochlorides, hydrobromides, phosphates, sulphates 
and the like, but also from organic acids, for example, acetates, 
citrates, fumarates, tartrates, maleates, methanesulphonates, 
p-toluenesulphonates and the like. 
The compounds of formula II which are used as starting materials in 
embodiment (a) of the process are novel and also form an object of the 
present invention. They can be prepared, for example, by reacting a 
compound of the formula 
##STR5## 
wherein R.sup.1, R.sup.2, R.sup.3, m, n, p, q and X' are as described 
above, with oxalyl chloride and reacting the resulting compound of the 
formula 
##STR6## 
wherein R.sup.1, R.sup.2, R.sup.3, m, n, p, q and X' are as defined above, 
with a compound of the formula 
##STR7## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as described 
above, and, if desired, cleaving off any alkoxycarbonyl or 
aralkoxycarbonyl group(s) present in the reaction product and, also if 
desired, alkylating, aralkylating or alkanoylating the product obtained. 
The reaction of a compound of formula III with oxalyl chloride is 
conveniently carried out in an inert organic solvent, such as, a 
halogenated aliphatic hydrocarbon, for example, dichloromethane and the 
like, at a temperature between about -78.degree. C. and the reflux 
temperature of the reaction mixture, preferably at about -78.degree. C. to 
about 0.degree. C. 
The reaction of a compound of formula IV with a compound of formula V is 
preferably carried out in the presence of an acid-binding agent, 
expediently a tertiary amine such as a trialkylamine, for example, 
triethylamine, diisopropylethylamine and the like, and in an inert organic 
solvent such as a halogenated aliphatic hydrocarbon, for example, 
dichloromethane and the like, at about room temperature. In a preferred 
procedure a compound of formula IV is reacted in situ with a compound of 
formula V. 
The optional cleavage of any alkoxycarbonyl or aralkoxycarbonyl group(s) 
which may be present in the reaction product can be carried out in the 
same manner to that described earlier in connection with the cleavage of 
these groups from a reaction product obtained according to embodiment (a) 
of the process. 
The optional alkylation, aralkylation or alkanoylation after the cleavage 
of any alkoxycarbonyl or aralkoxycarbonyl group(s) can be carried out 
according to known methods. Suitably, the alkylation or aralkylation is 
carried out by reductive alkylation or reductive aralkylation. 
The compounds of formulas III and V are known compounds or analogs of known 
compounds which can be prepared in a similar manner to the known 
compounds. Further, the Examples hereinafter contain detailed information 
containing the preparation of compounds of formula III. 
The compounds of formula I and their pharmaceutically acceptable salts are 
protein kinase inhibitors. The compounds of formula I and their 
pharmaceutically acceptable salts inhibit cellular processes, for example, 
cell proliferation and secretion, and can be used in the control or 
prevention of illnesses, for example, in the control or prevention of 
inflammatory disorders, such as, arthritis, immune diseases, psoriasis, 
contact dermatitis, in conjunction with organ transplants and also in 
oncology. They inhibit infection of cells with human immunodeficiency 
virus or Epstein-Barr virus and are thus useful in the treatment of AIDS 
and infectious mononucleosis. The compounds and salts of the present 
invention also inhibit smooth muscle contraction and can therefore be used 
against cardiovascular and bronchopulmonary disorders. Further, they are 
also useful in asthma therapy. The present compounds and salts also 
inhibit platelet aggregation and can be used in the control or prevention 
of thrombosis. Further, they inhibit the release of mediators from 
activated neutrophils and can therefore be used to control ischemic 
damage, for example, in the heart or brain. The present compounds and 
salts inhibit neurotoxicity induced by elevated glucose levels and are 
thus useful for the treatment of diabetic complications. The present 
compounds and salts stimulate hair growth and can therefore be used to 
prevent or repress baldness. 
The activity of the present compounds in inhibiting protein kinase C can be 
demonstrated by means of the in vitro test procedure described in Biochem. 
and Biophys. Research Comm. 19 (1979) 1218. 
The IC.sub.50 values in the following Table are that concentration of test 
compound which reduces by 50% the protein kinase-induced incorporation of 
.sup.32 P from [.gamma.-.sup.32 P]ATP into histone. 
TABLE 
______________________________________ 
Product of Example No. 
IC.sub.50 (nM) 
______________________________________ 
1 40 
6 30 
14 7 
______________________________________ 
The compounds of formula I and their aforementioned salts can be used as 
medicaments, for example, in the form of pharmaceutical preparations. The 
pharmaceutical preparations can be administered orally, for example, in 
the form of tablets, coated tablets, dragees, hard and soft gelatin 
capsules, solutions, emulsions or suspensions. However, they can also be 
administered rectally (for example, in the form of suppositories) or 
parenterally (for example, in the form of injectable solutions). 
For the manufacture of pharmaceutical preparations, the compounds of 
formula I and their aforementioned salts can be formulated with 
therapeutically inert, inorganic or organic carriers. Lactose, maize 
starch or derivatives thereof, talc, stearic acid or its salts and the 
like can be used, for example, as such carriers for tablets, coated 
tablets, dragees and hard gelatin capsules. Suitable carriers for soft 
gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid 
and liquid polyols and the like. Depending on the nature of the active 
substance no carriers are, however, generally required in the case of soft 
gelatine capsules. Suitable carriers for the manufacture of solutions and 
syrups are, for example, water, polyols, saccharose, invert sugar, glucose 
and the like. Suitable carriers for injectable solutions are, for example, 
water, alcohols, polyols, glycerine, vegetable oils and the like. Suitable 
carriers for suppositories are, for example, natural or hardened oils, 
waxes, fats, semi-liquid polyols and the like. 
The pharmaceutical preparations can also contain preserving agents, 
solubilizing agents, stabilizing agents, wetting agents, emulsifying 
agents, sweetening agents, coloring agents, flavoring agents, salts for 
varying the osmotic pressure, buffers, coating agents or antioxidants. 
They can also contain still other therapeutically valuable substances. 
Pharmaceutical compositions containing a compound of formula I or a salt 
thereof as defined above and a therapeutically inert carrier are also 
objects of the present invention. 
As mentioned above, the compounds of formula I and their aforementioned 
salts can be used in the control or prevention of illnesses, especially in 
the control or prevention of inflammatory, immunological, 
bronchopulmonary, dermatological and cardiovascular disorders, for the 
treatment of asthma, AIDS or diabetic complications or for the stimulation 
of hair growth. The dosage can vary within wide limits and will, of 
course, be adjusted to the individual requirements in each particular 
case. In general, in the case of oral administration to adults, a daily 
dosage of about 5 mg to about 500 mg should be appropriate, although the 
upper limit may be exceeded when this is found to be indicated. The daily 
dosage can be administered as a single dose or in divided doses.

EXAMPLE 1 
(A) A mixture of 4.09 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.41 g of 
methanol was added to a solution of 1.40 g of 
3-[1'-(tert.butoxycarbonyl)-7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'- 
pyrrolidin]-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 25 ml of dry 
DMF and stirred for 16 hours. The mixture was poured into 100 ml of water 
and extracted with ethyl acetate. The ethyl acetate extracts were washed 
with sodium chloride solution, dried and concentrated. There were obtained 
820 mg of 
3-[1'-(tert.butoxycarbonyl)-7,9-dihydrospiro[pyrido-[1,2-a]indole-8(6H).3' 
-pyrrolidin]-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione after 
chromatography on silica gel using dichloromethane/methanol (9:1) for the 
elution. 
(B) A solution of 780 mg of the product of (A) in 100 ml of dichloromethane 
was treated at 0.degree. C. with 5 ml of trifluoroacetic acid and the 
mixture was stirred for 2 hours. The solvent was removed under reduced 
pressure and the residue was chromatographed on silica gel using 
chloroform/methanol/acetic acid/water (60:18:2:3) for the elution. There 
were obtained 145 mg of 
3-[6,7,8,9-tetrahydrospiro[pyrido[1,2-a]indole-8,3'-pyrrolidin-10-yl]-4-(1 
-methyl-3-indolyl)-pyrrole-2,5-dione trifluoroacetate of melting point 
177.degree.-180.degree. C. 
The furandione starting material was prepared as follows: 
(i) 1.3 g of sodium hydride were added over 0.5 hour to a stirred, ice-cold 
solution of 12.85 g of ethyl 
6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 200 ml of DMF 
and the mixture was stirred for a further 0.5 hour. A solution of 9.2 g of 
ethyl bromoacetate in 50 ml of DMF was added dropwise to the cooled 
mixture. After a further 3 hours at room temperature the mixture was 
poured into 1.5 l of water and extracted with diethyl ether. The ethereal 
extracts were washed with water, dried and concentrated to give 16.3 g of 
ethyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-acetate. 
