.beta.-carbolines and their use as tranquilizers

New substituted .beta.-carbolines of formula I ##STR1## wherein R.sup.3 is hydrogen or a non-carboxyl based substituent, and R.sup.4-9 have various meanings, PA2 are valuable pharmaceutical products with long lasting action on the central nervous system.

CROSS REFERENCE TO RELATED APPLICATIONS 
This application is related to U.S. Pat. No. 4,371,536 and U.S. Ser. No. 
331,740 filed on Dec. 17, 1981, now U.S. Pat. No. 4,435,403, whose entire 
disclosures are incorporated by reference herein. 
BACKGROUND OF THE INVENTION 
The present invention relates to .beta.-carbolines which have a substituent 
in the 3-position that is not derived from a carboxylic acid, or which are 
unsubstituted in the 3-position. 
Up to now it has been assumed that the presence of a 3-carboxylic acid or a 
derivative of a 3-carboxylic acid was necessary for the pharmacological 
effect of the .beta.-carbolines. 
SUMMARY OF THE INVENTION 
It is an object of this invention to provide new .beta.-carbolines having 
pharmacological properties at least as good as those of the prior art but 
of significantly different structure. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects have been attained by providing .beta.-carbolines of formula 
(I): 
1. A .beta.-carboline of the formula 
##STR2## 
wherein R.sup.3 is H; halogen; or OR.sup.i wherein R.sup.i is H, 
C.sub.1-5 alkyl, cycloalkyl, aralkyl, aryl or a heterocyclic radical; 
NR.sup.II R.sup.III, wherein R.sup.ii is H, C.sub.1-5 alkyl, cycloalkyl, 
aralkyl or aryl, and R.sup.III is C.sub.1-5 alkyl, C.sub.1-3 acyl, 
C.sub.1-6 alkoxycarbonyl, carbamoyl, or R.sup.II and R.sup.III together 
with the connecting N atom form a saturated or unsaturated 5- or 
6-membered ring; 
SO.sub.n R.sup.i wherein n is a number of 0 to 2 and R.sup.I is as defined 
above; 
PO.sub.3 R.sup.IV R.sup.V wherein R.sup.IV and R.sup.V are H, C.sub.1-5 
alkyl, cycloalkyl, aralkyl or aryl, wherein R.sup.IV and R.sup.V can be 
the same or different, 
C.sub.1-5 alkyl, cycloalkyl, aralkyl, aralkenyl or aryl, wherein the alkyl 
radical can be substituted by 1 to 3 of halogen, OR.sup.I, NR.sup.II 
R.sup.III, SO.sub.n R.sup.i, COOR.sup.II R.sup.III, CSNR.sup.II R.sup.III, 
PO.sub.3 R.sup.IV R.sup.V, COR.sup.I or CN wherein R.sup.I, R.sup.II, 
R.sup.III, R.sup.IV, R.sup.V and n are as defined above; 
R.sup.4 is H, C.sub.1-5 alkyl, alkoxyalkyl, COR.sup.VI wherein R.sup.VI is 
H, C.sub.1-5 alkyl, cycloalkyl, aralkyl, OH, O-alkyl, O-cycloalkyl, 
O-aralkyl, NR.sup.II R.sup.II, wherein each R.sup.II is as defined above 
and both can be the same or different from one another or with the 
connecting N atom can form a 5- or 6-membered ring, or CSR.sup.VII wherein 
R.sup.VII is H, C.sub.1-5 alkyl, cycloalkyl or aralkyl, 
R.sup.5 -R.sup.8 each independently is H, halogen, NO.sub.2, OR.sup.I, 
NR.sup.II R.sup.III, PO.sub.3 R.sup.IV R.sup.V, SO.sub.2 NR.sup.I R.sup.V, 
COOR.sup.I, CONR.sup.II R.sup.III, CSNR.sup.II R.sup.III or COR.sup.I, 
wherein R.sup.I-V are as defined above, and 
R.sup.9 is H, C.sub.1-5 alkyl, C.sub.1-3 acyl, carbamoyl, C.sub.1-6 
alkoxycarbonyl or SO.sub.2 R.sup.VIII wherein r.sup.VII is methyl or 
p-tolyl. 
DETAILED DISCUSSION 
It has now been found that the new .beta.-carbolines of formula I have the 
same favorable effects on the central nervous system as known carbolines 
substituted in the 3-position by a radical containing carboxyl or derived 
from carboxyl, e.g., as described in the documents incorporated above; 
however, the new .beta.-carbolines have the advantage that their effect is 
longer lasting. 
The substituents in formula I have various meanings as described. The 
following discussion applies to all substituents regardless of position 
unless indicated otherwise. 
Unless stated otherwise, halogen according to this invention is fluorine, 
chlorine, bromine and iodine. 
Alkyl by itself or in combination with other atoms or functional groups, 
e.g., O, S, N, CON, CSN or PO.sub.3 includes straight chain or branched 
groups of up to 5 carbon atoms in each instance, e.g., methyl ethyl, 
n-propyl, isopropyl, n-butyl, n-pentyl, isobutyl, isopentyl, t-butyl, 
t-pentyl, etc. 
Cycloalkyl includes groups of 3-7 carbon atoms, e.g., cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc; suitable aryl groups 
include those of 6-10 carbon atoms, e.g., phenyl, 1- or 2-naphthyl, etc; 
suitable aralkyl groups are of 7-10 carbon atoms and include, e.g., benzyl 
etc. 
Suitable heterocyclic radicals include aromatic or non-aromatic, saturated 
or unsaturated hetero monocycles or bicycles of 5-8 total atoms in each 
ring and 1-3 hetero atoms (e.g., O, N or S) in each ring, the rest being 
C-atoms, e.g., pyrrolyl, pyrrolidinyl, piperidinyl, hexamethylenimino, 
heptamethylenimino, morpholyl, thiomorpholyl, piperazinyl, tetrazolyl, 
1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazolidinyl, pyrazolyl, 
pyrazolidinyl, isoxazolyl, oxazolyl, oxazolidinyl, thiazolyl, 
thiazolidinyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazolidinyl, and 
1,3,4-oxadiazolyl. 
Suitable aralkenyl groups are of 8-12 carbon atoms and include, e.g., 
styryl, etc. 
Suitable C.sub.1-3 -acyl groups are derived from aliphatic carboxylic 
acids, generally alkane carboxylic acids, i.e., alkanoyl. 
When R.sup.II and R.sup.III or R.sup.II and R.sup.II form a ring with the 
connecting N-atom which can be saturated, unsaturated or aromatic, they, 
thus, can be alkylene of 4 or 5 C-atoms, including oxa and/or --N-atoms in 
the 5 or 6-membered ring. 
The aromatic ring can be mono- or disubstituted in positions 5, 6, 7 and/or 
8, wherein substitution in the 5- and/or 6-position is preferred. 
The new compounds of formula I have valuable pharmacological properties. 
They are especially effective on the central nervous system and thus are 
suitable for use as psychopharmacological agents in human or veterinary 
medicine, i.e., as psychotropic agents. This is demonstrable by fully 
conventional protocols. 
The compounds according to this invention can be used to formulate 
pharmaceutical preparations, for example for oral or parenteral use in 
mammals, including man, according to known methods of galenic medicine. 
As adjuvants for the formulation of pharmaceutical preparations, the usual 
physiologically compatible organic and inorganic carriers are suitable for 
enteral and parenteral use which are inert toward the compounds of this 
invention. 
Examples of suitable carriers include water, salt solutions, alcohols, 
polyethyleneglycols, polyhydroxyethoxylated castor oils, gelatins, 
lactose, amylose magnesium stearate, talc, silicic acid, fatty acid mono- 
and diglycerides, pentaerythritol fatty acid esters, 
hydroxymethylcellulose, polyvinyl pyrrolidone and the like. 
The pharmaceutical preparations can be sterilized and/or combined with 
adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, 
emulsifiers, buffers and dyes. 
For parenteral use, especially suitable are injectable solutions or 
suspensions, particularly aqueous solutions of the active compounds in 
polyhydroxyethoxylated castor oil. 
For oral use, especially suitable are tablets, coated tablets or capsules 
with a talc and/or a hydrocarbon support or binder, such as lactose and 
corn or potato starch. Administration can also be achieved in liquid form, 
for example, as a juice to which a sweetener has optionally been added. 
The compounds according to this invention are usually formulated into a 
physiologically compatible carrier in a unit dosage of 0.05-10 mg of 
active ingredient. The compounds of this invention are usually employed in 
a dose of 0.1-300 mg per day, preferably 1-30 mg per day for each of the 
indications mentioned herein. In general, their administration is 
analogous to that of the well known tranquilizers, e.g., Librium and 
Stesloid taking into account the usual factors such as differential 
potencies. 
It is known that certain points in the central nervous system of 
vertebrates have a high specific affinity for bonding to 1,4- and 
1,5-benzodiazepines (Squires, R. F. and Braestrup, C., Nature (London) 266 
(1977), 734). These locations are called benzodiazepine receptors. The 
pharmacological properties of the compounds according to the invention 
were determined by determination of their ability to displace 
radioactively tagged flunitrazepam from these benzodiazepine receptors. 
The displacement activity of the compounds of this invention was determined 
by measurement of the IC.sub.50 and ED.sub.50 values. The IC.sub.50 value 
indicates the concentration at which a 50% displacement of the specific 
binding of .sup.3 H flunitrazepam (1.0 nM, 0.degree. C.) is achieved in 
samples with a total volume of 0.55 ml of a brain membrane suspension, for 
example of rats. 
The displacement test is carried out as follows: 
0.5 ml of a suspension of an untreated rat forebrain in 25 mM KH.sub.2 
PO.sub.4 at a pH=7.1 (5-10 mg of tissue per test) is incubated for 40-60 
minutes at 0.degree. C. together with .sup.3 H-diazepam (specific activity 
14.4 Ci/mmol, 1.9 nM) or .sup.3 H flunitrazepam (specific activity 87 
Ci/mmol, 1.0 nM). After incubation, the suspension is filtered through a 
glass frit, the residue is washed twice with cold buffer solution and the 
radioactivity is measured on a scintillation counter. 
