Note: Descriptions are shown in the official language in which they were submitted.
- 2170615
Alkoxy-Substituted B-Carbolines
The invention relates to alkoxy-~-carboline derivatives,
their production and use in pharmaceutical agents as well as
intermediate products to produce them.
It is known from numerous publications that ~-carbolines
have affinity to the benzodiazepine receptors and can be used as
psychopharmaceutical agents on the basis of their affinity to the
benzodiazepine receptors.
It has now been found, surprisingly enough, that the
compounds of formula I have an effect on the modulation point of
the AMPA receptor or on AMPA receptor-dependent ion channels and
correct the pathologically altered function of this receptor.
The synaptic function of the excitatory amino acid L-glutamate is
mediated mainly with AMPA receptors. Increased or reduced
glutamatergic neurotransmission in the central nervous system
leads to numerous neurological and psychiatric diseases. The
compounds of formula I therefore are suitable for the production
of pharmaceutical agents for symptomatic and preventive treatment
of neurological and psychiatric diseases.
The invention relates to the compounds of formula I
1\ ¦ R3
N-A-O ~ (I)
R R9
in which
2 21 7061 5
A means straight-chain or branched Cl5 alkylene, which
can be substituted with hydroxy, C16 alkoxy or Cl-6
alkanoyloxy, or - (CH2) n~CO~ (CH2) m~
n,m is 1, 2 or 3,
R1 and R2 are the same or different and mean hydrogen, C14
alkyl, C37 cycloalkyl, C4 9 cycloalkylalkyl, phenyl,
phenyl-C12 alkyl or
R1 and R2 together with the nitrogen atom form a
heterocyclic compound of formula (a)
N ~B (a)
in which
B means a direct bond, oxygen, sulfur, >CH-R5, ~COH-Rs or
>N-R5 and
R5 represents hydrogen, C1 4 alkyl, co ~ or a phenyl,
benzyl, benzoyl, ~-hydroxy-benzyl, phenethyl, 2-oxo-2-
phenethyl, 1-oxo-2-phenethyl or pyridine radical that
is optionally substituted with C1 4 alkyl, C1 4 alkoxy,
halogen, hydroxy, -CF3 or -O-CF3 in one to three
places, and
Y means oxygen, sulfur or >NH, and
R3 represents hydrogen, COOH, COO-C1-6 alkyl, CO-R6 or a
C612 aryl or hetaryl radical that is optionally
substituted in one to three places with C14 alkyl, C37
3 21 7061 5
cycloalkyl, halogen, C14 alkoxy-C12 alkyl, C14 alkoxy,
phenyl or amino,
R4 means hydrogen, C16 alkyl, C, 4 alkoxy-C12 alkyl and
R6 means C14 alkyl, C37 cycloalkyl, C79 bicycloalkyl or a
monocyclic or bicyclic C612 aryl radical that is
optionally substituted with C14 alkyl, C14 alkoxy or
amino, and
R9 means hydrogen, C16 alkyl, C16 alkanoyl, phenyl-C12
alkyl, optionally substituted benzenesulfonyl or C~ 4
allkanesulfonyl, as well as their stereoisomers and
salts.
If the compounds of formula I have chiral centers, the
invention encompasses all possible stereoisomers such as
enantiomers and diastereomers as well as their mixtures and
racemates.
The substituent can be in the A-ring in 5- to 8-position,
preferably in 5- or 6-position.
Straight-chain or branched C~ 5 alkylene is, for example,
methylene, ethylene, propylene, isopropylidene, l-methylethylene,
2-ethylpropylene, 2,2-dimethylethylene, l,l-dimethylethylene,
l,2-dimethylethylene, tetramethylene. The substituent of
alkylene radical A is in any position, preferably in 2-, 3- or 4-
position of the straight-chain alkylene radical.
In each case, alkyl contains both straight-chain and
branched-chain radicals, such as, for example, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, hexyl, 2,2-dimethylpropyl and 2-methylbutyl.