(ii) A solution of 4.2 g of the product of (i) in 100 ml of ethanol was 
treated with a suspension of Raney nickel in water and the mixture was 
heated at reflux for 4 hours. The cooled mixture was filtered and the 
residue was washed with ethyl acetate. The filtrate was extracted with 
ethyl acetate. The ethyl acetate solution was dried and the solvent was 
removed under reduced pressure to give 3.0 g of ethyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetate. 
(iii) 3.0 g of the product of (ii) were added to a solution of 1.4 g of 
sodium hydroxide in 100 ml of ethanol and the mixture was heated under 
reflux for 2 hours. The cooled mixture was filtered and the residue was 
dissolved in 100 ml of water and acidified with 2M hydrochloric acid. The 
resulting precipitate was filtered off, washed with water and dried. There 
were obtained 1.7 g of 
8-carboxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetic acid. 
(iv) A mixture of 100 mg of 
8-carboxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-acetic acid and 69 mg of 
ammonium carbonate was heated at 200.degree. C. for 1 hour. After cooling 
and chromatography on silica gel using dichloromethane/methanol (9:1) for 
the elution there were obtained 64 mg of 
7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione. 
(v) A solution of 100 mg of 
7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione in 
10 ml of THF was added dropwise to a suspension of 152 mg of lithium 
aluminium hydride in 20 ml of THF. After completion of the addition the 
mixture was heated at reflux for 20 hours. 20 ml of water were added to 
the cooled mixture and the resulting mixture was extracted with diethyl 
ether. The etheral extracts were washed with water, dried and 
concentrated. There were obtained 62 mg of 
7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]. 
(vi) A solution of 680 mg of 
7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine] in 20 ml of 
dichloromethane was added dropwise to an ice-cold solution of 660 mg of 
di-tert.butyl dicarbonate and 300 mg of triethylamine in 25 ml of 
dichloromethane. After completion of the addition the mixture was stirred 
for 16 hours and washed in succession with dilute hydrochloric acid, 
saturated aqueous sodium bicarbonate solution and water. The organic phase 
was dried and concentrated to give a gum which, upon trituration with 
n-hexane, gave 711 mg of 
1'-(tert.butoxycarbonyl)-7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyr 
rolidine]. 
(vii) 300 mg of oxalyl chloride were added dropwise to a solution of 700 mg 
of the product of (vi) in 50 ml of dichloromethane at 0.degree. C. After 4 
hours, the solvent was removed under reduced pressure and the residue was 
dissolved in 50 ml of dichloromethane. The solution was added dropwise to 
a solution of 450 mg of 1-methylindole-3-acetic acid and 540 mg of 
triethylamine in 50 ml of dichloromethane. After 48 hours, the mixture was 
concentrated and the residue was chromatographed on silica gel using 
dichloromethane/methanol (95:5) for the elution. There were obtained 370 
mg of 
3-[1'-(tert.butoxycarbonyl)-7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'- 
pyrrolidin]-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione. 
EXAMPLE 2 
(A) A mixture of 1.08 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.11 g of 
methanol was added to a solution of 380 mg of 
3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[ 
1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 10 ml of DMF 
and the mixtue was stirred for 16 hours and subsequently poured into 50 ml 
of water. The resulting mixture was extracted with dichloromethane and the 
extracts were washed with sodium chloride solution, dried and 
concentrated. Chromatography of the residue on silica gel using 
dichloromethane/methanol (9:1) for the elution gave 220 mg of 
3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[ 
1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione. 
(B) In a manner analogous to that described in Example 1(B), from 150 mg of 
the product of Example 2(A) and 1 ml of trifluoroacetic acid there were 
obtained 25 mg of 
3-[7',9'-dihydrospiro-[piperidine-3,8'(6'H)-pyrido[1,2-a]indol]-10'-yl]-4- 
(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione trifluoroacetate of melting point 
172.degree. C. 
The furandione starting material was prepared as follows: 
(i) A mixture of 5 g of ethyl 
6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate. 1.85 g of methyl 
acrylate and 250 mg of 1,1,3,3-tetramethylguanidine was dissolved in 250 
ml of acetonitrile and the solution was stirred overnight, poured into 500 
ml of water containing 20 ml of 2M hydrochloric acid and extracted with 
diethyl ether. The ethereal extracts were washed with water, dried and 
concentrated. There were obtained 6.33 g of methyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-propionat 
e. 
(ii) 4.0 g of the product of (i) were dissolved in 100 ml of ethanol and 
treated with a suspension of Raney nickel in water. After heating under 
reflux for 4 hours, the mixture was cooled and filtered, and the residue 
was washed with ethyl acetate. The filtrate was extracted with ethyl 
acetate and the extracts and washings were dried and concentrated. 3.3 g 
of methyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-pyrido[1,2-a]indole-8-propionate 
were obtained. 
(iii) 3.2 g of the product of (ii) were added to a solution of 1.55 g of 
sodium hydroxide in 100 ml of ethanol and the mixture was heated at reflux 
for 2 hours. The cooled mixture was filtered and the residue was dissolved 
in 100 ml of water and acidified with 2N hydrochloric acid. The resulting 
precipitate was filtered off, washed with water and dried. There were 
obtained 2.2 g of 
8-carboxy-6,7,8,9-tetra-hydropyrido[1,2-a]indole-8-propionic acid. 
(iv) A mixture of 2.2 g of the product of (iii) and 1.44 g of ammonium 
carbonate was heated at 200.degree. C. for 3 hours, cooled and then 
chromatographed on silica gel using dichloromethane/methanol (9:1) for the 
elution to give 610 mg of 
7',9'-dihydrospiro[piperdine-3,8'(6'H)-pyrido[1.2-a]indole]-2,6-dione. 
(v) A solution of 610 mg of the product of (iv) in 10 ml of THF was added 
dropwise to a suspension of 0.865 g of lithium aluminium hydride in 20 ml 
of THF. After completion of the addition, the mixture was heated at reflux 
for 20 hours. 20 ml of water were added slowly to the cooled mixture and 
the resulting mixture was extracted with diethyl ether. The ethereal 
extracts were washed with water, dried and concentrated. There were 
obtained 456 mg of 
7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indole]. 
(vi) A solution of 456 mg of the product of (v) in 25 ml of dichloromethane 
was added dropwise to an ice-cold solution of 415 mg of di-tert.butyl 
dicarbonate and 192 mg of triethylamine in 25 ml of dichloromethane. After 
completion of the addition, the mixture was stirred for 16 hours and 
washed in succession with dilute hydrochloric acid, saturated aqueous 
sodium bicarbonate solution and water. The organic phase was dried and 
concentrated. These were obtained 611 mg of 
1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2 
-a]indole]. 
(vii) 251 mg of oxalyl chloride were added dropwise to a solution of 611 mg 
of the product of (vi) in 50 ml of dichloromethane at 0.degree. C. After 4 
hours, the solvent was removed under reduced pressure and the residue was 
dissolved in 50 ml of dichloromethane. The resulting solution was added 
dropwise to a solution of 374 mg of 1-methylindole-3-acetic acid and 454 
mg of triethylamine in 50 ml of dichloromethane. After 48 hours, the 
mixture was concentrated and the residue was chromatographed on silica gel 
using dichloromethane/methanol (95:5) for the elution. There were obtained 
394 mg of 
3-[1-(tert.butoxycarbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[ 
1,2-a]-indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione. 
EXAMPLE 3 
(A) A solution of 150 mg of 
cis-3-[2-(tert.butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)- 
pyrido-[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml 
of DMF and 5 ml of 33% aqueous ammonia was heated at 100.degree. C. for 1 
hour in a sealed vessel. The cooled reaction mixture was extracted with 
ethyl acetate and the organic extracts were washed with water, dried and 
evaporated. Crystallization of the residue from ethyl acetate/n-hexane 
gave 120 mg of 
cis-3-[2-(tert.butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)- 
pyrido[1,2a-]indol]-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of 
melting point 225.degree.-228.degree. C. 
(B) 110 mg of the product of (A) were dissolved in 25 ml of a saturated 
solution of hydrogen chloride in ethyl acetate. The resulting solution was 
left to stand at room temperature for 18 hours and the solid which formed 
was filtered off to give 80 mg of cis-3-[2-amino-8', 
9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indol]-10-yl]-4-(1-met 
hyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 
288.degree.-289.degree. C. (decomposition). 
The furandione starting material was prepared as follows: 
(i) 720 mg of a 60% suspension of sodium hydride in mineral oil and 3.96 g 
of trimethylsulphoxonium iodide were dissolved in 60 ml of DMSO (dimethyl 
sulphoxide). The mixture was stirred at room temperature for 45 minutes 
under a nitrogen atmosphere. A solution of 2.8 g of 
8,9-dihydropyrido[1,2-a]indol-7(6H)-one in 15 ml of DMSO was added and the 
solution obtained was stirred for 0.5 hour. The mixture was poured into 
300 ml of water and extracted with ethyl acetate. The organic extracts 
were washed with water, dried and evaporated under reduced pressure to 
give 2.6 g of a solid. A sample was triturated with n-hexane to give 
8',9'-dihydrospiro[oxirane-2,7'(6'H)-pyrido[1,2-a]-indole] of melting 
point 104.degree.-107.degree. C. 