The test is then repeated, except that before the addition of the 
radioactively tagged benzodiazepine, a predetermined quantity or an excess 
quantity of the compound, whose displacement activity is to be determined, 
is added. The IC.sub.50 value can then be calculated on the basis of the 
values obtained. 
The ED.sub.50 value is the dose of the test substance that causes a 
reduction of the specific binding of the flunitrazepam to the 
benzodiazepine receptor in a living brain to 50% of the control value. 
Such an in vivo test is performed as follows. 
The test substance is normally injected subcutaneously to a group of mice 
in various doses. After 15 minutes, the .sup.3 H-flunitrazepam is 
administered to the mice intravenously. After another 20 minutes, the mice 
are killed, their frontal meninges are removed and the radioactivity of 
the frontal meninges is measured by scintillation counting. The ED.sub.50 
value is determined from the dose/effect curves. 
The compounds according to this invention exhibit an anti-aggressive effect 
on mice. The inhibition of aggression was determined on male mice (NMR of 
Mollegaard, DK) weighing 20-22 g. The mice are kept isolated in plastic 
cages for three weeks and then, when two mice are placed in the same cage, 
they spontaneously and almost immediately start fighting with one another. 
This aggression is effectively inhibited with a series of 
psychopharmacologically effective substances, including benzodiazepines 
(Valcelli, Mod. Probl. Pharmacopsych., 1979, 14, 143-156). 
The compounds of this invention completely inhibit aggression in a test 
described by Buus Lasse, Europ. J. Pharmacol., 1978, 47, 45-49. In this 
test, the compounds of this invention were administered subcutaneously and 
orally and the anti-aggressive effect was determined after half an hour. 
The results of such tests show that the compounds of this invention 
effectively inhibit aggression and effectively displace flunitrazepam from 
benzodiazepine receptors. They are, thus, very useful as tranquilizers, 
non-sedating anticonvulsants, antiaggressives and anxiolytics or for 
stress protection. As such, they can be used for treatment of the 
following illustrative indications: anxiety and tension conditions, with 
and without depressions; unrest; disturbances resulting from stress 
situations or an excess of stimulation, as well as pathological 
aggressiveness. 
The compounds according to this invention can be produced according to 
fully conventional methods. 
These include processes for producing the compounds of formula I, wherein 
(a) a 3-hydroxyalkyl compound of formula II 
##STR3## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as 
defined in formula I, is conventionally etherified, reduced, halogenated 
or reacted with an isocyanate of the formula O.dbd.C.dbd.N=R.sup.V and, 
optionally, is sulfonated or alkylated in the 9-position; 
(b) a compound of general formula III 
##STR4## 
wherein Z is H or alkoxy of up to 3 C atoms and R.sup.4, R.sup.5, 
R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as defined for formula I, is 
conventionally reacted with a compound of the formula R.sup.I MgHal, 
wherein R.sup.I is as defined above and Hal is Cl, Br or I, and optionally 
is then reacted with thionyl chloride; 
(c) a compound of formula IV 
##STR5## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, or R.sup.9 are as 
defined in formula I, is conventionally decarboxylated or reacted to form 
a 3-carboxylic acid azide and the carboxylic acid azide is thermally 
decomposed in the presence of an alcohol of the formula R.sup.I OH 
according to a Curtius rearrangement; 
(d) a 3-haloalkyl-.beta.-carboline of formula V obtained by halogenation 
according to (a) 
##STR6## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as 
defined in formula I, is conventionally reacted with a Wittig reagent of 
the formula Ph.sub.3 P.dbd.CH.dbd.Ph or a trialkylphosphite, or an amine 
of the formula HNR.sup.II R.sup.III wherein R.sup.II and R.sup.III are as 
defined in formula I, or an alcoholate of the formula MOR.sup.I, or an 
alkali mercaptide of the formula MSR.sup.I wherein M is an alkali metal 
and R.sup.I is as defined in formula I, and to obtain the compounds of 
formula I wherein R.sup.3 is alkylene SOR.sup.I or alkylene SO.sub.2 
R.sup.I, the 3-alkylene-SR.sup.I compounds obtained by reaction with 
alkali mercaptide are oxidized and optionally halogenated in the 
6-position and optionally the halogenated product thus obtained is reacted 
to form the 6-COOR.sup.I compound and optionally the 6-COOR.sup.I compound 
is transesterified, saponified or amidated; 
(e) a 3-amino-.beta.-carboline of formula VI obtained according to (c) from 
the 3-carboxylic acid azide by Curtius rearrangement 
(f) a 1,2,3,4-tetrahydro-.beta.-carboline of formula VII 
##STR7## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as 
defined above, is conventionally acylated, is reacted with 
2,5-dimethoxy-tetrahydrofuran, 1,4-dibromobutane or 1,5-dibromopentane or 
is reacted in a Sandmeyer reaction with dilute sulfuric acid, with 
hydrogen halide in the presence of copper(I) halide, with alkali metal 
cyanide, with R.sup.I OH or with (R.sup.I).sub.2 S, wherein R.sup.I is as 
defined above, and, if desired, a 3-SR.sup.I compound obtained from 
reaction with (R.sup.I).sub.2 S is oxidized to the corresponding 
3-SOR.sup.I or 3-SO.sub.2 R.sup.I compound and, if desired, the 3-SR.sup.I 
or 3-SOR.sup.I group is eliminated with Raney nickel/hydrogen and 
optionally then halogenated in the 6-position and the halogenated product 
thus obtained is reacted to form the 6-OR.sup.I or 6-COOR.sup.I compound 
and optionally the 6-COOR.sup.I compound is transesterified, saponified or 
amidated or nitrated in the 6-position and optionally the resulting nitro 
compound is reduced to the corresponding amino compound and optionally the 
amino compound is reacted with alkyl or allyl halide or sulfonated in the 
6-position and optionally the chlorosulfonyl compound thus obtained is 
reacted with an amine; 
(f) a 1,2,3,4-tetrahydro-.beta.-carboline of formula VII 
##STR8## 
wherein R.sup.VI, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are as 
defined for formula I, is conventionally dehydrogenated and, if desired, 
transesterified in the 4-position, nitrated in the 6- and 8-position, and 
optionally the resulting nitro compound is reduced to the amino compound 
and reacted with alkyl or allyl halide or the 4-carboxylic acid is reacted 
with methyllithium to form the 4-acetyl compound; 
(g) a 1,2,3,4-tetrahydro-.beta.-carboline of the formula VIII 
##STR9## 
wherein R.sup.VI is as defined above, is conventionally dehydrogenated 
and, if desired, transesterified in the 5-position or the 5-carboxylic 
acid nitrile is produced from the 5-carboxylic acid through the amide with 
hexamethylphosphoric triamide; 
(h) a 1,2,3,4-tetrahydro-.beta.-carboline of formula IX 
##STR10## 
wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined 
above, is heated with noble metal catalysts in an inert solvent to 
120.degree.-180.degree. C.; 
(i) an indole of formula X 
##STR11## 
wherein R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are as defined above, is 
reacted with an azadiene of formula XI 
##STR12## 
wherein R.sup.3 and R.sup.4 are as defined above and A and B and also A' 
and B' each independently, by themselves, are alkyl with 1-3 C atoms or 
together with the connecting N-atom, form pyrrolidino, piperidino, 
morpholino or piperazino, in the presence of acids at temperatures of 
50.degree.-200.degree. C. and optionally a resulting phosphonic acid 
monoester in the 3-position is converted to the phosphonic acid diester or 
a phosphonic acid diester is reacted with a dialkylamine in the presence 
of oxallyl chloride to form the phosphonic acid-monoester-dialkylamide. 
The etherification of the 3-hydroxyalkyl group according to process (a) can 
be performed in the presence of a strong base with the corresponding 
R.sup.I -halide, wherein R.sup.I is as defined in formula I. To produce 
alkyl ethers whose carbon chain is broken by an oxygen atom, and 
optionally is cyclized, the 3-hydroxyalkyl compound of formula II is 
converted into the appropriate tetrahydropyranyl or alkoxyethyl ether with 
dihydropyran or alkylvinyl ethers in the presence of a strong acid, such 
as p-toluenesulfonic acid or phosphorus oxychloride. 
The reaction is preferably carried out in the presence of an inert solvent, 
for example N-methyl-pyrrolidone at temperatures of 0.degree. to 
150.degree. C. The hydroxyalkyl group can be reduced to the alkyl groups 
with zinc powder and glacial acetic acid by trimethylsilyl ether. 
The 3-hydroxyalkyl group can be halogenated in the usual manner with a 
halogenation agent. For example, the 3-hydroxyalkyl group is chlorinated 
by thionyl chloride into a 3-chloralkyl group. 
The 3-hydroxyalkyl group is converted into the N-R.sup.I -carbamic 
acid-3-alkyl ester group with isocyanates of the formula 
O.dbd.C.dbd.N--R.sup.I, wherein R.sup.I is as defined in formula I. 
In addition, a tosyl group can be introduced in the 9-position of the 
.beta.-carboline with p-toluenesulfochloride in a basic medium, or an 
alkyl group introduced with N,N-dialkylformamide-dialkylacetal in the 
presence of a strong base. The following are examples of strong bases: 
diazabicyclooctane, diazabicyclononene, diazabicycloundecene, but also 
ethyldiisopropylamine, potassium-tert-butylate, potassium carbonate and 
powdered potassium hydroxide. For example, pyridine, 
4-dimethylaminopyridine, triethylamine and mixtures of these bases serve 
to form the basic medium. 
The Grignard reaction and optionally a subsequent reaction with thionyl 
chloride of compounds of general formula III according to process (b) 
occur in the usual manner. Decarboxylation of the 3-carboxylic acids of 
formula IV preferably takes place in a high-boiling organic base in the 
presence of copper powder at temperature of 150.degree. to 250.degree. C. 