4 2170615
In each case, cycloalkyl can stand for cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2-methyl-
cyclopropyl.
As cycloalkylalkyl radicals, for example, cyclopropylmethyl
and cyclohexylmethyl can be mentioned.
In each case, the phenyl-C~2 alkyl substituent can be
straight-chained or branched in the alkyl radical, such as, for
example, benzyl, phenethyl, ~-methylbenzyl.
As halogen, in each case fluorine, chlorine, bromine and
iodine are suitable.
Pyridine radical R5 is bound in 2-, 3- or 4-position.
Aryl and hetaryl radical * can be present as a monocyclic
or bicyclic compound and can contain 5-12 ring atoms, preferably
5-9 ring atoms, such as, for example, phenyl, biphenyl, naphthyl,
indenyl as aryl radical and thienyl, furyl, pyranyl, pyrrolyl,
pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl,
isooxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazol-2-yl,
1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl,
isoquinolyl, benzo[l]thienyl, benzofuryl as hetaryl radical with
1-3 heteroatoms, such as sulfur, oxygen and/or nitrogen.
As preferred heteroaryl radicals R3, isoxazol-3-yl,
isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-
oxadiazol-2-yl, thiazol-4-yl, thiazol-2-yl, pyrrol-2-yl, pyrrol-
3-yl, 2-thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-
4-yl and oxazol-5-yl, which optionally can be substituted, can be
mentioned. Preferred aryl R3 is phenyl that is optionally
substituted with halogen or C~ 4 alkoxy.
21 7061 5
Bicycloalkyl radical R6 is defined as bicycloheptyl and
bicyclooctyl. As monocyclic or bicyclic aryl radical R6, for
example, phenyl, biphenyl, naphthyl and indenyl can be mentioned.
The C16 alkanoyl radical is derived in each case from
straight-chain or branched aliphatic carboxylic acids, such as,
for example, formic acid, acetic acid, propionic acid, butyric
acid, trimethylacetic acid or caproic acid.
As sulfonic acid radicals R4, the known benzenesulfonic
acids, which can be substituted with halogen or C14 alkyl, as
well as C~ 4 alkanesulfonic acids, such as, for example,
methanesulfonic acid, p-toluenesulfonic acid, are suitable.
The physiologically compatible salts are derived from
inorganic and organic acids. Suitable are inorganic acids, such
as, for example, hydrohalic acids, such as hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid or organic
acids, such as, for example, aliphatic or aromatic mono- or
dicarboxylic acids, such as formic acid, acetic acid, maleic
acid, fumaric acid, succinic acid, lactic acid, tartaric acid,
citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for
example, C~ 4 alkanesulfonic acids, such as methanesulfonic acid
or benzenesulfonic acids that are optionally substituted by
halogen or C~ 4 alkyl, such as p-toluenesulfonic acid.
Preferred are compounds of formula I, in which
R1 and R2 together with the nitrogen atom form a
heterocyclic compound of formula
N B
6 2170615
,_
and
R3 represents hydrogen, COOH, COOC16 alkyl or a C6-12 aryl
or hetaryl radical that is optionally substituted in one to three
places with C~ 4 alkyl, C37 cycloalkyl, halogen, C14 alkoxy, C14
alkXY~C1-2-a~ky~ phenyl or amino, and
R4, R9 and A have the above meaning.
Especially preferred are compounds of formula I in which
A means straight-chain or branched C15 alkylene, which
can be substituted with hydroxy or C16 alkoxy,
R1 and R2 together with the nitrogen atom form the
heterocyclic compound /~
N B
/ (a)
R9 means hydrogen or C16 alkyl and
R3 means hydrogen, COOH or COOC16 alkyl as well as their
stereoisomers and salts.