(ii) A stirred solution of 6.27 g of triethylphosphonoacetate in 120 ml of 
dimethoxyethane was treated at room temperature under a nitrogen 
atmosphere with 1.12 g of a 60% suspension of sodium hydride in mineral 
oil. After 15 minutes, the solution obtained was treated with a solution 
of 2.8 g of the product of (i) in 20 ml of dimethoxyethane. The mixture 
was then heated to reflux for 20 hours. The cooled mixture was poured into 
300 ml of saturated ammonium chloride solution and the product was 
extracted with ethyl acetate. The organic extracts were washed with sodium 
chloride solution, dried and evaporated to give an oil which was purified 
by chromatography on silica gel using diethyl ether/n-hexane (1:3) for the 
elution. 2.05 g of ethyl 
8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indole]-2-carboxyla 
te were obtained. 
(iii) A solution of 2.0 g of the product of (ii) in 90 ml of ethanol was 
treated with a solution of 1.12 g of potassium hydroxide in 10 ml of 
water. The solution obtained was stirred for 6 hours and then poured into 
100 ml of 2M hydrochloric acid and the product was extracted with ethyl 
acetate. The organic extracts were washed with sodium chloride solution, 
dried and evaporated to give 1.74 g of 
8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indole]-2-carboxyli 
c acid. 
(iv) 1.16 g of the product of (iii) in 25 ml of acetone and 1 ml of water 
were cooled in an ice/salt bath. 586 mg of triethylamine and 678 mg of 
ethyl chloroformate were then added and the resulting solution was stirred 
for 0.5 hour. 406 mg of sodium azide were then added and the mixture was 
stirred at 0.degree. C. for 1 hour. The acetone was removed by evaporation 
and the residue was extracted with ethyl acetate. The organic extract was 
dried and evaporated. The residue was purified by chromatography on silica 
gel using diethyl ether/n-hexane (1:2) for the elution to give 980 mg of 
an oil. This oil was heated to 100.degree. C. in 25 ml of toluene for 2 
hours. The solvent was removed by evaporation to give 800 mg of 
8',9'-dihydrospiro-[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indol]-2-yl 
isocyanate. 
(v) A solution of 800 mg of the isocyanate of (iv) in 50 ml of dioxan was 
heated to 60.degree. C. for 2 hours with 5 ml of 2M hydrochloric acid and 
then at reflux for 1 hour. The solvent was removed under reduced pressure 
and the residue was partitioned between ethyl acetate and 2M sodium 
hydroxide solution. The organic extracts were washed with water, dried and 
evaporated. The obtained oil was purified by chromatography on silica gel 
using methanol/dichloromethane (1:19) for the elution, there being 
obtained 345 mg of 
cis-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indole]-2-amine 
and 90 mg of 
trans-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido-[1,2-a]indole]-2-am 
ine. 
(vi) A solution of 370 mg of the product of (v) in 30 ml of dichloromethane 
was treated at 0.degree. C. under a nitrogen atmosphere with 225 mg of 
triethylamine and 415 mg of di-tert.butyl dicarbonate. The solution 
obtained was stirred at 0.degree. C. for 3 hours and then at room 
temperature for 18 hours. The solvent was removed by evaporation and the 
residue was purified by chromatography on silica gel using diethyl 
ether/n-hexane (1:1) for the elution. Crystallization of the product from 
diethyl ether/n-hexane gave 330 mg of tert.butyl 
cis-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido-[1,2-a]indol]-2-ylcar 
bamate of melting point 114.degree.-116.degree. C. 
(vii) 152 mg of oxalyl chloride were added to a solution of 310 mg of the 
product of (vi) in 30 ml of diethyl ether under a nitrogen atmosphere. 
After 15 minutes, the solvent was removed under reduced pressure and the 
residue was dissolved in 30 ml of dichloromethane. 227 mg of 
1-methyl-3-indolylacetic acid and 240 mg of triethylamine were added to 
the solution and the solution obtained was stirred for 72 hours. The 
solvent was removed by evaporation and the residue was purified by 
chromatography on silica gel using ethyl acetate/n-hexane (1:1) for the 
elution. Crystallization from ethyl acetate gave 160 mg of 
cis-3-[2-(tert.-butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6'H) 
-pyrido[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione of 
melting point 210.degree.-213.degree. C. 
EXAMPLE 4 
(A) A solution of 90 mg of 
trans-3-[2-(tert.-butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6' 
H)-pyrido[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml 
of DMF and 5 ml of 33% aqueous ammonia was heated to 100.degree. C. for 1 
hour in a sealed vessel. The cooled mixture was extracted with ethyl 
acetate and the organic extracts were washed with water, dried and 
evaporated to dryness. Crystallization of the residue from ethyl acetate 
gave 70 mg of 
trans-3-[2-(tert.-butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6' 
H)-pyrido[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione 
of melting point 250.degree.-250.degree. C. 
(B) 65 mg of the product of (A) were dissolved in 25 ml of a saturated 
solution of hydrogen chloride in ethyl acetate. The resulting solution was 
left to stand at room temperature for 18 hours and the solid formed was 
filtered off to give 45 mg of 
trans-3-[2-amino-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]in 
dol]-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride in 
the form of an orange colored solid of melting point 
260.degree.-264.degree. C. (decomposition). 
The furandione starting material was prepared as follows: 
(i) A solution of 180 mg of 
trans-8',9'-dihydro-spiro[cyclopropane-1,7'(6'H)-pyrido[1,2-a]indole]-2-am 
ine [prepared as described in Example 3(v)] in 25 ml of dichloromethane was 
treated at 0.degree. C. under a nitrogen atmosphere with 110 mg of 
triethylamine and 230 mg of di-tert.butyl dicarbonate. The solution 
obtained was stirred at 0.degree. C. for 3 hours and then at room 
temperature for 3 hours. The solvent was removed by evaporation and the 
residue was purified by chromatography on silica gel using diethyl 
ether/n-hexane (1:1) for the elution. Crystallization of the product from 
diethyl ether/n-hexane gave 190 mg of tert.butyl 
trans-8',9'-dihydrospiro[cyclopropane-1,7'(6'H)-pyrido[1,2a]indol]-2-ylcar 
bamate of melting point 154.degree.-156.degree. C. 
(ii) 90 mg of oxalyl chloride were added to a solution of 180 mg of the 
product of (i) in 20 ml of diethyl ether under a nitrogen atmosphere. 
After stirring for 15 minutes, the solvent was removed under reduced 
pressure and the residue was dissolved in 20 ml of dichloromethane. 132 mg 
of 1-methyl-3-indolylacetic acid and 142 mg of triethylamine were added 
and the solution obtained was stirred for 72 hours. The solvent was 
removed by evaporation and the residue was purified by chromatography on 
silica gel using ethyl acetate/n-hexane (1:1) for the elution. 
Crystallization from ethyl acetate gave 100 mg of 
trans-3-[2-(tert-butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6'H 
)-pyrido[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione of 
melting point 187.degree.-193.degree. C. 
EXAMPLE 5 
(A) A solution of 700 mg of 
cis-3-[2-(tert.butoxy-carbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4' 
:4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 6 
ml of DMF and 6 ml of 33% aqueous ammonia was heated to 100.degree. C. for 
2.5 hours in a sealed vessel. The mixture was left to cool and the solid 
formed was filtered off and dried to give 400 mg of 
cis-3-[2-(tert.butoxycarbonyl)-2,3,3a,4, 
11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]-indol-10-yl]-4-(1-meth 
yl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 173.degree.-175.degree. 
C. 
(B) A stirred solution of 400 mg of the product of (A) in 15 ml of 
dichloromethane was treated with 3 ml of trifluoroacetic acid. After 0.5 
hour the solvent was removed under reduced pressure and the residue was 
triturated with 10 ml of methanol to give 270 mg of cis-3-[2,3,3a,4,11, 
11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3 
-indolyl)-1H-pyrrole-2,5-dione trifluoroacetate of melting point 
268.degree.-269.degree. C. 
The furandione starting material was prepared as follows: 
(i) 200 ml of a 2M solution of lithium borohydride in THF were added 
dropwise to a stirred solution of 100 g of methyl 
1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 600 ml of THF under a nitrogen 
atmosphere. After 3 hours, the mixture was cooled to 10.degree. C. and 
treated with 200 ml of 50% aqueous acetic acid. The solvents were removed 
under reduced pressure and the residue was partitioned between 
dichloromethane and saturated sodium bicarbonate solution. The organic 
extracts were dried and evaporated to dryness to give 92 g of 
1-benzyl-4-(hydroxymethyl)-2-pyrrolidinone. This was dissolved in 200 ml 
of pyridine and the solution was treated with 95 g p-toluenesulphonyl 
chloride. The solution obtained was stirred for 18 hours and then 
concentrated. The residue was partitioned between dichloromethane and 2M 
hydrochloric acid. The organic phase was washed with water, dried and 
evaporated to dryness. Crystallization of the residue from diethyl 
ether/n-hexane gave 115 g of 
1-benzyl-4-(p-toluenesulphonyloxy)-2-pyrrolidinone of melting point 
83.degree.-84.degree. C. 