To decompose the carboxyl group and simultaneously introduce a 
3-alkoxycarbonyl amino group (urethane group) according to process (c), 
the 3-carboxylic acid is first converted in known manner into the 
3-carboxylic acid azide. This is accomplished preferably by reacting the 
carboxylic acid with diphenylphosphoryl azide. The carboxylic acid azide 
is then subjected to Curtius rearrangement (Organic Reactions III 
(1946)337), whereby the desired urethanes are obtained in the presence of 
alcohols. 
Conversion of the 3-carboxylic acids into 3-alkoxycarbonylamino compounds 
can also be performed as a stew process without isolating the acid azide. 
According to a preferred embodiment, a .beta.-carboline-3-carboxylic acid 
dissolved in dimethyl sulfoxide is added to a solution of 
diphenylphosphorylazide in alcohol while triethylamine is added and 
refluxed. 
According to process (d), 3-halogenalkyl compounds of formula V obtained 
from 3-hydroxyalkyl by halogenation are reacted with the Wittig reagent of 
the formula Ph.sub.3 P.dbd.CH--Ph to produce corresponding 3-styryl 
compounds and a trialkylphosphite to produce corresponding 3-styryl 
kylphosphonoalkyl compounds. Moreover, the corresponding 3-halogenalkyl 
compounds of formula V are reacted to produce 3-alkylene-NR.sup.II 
R.sup.III compounds with an amine of formula HNR.sup.II R.sup.III, in 
which R.sup.II and R.sup.III have the meaning indicated in formula I and 
to produce 3-alkylene --SR.sup.I -or OR.sup.I compounds, with an alkali 
mercaptide of the formula MSR.sup.I or an alkali alcoholate of the 
formula MOR.sup.I, where M represents an alkali metal and R.sup.I has the 
meaning indicated in formula I. In each case, the reactions are carried 
out in an inert solvent at boiling heat. The Wittig reaction is preferably 
carried out in dimethylformamide or dimethyl sulfoxide, the reaction with 
trialkylphosphite in excess trialkylphosphite, the amination in alcohol 
preferably ethanol or propanol, and the reaction with alkali mercaptide or 
alcoholate preferably in N-methylpyrrolidone, tetrahydrofuran or dioxane. 
Oxidation of the thio compounds (3-alkylene-SR.sup.I to 
3-alkylene-SOR.sup.I or 3-alkylene SO.sub.2 R.sup.I or 3--SR.sup.I to 
3--SOR.sup.I or 3--SO.sub.2 R.sup.I) obtained according to process variant 
(d) or (e) takes place in a known manner. Suitable oxidizing agents 
include, for example, organic peroxy acids such as performic acid, 
peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, monoperphthalic 
acid, or inorganic peroxides, such as hydrogen peroxide dissolved in water 
or in diluted organic acids, inorganic oxidizers such as chromic acid, 
nitric acid, chlorine, bromine, halogen oxyacids, such as hypochlorous, 
chlorous, choric or iodic acid, tert-butylhypochlorite, organic N-halogen 
compounds such as N-chlorosuccinimide and N-bromosuccinimide. By choice of 
the reaction conditions known from the literature, the oxidation potential 
can be correspondingly adjusted and the reaction to produce the sulfoxides 
or sulfones can be controlled. 
According to process varient (e), the 3-amino compounds of formula VI 
obtained by the Curtius rearrangement of 3-carboxylic acid compounds via 
3-carboxylic acid azide in the 3-position, for example, are acylated or 
reacted with 2,5-dimethoxy-tetrahydrofuran, 1,4-dibromobutane or 
1,5-dibromopentane. 
The conversion of the 3-amino compounds into the corresponding 
3-hydroxy,3-halogen, 3-cyano, 3--OR.sup.I and 3--SR.sup.I compounds is 
also performed by known methods, for example, by the Sandmeyer reaction, 
in which the diazotized product is directly reacted with dilute sulfuric 
acid, hydrohalic acid in the presence of copper (I) halide, an alkali 
metal cyanide, R.sup.I OH or (R.sup.I).sub.2 S at elevated temperatures. 
3--SR.sup.I compounds can then be oxidized to 3--SOR.sup.I and 3--SO.sub.2 
R.sup.I compounds. 
The compounds obtained according to (d) or (e) then can be halogenated, 
nitrated or sulfonated for example in the 6-position. Compounds 
halogenated in the 6-position then can optionally be alkoxylated, 
thioalkylated, carboxylated or reacted with an amine, all conventionally. 
Halogenation in the 6-position takes place according to known methods. For 
this purpose, the starting material is dissolved in an inert solvent and 
reacted with the corresponding halogen, such as chlorine or bromine 
optionally in the presence of a basic catalyst at temperatues below room 
temperature. Inert solvents include, for example, chlorinated hydrocarbons 
such as methylene chloride, chloroform, dichloroethylene, etc. Pyridine 
and substituted pyridine, such as 4-dimethylaminopyridine, are suitable as 
basic catalysts. A basic catalyst is unnecessary for chlorination. 
To feed in iodine, it is advisable not merely to use elementary iodine but 
a mixture of iodine and iodic acid, whereby the reaction is preferably 
performed in glacial acetic acid at 80.degree. C. under protonic 
catalysis. The optional subsequent alkoxylation and thioalkylation of the 
halogen compounds also take place according to known methods. 
The 6-halogen compound, especially the 6-iodine compound, can be 
carbonylated, for example, with palladium (II) acetate and carbon monoxide 
in benzyl alcohol and in the presence of a tert-amine, for example 
triethylamine, tributylamine or pyridine. The 6-benzyloxycarbonyl compound 
thus obtained can then be saponified, transesterified or reacted with an 
amine; all in a known way. 
For transesterification, the available ester is heated for 3-6 hours to 
temperatures of 60.degree. to 120.degree. C. with an alcohol R.sup.I OH in 
the presence of catalytic quantities of R.sup.I ONa or NaH. The 
transesterification can optionally also take place with the alcohol 
R.sup.I OH in the presence of an acid catalyst such as p-toluene sulfonic 
acid, HCl, or CuCl.sub.2. 
Nitrated compounds can be reduced to the corresponding amino compounds and 
the amino compounds, if desired, can be reacted with alkyl and allyl 
halides. 
Nitration also takes place according to known methods. For this purpose, 
the starting material is reacted with nitric acid at temperatures below 
room temperature. Concentrated nitric acid refers to the commercial form, 
which, however, can also be enriched by fuming nitric acid. In the 
nitration, the acid acts as both reagent and solvent. 
The optional subsequent reduction of the resulting nitro compound into the 
corresponding amino compound also takes place by known methods. 
A preferred method is the reduction with hydrogen in the presence of metal 
catalysts such as Raney nickel, platinum in finely dispersed form or 
palladium on a suitable support such as carbon or calcium at normal 
pressure and room temperature. But it is also possible to use hydrogen in 
the nascent state, for example by zinc/hydrochloric acid. 
Production of sulfonic acids or sulfonic acid derivatives takes place 
according to known methods. For this purpose, the starting material is 
dissolved in an inert solvent such as methylene chloride, chloroform, and 
chlorosulfonic acid is added with cooling. 
To produce the corresponding alkylaminosulfonic acid derivatives, the 
product first thus-obtained is reacted with an alkylamine. 
Dehydrogenation of 1,2,3,4-tetrahydro-.beta.-carbolines of formulae VII and 
VIII according to (f) and (g) takes place according to known methods. 
In one method, the starting material is dissolved or suspended in an inert 
solvent. All aprotic solvents with boiling points above 100.degree. C. and 
which are inert to the starting materials are suitable. Examples include 
xylene, mesitylene, anisols, toluene, chlorobenzene, and diphenyl ether. 
Then elementary sulfur is added; the quantity should be approximately one 
mole equivalent of sulfur per double bond. A small excess is not only 
harmless but advisable. The reaction mixture is refluxed for several 
hours, wherein the course of the reaction is observed by thin-layer 
chromatography. 
Another method is dehydrogenation with DDQ (dichlorodicyanobenzoquinone) or 
chloranil in benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene 
chloride and dimethylethane at temperatures of 0.degree.-60.degree. C. 
with reaction times of 0.5-4 hours. 
Transesterification in the 4- or 5-position, nitration in the 6- and 
8-position and reduction of the nitrated compounds to the corresponding 
amino compounds and alkylation or allylation of the amino compounds with 
alkyl or allyl bromide can follow the dehydrogenation. The 4-acetyl 
compound can be produced from the 4-carboxylic acid with methyllithium and 
the 5-carboxylic acid nitrile can be produced from the 5-carboxylic acid 
by the amide with hexamethylphosphoric acid triamide. 
A further method (h) is the dehydrogenation of 
1,2,3,4-tetrahydro-.beta.-carbolines of formula IX with noble metal 
catalysts, such as platinum in finely dispersed form, palladium black or 
palladium carbon, in inert solvents, such as xylene, mesitylene or cumene 
at 120.degree.-180.degree. C. and reaction times of approximately 0.5-5 
hours. 
The reaction of an indole derivative and azadiene according to process 
variant (i) takes place in the presence of acids at temperatures of 
50.degree. and 200.degree. C., preferably 75.degree.-150.degree. C. The 
reaction is carried out, for example, so that the indole derivative of 
formula X and the azabutadiene of formula XI are heated in organic acids, 
for example, formic acid, acetic acid, propionic acid or trifluoroacetic 
acid or in an inorganic medium, for example, phosphoric acid, 
polyphosphoric acid or phosphoroxychloride, etc. Inert organic solvents, 
for example toluene, ethyl acetate, dioxane, dimethyloxyethane, 
acetonitrile, etc., can also be used as diluents. 
Catalytic quantities of inorganic acids such as sulfuric acid, hydrochloric 
acid, perchloric acid, etc., in inert solvent (as above) can also be used 
for the reaction. 
