FI107150B - Process for the preparation of therapeutically active imino-substituted cyclopent [b] indole derivatives - Google Patents

Description

107150

A process for the preparation of therapeutically active cyclopent [b] indole derivatives

Divided by application 920192 5

The invention relates to a process for the preparation of novel cyclopen [b] indole derivatives of the formula (III)

15 L

and pharmaceutically acceptable addition salts thereof, wherein R 3 is hydrogen or lower alkyl; R 20 is hydrogen, -OH, -O-C-N, lower alkoxy or tai

O

II

-OC- (lower alkyl) wherein R 12 is lower alkyl or phenyl-lower alkyl, and R 8 is hydroxy, amino-lower alkoxy, lower alkynyl, cycloalkyl, phenyl-lower alkyl, morpholino-lower alkyl, phenyl-cycloalkyl, lower -alkylcarbonyloxy or lower alkylaminocarbonyloxy.

The compounds of formula III prepared according to the invention

and pharmaceutically acceptable salts thereof are useful in reducing various memory deficits due to cholinergic deficiency, such as Alzheimer's disease. The compounds prepared according to the present invention also act as monoamine oxidase inhibitors and / or act as presynaptic α2-adrenergic receptor antagonists and are thus useful as antidepressants.

The compounds of formula III also exist as intermediates in the preparation of new compounds of formula (I) • R * 10, 1,1 / R 2 and their pharmaceutically acceptable acid addition salts wherein n is 2 and X is hydrogen. and R3 and R4 are as defined above, the dashed line represents a possible double bond, Rx is hydrogen, lower alkynyl, cycloalkyl, phenyl-lower alkyl or phenylcycloalkyl and R2 is hydrogen, formyl, benzyloxycarbonyl or lower alkylaminocarbonyl. The compounds of formula I are also useful as pharmaceuticals, as further described in parent application 920192 of this application.

Compounds of formula III are prepared according to the invention by: a) Compound of formula (XV) 30-2VN-R 30 - 4.

(xv) 3 107150 wherein R 3 is as defined above and R 12 is hydrogen, hydroxy or lower alkoxy, is reacted with hydroxylamine hydrochloride to form a compound of formula III wherein R 3 is as defined above, R 4 is as defined above for R 12 and R 8 is hydroxy, b) optionally reacting a compound of formula III wherein R 3 is as defined above, R 4 is hydrogen, hydroxy or lower alkoxy and R a is hydroxy, with a compound of formula Br-R 13 -NH 2 wherein R 13 is lower alkylene, of formula III wherein R 3 is as defined above, R 4 is hydrogen, hydroxy or lower alkoxy and R 8 is amino-lower alkoxy; or c) a compound of formula XV wherein R 3 is as defined above and R 12 is hydrogen, hydroxy, lower alkoxy or chloroacetyloxy, is reacted with an amine of formula NH 2 R 14 wherein R 14 is lower alkynyl, cycloalkyl, phenyl-lower alkyl, morpholino-lower alkyl, phenylcycloalkyl, to form a compound of Formula III wherein R 3 is as defined above, R 4 is the same as R 12 as hereinbefore defined, and R 4 is as defined above for R 14, d) optionally providing a compound of Formula III wherein R 3 is as defined hydrogen or lower alkoxy and R8 is hydroxy or phenyl-lower alkyl, reacting with an isocyanate of formula R17-N = C = O if R17 is lower alkyl to form a compound of formula III wherein R3 and R4 are as defined above and R 8 is a group R 17 -NH-CO-O- wherein R 17 is as defined above; e) optionally providing a compound of formula III wherein R 3 is as defined above, R 4 is hydrogen, hydroxy * or lower alkoxy; R8 is hydroxy, to react with an acyl chloride of formula R17-? ·, CO-C1 or an acyl anhydride of formula (R17-CO0) wherein R17 is lower alkyl to form a compound of formula III wherein R3 and R440107150 are as defined above and R 8 is a group -O-CO-R 17 wherein R 17 is as defined above.

Unless otherwise stated or implied, the following definitions apply throughout the specification and the accompanying claims.

The term lower alkyl means a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of such are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 10-t-butyl and straight and branched chain pentyl and hexyl.

The term cycloalkyl means a cycloalkyl group having from 3 to 7 carbon atoms.

The term halogen means fluorine, chlorine, bromine or iodine.

Throughout the specification and the appended claims, a particular formula or name denotes all stereoisomeric and tautomeric forms, if any.

In the process variant of the present invention, a) the compounds of formula XV used in the synthesis steps A to F described below and the compounds of formula III according to the synthesis steps G to N of the present invention are prepared by the symbols · * throughout the synthesis steps. N, X, R-1 to R8 are each as defined above unless otherwise stated.

Step A

A compound of formula IV wherein R 9 is hydrogen or methoxy is cyclized to give a compound of formula V 30. The reaction is typically carried out in aqueous sulfuric acid at 25-150 ° C.

j · · 5 107150 \ f ^ ί ™ *) »(IV)

rl J

, Η> · ^ Λ

X H O

R \ / * ^ (V) _ (<CH2) n 10 ^ I n j - *

X H

O

15 Lie B

The compound of formula V is reacted with a sulfate compound of formula (R10O) SO2 wherein R10 is lower alkyl or phenyl-lower alkyl in a conventional manner to give a compound of formula VI. Alternatively, a compound of formula V is reacted with a halide compound of formula R10-Hal wherein R10 is as defined above, in a conventional manner, to provide a compound of formula VI.