If R5 means a phenyl, benzyl, benzoyl, ~-hydroxybenzyl,
phenethyl, 2-oxo-2-phenethyl or l-oxo-2-phenethyl radical, which
is substituted, halogen and C14 alkoxy can be viewed as
preferred, especially the radical substituted with fluorine,
whereby the substitution in 4-position is preferred.
The production of the compounds of formula I is carried out
in a way known in the art, by
7 2170615
a) a compound of formula II
~ ~ ` ' (Il)
in which
R3, R4 and R9 have the above meaning, being reacted with an
amine of formula III
~ R1
X--A--N ~ (111)
R2
in which R1, R2 and A have the above meaning and X represents a
leaving group,
or
b) a compound of formula IV
X-A-
in which
A, R3, R4 and R9 have the above meaning and X represents a
8 2170615
leaving group, being reacted with an amine of formula V
R1
H--N ~ (\/)
\ R2
in which R1 and R2 have the above meaning, and optionally then
substituent R9 being introduced or cleaved or the physiologically
compatible salts being formed or the physiologically compatible
salts being converted to the free compounds of formula I or
racemates being separated.
The nucleophilic substitution of leaving group X according
to process variants a) and b) is performed under basic conditions
according to commonly used methods in an organic solvent that is
inert under the reaction conditions.
As leaving groups X, halogens such as chlorine, bromine or
iodine or organic sulfonic acid radicals such as the radical of
an alkanesulfonic acid, for example, mesylate, triflate or the
radical of an aromatic sulfonic acid, for example,
toluenesulfonic acid or bromobenzenesulfonic acid, are suitable.
As inert organic solvents, polar solvents such as
dimethylformamide, dimethylacetamide or alcohols, such as
ethanol, methanol or cyclic ethers, such as dioxane,
tetrahydrofuran, halogenated hydrocarbons, aromatic hydrocarbons
or mixtures of the above-mentioned solvents are suitable.
As bases, inorganic and organic bases are suitable.
Examples of inorganic bases are alkali or alkaline-earth
hydroxide, -carbonate, -bicarbonate or -alcoholate. Examples of
9 2170615
organic bases are tertiary organic amines, such as
tripropylamine, triethylamine, N-alkylmorpholine or
N-alkylpiperidine. Excess amine of formula V can also be used as
a base, however, or the reaction can be performed in the presence
of phase transfer catalysts.
The reaction temperature can be between 0C and boiling
temperature of the solvent.
The introduction of substituent R9 can be carried out
according to the commonly used alkylation, benzylation and
sulfonylation processes, for example, by a reactive derivative
such as the halide of substituent R9 being reacted in the
presence of bases with the carboline.
The cleavage of substituent R9 is carried out in the usual
way, basically or hydrogenolytically, according to the type of
substituent.
The compounds of formula I can be isolated from the reaction
mixture in a way known in the art and purified. Acid addition
salts can be converted in the usual way to the free bases and the
latter optionally in the known way to physiologically compatible
acid addition salts, for example by the solution being mixed with
a concentrated solution of the desired acid.
If the compounds of formula I contain a chiral center, the
optically active compounds can be obtained from the racemates
starting from optically active starting compounds or in a way
known in the art. The enantiomer separation can be carried out,
for example, by chromatography on optically active media, by
21 7061 5
reaction with optically active acids and then fractionated
crystallization.
The invention also encompasses the compounds of formula IV
R4
X-A-~ R9 R3 (1~
in which A, R3, R4, R9 and X have the above meaning. The starting
compounds of formula IV are valuable intermediate products for
the production of pharmacologically effective compounds, for
example, the compounds of formula I.
The production of the compounds of formula IV is carried out
according to processes known in the art, for example, by
a) a compound of formula II
R4
HO- ~ R3
R9 (1l?
in which R3, R4 and R9 have the above meaning, being etherified
with a compound of formula VI
X -A-Y
in which A and X have the above meaning, and Y is a leaving
group, or
11 21 70615
b) a compound of formula II being etherified with an
alcohol of formula VII Y -A -OH, and then leaving group X being
introduced.