(ii) A solution of 66.2 g of ethyl indole-2-carboxylate in 350 ml of DMF 
was added to a suspension of 12 g of sodium hydride (80% dispersion in 
mineral oil) in 80 ml of DMF. After stirring for 0.5 hour under a nitrogen 
atmosphere the solution obtained was treated with a solution of 115 g of 
1-benzyl-4-(p-toluenesulphonyloxy)-2-pyrrolidinone in 500 ml of DMF. After 
completion of the addition the mixture was heated to 60.degree. C. for 
0.75 hour and then at 70.degree. C. for 1 hour. The solution obtained was 
cooled in an ice bath and treated with water and 2M hydrochloric acid. 
After stirring for 15 minutes the precipitate formed was filtered off and 
dried to give 96.2 g of ethyl 
1-[(1-benzyl-5-oxo-3-pyrrolidinyl)methyl]-2-indolecarboxylate of melting 
point 93.degree.-94.degree. C. 
(iii) A solution of 95 g of the product of (ii) in 400 ml of THF was added 
to a stirred solution of 30.3 of potassium tert.butoxide in 1500 ml of THF 
under a nitrogen atmosphere. The mixture was stirred for 1.5 hours and 
then cooled to 10.degree. C. and treated with 300 ml of 1M hydrochloric 
acid. The precipitate formed was filtered off and dried, and the filtrate 
was concentrated to give a further precipitate. This precipitate was 
filtered off, dried and combined with the initially obtained precipitate 
to give a total of 54.6 g of 
2-benzyl-3,3a,4,11a-tetrahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indole-1 
,12(2H)-dione of melting point 228.degree.-229.degree. C. 
(iv) Raney nickel was added to a suspension of 12 g of the product of (iii) 
in 600 ml of ethanol and 300 ml of water. The mixture was heated to reflux 
for 3.25 hours, cooled and decanted. The ethanol was removed under reduced 
pressure and the residue was extracted with ethyl acetate. The catalyst 
was washed with 300 ml of ethyl acetate and the organic phase was washed 
with water, dried and concentrated. The precipitate formed was filtered 
off to give 5.4 g of 
2-benzyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido-[1,2-a]indo 
l-1one of melting point 121.degree.-123.degree. C. 
(v) A solution of 10 g of the product of (iv) in 150 ml of THF was added to 
a stirred 1M solution of borane in 60 ml of THF at 0.degree. C. under 
nitrogen. The resulting solution was heated to reflux for 1.5 hours, 
cooled, treated with 30 ml of methanol and 15 ml of 5M sodium hydroxide 
solution and subsequently heated to reflux for 1.5 hours. The solvent was 
removed under reduced pressure and the residue was partitioned between 
dichloromethane and water. The organic phase was washed with saturated 
sodium bicarbonate solution and with water, dried and evaporated to 
dryness to give 8 g of 
cis-2-benzyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]i 
ndole of melting point 91.degree.-93.degree. C. 
(vi) A solution of 23.5 g of the product of (v) in 500 ml of methanol was 
added to 12 g of 10% palladium-on-charcoal and 24 g of ammonium formate. 
The mixture was heated to reflux under a nitrogen atmosphere for 2.5 
hours. The cooled mixture was filtered and the filter residue was washed 
with methanol. The filtrate and washings were evaporated and the residue 
was partitioned between dichloromethane and water. The aqueous phase was 
extracted with dichloromethane and the organic extracts were dried and 
evaporated to give 16.9 g of 
cis-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indole. 
(vii) A stirred solution of the product of (vi) in 500 ml of 
dichloromethane was treated at 0.degree. C. under a nitrogen atmosphere 
with 18.6 g of di-tert.butyl dicarbonate and 8.7 g of triethylamine. The 
solution obtained was stirred for 18 hours, washed with water, dried and 
the solvent was evaporated. The residue was crystallized from diethyl 
ether/dichloromethane to give 15.2 g of 
cis-2-(tert.butoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5 
]-pyrido[1,2-a]indole of melting point 143.degree.-144.degree. C. 
(viii) 1.95 g of oxalyl chloride were added to a solution of 4.9 g of the 
product of (vii) in 150 ml of dichloromethane at 0.degree. C. under a 
nitrogen atmosphere. After 15 minutes, the solvent was removed under 
reduced pressure and the residue was dissolved in 150 ml of 
dichloromethane. 2.97 g of 1-methyl-3-indolylacetic acid and 6.5 ml of 
triethylamine were added to this solution at 0.degree. C. The mixture was 
then stirred for 72 hours. The solvent was removed by evaporation and the 
residue was purified by chromatography on silica gel using ethyl 
acetate/n-hexane (1:1) for the elution to give 2.1 g of 
cis-3-[2-tert.butoxycarbonyl)-2,3,3a,4, 
11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methy 
l-3-indolyl)furan-2,5-dione of melting point 209.degree. C. after 
recrystallization from ethyl acetate/n-hexane. 
EXAMPLE 6 
A solution of 120 mg of 
cis-[3-2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2- 
a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione acetate in 6 ml of DMF 
and 5 ml of 33% aqueous ammonia was heated to 120.degree. C. in a sealed 
vessel for 3 hours. The solvent was removed under reduced pressure and the 
residue was partitioned between ethyl acetate and aqueous sodium 
bicarbonate solution. The organic phase was dried, concentrated and 
treated with a saturated solution of hydrogen chloride in ethyl acetate. 
The obtained precipitate was filtered off and dried to give 80 mg of 
cis-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido-[1,2 
-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride 
of melting point 308.degree.-310.degree. C. 
The furandione acetate used as the starting material was prepared as 
follows: 
(i) A stirred solution of 5 g of 
cis-3-[2-(tertbutoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4 
,5]-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione 
[prepared as described in Example 5(viii)] in 200 ml of dichloromethane 
was treated with 30 ml of trifluoroacetic acid. After 0.5 hour the solvent 
was removed under reduced pressure and the residue was purified by 
chromatography on silica gel using dichloromethane/methanol/acetic 
acid/water (90:18:3:2) for the elution. Removal of the solvent gave 4.5 g 
of cis-3-[2,3,3a,4,11, 
11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3 
-indolyl)furan-2,5-dione trifluoroacetate of melting point 
199.degree.-201.degree. C. 
(ii) 28.5 mg of sodium cyanoborohydride were added to a stirred solution of 
250 mg of the product of (i) and 67.5 mg of 40% aqueous formaldehyde in 33 
ml of acetonitrile. After 0.5 hour the solvent was removed by evaporation 
and the residue was purified by chromatography on silica gel using 
dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. 
Evaporation gave 140 mg of 
cis-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2- 
a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione acetate. A sample of 
this solid was stirred with a saturated solution of hydrogen chloride in 
ethyl acetate and the resulting precipitate was filtered off and dried to 
give 
cis-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1,2- 
a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride of 
melting point 183.degree.-186.degree. C. 
EXAMPLE 7 
A solution of 200 mg of 
cis-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-1 
0-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione trifluoroacetate [prepared as 
described in Example 6(i)] and 760 mg of benzaldehyde in 30 ml of methanol 
was shaken with 20 mg of 10% palladium-on-charcoal under a hydrogen 
atmosphere. The catalyst was filtered off and the filtrate was evaporated 
to dryness. The residue was purified by chromatography on silica gel using 
methanol/dichloromethane (1:19) for the elution to give an oil which was 
dissolved in 4 ml of DMF. The solution obtained was treated with 2.5 g of 
1,1,1,3,3,3-hexamethyldisilazane and then 250 mg of methanol and the 
mixture was stirred at room temperature for 4 days. The solvent was 
removed by evaporation and the residue was partitioned between ethyl 
acetate and sodium bicarbonate solution. The organic phase was dried, 
concentrated and then treated with a saturated solution of hydrogen 
chloride in ethyl acetate to give a precipitate which was filtered off and 
dried. There were thus obtained 60 mg of 
cis-3-[2-benzyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2- 
a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of 
melting point 228.degree.-232.degree. C. 