'' 25 * 9

Vx. <«*>» (V) + CR100) 2S02-► <VI>

30 X

»♦♦ B 0 K10

Lie C

The compound of Formula IX obtained from Step B is subjected to a cleavage reaction to provide a compound of Formula X. Typically, the compound of formula IX is finally reacted with the BBr 3 / tetrabydrofuran complex and the resulting product is hydrolyzed in a conventional manner.

5 CH3 ° ^^ f <®i>.

. I / BBr3 H2 ° —-► -►

X

Rio 0 (R10 «H) 15 (IX) H \ s * n (X)

> <fV / <CHA

*> Ly

»10 0

Step D

In a special case, a compound of formula XI is reacted with chloroacetyl chloride in the presence of aluminum chloride in a conventional manner to give a compound of formula XII (Friedel-Crafts reaction).

30 ____ [(CHj) "y ^^^ y + C1CH2'c '35 (XI)' 0» io 0 7 107150

O

(XII)

Ri 0

10 Step E

The compound of formula XII is reacted with peracid, preferably m-chloroperbenzoic acid, in a conventional manner to give a compound of formula XIII (Baeyer-Villiger reaction).

15 A / y ^ x {«ay.

“» UuLy 20 (XII) + Peracid1 ► r |

Rio o (XIII)

Step F

The compound of formula XIII is preferably hydrolyzed in the presence of a base such as sodium hydroxide to give a compound of formula XIV.

HO. ^ S

/ iCH2> n -: ·· 30 (XIII) + H20 / Na0H-► ^ | (XIV) R10 o 8 107150

Step G

A compound of formula XV wherein R12 is hydrogen, a mat or hydroxy obtained by any of the above steps is reacted with hydroxylamine hydro-5 chloride in a conventional manner to give a compound of formula XVI. Typically, this reaction is carried out by first suspending the compound of formula XV in ethanol and adding aqueous sodium acetate and aqueous hydroxylamine hydrochloride to the suspension and stirring the resulting mixture at 25-150 ° C.

15 {β1> ·, 1 / + ΝΗ, ΟΗ · HC1

II

x / | r3 o 20 (XV) R12 ✓-- f (XVI) rri j »—- / - 'γν7

X I N

* 3 1

HO

30 Step H

The compound of formula XVI is reacted with an amino-lower alkyl bromide of formula Br-R 13 -NH 2, wherein -R 13 -NH 2 is an amino-lower alkyl group, in a conventional manner to give a compound of formula XVII.

9 107150

\ l J

-►

(XVI) + Br-R 13 -NH 2 χ | 'OF

* 3 I

(XVII) 0 * R13 · NH *

Step I

The compound of formula XV is reacted with a primary amine of formula R14-NH2 wherein R14 is lower alkynyl, cycloalkyl, phenyl-lower alkyl, or phenylcycloalkyl in a conventional manner to give the imine of formula XVIII.

This reaction is preferably carried out in the presence of titanium (IV) isopropoxide and a suitable solvent such as acetonitrile. Typically, this reaction is conducted at a temperature of 0 to 80 ° C. This method is more advantageous than that employing titanium tetrachloride or one carried out in a closed glass tube at elevated temperature using molecular sieves as a dewatering agent.

Ri 2 s ---- \ - 25 <CH2> n H I | j <XV> + Η ^ "'30 *> ^" * R14 «· 4 (XVIII) 10 107150

Step J

The compound of formula XV is reacted with titanium (IV) isopropoxide and a secondary amine of formula H-NA wherein the group -NA is 5 / "λ

-No

followed by reduction with sodium cyanoborohydride using conditions similar to those described by R.J. Mattson et al., J. Org. Chem. , 55, 2552-4 (1990) to give a compound of formula XX.

R12 X "N

/ -N-f (CH 2).

(XV) + H - N ^ A --- f jl J

X i J

(XX, "Q

20 Step K

A compound of formula XVI wherein R12 is not hydroxy is reacted with an isocyanate of formula R17-N = C = O in substantially the same manner as in Step T to give a compound of formula XXX.

25 (XVI) + r17 - N - C - (R12 «-0H) e» ,,.

30 -►l J

.wv '

R, N

3% 0 35 # \ (R12 * -0H) o N - h {XXX) * 17 11 107150

Step L

The compound of formula XVI is reacted with an acyl chloride of formula R17-CO-Cl or an acid anhydride of formula (R17CO) 20 in a conventional manner to give a compound of formula XXXI.

R12 ^ r17 - CO - Cl / {CH2> b

(XVI) + it \ \ [I J

10 (R17-C0) 20

X R, N

3% 0 15 (XXXI) 17

The compounds of the formula III prepared according to the invention are useful in the treatment of various memory impairments with cholinergic insufficiency, such as Alzheimer's disease. The compounds of the formula III also act as monoamine oxidase inhibitors and / or act as CNS α2 adrenergic receptors and are thus useful as antidepressants.

The ability to ameliorate such memory deficits is manifested by the ability of these compounds to act as inhibitors of the enzyme acetylcholinesterase, thereby increasing brain acylcholinesterase levels.