As leaving group Y, the groups mentioned under X are
suitable. The etherification is carried out in the usual way in
the presence of bases. The introduction of leaving group X is
performed with commonly used methods.
In so far as the production of the starting compounds is not
described, the latter are known or can be produced analogously to
the known compounds or processes that are describèd here.
For example, the production of the hydroxy derivatives of
formula II can be carried out according to EP-A-130 140, EP 0161
574, EP 0305 322, WO 92/21679 and WO 92/22549.
The compounds of formula I as well as their physiologically
compatible salts can be used as pharmaceutical agents owing to
their effect on the modulation point of the quisqualate receptor
or of the quisqualate receptor-dependent ion channel.
The pharmacological effectiveness of the compounds of
formula 1 was determined by means of the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled
conditions (0600-1800 hours light/dark cycle, with free access to
food and water), and their assignment to groups was randomized.
The groups consisted of 5-16 animals. The observation of the
animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricles of mice that were
able to move freely. The applicator consisted of a cannula with
a stainless steel device, which limited the depth of injection to
12 2170615
..
3.2 mm. The applicator was connected to an injection pump. The
injection needle was inserted perpendicular to the surface of the
skull according to the coordinates of Montemurro and Dukelow.
The animals were observed for up to 180 seconds until clonic or
tonic seizures set in. Clonic movements that lasted longer than
5 seconds were counted as seizures. The beginning of the clonic
seizures was used as an end point for the determination of the
seizure threshold. The dose that was necessary to increase or
reduce the seizure threshold by 50% (THRD50) was determined in 4-
5 experiments. The THRDso and the fiduciary limit were
determined in a regression analysis.
The results of these tests show that the compounds of
formula I and their acid addition salts influence functional
disorders of the AMPA receptor. They are therefore suitable for
the production of pharmaceutical agents for symptomatic and
preventive treatment of diseases that are triggered by alteration
of the function of the AMPA receptor complex.
The treatment with the compounds according to the invention
prevents or delays cell damage and functional disorders that
result because of disease and moderates the symptoms that thus
result.
The diseases that can be triggered by dysfunction of
excitatory amino acids or altered glutamatergic neurotransmission
fall into the category of, for example, neurodegenerative
diseases such as Parkinson's disease, Huntington's disease,
Alzheimer's disease, senile dementia, multiple infarction
dementia, amyotrophic lateral sclerosis, olivopontocerebellar
13 2 1 706 1 5
degeneration, epilepsy; cell damage by hypoglycemia, hypoxia,
ischemia and disorders of energy metabolism; neuronal damage that
is triggered by damage to the brain, such as stroke, brain trauma
and asphyxia as well as psychoses, schizophrenia, anxiety
conditions, attacks of pain, migraines and vomiting. Also,
functional disorders such as memory disorders (amnesia), learning
process disorders, vigilance symptoms and withdrawal symptoms
after chronic intake of addictive agents such as sedatives,
hallucinogens, alcohols, cocaine and opiates are based on the
dysfunction of glutamatergic neurotransmission.
The indications can be shown by commonly used
pharmacological tests.
The invention also encompasses pharmaceutical agents that
contain the mentioned compounds, their production as well as the
use of the compounds according to the invention for production of
pharmaceutical agents that are used for treatment and prophylaxis
of the above-mentioned diseases. The pharmaceutical agents are
produced according to processes known in the art, by the active
ingredient being put with suitable vehicles, adjuvants and/or
additives into the form of a pharmaceutical preparation, which is
suitable for enteral or parenteral administration. The
administration can be carried out orally or sublingually as a
solid in the form of capsules or tablets or as a liquid in the
form of solutions, suspensions, elixirs or emulsions or rectally
in the form of suppositories or in the form of injection
solutions that can also be administered subcutaneously. As
adjuvants for the desired pharmaceutical agent formulation, inert
14 21 7061 5
organic and inorganic media that are known to one skilled in the
art, such as, for example, water, gelatin, gum arabic, lactose,
starch, magnesium stearate, talc, vegetable oils,
polyalkyleneglycols, etc., are suitable. Moreover,
preservatives, stabilizers, wetting agents, emulsifiers, or salts
can optionally be contained to alter the osmotic pressure or
buffer.