EXAMPLE 8 
A stirred suspension of 200 mg of 
cis-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]-indol- 
10-yl]-4-(1-methyl-3indolyl)furan-2,5-dione trifluoroacetate [prepared as 
described in Example 6(i)] in 15 ml of acetic acid was treated with 100 mg 
of acetone. After 5 minutes, 38 mg of sodium borohydride were added. The 
mixture was then heated to 50.degree. C. for 10 minutes. A further 200 mg 
of acetone and 50 mg of sodium borohydride were added and the mixture was 
heated at 50.degree. C. for 1.5 hours. The solvent was removed under 
reduced pressure and the residue was purified by chromatography on silica 
gel using methanol/dichloromethane (1:9) for the elution. The obtained oil 
was dissolved in 5 ml of DMF and the solution obtained was treated with 
2.5 g of 1,1,1,3,3,3-hexamethyldisilazane followed by 250 mg of methanol 
and stirred at room temperature for 18 hours. The solvents were removed 
by evaporation and the residue was partitioned between ethyl acetate and 
aqueous sodium bicarbonate solution. The organic extracts were dried and 
concentrated. 0.5 ml of a saturated solution of hydrogen chloride in ethyl 
acetate was then added to give a precipitate which was filtered off and 
dried. There were thus obtained 80 mg of 
cis-3-[2-isopropyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1 
,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride 
of melting point 318.degree.-320.degree. C. 
EXAMPLE 9 
A stirred solution of 200 mg of cis-3-[2,3,3a, 
4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-met 
hyl-3-indolyl)furan-2,5-dione trifluoroacetate [prepared as described in 
Example 6(i)] in 40 ml of acetic acid was heated to 55.degree. C. 67 mg of 
sodium borohydride were then added and the solution obtained was heated at 
55.degree. C. for 1 hour. The solvent was removed under reduced pressure 
and the residue was purified by chromatography on silica gel using 
methanol/dichloromethane (1:9) for the elution. The obtained oil was 
dissolved in 2 ml of DMF and the solution obtained was treated with 1 g of 
1,1,1,3,3,3-hexamethyldisilazane followed by 100 mg of methanol. The 
mixture was stirred for 18 hours, the solvents were removed under reduced 
pressure and the residue was partitioned between ethyl acetate and aqueous 
sodium bicarbonate solution. The organic extracts were dried, concentrated 
and treated with a saturated solution of hydrogen chloride in ethyl 
acetate. The obtained precipitate was filtered off and dried to give 35 mg 
of 
cis-3-[2-ethyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a 
]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of 
melting point 327.degree.-329.degree. C. 
EXAMPLE 10 
A solution of 4.5 g of 
cis-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-1 
0-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione trifluoroacetate [prepared as 
described in Example 6(i)] and 6 g of 40% aqueous formaldehyde in 200 ml 
of methanol was heated to reflux for 2.5 hours with Raney nickel. The 
cooled solution was filtered and the filtrate was evaporated. The obtained 
solid was dissolved in 20 ml of DMF and 20 ml of 33% aqueous ammonia and 
the solution obtained was heated at 140.degree. C. in a sealed vessel. The 
cooled solution was partitioned between ethyl acetate and sodium 
bicarbonate solution. The organic extracts were dried and evaporated. The 
residue was purified by chromatography on silica gel using 
dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. 
Crystallization from methanol gave 70 mg of 
cis-3-[2-formyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2- 
a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 
334.degree.-336.degree. C. 
EXAMPLE 11 
(A) A mixture of 0.59 ml of 1,1,1,3,3,3-hexamethyldisilazane and 45 mg of 
methanol was added to a solution of 150 mg of 
3-[1-(tert.butoxy-carbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1, 
2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione in 10 ml of DMF 
and stirred for 72 hours. The solvent was removed by evaporation and the 
residue was treated with 10 ml of methanol. After evaporation, the residue 
was subjected to chromatography on silica gel using dichloromethane/ethyl 
acetate (4:1) for the elution. There were obtained 120 mg of 
3-[1-(tert.butoxycarbonyl)-1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2 
-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting 
point 232.degree.-235.degree. C. 
(B) A suspension of 110 mg of the product of (A) in 1 ml of ethyl acetate 
was treated with 5 ml of a saturated solution of hydrogen chloride in 
ethyl acetate and stirred for 24 hours. The suspension was filtered and 
the solid was dried to give 85 mg of 
3-[1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl]-4-(1-me 
thyl)-3-indolyl)-1H-pyrole-2,5-dione hydrochloride of melting point 
342.degree. C. (decomposition). 
The furandione starting material was prepared as follows: 
(i) A solution of 17.7 g of ethyl 
2-(ethoxy-carbonyl)-2,3-dihydro-1-oxo-1H-pyrrolo[1,2-a]indole-2-acetate in 
200 ml of methanol was treated under a nitrogen atmosphere with 1.5 g of 
10% palladium-on-charcoal and 10 g of ammonium formate. The mixture was 
heated at reflux for 1.5 hours, then cooled and filtered. The filtrate was 
concentrated and the residue was partitioned between ethyl acetate and 
water. The organic layer was washed with sodium chloride solution and 
dried. Evaporation of the solvent gave 16.5 g of ethyl 
2-(ethoxycarbonyl)-2,3-dihydro-1-hydroxy-1H-pyrrolo[1,2-a]indole-2-acetate 
(ii) A solution of 16.5 g of the product of (i) in 200 ml of 
dichloromethane was treated under a nitrogen atmosphere with 14 ml of 
triethylamine and 7.6 g of acetic anhydride. Then the solvent was removed 
by evaporation. The residue was evaporated with toluene and then dissolved 
in methanol under a nitrogen atmosphere. 1.5 g of 10% 
palladium-on-charcoal and 10 g of ammonium formate were added and the 
mixture was heated at reflux for 4 hours. The suspension was cooled and 
filtered, and the filtrate was concentrated. The residue was partitioned 
between ethyl acetate and water. The organic phase was dried and 
concentrated. Chromatography of the residue on silica gel using ethyl 
acetate/n-hexane (1:3) for the elution gave 9.65 g of ethyl 
2-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-acetate. 
(iii) A solution of 1.2 g of the product of (ii) in 25 ml of ethanol was 
treated with 7.6 ml of 2M aqueous sodium hydroxide and the mixture was 
heated under reflux for 17 hours. The solution was concentrated and the 
residue was diluted with water. The solution was washed with ethyl acetate 
and acidified with 2M aqueous hydrochloric acid. The mixture was extracted 
with dichloromethane and the extracts were washed with sodium chloride 
solution. The organic phase was dried and concentrated. Trituration of the 
residue with diethyl ether gave 714 mg of 
2-carboxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-acetic acid of melting 
point 211.degree.-215.degree. C. (decomposition). 
(iv) A mixture of 650 mg of the product of (iii) and 480 mg of ammonium 
carbonate was heated at 200.degree. C. under a nitrogen atmosphere. After 
cooling, the residue was partitioned between dichloromethane and water. 
The organic phase was dried and concentrated to give 594 mg of 
1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione of 
melting point 215.degree.-220.degree. C. 
(v) A solution of 580 mg of the product of (iv) in 5 ml of THF was added 
under a nitrogen atmosphere to a stirred suspension of 920 mg of lithium 
aluminum hydride in 10 ml of THF. The mixture was heated at reflux for 2 
hours, cooled and treated with 10 ml of water and 2 ml of 2M aqueous 
sodium hydroxide. The suspension was filtered and the solid was washed 
with ethyl acetate. The filtrate was separated and the aqueous layer was 
extracted with ethyl acetate. The organic solutions were washed with 
sodium chloride solution and concentrated to give 510 mg of 
1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole] of melting point 
90.degree.-92.degree. C. 
(vi) A solution of 500 mg of the product of (v) in 15 ml of dichloromethane 
was treated with 0.4 ml of triethylamine and 580 mg of di-tert.butyl 
dicarbonate and stirred for 17 hours. The solvent was removed by 
evaporation. Chromatography of the residue on silica gel using ethyl 
acetate/n-hexane (1:2) for the elution gave 440 mg of 
1-(tert.butoxycarbonyl)-1',3'-dihydrospiro-[pyrrolidine-3,2'-pyrrolo[1,2-a 
]indole] of melting point 104.degree.-106.degree. C. 
(vii) In a manner analogous to that described in Example 1(vii) from 430 mg 
of the product of (vi) there were obtained 160 mg of 
3-[1-(tert.butoxycarbonyl)-1',3'-dihydrospiro-[pyrrolidine-3,2'-pyrrolo[1, 
2-a]indol]-9'-yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione. 
EXAMPLE 12 
A solution of 360 mg of 
3-[1',3'-dihydro-1-methylspiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol-9'-yl] 
-4-(1-methyl-3-indolyl)-furan-2,5-dione in 10 ml of DMF was treated with 
1.7 ml of 1,1,1,3,3,3-hexamethyldisilazane and 128 mg of methanol. The 
solution was heated at 60.degree. C. for 17 hours and the solvent was 
removed by evaporation. The residue was evaporated with 10 ml of methanol 
and purified by chromatography on silica gel using 
dichloromethane/methanol (9:1) for the elution. The solid obtained was 
suspended in ethyl acetate and treated with a saturated solution of 
hydrogen chloride in ethyl acetate. After stirring, the suspension was 
filtered and the solid was washed with diethyl ether to give 250 mg of 
3-[1',3'-dihydro-1-methylspiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indol]-9'-yl 
]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting 
point 250.degree.-252.degree. C. 