The reaction is ended after several hours. The course of the reaction can 
be observed by thin-layer chromatography. Once the starting material is 
reacted after approximately 3-10 hours, the reaction mixture is then 
processed in the usual manner. 
A phosphonic acid diester produced according to method (i) can, if desired, 
be reacted with a dialkylamine in the presence of oxallyl chloride to form 
the phosphonic acid monoester dialkylamide. 
The substituted .beta.-carboline-3-carboxylic acid esters required as 
starting materials can be obtained in a known manner by aromatization of 
correspondingly substituted tetra- or 
dihydro-.beta.-carboline-3-carboxylic acid esters which in turn are 
accessible through Pictet-Spengler or Bischler-Napieralski cyclizations 
from correspondingly substituted tryptophan esters. 
More advantageous is the cyclization of suitable unsaturated tryptophan 
derivatives, for example of .alpha.isocyano-indole-3-acryl esters which 
directly provide the desired .beta.-carboline-3-carboxylic acid ester in 
one stage. 
However, especially simple is the novel and surprising regiospecific 
reaction of optionally substituted indoles with 2-azabutadiene-3 
derivatives according to process variant (i), which provide high yields of 
optionally substituted .beta.-carboline-3-derivatives in one stage. This 
novel process is not restricted to the synthesis of 
.beta.-carboline-3-carboxylic acid esters but can also be applied to the 
case of variably substituted 2-azadienes (for example, 3-aryl, 
3-sulfamoyl, 3-sulfonyl, 3-dialkoxyphosphonyl) in the 3-position for the 
one-stage synthesis of the corresponding .beta.-carboline-3-derivatives 
from indoles. 
The various options of basic process (i) are disclosed in detail in FRG 
Patent Applications Nos. P 3240513.8 and P 3240511.1, both of Oct. 29, 
1982 and corresponding respectively to U.S. Ser. Nos. 547,555 and 546,356, 
filed on Oct. 28, 1983, all of whose disclosures are entirely incorporated 
by reference herein. 
The chemical reactions described above are generally disclosed in terms of 
their broadest application to the preparation of the compounds of this 
invention. Occasionally, the reactions may not be applicable as described 
to each compound included within the disclosed scope. The compounds for 
which this occurs will be readily recognized by those skilled in the art. 
In all such cases, either the reactions can be successfully performed by 
conventional modifications known to those skilled in the art, e.g., by 
appropriate protection of interfering groups, by changing to alternative 
conventional reagents, by routine modification of reaction conditions, 
etc., or other reactions disclosed herein or otherwise conventional, will 
be applicable to the preparation of the corresponding compounds of this 
invention. In all preparative methods, all starting materials are known or 
readily preparable from known starting materials. 
All of the starting materials needed for the above-described processes are 
either known or readily preparable using fully conventional methods from 
known or available compounds. See, e.g., the references mentioned above, 
among others. 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. In the following 
examples, all temperatures are set forth uncorrected in degrees Celsius; 
unless otherwise indicated, all parts and percentages are by weight. 
Production of 3-hydroxymethyl-.beta.-carbolines 
A. 4.3 g of .beta.-carboline-3-carboxylic acid ethyl ester are added to 900 
mg of lithium alanate in portions in 200 ml of tetrahydrofuran at 
4.degree. C. under argon. It is then stirred for 30 minutes at room 
temperature and then for 1.5 hours at 80.degree. C. both temperature. Then 
30 ml of a 1N aqueous NaOH solution is added by drop during cooling with 
ice, suctioned off from the precipitate, the filtrate is somewhat 
concentrated, and the precipitated crystals are suctioned off. 3.15 g of 
3-hydroxymethyl-.beta.-carboline with a 230.degree. C. melting point are 
obtained. 
The .beta.-carboline-3-carboxylic acid ethyl ester can be produced as 
follows: 
a. 2 g of .alpha.-isocyano-indolyl-3-ethyl acrylate and 200 mg of 
1,4-diazabicyclo [2.2.2] octane are brought to boiling in 200 ml of xylene 
for 18 hours under nitrogen. After evaporation and crystallization from 
ethanol or acetonitrile, 1,7 g of .beta.-carboline-3-carboxylic acid ethyl 
ester with a 239.degree. C. melting point are obtained. 
b. 1.2 g of indole and 3.2 g of 
3-dimethylamino-2-(dimethylaminomethyleneamino-ethyl acrylate (produced 
according to W. Kantlehner et al., Liebigs Ann. Chem., 1980, 344) A)) are 
dissolved in 17 ml of glacial acetic acid under nitrogen and refluxed 
until not starting indole is any longer visible (6 hours) by thin-layer 
chromatography. After distilling off of most of the solvent, it is poured 
in water and the crystallate suctioned off. After recrystallization from 
acetonitrile, 1.45 g of the title compound with a 234.degree. C. melting 
point are obtained. 
B. Analogously, the following are produced from the corresponding esters: 
6-bromo-3-hydroxymethyl-.beta.-carboline, 285.degree.-290.degree. C. 
melting point; 
6-iodo-3-hydroxymethyl-.beta.-carboline; 
4-methyl-3-hydroxymethyl-.beta.-carboline, 219.degree.-225.degree. C. 
melting point (ethyl acetate/ethanol); 
4-propyl-3-hydroxymethyl-.beta.-carboline, 180.degree.-182.degree. C. 
melting point; 
6-amino-3-hydroxymethyl-.beta.-carboline, 220.degree. C. melting point; 
5-benzyloxy-4-methoxymethyl-3-hydroxymethyl-.beta.-carboline, 
188.degree.-190.degree. C. melting point (ethyl acetate/methanol); 
6-chloro-3-hydroxymethyl-.beta.-carboline, 285.degree.-297.degree. C. 
melting point (tetrahydrofuran). 
C. Production of 6-acetylamino-3-hydroxymethyl-.beta.-carbolines 
106 mg of 6-amino-3-hydroxymethyl-.beta.-carboline are stirred in in 3 ml 
of glacial acetic acid with 52 mg of acetic anhydride at room temperature 
for 1.5 hours. After filtering and concentration, recrystallization from 
ethanol/cyclohexane takes place and 24 mg of 
6-acetylamino-3-hydroxymethyl-.beta.-carboline are obtained.

EXAMPLE 1 
6-bromo-0-(tetrahydropyran-2-yl)-.beta.-carboline-3-methanol 
1.2 g of 6-bromo-3-hydroxymethyl-.beta.-carboline are stirred in 30 ml of 
N-methylpyrrolidone together with 180 mg of p-toluenesulfonic acid and 30 
ml of dihydropyran for 3 hours at 110.degree. C. bath temperature. After 
evaporation in a bulb tube, the residue is chromatographed on silica gel 
with chloroform/ethanol=10:2. 700 mg of 
6-bromo-0-(tetrahydropyran-2-yl)-.beta.-carboline-3-methanol with a 
224.degree.-226.degree. C. melting point are obtained from the 
corresponding fractions by recrystallization from ethyl acetate. 
EXAMPLE 2 
6-bromo-9-tosyl-0-(tetrahydropyran-2-yl)-.beta.-carboline-3-methanol 
700 mg of 6-bromo-0-(tetrahydropyran-2-yl)-.beta.-carboline-3-methanol 
together with 0.7 ml triethylamine, 90 mg of dimethylaminopyridine and 400 
mg of p-toluenesulfochloride are refluxed in 50 ml of methylenechloride 
for one hour. It is then washed once with 2N aqueous HCl and twice with 
water and the organic phase is dried, filtered and concentrated. The 
residue is recrystallized from ethyl acetate/cyclohexane or from toluene 
and 900 mg of 
6-bromo-9-tosyl-0-(tetrahydropyran-2-yl)-.beta.-carboline-3-methanol with 
a 212.degree.-215.degree. C. melting point are obtained. 
EXAMPLE 3 
3-(1-ethyl-1-hydroxypropyl)-.beta. -carboline 
480 mg of .beta.-carboline-3-carboxylic acid estyl ester are dissolved in 
40 ml of tetrahydrofuran and added drop by drop to a Grignard solution 
consisting of 144 mg of magnesium chips and 660 mg of ethylbromide in 10 
ml of diethyl ether. After 2 hours of reflux it is mixed with aqueous 
ammonium chloride solution and extracted with methylene chloride. After 
drying, filtering and evaporation, the residue is chromatographed on 
silica gel with toluene/glacial acetic acid/water=10:10:1 as eluant. 120 
mg of 3-(1-ethyl-1-hydroxy-propyl)-.beta.-carboline are obtained as oil. 
EXAMPLE 4 
3-(1-hydroxyethyl)-.beta.-carboline 
Analogously to example 3,3-(1-hydroxyethyl)-.beta.-carboline with a 
172.degree.-174.degree. C. melting point (ethyl acetate/hexane) is 
produced from 3-formyl-.beta.-carboline. 
EXAMPLE 5 
3-methyl-.beta.-carboline 
2 g of 3-hydroxymethyl-.beta.-carboline, 3.7 g of sodium iodide and 2.5 ml 
of chlorotrimethylsilane are stirred in 50 ml of N,N-dimethylformamide at 
a bath temperature of 35.degree. C. for 4 hours. 3 g of zinc powder and 10 
ml of glacial acetic acid are added to the resulting yellow suspension and 
stirred for another 18 hours at 80.degree. C. The reaction mixture is 
allowed to clarify on Celite and the filtrate is concentrated under 
vacuum. The resulting oil is chromatographed on silica gel (methylene 
chloride/ethanol: 9+1). 0.825 g of 3-methyl-.beta.-carboline with a 
255.degree.-256.degree. C. melting point was obtained. 