The pharmaceutical preparations can be present in solid
form, for example, as tablets, coated tablets, suppositories,
capsules, or in liquid form, for example, as solutions,
suspensions or emulsions.
As vehicle systems, near-interface adjuvants such as salts
of bile acids or animal or plant phospholipids, but also mixtures
of them, as well as liposomes or their components, can also be
used.
For oral administration, especially tablets, coated tablets
or capsules with talc and/or hydrocarbon vehicles or binders,
such as, for example, lactose, corn or potato starch, are
suitable. Administration can also be done in liquid form, such
as, for example, as juice, to which sweetener is optionally
added.
For the parenteral administration, especially injection
solutions or suspensions, especially aqueous solutions of the
active compounds in polyhydroxyethoxylated castor oil, are
suitable.
The dosage of the active ingredients can vary depending on
the method of administration, the age and weight of the patient,
lS 2 1 706 1 5
the type and severity of the disease to be treated, and similar
factors. The daily dose can be given as a single dose to be
administered one time or divided into 2 or more daily doses.
The compounds are introduced in a dosage unit of 0.05 to 500 mg
of active substance in a physiologically compatible vehicle. In
general, a dose of 0.1 to 1000 mg/day (0.001 to 10 mg/kg),
preferably 0.1 to 100 mg/day, is used.
The following examples are to explain the production of the
compounds of formula I:
16 21 70615
.
Example 1
5-~3-[4-(4-Fluorobenzoyl)-piperidin-1-yl]-propoxy~-4-
methoxYmethyl-~-carboline-3-carboxylic acid isopropYl ester
628 mg of 5-hydroxy-4-methoxymethyl-~-carboline-3-carboxylic
acid isopropyl ester is introduced in 100 ml of acetone, mixed
with 600 mg of potassium carbonate and 760 mg of (4-
fluorophenyl)-[1-(3-methylsulfonyloxypropyl)-4-piperidyl]-ketone
and refluxed for 3 hours under argon. After the organic phase is
concentrated by evaporation, it is chromatographed on silica gel
with hexane and acetone = 1 + 1. The desired fractions are
concentrated by evaporation and absorptively precipitated with
ether. 630 mg of 5-{3-[4-(4-fluorobenzoyl)-piperidine]-propoxy}-
4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester of
melting point 161-162C is obtained.
The (4-fluorophenyl)-1[1-(3-methylsulfonyloxy-propyl)-4-
piperidyl]-ketone is obtained according to methods known in the
literature by alkylation of 4-(4-fluorobenzoyl)-piperidine with
3-bromopropanol-1 and potassium carbonate in dimethylformamide
and subsequent reaction with methanesulfonic acid and
triethylamine in methylene chloride.