Cholinesterase Inhibition Assay

Cholinesterases are found throughout the body, both in ali-30 butter and serum. However, only the distribution of brain acetylcholinesterase (AChE) correlates with cholinergic central nervous system. It has been suggested that this same nervousness be attenuated in Alzheimer's patients. We have determined inhibition of acetylcholinesterase activity in 35 rat rat striatum in vitro.

12 107150

In vitro inhibition of acetylcholinesterase in rat striatum

Acetylcholinesterase (AChE), sometimes referred to as true or specific cholinesterase, is found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. Acetylcholinesterase can be distinguished from other cholinesterases by substrate, specific inhibition and local distribution. Its distribution in the brain 10 correlates approximately with cholinergic nervous system, with the highest concentrations found in nerve terminals.

It is generally accepted that the physiological role of acetylcholinesterase is rapid hydrolysis and inactivation of acetylcholine. Inhibitors of acetylcholinesterase have clear cholinomimetic effects in cholinergic nervous system and have been used therapeutically in the treatment of foliage, muscle weakness and gut flushing. However, recent studies have shown that acetylcholinesterase inhibitors could be used in the treatment of Alzheimer's disease.

The method described below was used in this invention to determine cholinesterase activity. This is a modification of the method described by Ellman et al., Biochem. Pharmacol. X, 88 (1961).

Method: A. Reagents 1. 0.05 M phosphate buffer, pH 7.2 (a) 6.85 g NaH 2 PO 4. H 2 O / 10 0 ml dist. water 30 (b) 13.40 g Na2HPO44.7H2O / 100 ml dist. water (c) is added to (a) (b) until the pH is 7.2 (d) diluted 1:10 2. Substrate in buffer (a) 198 mg acetylthiocholine chloride (10 mM) 35 (b) is diluted in 100 ml: 0.05 M Phosphate Buffer · *, pH 7.2 (reagent 1).

13 107150 3. In DTNB buffer (a) 19.8 mg of 5,5-dithiobisnitrobenzoic acid (BTNB) (0.5 mM) (b) is diluted in 100 ml of 0.05 M phosphate buffer, pH 7.2 ( reagent 1).

4. Prepare a 2 mM stock solution of the test compound in a suitable solvent and dilute with 0.5 mM DTNB (reagent 3). The compounds are diluted successively (1:10) so that the final concentration (in the cuvette) is 10 10 10 M and their activity is assayed. If active, the IC 50 is determined from the inhibitory activity at various concentrations.

B. Tissue preparation

Male Wistar rats are decapitated, brain is rapidly removed, corpora stria is dissected, weighed and homogenized in 19 volumes (about 7 mg protein / ml) of 0.05 M phosphate buffer, pH 7.2 using a Potter-Elvehjem homogenizer. Take 25 microliters of the homogenate and add 1 of either solvent or 20 solutions of different concentrations of test compound and preincubate for 10 minutes at 30 ° C.

C. Test

Enzyme activity was measured on a Beckman DU-50 spectrophotometer. This method can be used to determine IC50 values and kinetic constants.

Instruments

Kinetics Soft-Pac Module # 598273 (10) Program # 6 Kindata Source - Vis 30 Allon Concentration - 412nm Cuvettes - 2ml Cuvettes Using Auto 6 Sampler Reference - One for each substrate concentration 35 intervals - 15 seconds (15 or 30 seconds for kinetic measurements) • h 14 107150 total time - 5 minutes (5 or 10 minutes for kinetic measurements) curve - yes spacing - automatic scale 5 curve slope - ascending results - yes (give curve) factor - 1

The reagents added to the reference and sample cells are:

Comparison: 0.8 ml phosphate buffer / DTNB

0.8 ml phosphate buffer / substrate Amendment 0.8 ml phosphate buffer / DTNB / enzyme 0.8 ml phosphate buffer / substrate Compound 0.8 ml phosphate buffer / DTNB / compound / enzyme 0.9 ml phosphate buffer / substrate

Reference values are determined for each run to control non-enzymatic hydrolysis of the substrate and are automatically subtracted by the Kindata software included in the Soft-Pac kinetic module. This program also calculates the variability of absorbance for each cell.

IC50 determinations:

The substrate concentration is 10mM diluted 1: 2 to give a final concentration of 25mM. The DNTB concentration is 0.5 mM to give: - a concentration of 0.25 mM. Percentage inhibition == [(slope control - slope compound) / slope control] x 100. IC 50 values are determined by log probit analysis. Table 1 shows the results obtained with this experiment for a compound of the present invention and physostigmine ... (reference compound).

15 107150

Table 1 Inhibitory effect,

_ compound (uM) brain AChE

4-Methyl-3-phenylmethyl-imino-6,2 1,2,3,4-tetrahydro-cyclopent [b] -10-indol-7-ylmethyl-carbamate Physostigmine 0.006 This utility is further described by the ability of these compounds to inhibit the monoamine oxidase enzyme, to increase brain biogenic amines. and act as antidepressants.

Type A and Type B Monoamine Oxidase Inhibitory Activity in Rat Brain Synaptosomes Purpose To determine the selective inhibition of two monoamine oxidase species (MAO).

Introduction 25 Metabolic deamination of amines has been known and two forms of monoamine oxidase, called "Type A" and "Type B", have been described. The existence of these two forms is based on different substrate and inhibitor specificities. Serotonin (5HT) and nore-30 pinephrine (NE) act as substrates for type A MAO, S-phenethylamine (PEA) and benzylamine act as substrates for type B MAO, whereas dopamine (DA) and tyramine serve as substrates for both types. substrates. Chlorgyline is a selective inhibitor of the type A enzyme, 35 deprenyl and pargyline are selective inhibitors of the type B enzyme, and tranylcypromine and iproniazid are non-selective inhibitors (2).