EXAMPLE 6 
3,9-dimethyl-.beta.-carboline 
0.182 g of 3-methyl-.beta.-carboline (example 5), 0.5 ml of 
N,N-dimethylformamide-dimethylacetal (90%) and 0.02 g of 
diazabicyclooctane (Dabco) are stirred in 30 ml of absolute 
N,N-dimethylformamide for 15 hours at 110.degree. C. The solvent is 
distilled off under vacuum and the residue is chromatographed on silica 
gel. (Methylene chloride/ethanol: 9+1). 0.095 g of 
3,9-dimethyl-.beta.-carboline with a 134.degree. C. melting point 
(decomposition) is obtained. 
EXAMPLE 7 
N-phenyl-carbamic acid-(.beta.-carboline-3-yl-methyl)-ester 0.198 g of 
3-hydroxymethyl-.beta.-carboline are dissolved in 30 ml of toluene and 
mixed with 0.1 ml of phenylisocyanate. The solution is stirred for 4 hours 
at 70.degree. C. bath temperature. After cooling, the precipitate is 
filtered off, washed with toluene and dried under vacuum. 0.188 g of 
N-phenyl-carbamic acid-(.beta.-carboline-3-yl-methyl)ester with a 
153.degree.-155.degree. C. melting point (decomposition) is obtained. 
EXAMPLE 8 
N-methyl-carbamic 
acid-(9-methylcarbamoyl-.beta.-carbolin-3-yl-methyl)-ester 0.238 g of 
N-methylcarbamic 
acid-(9-methylcarbamoyl-.beta.-carboline-3-yl-methyl)-ester with a 
153.degree.-154.degree. C. melting point (decomposition), as in example 7, 
is obtained from 0.198 g of 3-hydroxymethyl-.beta.-carboline and 0.22 ml 
methylisocyanate. 
EXAMPLE 9 
3-chloromethyl-.beta.-carboline 
400 mg of 3-hydroxymethyl-.beta.-carboline are refluxed in 8 ml of thionyl 
chloride for one hour. After evaporation, 450 mg of 
3-chloromethyl-.beta.-carboline are obtained as hydrochloride. 
EXAMPLE 10 
3-(1-chloroethyl)-.beta.-carboline 
Analogously to example 9,3-(1-chlorethyl)-.beta.-carboline with a melting 
point starting at 225.degree. C. (while decomposing) is produced from 
3-(1-hydroxyethyl)-.beta.-carboline. 
EXAMPLE 11 
3-(1-ethoxyethyl)-.beta.-carboline 
200 mg of 3-(1-hydroxyethyl)-.beta.-carboline (example 4) are refluxed in 1 
ml of thionyl chloride for 3 hours. After distilling off, it is 
chromatographed on silica gel with methylene chloride/ethanol=10:1 as 
eluant. 117 mg of 3-(1-ethoxyethyl)-.beta.-carboline are obtained as oil. 
EXAMPLE 12 
3-styryl-.beta.-carboline 
0.51 g of 3-chloromethyl-.beta.-carboline (example 9) and 0.524 g 
triphenylphosphine are refluxed in 30 ml of absolute N,N-dimethylformamide 
for 20 hours. The solvent is distilled off under vacuum, the reaction 
product is picked up in 30 ml of methanol and mixed with an equivalent 
amount of benzaldehyde. To this is added drop by drop within 10 minutes a 
solution of 0.075 g of sodium and 10 ml of absolute methanol and then 
refluxed for 14 hours. The solvent is drawn off under vacuum and the 
residue picked up in methylene chloride, filtered on Celite and the 
filtrate concentrated under vacuum. The resulting reaction mixture is 
chromatographed on silica gel (methylene chloride/ethanol=9:1). 0.150 g of 
3-styryl-.beta.-carboline with a 204.degree.-207.degree. C. melting point 
is obtained. 
EXAMPLE 13 
3-N,N-dimethylaminomethyl-.beta.-carboline 300 mg of 
3-chloromethyl-.beta.-carboline hydrochloride (example 9) are refluxed in 
10 ml of ethanol with 5 ml of diethylamine for one hour. After evaporation 
it is dispersed in methylene chloridaqueous ammonia. The organic phase is 
dried, evaporated and recrystallized from acetone. 100 mg of 
3-N,N-dimethylaminomethyl-.beta.-carboline with a 122.degree.-123.degree. 
C. melting point are obtained. 
EXAMPLE 14 
3-methylthiomethyl-.beta.-carboline 126 mg of 
3-chloromethyl-.beta.-carboline hydrochloride (example 9) are added to a 
suspension of sodium methyl mercaptide prepared from 33 mg of 80% sodium 
hydride and methyl mercaptan in 10 ml of absolute tetrahydrofuran and 
refluxed for one hour. After dilution with water, the methylene chloride 
is extracted. The organic phase is washed with sodium bicarbonate 
solution, dried, filtered and concentrated. After recrystallization from 
diisopropyl ether with a little ethyl acetate, 55 mg of 
3-methylthiomethyl-.beta.-carboline with a 156.degree.-157.degree. C. 
melting point are obtained. 
EXAMPLE 15 
3-methylsulfinylmethyl-.beta.-carboline 
160 mg of 3-methylthiomethyl-.beta.-carboline are stirred in 15 ml of 
methylene chloride with 163 mg of m-chloroperbenzoic acid for 3 hours at 
room temperature. After extraction with semiconcentrated sodium 
bicarbonate solution, the organic phase is dried, filtered and 
concentrated. The residue is stirred with ethyl acetate/ethanol. 76 mg of 
3-methylsulfinylmethyl-.beta.-carboline with a 175.degree.-178.degree. C. 
melting point are obtained as a residue. 
EXAMPLE 16 
3-methylsulfonylmethyl-.beta.-carboline 
190 mg of methylthiomethyl-.beta.-carboline are mixed in 25 ml of methylene 
chloride with 382 mg of m-chloroperbenzoic acid and refluxed for one hour. 
After extraction with 30 ml of semiconcentrated sodium bicarbonate 
solution, the organic phase is dried, filtered and concentrated. After 
recrystallization from ethanol, 56 mg of 
3-methylsulfonylmethyl-.beta.-carboline with a 218.degree.-220.degree. C. 
melting point are obtained. 
EXAMPLE 17 
3-diethylphosphonomethyl-.beta.-carboline 
504 mg of 3-chloromethyl-.beta.-carboline hydrochloride are stirred with 4 
ml of triethylphospite for 2 hours at 120.degree.-130.degree. C. and after 
cooling, are chromatographed on silica gel with methylene 
chloride/methanol=10:2. 57 mg of 3-diethylphosphonomethyl-.beta.-carboline 
are obtained as oil. 
EXAMPLE 18 
6-iodine-3-methylsulfinyl-.beta.-carboline 
1.07 g of 3-methylthio-.beta.-carboline are stirred in 10 ml of glacial 
acetic acid with 0.24 ml of water, 0.06 ml of concentrated sulfuric acid, 
0.172 g of iodic acid and 0.442 g of iodine at 80.degree. C. bath 
temperature for 4 hours. After addition of 172 mg of iodic acid and 442 mg 
of iodine, heating at 80.degree. C. is continued for another 3 hours. 
After suctioning off of the precipitated crystals, 0.7 g of 
6-iodo-3-methylsulfinyl-.beta.-carboline with a 280.degree.-285.degree. C. 
melting point is obtained. 
EXAMPLE 19 
6-benzyloxycarbonyl-3-methylsulfinyl-.beta.-carboline 1.3 g of 
6-iodo-3-methylsulfinyl-.beta.-carboline are carbonylated in 21 ml of 
benzylalcohol with 0.96 ml of tributylamine and 38 mg of palladium (II) 
acetate under 1 atmosphere of carbon monoxide for 4 hours at 110.degree. 
C. After distilling off of the benzyl alcohol, it is picked up in 75 ml of 
methylene chloride and extracted once with 50 ml of 1N aqueous 
hydrochloric acid, once with saturated bicarbonate solution and once with 
saturated sodium chloride solution. The organic phase is dried, filtered 
and concentrated and the residue is recrystallized from ethyl 
acetate/hexane, whereby 630 mg of 
6-benzyloxycarbonyl-3-methylsulfonyl-.beta.-carboline with a 
220.degree.-223.degree. C. melting point are obtained. 
EXAMPLE 20 
6-ethoxycarbonyl-3-methylsulfinyl-.beta.-carboline 
270 mg of 6-benzyloxycarbonyl-3-methylsulfinyl-.beta.-carboline are 
refluxed for 1.5 hours with an alcoholate solution prepared from 27 mg 80% 
sodium hydride and 15 ml of absolute ethanol. After concentration, it is 
picked up in ethyl acetate and suctioned off. 78 mg of 
6-ethoxycarbonyl-3-methylsulfinyl-.beta.-carboline with a 
240.degree.-243.degree. C. melting point are obtained. 
EXAMPLE 21 
6-ethoxycarbonyl-.beta.-carboline 
150 mg of 6-carboxyethyl-3-methylsulfinyl-.beta.-carboline are hydrogenated 
in 20 ml N-methylpyrrolidinone at 60.degree. C. for 2 hours under a 
pressure of 50 bar of hydrogen in the presence of 100 mg Raney nickel 
(type B-113-Z). After suctioning off over a G-4 frit, it is evaporated and 
the residue boiled with ethyl acetate and 3 drops of ethanol. After 
suctioning off, 68 mg of 6-ethoxycarbonyl-.beta.-carboline with a 
243.degree.-244.degree. C. melting point are obtained. 
EXAMPLE 22 
6-dimethylaminocarbonyl-.beta.-carboline 
150 mg of 6-ethoxycarbonyl-.beta.-carboline are heated in 5 ml of ethylene 
gylcol with 2 ml of dimethylamine solution for 20 hours to 100.degree. C. 
After cooling, it is placed on ice, extracted with ethyl acetate and the 
organic phase is dried, filtered and concentrated. 50 mg of 
6-dimethylaminocarbonyl-.beta.-carboline are obtained as oil after 
chromatography on silica gel with methylene chloride/ethanol=10:1. 