The furandione starting material was prepared as follows: 
(i) A solution of 1.96 g of 
1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione 
[prepared as described in Example 11(iv)] in 10 ml of DMF was added 
dropwise to a stirred suspension of 330 mg of a 60% dispersion of sodium 
hydride in mineral oil in 10 ml of DMF. The mixture was treated with 1 ml 
of iodomethane and stirred for 17 hours. The mixture was diluted with 
water, neutralized with 1M aqueous hydrochloric acid and extracted with 
ethyl acetate. The extracts were washed with sodium chloride solution, 
dried and the solvent was removed by evaporation. Crystallization of the 
residue from ethyl acetate/n-hexane gave 1.81 g of 
1',3'-dihydro-1-methylspiro-[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-di 
one of melting point 154.degree.-156.degree. C. 
(ii) In a manner analogous to Example 11(v), from 1.8 g of the product of 
(i) there were obtained 1.07 g of 
1',3'-dihydro-1-methylspiro-[pyrrolidine-3,2'-pyrrolo[1,2-a]indole] of 
melting point 81.degree.-83.degree. C. 
(iii) A solution of 1.03 g of the product of (ii) in 10 ml of ethyl acetate 
was treated with 2 ml of a saturated solution of hydrogen chloride in 
ethyl acetate. After 1 hour, the solvent was removed by evaporation and 
the residue was dissolved in 20 ml of dichloromethane under a nitrogen 
atmosphere. The solution was cooled to -78.degree. C. and treated with 0.4 
ml oxalyl chloride. After 15 minutes, a mixture of 860 mg of 
1-methyl-indole-3-acetic acid and 2.5 ml of triethylamine dissolved in 20 
ml of dichloromethane was added. The mixture was stirred at -78.degree. C. 
for 1 hour and then left to warm to room temperature. The solvent was 
removed by evaporation and the residue was subjected to chromatography on 
silica gel using dichloromethane/methanol/acetic acid/water (120:14:3:2) 
for the elution. The product was dissolved in dichloromethane and the 
solution was washed with saturated aqueous sodium bicarbonate. The organic 
phase was dried and evaporated to give 380 mg of 
3-[1',3'-dihydro-1-methylspiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole-9'-yl 
]-4-(1-methyl-3-indolyl)-furan-2,5-dione. 
EXAMPLE 13 
In a manner analogous to that described in Example 11, from 285 mg of 
3-[8,9-dihydro-1'-methylspiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidin]-10- 
yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione there were obtained 232 mg of 
3-[8,9-dihydro-1'-methylspiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidin]-10- 
yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting 
point 220.degree. C. (decomposition). 
The furandione starting material was prepared as follows: 
(i) A stirred solution of 2.52 ml of diisopropylamine in 20 ml of THF was 
cooled in a bath at -78.degree. C. under an argon atmosphere and treated 
with 11.25 ml of a 1.6M solution of n-butyllithium in n-hexane. The 
mixture was treated with a solution of 2.85 g of ethyl 
6,7,8,9-tetrahydropyrido[1,2-a]indole-7-carboxylate in 80 ml of THF. After 
10 minutes, 1.46 ml of ethyl bromoacetate were added and the cooling bath 
was removed. The mixture was stirred and then diluted with diethyl ether. 
The solution was washed in succession with saturated aqueous ammonium 
chloride, water and sodium chloride solution and then dried. The solvent 
was removed by evaporation and the residue was subjected to chromatography 
on silica gel using ethyl acetate/n-hexane (1:9) for the elution to give 
2.55 g of ethyl 
7-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido-[1,2-a]indole-7-acetate. 
(ii) In a manner analogous to that described in Example 11(iii), from 2.5 g 
of the product of (i) there were obtained 1.95 g of 
7-(carboxy)-6,7,8,9-tetrahydropyrido[1,2-a]indole-7-acetic acid of melting 
point 185.degree.-188.degree. C. 
(iii) In a manner analogous to that described in Example 11(iv), from 2.02 
g of the product of (ii) there were obtained 1.8 g of 
8,9-dihydrospiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidine]-2',5'-dione of 
melting point 208.degree.-210.degree. C. 
(iv) In a manner analogous to that described in Example 12(i), from 1.04 g 
of the product of (iii) there were obtained 780 mg of 
8,9-dihydro-1'-methylspiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidine]-2',5' 
-dione of melting point 158.degree.-164.degree. C. 
(v) In a manner analogous to that described in Example 11(v), from 930 mg 
of the product of (iv) there were obtained 470 mg of 
8,9-dihydro-1'-methylspiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidine] of 
melting point 55.degree.-58.degree. C. 
(vi) In a manner analogous to that described in Example 12(iii), from 460 
mg of the product of (v) there were obtained 280 mg of 
3-[8,9-dihydro-1'-methylspiro[pyrido[1,2-a]indole-7(6H),3'-pyrrolidin]-10- 
yl]-4-(1-methyl-3-indolyl)-furan-2,5-dione of melting point 
238.degree.-240.degree. C. 
EXAMPLE 14 
A mixture of 1.21 g of 1,1,1,3,3,3-hexamethyldisilazane and 132 mg of 
methanol was added to a solution of 400 mg of 
trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]-pyrido[1 
,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride in 30 
ml of DMF and stirred for 48 hours. A further 100 mg of methanol and 0.95 
g of 1,1,1,3,3,3-hexamethyldisilazane were added, the mixture was heated 
to 45.degree. C. for 2 hours and then left to stand at room temperature. 
The solvent was removed under reduced pressure and the residue was 
dissolved in ethyl acetate, dichloromethane and methanol. The solution 
obtained was washed with saturated sodium bicarbonate solution and the 
organic layer was concentrated. A saturated solution of hydrogen chloride 
in ethyl acetate was added and the precipitate obtained was filtered off. 
The solid was suspended in water and stirred, then filtered off and dried. 
The solid obtained was suspended in ethyl acetate and stirred, then 
filtered off and dried to give 235 mg of 
trans-3-(2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1, 
2-a]indol-10-yl)-4 -(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride 
of melting point &gt;330.degree. C. 
The furandione hydrochloride used as the starting material was prepared as 
follows: 
(i) From a mixture of 29.3 g of diethyl 
6,7-dihydro-9-hydroxypyrido[1,2-a]indole-7,8-dicarboxylate, 100 ml of 
pyridine and 30 ml of acetic anhydride, the solvents were removed under 
reduced pressure and the residue was partitioned between ethyl acetate and 
2M hydrochloric acid. The organic extract was washed with saturated sodium 
bicarbonate solution and water, dried and evaporated to give 33 g of 
diethyl 9-acetoxy-6,7-dihydropyrido[1,2-a]indole-7,8-dicarboxylate. 
(ii) A solution of 33 g of the product of (i) in 250 ml of ethanol and 25 g 
of triethylamine was hydrogenated over 10% palladium-on-charcoal. The 
catalyst was filtered off and the filtrate was evaporated. The residue was 
partitioned between ether and water and the organic layer was washed in 
succession with 2M hydrochloric acid, water and saturated sodium 
bicarbonate solution. The organic extract was dried and evaporated. The 
oil obtained was dissolved in ethanol and the solution was treated with 
sodium ethoxide and stirred for 1 hour. The solution was cooled to 
0.degree. C. and the solid was filtered off and dried to give 15.9 g of 
trans-diethyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-7,8-dicarboxylate of 
melting point 74.degree.-76.degree. C. 
(iii) A stirred solution of 10.0 g of the product of (ii) in 150 ml of THF 
was treated at 0.degree. C. under a nitrogen atmosphere with 40 ml of a 1M 
solution of lithium aluminium hydride in diethyl ether. After stirring, 
1.4 ml of water were added, followed by 2.3 ml of 2M sodium hydroxide and 
3.5 ml of water. The precipitate was filtered off and washed with 
THF/diethyl ether (1:1). The filtrate was evaporated to give 6.8 g of 
trans-6,7,8,9-tetrahydropyrido[1,2-a]indole-7,8-dimethanol of melting 
point 162.degree.-163.degree. C. 
(iv) A stirred solution of 6.8 g of the product of (iii) in 150 ml of 
dichloromethane was treated with 35 ml of triethylamine and then 11.3 g of 
methanesulphonic anhydride were added. The solution was stirred under a 
nitrogen atmosphere and then diluted with dichloromethane. The solution 
was washed with water, 2M hydrochloric acid and water, dried and 
evaporated. Ethanol was added and the solvent was removed under reduced 
pressure to give 10.3 g of 
trans-6,7,8,9-tetrahydro-7,8-bis[(methanesulphonyloxy)methyl]pyrido[1,2-a] 
indole. A sample was purified by chromatography on silica gel using ethyl 
acetate/petroleum ether (2:1) for the elution to give a solid of melting 
point 139.degree.-141.degree. C. 