Although there are various methods for measuring MAO activity, the described method involves extraction of deaminated metabolites of 5 [3 H] -5HT or [14 C] -β-phenethylamine. According to this method, MAO-A and MAO-B activity can be measured either simultaneously or separately (3).

Method 10 A. Reagents 1. Phosphate buffer (0.5 M), pH 7.4: 134.4 g of NaH 2 PO 4 .7H 2 0 are diluted to 1 liter with distilled water (A), 17.3 g of Na 2 HPO 4 are diluted to 250 ml with distilled water (B). . Adjust the pH of A to 7.4 by slowly adding the required amount of B. Dilute 1:10 with distilled water (0.05 M phosphate buffer, pH 7.4).

2. 0.25 M sucrose (phosphate buffered): 21.4 g of sucrose is diluted to 250 ml with 0.05 M phosphate buffer.

2 0 3. Substrate for MAO A. Serotonin creatine sulfate (5HT) is available from Sigma Chemical Company. A 5 mM stock solution in 0.01 N hydrochloric acid is prepared. This is used to dilute the intrinsic activity of [3 H] -5HT.

'' 25b. [3H] -5-Hydroxytryptamine Binoxalate (20-30 Ci / mmol) is obtained from New England Nuclear.

c. Add 12 μΐ of [3 H] -5HT to 2 ml of 5 mM 5HT solution. (The final amine concentration in the assay is 200 μΜ; see below).

4. Substrate for MAO B: a. Β-Phenethylamine (PEA) is obtained from Sigma Chemical.

Company. It is prepared as a 5 mM stock solution in 0.01 N hydrochloric acid. This is used to dilute the intrinsic activity of [14 C] -PEA.

• V

17107150 b. Β- [ethyl-1-14C] -phenethylamine hydrochloride (40-50 mCi / mmol) is obtained from New England Nuclear.

c. Add 12 μΐ of [14 C] -ΡΕΑ to 2 ml of 5 mM PEA solution. (The final amine concentration in the assay is 200 μΜ; see 5 below).

5. Similar amounts of MAO-A (5HT) and MAO-B (PEA) substrate are combined to simultaneously study both types of MAO, ie mixed 2.5 mM 5HT and 2.5 mM PEA stock solution, of which 40 μΐ gives 200 μΜ: η is the final concentration-10 for both amines in the assay. When testing only one type of MAO, separate 5 mM stock solutions are diluted 1: 1 with distilled water before 40 μΐ is added to the incubation mixture; that is to say, the same end-point concentration of 200 μ lopp: η.

15 B. Tissue Preparation

Male Wistar rats weighing 150-250 g were sacrificed and the brain was rapidly removed. The entire brain except the cerebellum was homogenized in 30 volumes of ice cold phosphate buffered 0.25 M sucrose-20 using a Potter-Elvehjem homogenizer. The homogenate was centrifuged at 1,000 g for 10 minutes and the supernatant (S1) was decanted and centrifuged again at 18,000 g for 20 minutes. The resulting granule (P2) was resuspended in 0.25 M sucrose and used as a tissue source of mitochondrial MAO.

C. Experiment with 10 μΐ 0.5 M phosphate buffer, pH 7.4, 50 μΐ water, or appropriate drug concentration, 400 μΐ tissue suspension. The tubes are pre-incubated for 15 minutes at 37 ° C and the experiment is started by adding 40 μΐ of combined substrate ([3 H] -5HT and .. [14 C] -PEA) every 15 seconds. The tubes were incubated for 30 min at 37 ° C and the reaction was terminated by the addition of 0.3 mL of 2N hydrochloric acid. Control tissue samples were determined by addition of acid before the radioactive substrate. The oxidation products of the reaction were extracted with ethyl acetate / toluene 18107150 (1: 1). 5 ml of this mixture was added to the tubes, the resulting mixture was stirred for 15 seconds to extract the deaminated metabolites to the organic phase and this was allowed to separate from the aqueous phase. The tubes were placed in an acetone / -5 dry ice bath to freeze the aqueous layer. Once this layer is frozen, the upper organic layer is poured into a scintillation vessel. Add 10 ml of Liquiscint and count the samples using a 14C slit in one channel and a 3H slit in the other. IC 50 values are determined using log probit analysis.

References 1. Johnston, J.P .: Some observations upon a novel inhibitor of monoamine oxidase in brain tissue. Biochem. Pharmacol. 17, 1285-1295 (1968); 2. Fowler, C.J. and Ross, S.B .: Selective Inhibitors of Monoamine Oxidase A and B: Biochemical, Pharmacological and Clinical Properties. Med. Res. Rev. 4. 323-328 (1984); 3. Kindt, M.V., Youngster, S.K., Sonsalla, P.K., 20 Duvoisin, R.C. and Heikkilä, R.E .: The Role of Monoamine Oxidase-A (MAO-A) in Bioactivation and Nigrostriatal Dopaminergic Neurotoxicity of the MPTP Analog, 2'Me-MPTP. Eur. J. Pharmacol. 46. 313-318 (1988).