EXAMPLE 23 
6-piperidino-4-methyl-.beta.-carboline 
2.5 g of 6-piperidino-4-methyl-.beta.-carboline-3-carboxylic acid are 
heated with 520 mg of copper powder in 50 ml of quinoline for 1.5 hours to 
190.degree.-220.degree. C. bath temperature. After distilling off the 
quinoline in a bulb tube, it is dispersed in ethyl acetate/10% aqueous 
ammonia. The precipitate that is formed is filtered off and absorptively 
precipated with ethanol. The combined evaporation residue of the ethanol 
extraction and the ethyl acetate phase yields 690 mg of 
6-piperidino-4-methyl-.beta.-carboline with a 235.degree.-238.degree. C. 
(decomposition) melting point by crystallization from 
ethylacetate/diisopropylether. 
EXAMPLE 24 
6-N,N-dimethylsulfonamido-.beta.-carboline 
Analogously, 6-N,N-dimethylsulfonamido-.beta.-carboline is produced from 
6-N,N-dimethylsulfonamido-.beta.-carboline-3-carboxylic acid; melting 
point: 223.degree.-226.degree. C. (ethanol). 
EXAMPLE 25 
3-tert-butoxycarbonylamino-.beta.-carboline 
0.25 g of .beta.-carboline-3-carboxylic acid are dissolved in 4 ml of 
dimethylsulfoxide while being heated. 10 ml of tert-butanol, 0.25 ml of 
diphenylphosphoryl azide and 0.17 ml of triethylamine are added to the 
solution. The reaction mixture is refluxed for 15 minutes. The crystals 
precipitated during cooling are filtered off, the tert-butanol is 
evaporated from the filtrate under vacuum and the residue is mixed with 10 
ml of water. 0.025 g of 3-tert-butoxycarbonylamino-.beta.-carboline with a 
185.degree.-190.degree. C. melting point (methanol) is obtained from the 
resulting precipitate by chromatography on silica gel (methylene chloride 
with 5% methanol). 
EXAMPLE 26 
3-methoxycarbonylamino-.beta.-carboline 
4 g of .beta.-carboline-3-carboxylic acid azide are refluxed in 250 ml of 
methanol for 6 hours. Then the solution is evaporated and the residue is 
recrystallized twice from ethyl acetate. 0.14 g of 
3-methoxycarbonylamino-.beta.-carboline with a 236.degree.-238.degree. C. 
melting point are obtained. 
The .beta.-carboline-3-carboxylic acid azide needed as starting material is 
produced as follows: 
3.4 g of diphenylphosphoryl azide and 2.2 ml of triethylamine are added to 
the solution of 3.3 g .beta.-carboline-3-carboxylic acid in 85 ml of 
dimethylsulfoxide. The solution temporarily turns purple and a precipitate 
results. After the solution is left standing overnight, the precipitate is 
filtered off and the filtrate is mixed into 0.8 l of water. The 
precipitate is suctioned off and dried. Melting point: 138.degree. C. 
(deflagration). 
EXAMPLE 27 
3-acetamino-.beta.-carboline 
2 g of 3-amino-.beta.-carboline are suspended in 35 ml of pyridine and 
mixed with 4 ml of acetic anhydride. The aminocarboline dissolves during 
slight heating. After 20 minutes the solution is evaporated. The 
crystalline residue is washed with water and is recrystallized from ethyl 
acetate. Yield: 1.5 g of 3-acetamino-.beta.-carboline with a 
200.degree.-203.degree. C. melting point. 
EXAMPLE 28 
3-(I-pyrrolyl)-.beta.-carboline 
0.74 g of 3-aminocarboline and 0.54 g of 2,5-dimethoxytetrahydrofuran are 
heated in 10 ml of glacial acetic acid for 15 minutes in a steam bath. 
After cooling, the precipitated crystals are suctioned off and are 
chromatographed on silica gel with a mixture of 10 parts of methylene 
chloride and one part of ethanol. 
Yield: 0.12 g of 3-(I-pyrrolyl)-.beta.-carboline; melting point: 
165.degree.-170.degree. C. 
EXAMPLE 29 
3-piperidino-.beta.-carboline 
549 mg of 3-amino-.beta.-carboline are refluxed for 4 hours with 1.5 g of 
1,5-dibromopentane and 1 g of diazabicycloundecene in 25 ml of 
tetrahydrofuran and 5 ml of absolute ethanol. After evaporation, the 
product is chromatographed on silica gel with cyclohexane/ethyl 
acetate=1:1 as eluant. 50 mg of 3-piperidino-.beta.-carboline are obtained 
as oil. 
EXAMPLE 30 
3-hydroxy-.beta.-carboline 
0.75 g of 3-amino-.beta.-carboline are dissolved in 85 ml of 6-molar 
sulfuric acid and at 0.degree. C. mixed with a solution of 0.435 g of 
sodium nitrite in 10 ml of water. The reaction mixture is stirred for an 
hour at 0.degree. C. and then added drop by drop to 320 ml of boiling 
2-molar sulfuric acid and then refluxed for another 20 minutes. After 
standing overnight, the product is neutralized with sodium hydroxide and 
extracted with a mixture consisting of 10 parts of ethyl acetate and one 
part of ethanol. The ethyl acetate extract is washed once with water, 
dried and evaporated. The evaporation residue is recrystallized from 
dimethylformamide. Thus 0.2 g of 3-hydroxy-.beta.-carboline are obtained 
EXAMPLE 31 
3-bromo-.beta.-carboline 
2 g of 3-amino-.beta.-carboline, suspended in 25 ml of 48% hydrobromic 
acid, are mixed with 6 ml of a 2-molar sodium nitrite solution at 
0.degree.-5.degree. C. The mixture is added at 0.degree.-5.degree. C. to a 
solution of 2.1 g of copper-I-bromide in 20 ml of 24% hydrobromic acid. 
The reaction mixture is heated briefly in a steam bath and then repeatedly 
extracted with a mixture consisting of 9 parts of ethyl acetate and one 
part of ethane. The combined extracts are evaporated, the residue 
chromatographed (silica gel, methylene chloride/methanol=19:1). The main 
fraction crystallizes on treatment with ethyl acetate. Yield: 0.5 g of 
3-bromo-.beta.-carboline; melting point: 300.degree. C. 
EXAMPLE 32 
The 3-chloro-.beta.-carboline is produced analogously to Example 31. 
Melting point: 307.degree.-308.degree. C. 
EXAMPLE 33 
3-ethoxy-.beta.-carboline 
1 ml of isoamylnitrite is added to a suspension of 1 g of 
3-amino-.beta.-carboline in 100 ml of ethanol and 2 ml of concentrated 
sulfuric acid. The mixture is stirred at room temperature for an hour and 
then refluxed for an hour. As a result, a clear solution is obtained. 
After cooling, it is poured into a mixture of 100 ml of water and 100 ml 
of saturated sodium bicarbonate solution. It is extracted three times with 
100 ml of ether each time and the evaporation residue of the combined 
ether extracts is chromatographed (silica gel, methanol/chloroform=95:5) 
and recrystallized from hexane. Yield: 0.3 g of 3-ethoxy-.beta.-carboline 
with a melting point of 130.degree.-133.degree. C. 
EXAMPLE 34 
The 3-methoxy-.beta.-carboline with a 184.degree.-189.degree. C. melting 
point is produced analogously to Example 33. 
EXAMPLE 35 
3-propoxy-.beta.-carboline 
184 mg of 3-amino-.beta.-carboline are mixed with 0.5 ml of i-amylnitrite 
in 15 ml of n-propanol at room temperature and stirred for 15 minutes. 
Then it is heated for 4.5 hours to 80.degree. C. bath temperature. After 
concentration, it is chromatographed on silica gel with 
methylene/chloride/acetone=1:1 as eluant. After concentration and 
recrystallization of the corresponding fractions from diisopropyl 
ether/cyclohexane, 120 mg of 3-propoxy-.beta.-carboline with a 
147.degree.-151.degree. C. melting point are obtained. 
EXAMPLE 36 
The following are produced in accordance with the process indicated in 
Example 35: 
3-isopropoxy-.beta.-carboline (petroleum ether absorptively precipitated) 
3-benzyloxy-.beta.-carboline, melting point: 174.degree.-175.degree. C., 
(diisopropyl ether/cyclohexane); 
3-cyclohexyloxy-.beta.-carboline, melting point: 138.degree.-139.degree. 
C., (diisopropyl ether/cyclohexane); 
3-(1-methoxyethoxy)-.beta.-carboline, melting point: 83.degree.-85.degree. 
C., (diisopropyl ether/cyclohexane); 
3-t-butoxy-.beta.-carboline, melting point: 208.degree.-212.degree. C., 
(diisopropyl ether/cyclohexane); 
3-butoxy-.beta.-carboline, melting point: 114.degree.-115.degree. C., 
(cyclohexane); 
3-isopentoxy-.beta.-carboline, melting point: 95.degree. C. 
EXAMPLE 37 
3-ethylthio-.beta.-carboline 
732 mg of 3-amino-.beta.-carboline in 7 ml of diethyldisulfide are heated 
to 80.degree. C. and mixed with 1 ml of isoamylnitrite. After 0.5 hours of 
heating to 80.degree. C., it is again mixed with 1 ml of isoamylnitrite 
and heated to 80.degree. C. for 1.5 hours. After distilling off, the 
residue is chromatographed twice on silica gel with ethyl 
acetate/cyclohexane as eluant. After absorptive precipitation of the 
corresponding evaporated fraction with cyclohexane/diisopropyl ether, 206 
mg of 3-ethylthio-.beta.-carboline with a 132.degree.-133.degree. C. 
melting point are obtained. 
EXAMPLE 38 
The following are produced in a corresponding manner: 
4-methyl-3-methylthio-.beta.-carboline with 183.degree.-185.degree. C. 
melting point (absorptively precipitated diisopropyl ether/cyclohexane); 
3-benzylthio-.beta.-carboline with a 150.degree. C. melting point (ethyl 
acetate/diisopropyl ether); 
3-methylthio-.beta.-carboline with a 178.degree.-179.degree. C. melting 
point, (chromatographically purified). 