Produced analogously are:
6-{3-[4-(4-Fluorobenzoyl)-piperidin-1-yl}-propoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester,
melting point 153-155C
5-{3-[4-(4-fluorobenzoyl)-piperidin-1-yl-]-propoxy}-4-ethyl-
~-carboline-3-carboxylic acid isopropyl ester, melting point 178-
180C
17 2 1 706 1 5
5-{3-[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-methyl-
B-carboline-3-carboxylic acid-isopropyl ester, melting point 168-
170C
5-{3-[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-B-
carboline-3-carboxylic acid isopropyl ester, melting point 182-
184C
6-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-methyl-
B-carboline-3-carboxylic acid isopropyl ester
5-{3t4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-B-carboline
6-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-B-carboline
5-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-ethyl-B-
carboline
6-{3t4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-methyl-
B-carboline
5-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-B-
carboline
5-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-9-methyl-B-carboline-3-carboxylic acid isopropyl
ester, melting point 115-117C
6-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-9-methyl-B-carboline-3-carboxylic acid isopropyl
ester, melting point 110-111C
5-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-9-methyl-B-carboline
~_ 18 2170615
6-{3[4-(4-fluorobenzoyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-9-methyl-~-carboline
Example 2
5-~3~4-Phenyl-piperazin-1-yl]-propoxy~-4-methoxymethyl-~-
carboline-3-carboxYlic acid isopropyl ester
450 mg of 5-(3-chloropropoxy)-4-methoxymethyl-B-carboline-3-
carboxylic acid isopropyl ester is stirred in 20 ml of
dimethylformamide with 245 mg of 4-phenylpiperazine and 0.21 ml
of triethylamine at 100C bath temperature for 18 hours under
argon. After the solvent is distilled off, it is taken up in
methylene chloride, and washed once each with water and saturated
common salt solution. The organic phase is dried, filtered and
concentrated by evaporation. The residue is chromatographed on
silica gel with ethyl acetate. 420 mg of 5-{3[4-phenyl-
piperazin-1-yl]-propoxy}-4-methoxymethyl-~-carboline-3-carboxylic
acid isopropyl ester of melting point 176-177C is obtained.
The 5-(3-chloropropoxy)-4-methoxymethyl-~-carboline-3-
carboxylic acid isopropyl ester required as starting material
(melting point 178-180C) is obtained by etherification of 5-
hydroxy-4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl
ester with 1-bromo-3-chloropropane and potassium carbonate in
dimethylformamide.
Example 3
According to the process indicated in Example 2, the
following compounds are produced from 5-(3-chloropropoxy)-4-
19 2 1 706 1 5
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester and a
secondary amine:
5-t3-(4-Benzyl-piperazin-1-yl)-propoxy]-4-methoxymethyl-~-
carboline-3-carboxylic acid isopropyl ester, melting point 112-
114C
5-[3-morpholin-1-yl)-propoxy]-4-methoxymethyl-B-carboline-3-
carboxylic acid isopropyl ester, melting point 161-162C
5-{3-[4-(3,4,5-trimethoxyphenyl)-piperazin-1-yl]-propoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester,
melting point 135-136C
5-{3-[4-(4-fluorobenzyl)-piperidin-1-yl-]-propoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester,
melting point 126-128C
5-{3-[4-(4-fluoro-~-hydroxybenzyl)-piperidin-1-yl]-propoxy}-
4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester,
melting point 110-115C
5-{3-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-propoxy}-
4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
5-[3-(4-benzoyl-piperidin-1-yl)-propoxy]-4-methoxymethyl-~-
carboline-3-carboxylic acid-isopropyl ester, melting point 133-
135C
5-{3-[4-(4-fluorophenethyl)-piperidin-1-yl]-propoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
5-{3-[4-(2-oxo-2-(4-fluorophenethyl)-piperidin-1-yl~-
propoxy}-4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl
ester
-
21 70615
5-{3-[4-(1-oxo-2-(4-fluorophenethyl)-piperidin-1-yl]-
propoxy}-4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl
ester
Example 4
5-~4-r4-(4-FluorobenzoYl)-piperidin-1-yl-~-butoxy~-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
235 mg of 5{4-[4-(4-fluorobenzoyl)-piperidin-1-yl]-butoxy}-
4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester of
melting point 103-105C is obtained analogously to the process
according to Example 2 from 520 mg of 5-t4-chlorobutoxy)4-
methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester,
melting point 147-148C, and 411 mg of 4-(4-fluorobenzoyl)-
piperidine.