Table 2 shows the results of the MAO inhibition test for the present invention (25 representative compounds).

• · Λ ·.

19 107150

Table 2 Inhibitory Concentration 50050 (μ 5) 5-Compound-MAO-A-MAO-β-4-Methyl-2 - [(2-phenyl-15,2,7,7-cyclopropyl) -iraino] -1,2,3,4-tetrahydro-cyclo-10 pent [ b] Indol-7-ylmethylcarbamate (Reference Compounds) Deprenyl 0.14 0.016 Tranylcypromine 0.19 9.12 The present inventors have also performed the clonidine binding assay described below to confirm the interaction of the compounds of this invention and the α2 receptors.

3H-Clonidine Binding: A2 Receptor Derivation Certain antidepressants have been shown to increase the neuronal release of norepinephrine by the putative pre-synaptic α2 receptor blockade, and this property may be important for the mechanism of action of these compounds. See footnotes 1, 2 and 3 below. The 3H-clonidine binding assay determines the interaction of the compound with ... the central? 2 receptor.

Method A. Reagents 1. a. 57.2 g Tris.HCl, 16.2 g Tris base dilute-35 are made up to 1 liter (0.5 M Tris buffer, pH 7.7).

20 1 07 1 50 b. Dilute 1:10 with distilled water (0.05 M Tris buffer, pH 7.7).

2. Tris buffer containing physiological ions.

a. Stock buffer NaCl 7,014 g, KCl 0,372 g, CaCl 2 5 0,222 g is diluted to 100 ml in 0,5 M Tris buffer,

MgCl 2 0.204 g.

b. Dilute 1:10 with distilled water. This gives 0.05 M Tris.HCl, pH 7.7; containing NaCl (120 mM), KCl (5 mM), CaCl2 (2mM) and MgCl2 (ImM).

3. [4-3H] -clonidine hydrochloride (20 -30 Ci / mmol) is obtained from New England Nuclear. For IC50 determinations, dilute 3-H-clonidine to 120 nM and add 50 μΐ to each tube (final concentration is 3 nM in the 2 ml assay).

4. Clonidine.HCl is obtained from Boehringer Ingelheim · 15 mM Clonidine stock solution is prepared to determine non-specific binding. In this case, the final concentration in the assay is 1 μΜ (20 μΐ to 2 ml).

5. Test compounds. For most assays, the stem is prepared with a 1 mM stock solution in a suitable solvent and diluted sequentially so that the final concentration in the assay is 10-5-5M. Seven concentrations are used for each experiment and, depending on the potency of the drug, higher or lower concentrations can be used.

25 B. Tissue Grafting

Male Wistar rats were sacrificed by removing the head. and the cortex tissue was rapidly removed. This tissue was homogenized in 50 volumes of 0.05 Tris buffer, pH 7.7 (buffer 1b) with Brinkman Polytron and centrifuged for 30 minutes at 40,000 g. The supernatant was discarded and the precipitate was re-homogenized in the original amount of 0.05 M Tris buffer, pH 7.7 and centrifuged again as above. The supernatant was discarded and the final precipitate was re-homogenized in 50 volumes of 2b buffer.

35 This tissue suspension is kept on ice. The final tissue concentration is 10 mg / ml. Specific binding is 1% of total ligand added and 80% of total bound ligand.

C. Experiment 5,100 µl of 0.5 M Tris physiological salts, pH 7.7 (buffer 2a), 830 μΐ of water, 20 μΐ of solvent (for total binding) or 0.1 mM clonidine (for non-specific binding) ) or a suitable drug concentration, 50 μΐ of 3H-clonidine stock solution, 1000 µl of tissue suspension. The tissue homogenates are incubated for 20 minutes at 25 ° C with 3 nM 3H-clonidine and varying drug concentrations, then immediately filtered under vacuum with Whatman GF / B filters. The filters are washed three times with five ml of ice-cold 0.05 M Tris buffer, pH 7.7, and transferred to scintillation tubes. To each sample is added 10 ml of Liquiscint counting solution and counted by liquid scintillation spectroscopy. Specific clonidine binding is defined as the difference between total binding and the value obtained by log probit analysis. The percentage inhibition obtained for drug concentration of 20 is based on the average of three assays.

References 1. P.F. Von Voigtlander, "Antidepressant and Antipsychotic Agents" in Annual Reports in Medicinal Chemistry, F.H. Clarke, Ed., Chapter 1, Academic Press, New York, N.Y. (1976); 2. S. Clements - Jewelery, Neuropharmacol. , 17, 779 (1978); 3. C.B. Smith'ja P.J. Hollingsworth, Adrenergic 30 Receptors and Mechanism of Action of Antidepressant

Tretments "in Biochemical and Pharmacoligical Aspects of Depression, K.F. Tipton and M.B.H. Youdim, eds., Taylor and Francis, New York, N.Y., Chapter 4 (1989).

Table 3 shows the results of the 3H-clonidine binding assay for 35 compounds of the present invention.

• 22 107150

Table 3 Binding of 3H-Clonidine to 5-Compound-IC (μΜ) -4-Methyl-3-Phenylmethyl-0,85 Imino-1,2,3,4-Tetrahydro-cyclopent [b] indol-7-ol 10 (Reference Compound) amitriptyline 3.9 15

Effective amounts of the compounds of the invention may be administered to a patient by any of the following methods, for example, orally in the form of capsules or tablets, parenterally sterile solutions or suspensions, and, in some cases, intravenously as sterile solutions. The free base end products, which are effective as such, can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts, their stability, their better crystallization * ... 25 due to its higher solubility and similar properties.