(v) A solution of 8.0 g of the product of (iv) and 20.0 g of benzylamine in 
700 ml of toluene was heated to reflux under a nitrogen atmosphere. The 
solvent was removed under reduced pressure and the residue was purified by 
chromatography on silica gel using methanol/dichloromethane (1:50 to 1:20) 
for the elution to give 6.55 g of 
trans-2-benzyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a 
]indole of melting point 114.degree.-116.degree. C. 
(vi) A solution of 3.0 g of the product of (v) in 150 ml of methanol was 
treated with 3.0 g of ammonium formate and 1.2 g of 10% 
palladium-on-charcoal. The mixture was heated to reflux and then filtered. 
The catalyst was washed with methanol and the filtrates were evaporated. 
The residue was partitioned between ethyl acetate and water and the solid 
was filtered off. This solid was suspended in a saturated solution of 
hydrogen chloride in ethyl acetate and stirred, then filtered off and 
dried to give 2.0 g of 
trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indole 
hydrochloride of melting point 308.degree.-311.degree. C. 
(vii) A solution of 1.97 g of the product of (vi) in 300 ml of 
dichloromethane was treated with 1.72 g of triethylamine. The mixture 
obtained was cooled to 0.degree. C. under a nitrogen atmosphere and was 
treated with 1.87 g of di-tert.butyl dicarbonate. After stirring, the 
mixture was washed with water, 2M hydrochloric acid, water and saturated 
sodium bicarbonate solution and then dried. The solvent was removed under 
reduced pressure to give 2.4 g of a solid. A sample was triturated with 
petroleum ether to give 
trans-2-(tert.-butoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4': 
4,5]-pyrido[1,2-a]indole of melting point 217.degree.-218.degree. C. 
(viii) 1.08 g of oxalyl chloride were added to a solution of 2.7 g of the 
product of (vii) in 100 ml of dichloromethane at 0.degree. C. After 0.25 
hour, the solvent was removed under reduced pressure and the residue was 
dissolved in dichloromethane. The solution was added to a stirred solution 
of 2.5 ml triethylamine and 1.64 g of 1-methylindole-3-acetic acid in 50 
ml of dichloromethane. After 24 hours, the solution was washed with water 
and saturated sodium bicarbonate solution, dried and evaporated. The 
residue was purified by chromatography on silica gel using ethyl 
acetate/petroleum ether (1:1) for the elution to give 1.2 g of 
trans-3-[2-(tert.butoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4 
':4,5]pyrido[1,2-a]indol-10-y1]-4-(1-methyl-3-indolyl)furan-2,5-dione of 
melting point 265.degree.-266.degree. C. 
(ix) A suspension of 900 mg of the product of (viii) in 5 ml of ethyl 
acetate was treated with 10 ml of a saturated solution of hydrogen 
chloride in ethyl acetate. After 2 hours, the solid was filtered off and 
dried to give 720 mg of 
trans-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol 
-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride of melting 
point&gt;340.degree. C. 
(x) A suspension of 640 mg of the product of (ix) in 190 ml of methanol was 
treated with Raney nickel and 325 mg of 40% aqueous formaldehyde and the 
mixture obtained was heated to reflux for 3 hours. After each 0.5 hour a 
further 250 mg of aqueous formaldehyde were added. The cooled supernatant 
was decanted off and the residue was washed with methanol. The organic 
solution was evaporated and the residue was suspended in ethyl acetate and 
treated with a saturated solution of hydrogen chloride in ethyl acetate. 
The solid was filtered off and dried to give 445 mg of 
trans-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]pyrido[1, 
2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride of 
melting point 244.degree.-247.degree. C. 
EXAMPLE 15 
In a manner analogous to that described in Example 11, from 
trans-3-[2-(tert.butoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4 
':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione 
[prepared as described in Example 14], there was obtained 
trans-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol 
-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of 
melting point 269.degree.-273.degree. C. 
EXAMPLE 16 
In a manner analogous to that described in Example 14, from 
(+)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indo 
le formate there was obtained 
(+)-trans-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]-pyri 
do[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione 
hydrochloride of melting point 325.degree.-328.degree. C.; 
[.alpha.].sub.D.sup.20 =+65.1.degree. (MeOH, c=0.06). 
The pyridoindole formate used as the starting material was prepared as 
follows: 
(i) A suspension of 11.0 g of 
trans-6,7,8,9-tetrahydro-7,8-bis[(methanesulphonyloxy)methyl]pyrido[1,2-a] 
indole [prepared as described in Example 14(iv)] in 60 ml of ethanol was 
treated with 26 ml of (S)-.alpha.-methylbenzylamine and heated to reflux 
for 18 hours. The cooled solution was concentrated and the precipitate was 
filtered off and purified by chromatography on silica gel using ethyl 
acetate/petroleum ether (2:1) for the elution. There were obtained 2.1 g 
of trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3' 
,4':4,5]pyrido[1,2-a]indole, diastereomer A, of melting point 153.degree. 
C., [.alpha.].sub.D.sup.20 =+17.7.degree. (CHCl.sub.3, c=0.51), and 1.6 g 
of 
trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4' 
:4,5]pyrido[1,2-a]indole, diastereomer B, of melting point 
154.degree.-156.degree. C.; [.alpha.].sub.D.sup.20 =-54.2.degree. 
(CHCl.sub.3, c=0.49). 
(ii) A suspension of 1.4 g of the obtained diastereomer A in 80 ml of 
methanol was treated with 10% palladium-on-charcoal and 1.4 g of ammonium 
formate. The mixture was heated to reflux, then cooled and filtered. The 
catalyst was washed with methanol and the filtrates were evaporated. 
Crystallization from ethyl acetate gave 0.87 g of 
(+)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indo 
le formate of melting point 188.degree.-190.degree. C.; 
[.alpha.].sub.D.sup.20 =+49.degree. (MeOH, c=0.04). 
EXAMPLE 17 
In a manner analogous to that described in Example 14, from 
(-)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]ind 
ole formate there was obtained 
(-)-trans-3-[2,3,3a,4,11,11a-hexahydro-2-methyl-1H-pyrrolo[3',4':4,5]-pyri 
do[1,2-a]indol-10yl]-4-(1-methyl-3-indoly)-1H-pyrrole-2,5-dione 
hydrochloride of melting point 339.degree.-340.degree. C.; 
[.alpha.].sub.D.sup.20 =-108.degree. (MeOH, c=0.02). 
The pyridoindole formate used as the starting material was prepared as 
follows: 
In a manner analogous to that described in Example 16 (ii), from 
trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4' 
,4,5]pyrido[1,2-a]indole, diastereomer B, [prepared as described in Example 
16(i)] there was obtained 
(-)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indo 
le formate of melting point 208.degree.-212.degree. C.; 
[.alpha.].sub.D.sup.20 =-49.9.degree. (MeOH, c=0.05). 
EXAMPLE 18 
In a manner analogous to that described in Example 15, from 
(+)-trans-3-[2-(tert.butoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[ 
3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione, 
prepared in a manner analogous to that described in Example 14 (vii) and 
(viii) from 
(+)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]ind 
ole formate [prepared as described in Example 16]), there was obtained 
(+)-trans-3-(2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]i 
ndole-10-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of 
melting point 276.degree.-280.degree. C.; [.alpha.].sub.D.sup.20 
=+50.1.degree. (MeOH, c=0.05). 
EXAMPLE 19 
In a manner analogous to that described in Example 15, from 
(-)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indo 
le formate [prepared as described in Example 17] there was obtained 
(-)-trans-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]i 
ndol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of 
melting point &gt;330.degree. C. (decomposition); [.alpha.].sub.D.sup.20 
=-59.6.degree. (MeOH, c=0.06). 
EXAMPLE 20 
A solution of 100 mg of 
(+)-trans-3-[2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]i 
ndol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione hydrochloride in 4 ml of 
DMF and 4 ml of 33% aqueous ammonia was heated to 140.degree. C. in a 
sealed vessel. The solvent was removed under reduced pressure and the 
residue was triturated with ethyl acetate to give 12 mg of 
(+)-trans-3-[2-formyl-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrid 
o[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting 
point 316.degree.-318.degree. C.; [.alpha.].sub.D.sup.20 =+59.degree. 
(MeOH, c=0.05). 
The furandione hydrochloride, melting point &gt;340.degree. C., used as the 
starting material was prepared as described in Example 14 from 
(+)-trans-2,3,3a,4,11,11a-hexahydro-1H-pyrrole[3',4':4,5]-pyrido[1,2-a]ind 
ole formate (obtained as described in Example 16). 