Produced analogously are:
6-{4-[4-(4-Fluorobenzoyl)-piperidin-1-yl-]-butoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
5-{4-[4-(4-fluoro-~-hydroxybenzyl)-piperidin-1-yl-}-butoxy}-
4-methyl-B-carboline-3-carboxylic acid isopropyl ester
5-{4-[4-(4-fluoro-~-hydroxybenzyl)-piperidin-1-yl-]-butoxy}-
4-methoxymethyl-~-carboline
Example S
5-~2-r4-(4-FluorobenzoYl)-Piperidin-1-yl-]-ethoxy~-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
195 mg of 5-{2-[4-(4-fluorobenzoyl)-piperidin-1-yl]-ethoxy}-
4-methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester of
21 21 7061 5
melting point 161-163C is obtained analogously to the process
according to Example 2 from 510 mg of 5-(2-chloroethoxy)-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester,
melting point 194-195C, and 311 mg of 4-(4-fluorobenzoyl)-
piperidine.
Produced analogously are:
6-{2-[4-(4-Fluorobenzoyl)-piperidin-1-yl-]-ethoxy}-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
5-{2-[4-(4-fluorobenzoyl)-piperidin-1-yl-]-ethoxy}-4-
methoxymethyl-B-carboline
5-{2-[4-(4-fluoro-~-hydroxybenzyl)-piperidin-1-yl-]-ethoxy}-
4-methoxymethyl-9-methyl-~-carboline
Example 6
5~~3~ r 4-(4-Fluorobenzoyl)-piperidino~-2-hydroxypropoxy~-4-
methoxymethyl-~-carboline-3-carboxylic acid isopropyl ester
700 mg of 4-methoxymethyl-5-(2,3-epoxypropoxy)-~-carboline-
3-carboxylic acid isopropyl ester is dissolved in 50 ml of
propan-2-ol and mixed with 380 mg of 4-(4-fluorobenzoyl)-
piperidine. After five hours of reflux under argon, the organic
phase is concentrated by evaporation, and the residue is
chromatographed on silica gel with methylene chloride and ethanol
= 1000 + 50. 655 mg of 5-{3-[4-(4-fluorobenzoyl)-piperidino]-2-
hydroxypropoxy}-4-methoxymethyl-~-carboline-3-carboxylic acid
isopropyl ester of melting point 143C is obtained.
4-Methoxymethyl-5-(2,3-epoxypropoxy)-~-carboline-3-
carboxylic acid isopropyl ester is obtained according to methods
22 2 1 706 1 5
.
known in the literature by etherification of 5-hydroxy-4-
methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester with
epichlorohydrin and potassium carbonate in dimethylformamide.
Produced analogously are:
5-{3-t4-(4-Fluorobenzoyl)-piperidino]-2-hydroxypropoxy}-4-
ethyl-B-carboline-3-carboxylic acid isopropyl ester, melting
point 119-129C.
5-{3-[4-(2-furoyl-1-piperazinyl]-2-hydroxypropoxy}-4-
methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester,
melting point 198-200C.
Example 7
5-~3-~4-(4-Fluorobenzoyl)-Piperidino~-2-methoxypropoxy~-4-
methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester
435 mg of 5-{3-[4-(4-fluorobenzoyl)-piperidino]-2-
hydroxypropoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid
isopropyl ester is mixed in 40 ml of ethylene glycol dimethyl
ether with 20 mg of sodium hydride (90~) and cooled to 0C in an
ice bath. 0.05 ml of methyl iodide is instilled in this reaction
mixture and stirred for 4 hours. After heating to room
temperature, it is stirred for another 2 hours. After the
solvent is concentrated by evaporation, the residue is
chromatographed on silica gel with methylene chloride and ethanol
= 1000 + 50. 175 mg of 5-{3-[4-(4-fluorobenzoyl)-piperidino]-2-
methoxypropoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid
isopropyl ester of melting point 137-139C is obtained.