EXAMPLE 39 
6-nitro-3-methylthio-.beta.-carboline 
970 mg of 3-methylthio-.beta.-carboline are stirred for 4 hours at room 
temperature with 60 ml of 65% nitric acid. After introduction of the 
preparation into water, it is suctioned off and dried. 950 mg of 
6-nitro-3-methylthio-.beta.-carboline with a &gt;250.degree. C. melting point 
are obtained. 
EXAMPLE 40 
6-amino-3-methylthio-.beta.-carboline 
950 mg of 6-nitro-3-methylthio-.beta.-carboline are hydrogenated in 80 ml 
of tetrahydrofuran and 80ml of ethanol with 200 mg of palladium/carbon 
(10%) for 7.5 hours at room temperature under normal hydrogen pressure. 
After filtration and concentration, the residue is chromatographed on 
silica gel with methylene chloride/acetone=1:1 as eluant. 600 mg of 
6-amino-3-methylthio-.beta.-carboline with a 202.degree. C. melting point 
are obtained. 
EXAMPLE 41 
6-diallylamino-3-methylthio-.beta.-carboline 
229 mg of 6-amino-3-methylthio-.beta.-carboline are heated in 15 ml of 
ethanol (absolute) with 0.27 ml of allylbromide and 0.37 ml of 
diazabicycloundecene for 3 hours to 70.degree. C. After concentration to 
dryness, it is dispersed in ethyl acetate/saturated sodium chloride 
solution. The organic phase is dried, filtered and concentrated. After 
trituration of the residue with diispropyl ether, 70 mg of 
6-diallylamino-3-methylthio-.beta.-carboline with a 110.degree. C. melting 
point are obtained. 
EXAMPLE 42 
6-diethylamino-.beta.-carboline 
150 mg of 6-amino-3-methylthio-.beta.-carboline are refluxed for 2 hours in 
5 ml of ethanol with a spatula tip of Raney nickel. 22 mg of 
6-diethylamino-.beta.-carboline as oil are obtained after filtering and 
evaporation. 
EXAMPLE 43 
6-amino-.beta.-carboline 
660 mg of 6-nitro-3-methylthio-.beta.-carboline are hydrogenated in 50 ml 
of N-methylpyrrolidone with 3 g of Raney nickel at 50 bar of H.sub.2 
pressure and 60.degree. C. for 2 hours. After filtering, it is evaporated 
and the residue chromatographed on silica gel with methylene 
chloride/ethanol=10:2 as eluant. 320 mg of 6-amino-.beta.-carboline as oil 
are obtained. 
EXAMPLE 44 
6-diallylamino-.beta.-carboline 
360 mg of 6-amino-.beta.-carboline are heated in 20 ml of ethanol with 0.54 
ml of allylbromide and 0.74 ml diazabicycloundecene for 3 hours at 
70.degree. C. After concentration to dryness and dispersing in ethyl 
acetate/saturated sodium chloride solution, the organic phase is 
separated, dried, filtered and concentrated. The residue is 
chromatographed on silica gel with cyclohexane/ethyl acetate=1:1 as eluant 
and 50 mg of 6-diallylamino-.beta.-carboline as oil are obtained. 
EXAMPLE 45 
6-chlorosulfonyl-3-methylthio-.beta.-carboline and 
6,8-bis-(chlorosulfonyl)-3-methylthio-.beta.-carboline 
400 mg of 3-methylthio-.beta.-carboline are added in portions to 1 ml of 
chlorosulfonic acid at 0.degree. C. After one hour at room temperature, it 
is slowly put on ice, suctioned off, and the residue dried and then heated 
in 5 ml of thionylchloride with 2 drops of dimethylformamide. 500 mg of a 
mixture of 6-chlorosulfonyl-3-methylthio-.beta.-carboline and 
6,8-bis-(chlorosulfonyl)-3-methylthio-.beta.-carboline are obtained after 
concentration. 
EXAMPLE 46 
6-dimethylaminosulfonyl-3-methylthio-.beta.-carboline and 
6,8-bis-(dimethylaminosulfonyl)-3-methylthio-.beta.-carboline 
200 mg of the mixture obtained according to example 45 are mixed with 10 ml 
of an ice cold 40% dimethylamine solution and heated for 5 minutes to 
100.degree. C. After cooling, it is diluted with water and extracted with 
ethyl acetate. After chromatography on silica gel with methylene 
chloride/ethanol=95:5 as eluant, 130 mg of 
6-dimethylaminosulfonyl-3-methylthio-.beta.-carboline with a 
298.degree.-300.degree. C. melting point are obtained as well as 90 mg of 
6,8-bis-(dimethylaminosulfonyl)-3-methylthio-.beta.-carboline with a 
249.degree.-265.degree. C. melting point. 
EXAMPLE 47 
6-diallylaminosulfonyl-3-methylthio-.beta.-carboline and 
6,8-bis-(diallylaminosulfonyl)-3-methylthio-.beta.-carboline 
The following are produced analogously to example 46: 
6-diallylaminosulfonyl-3-methylthio-.beta.-carboline, melting point: 
211.degree. C.; and 
6,8-bis-(diallylaminosulfonyl)-3-methylthio-.beta.-carboline, melting 
point: 148.degree. C. 
EXAMPLE 48 
.beta.-carboline-4-carboxylic acid ethyl ester 
0.9 of 1,2,3,4-tetrahydro-.beta.-carboline-4-carboxylic acid ethyl ester 
hydrochloride is stirred with 0.22 g sulfur powder in 9 ml of 
dimethylsulfoxide under argon for 1.5 hours at 130.degree. C. From the 
evaporated reaction mixture, 0.4 g of .beta.-carboline-4-carboxylic 
acid-ethyl ester hydrochloride with a 238.degree.-240.degree. C. melting 
point can be extracted with ethanol. 
The starting material is produced from the 
1,2,3,4-tetrahydro-.beta.-carboline-4-carboxylic acid by esterification 
with ethanol and thionyl chloride in a known manner. 
EXAMPLE 49 
.beta.-carboline-4-carboxylic acid propyl ester 
The compound is produced by transesterification of the 
.beta.-carboline-4-carboxylic acid-ethyl ester-hydrochloride with 
n-propanol. 
EXAMPLE 50 
6-nitro and 8-nitro-.beta.-carboline-4-carboxylic acid-ethyl ester 
1 g .beta.-carboline-4-carboxylic acid-ethyl ester-hydrochloride are 
introduced into 20 ml of 65% nitric acid at room temperature while 
stirring. After 15 minutes, it is heated to 75.degree. C. for one hour. 
After cooling, the reaction mixture is poured into ice water. The 
precipitate is suctioned off and recrystallized from ethyl acetate. Yield: 
0.56 g of 6-nitro-.beta.-carboline-4-carboxylic acid-ethyl ester nitrate. 
Melting point: 218.degree.-220.degree. C. 
The 8-nitro-.beta.-carboline-4-carboxylic acid ethyl ester can be isolated 
from the above-mentioned glacial acetic acid mother liquor or 
chromatographically, from the not yet recrystallized raw product (silica 
gel, toluene-glacial acetic acid-water=10:10:1). 
EXAMPLE 51 
6-amino and 8-amino-.beta.-carboline-4-carboxylic acid ethyl ester 
3.3 g of mixture of 6-nitro and 8-nitro-.beta.-carboline-4-carboxylic acid 
ethyl ester (example 50) are hydrogenated in 400 ml of ethanol and with 
addition of 20 g of Raney nickel at normal pressure and room temperature. 
The isomer mixture is separated by chromatography on silica gel 
(toluene/glacial acetic acid/water=10:10:1). After crystallization from 
ethyl acetate, 0.5 g of 6-amino-.beta.-carboline-4-carboxylic acid ethyl 
ester with a &gt;340.degree. C. melting point are isolated as more polar 
components. 
The isomer more nonpolar 8-amino-.beta.-carboline-4-carboxylic acid ethyl 
ester is obtained in a yield of 0.2 g with a 262.degree.-265.degree. C. 
melting point by dissolution in hot ethyl acetate, cooling, filtering and 
evaporation of the mother liquor. 
EXAMPLE 52 
6-diallylamino-.beta.-carboline-4-carboxylic acid ethyl ester 
A solution of 0.28 g of 6-amino-.beta.-carboline-4-carboxylic acid ethyl 
ester, 0.18 g of diazabicycloundecane and 0.26 g of allylbromide in 5 ml 
of ethanol is heated for 3 hours to 70.degree. C. Then the solution is 
evaporated. The evaporation residue is extracted with ethyl acetate and 
water, the combined extracts are evaporated and chromatographed on silica 
gel with methylene chloride/methanol=5:1. Yield: 0.05 g. 
EXAMPLE 53 
4-acetyl-.beta.-carboline 
The reaction of .beta.-carboline-4-carboxylic acid with methyllithium 
analogous to the process described by C. Tegner (Act. Chem. Scand. 6, 
782-90) for the reaction of benzoic acid with methyllithium yields 
4-acetyl-.beta.-carboline. 
The .beta.-carboline-4-carboxylic acid needed as starting material is 
produced from .beta.-carboline-4-carboxylic acid ethyl ester (example 48) 
by heating with aqueous alcoholic sodium hydroxide solution. 
EXAMPLE 54 
.beta.-carboline-5-carboxylic ethyl ester 
0.86 g of 5-ethoxycarbonyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxylic 
acid are refluxed for 50 minutes in 200 ml of xylene with 0.65 g of 10% 
palladium/carbon. The solution is evaporated after filtering off of the 
catalyst. The residue is boiled first with xylene and then with ethanol. 
The extracts are mixed, evaporated and chromatographed on silica gel with 
ethanol/methylene chloride 1:10. 
After treatment with ether, 0.48 g .beta.-carboline-5-carboxylic acid ethyl 
ester with a 195.degree.-201.degree. C. melting point is obtained. 