Acids useful for the preparation of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids such as tartaric, citric, acetic, , sea * succinic, maleic, fumaric and oxalic acids.

The active compounds of the formula III may be administered orally, for example, with an inert diluent or an acceptable carrier, or may be enclosed in gelatin capsules, or compressed into tabs. For oral therapeutic administration, the active compounds of formula III may be mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of the active compound, but the amounts may vary depending on the particular form and may conveniently be between 4 and about 70% by weight of the unit. The amount of active compound 10 in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations are prepared so that the dosage unit form for oral administration contains between 1.0 and 300 milligrams of active compound.

Tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose; disintegrating agents such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotex; a lubricant such as colloidal silica; and a sweetening agent such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl saline. 25 plates or orange spice can be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various substances which modify the physical form of the dosage unit, for example as coatings. Thus, tabs or pills may be coated with sugar, shellac, or other enteric coatings. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, coloring agents, coloring agents, and flavoring agents. The substances used in the preparation of these various compositions must be pharmaceutically pure and non-toxic.

For parenteral administration, the active compounds of Formula III may be mixed with a solution or suspension. These preparations should contain at least 0.1% of the active compound, but may be varied from 0.5 to 30% by weight thereof. The amount of active compound in such compositions is such that a suitable dose will be obtained. Preferred compositions are prepared so that the parenteral dosage unit form contains between 0.5 and 100 milligrams of active compound.

The solutions and suspensions may also contain the following ingredients: a sterile solvent such as water for injections, saline, oil, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers, weft acetates, citrates or phosphates, and pressure regulators such as sodium chloride or dextrose. The parenteral preparation can be enclosed in disposable syringes or multiple dose glass or plastic containers.

. The following examples further illustrate the invention and the preparation of starting materials for use in the process of the invention.

Example 1 3-Hydroxyimino-7-methoxy-1,2,3,4-tetrahydro-cyclo · -30 pent [b] indole ··· A stirred solution of 1,2-cyclopentadienone mono-4-methoxyphenylhydrazone (6 , 0 g) in 100 ml of 10% sulfuric acid, heated in a steam bath for 4 hours and allowed to cool to room temperature and filtered to give 1,4-dihydro-7-methoxycyclopent [b] indole 25 107150 3 (2H) -one as a solid . To the indole (2.6 g) in 25 mL of 95% ethanol was added hydroxylamine hydrochloride (1.7 g) in 15 mL of water and sodium acetate (2.1 g) in 15 mL of water. The mixture was heated at reflux temperature for 2.5 hours and allowed to stand overnight. The ethanol was removed in vacuo and the resulting solid was collected and purified by flash chromatography to give 0.8 g of a mixture of oxime isomers.

Analysis for C 12 H 12 N 2 O 2

Calculated: 66.65% C 5.59% H 12.95% N

found: 66.39% C 5.51% H 12.91% N

Example 2 3-Hydroxyimino-1,2,3,4-tetrahydro-cyclopent [b] indole To a stirred solution of 1,4-dihydro-cyclopent [b] indol-3 (2H) -one [Elks et al. ., J. Chem. Soc., 624 (1944)] (10 g) in 100 mL of 95% EtOH was added hydroxylamine hydrochloride (8.3 g) in 20 mL of water and sodium acetate (9.7 g) in 20 mL of water. The mixture was refluxed for 2 hours and allowed to cool at room temperature overnight. The ethanol was removed in vacuo and the resulting solid was collected and recrystallized from 95% ethanol to give 4.5 g of the mostly second oxime isomer in the first precipitation and 3.0. 25 g of a mixture of oxime isomers in the second precipitation. A sample of 1.5 g of one isomer was recrystallized to give 0.9 g of analytically pure material. Analysis <31: 1Η10Ν2Ο lie

Calculated 70.95% C 5.41% H 15.04% N

Found: 70.71% C, 5.32% H, 14.94% N

**; Example 3 3-Hydroxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indole

To a stirred solution of 1,4-dihydro-4-35 methylcyclopent [b] indol-3 (2H) -one (3.0 g) in 30 mL • 26 10 7 50% ethanol was added. hydroxylamine hydrochloride (2.25 g) in 9 ml water; and sodium acetate (4.4 g) in 9 ml water. The mixture was refluxed for 4 hours and another 1.1 g of hydroxylamine hydrochloride in 5 ml of water and 2.2 g of sodium acetate in 5 ml of water were added. After refluxing for two hours, the mixture was allowed to stand at room temperature overnight. The precipitated material was collected and recrystallized from 95% ethanol to give 1.9 g of analytically pure material.

10 Analysis for C 12 H 12 N 2 O

Calculated: 71.98% C 6.04% H 13.99% N

found: 72.18% C 6.11% H 14.00% N

Example 4 3- (2-Aminoethyl) oxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indole

To a stirred suspension of 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indole (5.0 g) in methylene chloride (50 mL) was added 50% NaOH: a (50 ml) and tetrabutylammonium bromide (800 mg) and bromo-20-methylamine hydrobromide (7.6 g). The reaction mixture was stirred overnight at room temperature. The layers were separated and the aqueous layer was extracted with methylene chloride (50 mL). The organic layers were combined, dried (Na 2 SO 4) and concentrated. The product was purified by flash chromatography. Eluting with 10% methanol / methylene chloride to give 1.1 g of purified material.