EXAMPLE 21 
In a manner analogous to that described in Example 1(A), from 
3-[7,9-dihydro-1'-methylspiro[6H-pyrido[1,2-a]indole-8,3'-piperidin]-10-yl 
]-4-(1-methyl-3-indolyl)furan-2,5-dione acetate there was obtained 
3-[7,9-dihydro-1'-methylspiro[6H-pyrido[1,2-a]indole-8,3'-piperidin]-10-yl 
]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 
144.degree.-146.degree. C. 
The furandione used as the starting material was prepared as follows: 
(i) A solution of 400 mg of 
3-[1-(tert.butoxy-carbonyl)-7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido 
[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 10 ml of 
ethyl acetate was treated with 10 ml of a saturated solution of hydrogen 
chloride in ethyl acetate and stirred. The solvent was removed under 
reduced pressure and the residue was triturated with diethyl ether to give 
240 mg of 
3-[7',9'-dihydrospiro[piperidine-3,8'(6'H)-pyrido[1,2-a]indol-10'-yl]-4-(1 
-methyl-3-indolyl)furan-2,5-dione hydrochloride of melting point 
162.degree.-165.degree. C. 
(ii) A solution of 238 mg of the product of (i) in 20 ml of DMF was treated 
with 100 mg of potassium carbonate and 100 mg of dimethyl sulphate. The 
mixture obtained was stirred, then diluted with water and extracted with 
dichloromethane. The organic extracts were washed with sodium chloride 
solution, dried and evaporated. Purification by chromatography on silica 
gel using dichloromethane/methanol/acetic acid/water (90:21:2:3) for the 
elution gave 75 mg of 
3-[7,9-dihydro-1'-methylspiro[6H-pyrido[1,2-a]indole-8,3'-piperidin]-10-yl 
]-4-(1-methyl-3-indolyl)furan-2,5-dione acetate of melting point 
174.degree.-178.degree. C. 
EXAMPLE 22 
(A) A mixture of 285 mg of 1,1,1,3,3,3-hexamethyldisilazane and 31 mg of 
methanol was added to a solution of 100 mg of 
3-[2-(tert.butoxy-formamido)-7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyr 
ido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 2 ml of 
DMF and stirred at 60.degree. C. under a nitrogen atmosphere. The mixture 
was poured into 10 ml of water and extracted with ethyl acetate. The 
organic extracts were washed with sodium chloride solution, dried and 
evaporated to give 85 mg of 
3-[2[(tert.butoxyformamido-7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyrid 
o[1,2-a]indol]-10'-yl]-4-(1-methyl-3indolyl)-1H-pyrrole-2,5-dione of 
melting point 113.degree.-114.degree. C. 
(B) A solution of 85 mg of the product of (A' in 5 ml of ethyl acetate was 
treated with 10 ml of a saturated solution of hydrogen chloride in ethyl 
acetate and the mixture was stirred. The solvent was removed under reduced 
pressure and the residue was purified by chromatography on silica gel 
using dichloromethane/methanol/acetic acid/water (90:21:2:3) for the 
elution to give 22 mg of 
3-[2-amino-7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indol]-1 
0'-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting 
point 190.degree. C. (decomposition). 
The furandione starting material was prepared as follows: 
(i) A suspension of 1.5 g of sodium hydride in 50 ml of DMF was treated 
with a solution of 14.35 g of ethyl 
6,7-cihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 50 ml of DMF 
under a nitrogen atmosphere. The mixture was stirred and was then treated 
with a solution of 13.7 g of tert.butyl 4-bromobutyrate in 50 ml of DMF. 
The mixture was then heated to 60.degree. C. for 48 hours, cooled, poured 
into 500 ml of water and extracted with dichloromethane. The organic 
extracts were washed with sodium chloride solution, dried and evaporated 
to give 9.5 g of tert.butyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-butyrate 
of melting point 104.degree. C. 
(ii) A solution of 9.5 g of the product of (i) in 200 ml of ethanol was 
treated with a suspension of Raney nickel in water and the mixture was 
heated at reflux. The cooled mixture was filtered and the residue was 
washed with ethyl acetate. The filtrate was extracted with ethyl acetate 
and the organic extracts were dried and evaporated to give 7.80 g of 
tert.butyl 
8-(ethoxycarbonyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-butyrate. 
(iii) A solution of 7.78 g of the product of (ii) in 50 ml of THF was added 
to a solution of 2.83 g of potassium tert.butoxide in THF. The mixture was 
stirred under a nitrogen atmosphere, then poured into 100 ml of water and 
extracted with ethyl acetate. The organic extracts were dried and removed 
by evaporation to give 1.25 g of tert.butyl 
7',9'-dihydro-2-oxospiro[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indole]-3-car 
boxylate of melting point 129.degree.-131.degree. C. 
(iv) A solution of 1.20 g of the product of (iii) in 100 ml of 
dichloromethane was treated with 5 ml of trifluoroacetic acid at 
-10.degree. C. under a nitrogen atmosphere. The solution was stirred and 
then toluene was added. The solvents were removed under reduced pressure 
and the residue was purified by chromatography on silica gel using 
dichloromethane/ methanol (95:5) for the elution to give 0.70 g of 
7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indol]-2-one of 
melting point 128.degree.-130.degree. C. 
(v) A solution of 0.73 g of hydroxylamine hydrochloride and 1.41 g of 
potassium hydroxide in water was added to a solution of 0.50 g of the 
product of (iv) in methanol and the solution obtained was heated to 
reflux. The cooled reaction mixture was neutralized with a saturated 
solution of ammonium chloride and extracted with diethyl ether. The 
ethereal extracts were dried and evaporated to give 0.43 g of 
7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indol]-2-one oxime 
of melting point 211.degree. C. (decomposition). 
(vi) A solution of 1.0 g of the product of (v) in THF was added to a 
suspension of 300 mg of lithium aluminium hydride in THF. The mixture was 
then heated to reflux, then cooled, poured into 100 ml of water and 
extracted with diethyl ether. The ethereal extracts were washed with 1M 
hydrochloric acid and the acid washings were made basic with 2M sodium 
hydroxide and extracted with dichloromethane. The organic extracts were 
dried and evaporated to give 550 mg of 
7',9'-dihydrospiro[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indol]-2-amine. 
(vii) A solution of 850 mg of the product of (vi) in 10 ml of 
dichloromethane was added to an ice-cold solution of 765 mg of 
di-tert.butyl dicarbonate and 354 mg of triethylamine in dichloromethane. 
The mixture was stirred, then washed with water and with saturated sodium 
bicarbonate, dried and evaporated to give 1.20 g of 
2-(tert.butoxyformamido)-7',9'-[cyclopentane-1,8'(6'H)-pyrido[1,2-a]indole 
. 
(viii) 493 mg of oxalyl chloride were added to a solution of 1.20 g of the 
product of (vii) in 50 ml of dichloromethane at -78.degree. C. A solution 
of 735 mg of 1-methylindole-3-acetic acid and 1.78 g of triethylamine in 
50 ml of dichloromethane was added at -78.degree. C. under a nitrogen 
atmosphere. The mixture was then stirred at room temperature for 18 hours 
and the solvent was removed under reduced pressure. The residue was 
purified by chromatography on silica gel using dichloromethane/methanol 
(95:5) for the elution to give 643 mg of 
3-[2-(tert.butoxyformamido)-7',9'-dihydro-spiro[cyclopentane-1,8'(6'H)-pyr 
ido[1,2-a]indol]-10'-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione of melting 
point 123.degree.-125.degree. C. 
EXAMPLE 23 
In a manner analogous to that described in Example 14, from 
trans-3-[2-(tert.butoxyformamido)-8',9'-dihydrospiro[cyclopropane-1,7'(6'H 
)pyrido[1,2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione (prepared 
as described in Example 4) there was obtained 
trans-3-[8',9'-dihydro-2-dimethylaminospiro[cyclopropane1,7'(6'H)pyrido[1, 
2-a]indol]-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride 
of melting point 258.degree.-261.degree. C. (decomposition). 
The following Examples illustrate typical pharmaceutical preparations 
containing compounds provided by the present invention: 
EXAMPLE A 
Tablets containing the following ingredients may be produced in a 
conventional manner: 
______________________________________ 
Ingredient Per tablet 
______________________________________ 
Compound of formula I 
5.0 mg 
Lactose 125.0 mg 
Maize starch 75.0 mg 
Talc 4.0 mg 
Magnesium stearate 
1.0 mg 
Tablet weight 210.0 mg 
______________________________________ 
EXAMPLE B 
Capsules containing the following ingredients may be produced in a 
conventional manner: 
______________________________________ 
Ingredient Per capsule 
______________________________________ 
Compound of formula I 
10.0 mg 
Lactose 165.0 mg 
Maize starch 20.0 mg 
Talc 5.0 mg 
Capsule fill weight 
200.0 mg 
______________________________________