The starting material required for the synthesis is produced as follows: 
A. 4-ethoxycarbonyl-3-(2-nitrovinyl)-indole 
5 g of 4-ethoxycarbonyl indole are added to a solution of 3.1 g of 
dimethylamino-2-nitroethylene in 20 ml of trifluoroethyl acetate 
refrigerated under argon. The reaction mixture is introduced into ice 
water after it had been standing overnight at room temperature. The 
aqueous phase is repeatedly extracted with ethyl acetate. The combined 
ethyl acetate extracts are extracted first with sodium bicarbonate 
solution, then a saturated sodium chloride solution, dried and evaporated. 
The residue is recrystallized from ethanol. Yield: 4.5 g of 
4-ethoxycarbonyl-3-(2-nitrovinyl)-indole. Yellow crystals with a 
197.degree.-199.degree. C. melting point. 
B. 3-(2-aminoethyl)-4-ethoxycarbonyl indole 
0.5 g of 4-ethoxycarbonyl-3-(2-nitrovinyl)indole are heated under nitrogen 
for 45 minutes in the steam bath in 50 ml of formic acid with 1.5 g of 10% 
palladium-carbon. The palladium carbon is then filtered off, the filtrate 
evaporated, the evaporation residue [3-(2-aminoethyl)-4-ethoxycarbonyl 
indole] is then further reacted immediately. 
C. 5-ethoxycarbonyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxylic acid 
3.03 g of 3-(2-aminoethyl)-4-ethoxycarbonylindole are picked up in 13 ml 1N 
hydrochloric acid and a little water. The clear filtered solution is added 
drop by drop while stirring to a solution of 1.25 g of gloyoxylic acid 
monohydrate in 40 ml of water cooled to 15.degree. C. The reaction mixture 
is adjusted to pH 4 with sodium hydroxide solution. After having been left 
standing for one hour at 15.degree. C., the precipitate is suctioned off. 
The filtrate is left standing overnight at room temperature. 800 mg of 
5-ethoxycarbonyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxylic acid 
crystallize as yellow crystals with a 229.degree.-231.degree. C. melting 
point. 
EXAMPLE 55 
6,7-dimethoxy-4-ethyl-.beta.-carboline 
6,7-dimethoxy-4-ethyl-.beta.-carboline with a 197.degree. C. melting point 
is obtained according to the method in example 54. 
6,7-dimethoxy-4-ethyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxylic 
acid required as starting material is obtained in the following manner: 
(A) 1.3 g of isopropyl-[1-(5,6-dimethoxyindol-3-yl)-propyl]-amine and 1.3 
ml of nitromethane in 50 ml of acetonitrile, after addition of 320 mg of 
n-tributylphosphine in 20 ml of acetonitrile, are refluxed for 3 hours 
under an N.sub.2 atmosphere. 
The reaction mixture is concentrated to dryness and picked up in methylene 
chloride. The organic phase is extracted with 0.5N hydrochloric acid, 
washed with saturated sodium chloride solution and the organic phase is 
dried on Sikkon. After distilling off of the solvent, the resulting raw 
product is chromatographed on silica gel (methylene chloride). 0.98 g of 
2-(5,6-dimethoxyindol-3-yl)1-nitrobutane is obtained as an oil. 
(B) 2-(5,6-dimethoxyindol-3-yl)-1-aminobutane 
0.98 g of 2-(5,6-dimethoxyindol-3-yl)-1-nitrobutane is reduced in 20 ml of 
ethanol with 1 g of Raney nickel catalyst at room temperature under a 
hydrogen atmosphere of 50 bar. The catalyst is filtered off and the 
filtrate evaporated. 
2-(5,6-dimethoxyindol-3-yl)-1-aminobutane is obtained in quantitative yield 
which is immediately further reacted according to example 54(C) to 
6,7-dimethoxy-4-ethyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxylic 
acid. 
EXAMPLE 56 
5-benzyloxy-4-methoxymethyl-.beta.-carboline 
0.9 g of 
5-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxyl 
ic acid is suspended in 20 ml of xylene and refluxed for 1.5 hours. The 
solvent is distilled off under vacuum. The residue is picked up in 20 ml 
dimethylsulfoxide, mixed with 0.14 g of sulfur and stirred for 1 hour at 
140.degree. C. bath temperature. Dimethylsulfoxide is distilled off under 
vacuum. The resulting yellow oil is absorptively extracted with 
diisopropyl ether. 
The crystalline residue is recrystallized from ethyl acetate. 0.320 g of 
5-benzyloxy-4-methoxymethyl-.beta.-carboline with a 
189.degree.-191.degree. C. melting point is obtained. 
The 
5-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-.beta.-carboline-1-carboxyl 
ic acid required as starting material is synthesized according to the 
method indicated in example 54. 
EXAMPLE 57 
5-acetyl-.beta.-carboline 
5-acetyl-1,2,3,4-tetrahydro-.beta.-carboline is also dehydrogenated 
according to the method described in example 54 (production of 
.beta.-carboline-5-carboxylic acid ethyl esters). The 
5-acetyl-.beta.-carboline is obtained in a 10% yield. 
The 5-acetyl-1,2,3,4-tetrahydro-.beta.-carboline required as starting 
material is produced starting from 4-acetyl-indole by the 
4-acetyl-3-(2-nitrovinyl)-indole according to the method described in 
example 54 for production of 
1,2,3,4-tetrahydro-.beta.-carboline-5-carboxylic acid ethyl ester. 
EXAMPLE 58 
.beta.-carboline-5-carboxylic acid nitrile 
.beta.-carboline-5-carboxylic acid nitrile is produced, analogously to the 
process of R. S. Monson and D. N. Priest [Canad. J. Chem. 49, 2897 (1971)] 
by boiling of the amide in hexamethylphosphoric triamide. 
The .beta.-carboline-5-carboxylic acid amide required as starting material 
is obtained by reaction of .beta.-carboline-5-carboxylic acid ethyl ester 
with saturated aqueous ammonia solution at 0.degree. C. 
EXAMPLE 59 
.beta.-carboline-5-carboxylic acid-butyl ester 
The compound is produced from .beta.-carboline-5-carboxylic acid ethyl 
ester by boiling in n-butanol with addition of a catalytic amount of 
p-toluenesulfonic acid. 
EXAMPLE 60 
.beta.-carboline-3-phosphonic acid-diethyl ester 
A mixture of 0.24 g of inole and 0.83 g of azadiene A (see below) is heated 
in 3.4 ml of acetic acid for 3 hours to 140.degree. C. (bath temperature). 
When the solution is poured into ice water, 0.28 g of 
.beta.-carboline-3-phosphonic acid-diethyl ester with a 196.degree. C. 
melting point crystallizes. 
EXAMPLE 61 
5-benzyloxy-.beta.-carboline-3-phosphonic acid-diethyl ester 
Analogously to example 60, 0.50 g of the title compound with a 188.degree. 
C. melting point (from diethyl ether/benzene) is obtained from 0.45 g of 
4-benzylozy-indole. 
EXAMPLE 62 
5-ethoxymethyl-.beta.-carboline-3-phosphonic acid-diethyl ester 
The title compound is obtained from 4-ethyoxymethylindole analogously to 
example 60. 
EXAMPLE 63 
.beta.-carboline-3-phosphonic acid-monoethyl ester 
Analogously to example 60, the monoester with &gt;320.degree. C. melting point 
(decomposition) is obtained in the presence of a catalytic amount of 
sulfuric acid. 
EXAMPLE 64 
.beta.-carboline-3-phosphonic acid-monoethyl-monomethyl ester 
0.28 g of the monoethyl ester of example 63 is dissolved in methanol and 
left standing overnight with excess ether diazomethane solution. 0.21 g of 
the title compound is obtained. 
EXAMPLE 65 
5-benzyloxy-.beta.-carboline-3-phosphonic acid-monoethyl ester-diethylamide 
A mixture of 0.2 g of 5-benzyloxy-.beta.-carboline-3-phosphonic acid 
diethyl ester (example 61) and 0.1 g of oxalyl chloride in 10 ml of 
dichloromethane is stirred for 24 hours at room temperature and then mixed 
with an excess of diethylamine. It is heated to boiling for 2 more hours 
for completion of the reaction. It is diluted with acetic acid and 
extracted with water. The evaporation residue of the organic phase yields 
0.15 g of the title compound after crystallization from tetrahydrofuran. 
EXAMPLE 66 
3-phenyl-.beta.-carboline 
Analogously to example 60, the title compound with a 228.degree. C. melting 
point (from isopropanol) is obtained from indole and N.sup.2 
-(2-dimethyl-amino-1-phenylvinyl)-N.sup.1,N.sup.1 -dimethylformamidine 
(azadiene B). 
EXAMPLE 67 
5-methyl-.beta.-carboline-3-sulfonic acid-dimethylamide 
Analogously to example 60, the title compound is obtained from 
4-methylindole and azadiene C. 
Azadienes A-C used in examples 60-67 are produced in the following manner: 
Azadiene A: 
2-dimethylamino-1-(dimethylaminomethyleneamino)-ethylene-phosphonic 
acid-diethyl ester 
A mixture of 3.7 g of aminomethanephosphonic acid-diethyl ester and 15 g of 
the aminal ester tert-butyoxy-N,N,N',N'-tetramethylmethanediamine is 
heated to about 160.degree. C. for 6 hours. 4.2 g are obtained after 
fractionating of the residue in a bulb tube at 160.degree.-165.degree. C. 
Azadiene B: 
N.sup.2 -(2-dimethylamino-1-phenylvinyl)-N.sup.1,N.sup.1 
-dimethylformamidine 
According to W. Kantlehner et al., Liebigs Ann. Chem. 1980, 344. 
Azadiene C: 
2-dimethylamino-1-(dimethylaminomethyleneamino)-ethylene-sulfonic 
acid-dimethylamide 
Production takes places analogously to azadiene A from aminomethanesulfonic 
acid-dimethylamide and aminal ester. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.