Example 5 4-t-Butyloxycarbonyl-1,4-dihydro-cyclopent [b] -30 indol-3 (2H) -one

To a stirred solution of 1,4-dihydrocyclopent [b] indol-3 (2H) -one (10.0 g) in acetonitrile (100 mL) was added di-t-butylpyrocarbonate (15 g) and 4-dimethylaminopyridine (700 g). mg). The mixture was stirred overnight at room temperature under nitrogen. Solvent

• V

107150 27 was removed under reduced pressure and the residue was purified by flash column chromatography to give 4-t-butyloxycarbonyl-1,4-dihydro-cyclopent [b] indole-3 (2H) -one (4.5 g) as a solid.

5 Analysis for C16H17NO3

Calculated: 70.83% C 6.32% H 5.16% N

found: 71.04% C 6.35% H 5.16% N

Example 6 7-Chloroacetyl-1,4-dihydro-4-methyl-cyclopent [b] -10 indol-3 (2H) -one

Aluminum chloride (8.5 g) was suspended in methylene chloride (20 ml) at 0 ° C, chloroacetyl chloride (7.2 g) was added slowly and the mixture was stirred for 5 minutes. This mixture was added dropwise to a stirred solution of 1,4-dihydro-4-methylcyclopent [b] indol-3 (2H) -one (6.0 g) in 100 mL of methylene chloride at 0 ° C. The mixture was stirred at 0 ° C for 45 minutes after which a similar methylene chloride solution of aluminum chloride and chloroacetyl chloride was added dropwise. Half an hour hereinafter 20-Keen, the reaction mixture was poured slowly into stirred ice / water-in-the-mixtures. The layers were separated and the methylene chloride layer was washed with sodium bicarbonate, dried (Na 2 SO 4) and concentrated to an oil. Purification by flash chromatography on silica gel eluting with hexane / acetone gave. 7-Chloroacetyl-1,4-dihydro-4-methyl-cyclopent [b] indol-3 (2H) -one (4.5 g).

Analysis for C14H12ClNO2

Calculated: 64.25% C 4.62% H 5.35% N

found: 64.35% C 4.61% H 5.24% N

Example 7 · * 7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent [b] indol-3 (2) -one

To a stirred solution of 7-chloroacetyl-oxy-1,4-dihydro-4-methyl-cyclopent [b] indol-3 (2H) -one 35 (2.0 g) in chloroform (100 mL) was added sodium phosphate. 150 g (1.02 g) and m-chloroperbenzoic acid (2.5 g, 50-60% pure). The mixture was stirred at room temperature under nitrogen for 14 hours. Saturated sodium bicarbonate solution (50 mL) was added, the layers were separated and the organic layer was washed with water (2 x 50 mL). The solution was dried (Na 2 SO 4), filtered and concentrated to give a yellow oil which crystallized on standing. Recrystallization from ethanol gave 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent [b] indol-3 (2H) -one (1.1 g).

10 Analysis for C 14 H 12 ClNO 3

Calculated: 60.55% C 4.36% H 5.04% N

found: 60.47% C 4.33% H 4.98% N

Example 8 1,4-Dihydro-7-methylaminocarbonyloxy-4-methyl-15-cyclopent [b] indol-3 (2H) -one 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent [b] indol-3 (2H) -one (5.0g) was suspended in ethanol (100ml) and then 10% sodium hydroxide solution (50ml) was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo, methylene chloride (100 mL) was added along with 10% hydrogen chloride solution until the aqueous layer was neutralized. The layers were separated and the aqueous phase extracted with methylene chloride (2 x 100 mL). The organic layer was dried (Na 2 SO 4) and concentrated. And the residue was recrystallized from 95% ethanol to give 1,4-dihydro-7-hydroxy-4-methylcyclopent [b] indol-3 (2H) -one as a white solid. Phenol was dissolved in methylene chloride (100 mL) and 1,8-diaza-bicyclo [5.4.0] undec-7-ene (0.4 g) and methyl isocyanate (1.4 g) were added and the mixture was stirred overnight.

The mixture was concentrated in vacuo to give an oily solid which was crystallized from ethanol to give 1,4-dihydro-7-methylaminocarbonyloxy-4-methylcyclopent [b] indol-3 (2H) -one (1.1 g).

35 Analysis for C 14 H 14 N 2 O 3 29 107150

Calculated: 65.11% C 5.46% H 10.85% N

found: 65.20% C 5.32% H 10.74% N

Example 9 3-Acetyloxyimino-4-methyl-1,2,3,4-tetrahydro-5-cyclopent [b] indol-7-ylacetate 7-chloroacetyl-azi-1,4-dihydro-4-methylcyclopent [b] indol-3- (2) -one (8.0 g) was suspended in ethanol (200 ml) and a solution of sodium acetate (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) was added and the mixture was refluxed for three hours. The mixture was concentrated in vacuo and the residue was recrystallized from 95% ethanol to give 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol as a white solid. The oxime was dissolved in tetrahydrofuran (100 mL) and acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg) were added and the mixture was stirred under nitrogen at room temperature overnight. The mixture was concentrated in vacuo, methylene chloride (100 mL) was added and the solution washed with water (50 mL), 5% sodium bicarbonate and water (50 mL). After drying (Na 2 SO 4), the solvent was removed in vacuo and the product recrystallized from ethanol to give 3-acetyloxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indol-7-yl acetate (1). , 7g).

. Analysis for C16H16N2O2

Calculated: 63.99% C 5.37% H 9.33% N

found: 63.56% C 5.37% H 9.29% N

Example 10 4-Methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-0-cyclopent [b] indol-7-ol ··· A stirred suspension of 7-chloroacetyloxy-1,4- dihydro-4-methylcyclopent [b] indol-7-ol (6.0 g) in toluene (50 ml), benzylamine (9.2 g) was added and the mixture was heated at reflux temperature with azeotropic removal of water on a Dean Stark apparatus. 1

"♦ V

30 107150

After 4 hours the product was completely formed by TLC. The mixture was allowed to cool to room temperature and filtered, and the solid was washed with acetonitrile. The filtrate and washings were combined, concentrated, and purified by flash chromatography on silica gel (2: 1 hexane / acetone as eluent). Crystals formed in the product-containing fractions were collected by filtration to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol (1.1 g) and the filtrate was concentrated 10 was fed to give an oil (3.0 grams) which crystallized on standing.

Analysis for C19H18N2O

Calculated: 78.59% C 6.25% H 9.65% N

found: 78.62% C 6.21% H 9.63% N

Example 11 4-Methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate

To a stirred solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol 20 (2.0 g) in methylene chloride (40 ml) was added 1, 8-Diazabicyclo [5.4.0] undec-7-ene (0.16 g) and methyl isocyanate (0.39 g) in methylene chloride (10 ml) dropwise. The reaction was monitored by TLC and after three hours the solution was concentrated and the precipitate was collected and crystallized. Reaction from acetonitrile to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate (1.85 g).

Analysis for C21H21N3O2

Calculated: 72.60% C 6.09% H 12.09% N

Found: 72.59% C, 6.01% H, 12.05% N

: ·· Example 12 4-Methyl-3 - [(2-phenyl-cyclopropyl) -imino] -1,2,3,1-4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate

To a stirred suspension of 1,4-dihydro-7-35 hydroxy-4-methylcyclopent [b] indol-3 (2H) -one (5.0 g) in 31107150 acetonitrile (100 mL) was added phenylcyclopropylamine hydrochloride (4 , 2 g) and triethylamine (2.5 g). The solution was stirred at room temperature under nitrogen while titanium (IV) isopropoxide was added dropwise.

The mixture was stirred for 3 hours and quenched with ice / water. The mixture was filtered, the solid washed with methylene chloride, the layers separated and the organic part dried (Na 2 SO 4). After concentration, the crude product was purified by flash chromatography eluting with hexane / acetone (2: 1) to give 4-methyl-3 - [(2-phenylcyclopropyl) imino] -1,2,3,4-tetrahydrocyclopent [b] indol-7-ol. To a stirred solution of this product (1.0 g) in methylene chloride (9.0 mL) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (68 mg) and methyl iso- isocyanate (0.18 g) in methylene chloride (1.0 mL). The reaction was monitored by TLC and after half an hour the solution was concentrated and the precipitate was collected and recrystallized twice from acetonitrile to give 4-methyl-3 - [(2-phenylcyclopropyl) imino] -20-1,2,3,4-tetrahydrocyclopent [b] indol -7-ylmethylcarbamate (0.55 g).

Analysis for C21H21N3O2

Calculated: 73.97% C 6.21% H 11.25% N

found: 73.57% C 6.25% H 11.13% N

. Example 13 3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent [b] indole. 3 (2H) -one (15.0 g) and cyclopropylamine 30 (9.6 g) were dissolved in 300 ml of toluene and cooled to -10 ° C. Titanium tetrachloride (6.3 g) was dissolved in 50 ml of toluene and added slowly to the first solution. The reaction mixture was allowed to warm to room temperature and stirred overnight. The following day, 1.5 eq-35 equivalents of amine (4.6 g) were added and the mixture was stirred for one hour • 32 107150. The reaction mixture was filtered through a pad of silica gel eluting with 3: 1 hexane: ethyl acetate to afford a yellow oil after removal of the solvents.

3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydro-cyclo-5 pent: [b] -indol-7-ol was isolated by flash chromatography and; after recrystallization from ethyl acetate as a pale yellow solid (3.3 g).

Analysis for C15H16N2O

Calculated: 74.97% C 6.71% H 11.66% N

Found: 74.57% C, 6.54% H, 11.37% K

Example 14 3-Methylaminocarbonyloxyimino-4-methyl-1,2,4-tetrahydro-cyclopent [b] indol-7-ylmethylcarbamate Dihydrate 15 To a stirred suspension of 3-hydroxyimino-4-methyl -methyl-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol (3.0 g) in methylene chloride (100 ml) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (630 mg) and methyl isocyanate (1.9 g) and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting solid was recrystallized from ethanol to give 3-methylaminocarbonyloxyimino-4-methyl-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate hemihydrate (1.7 g).

25 Analysis for C16H18N4O4.0.5H2O

Calculated: 56.68% C 5.66% H 16.53% N

found: 56.57% C 5.46% H 16.68% N

Example 15 4-Methyl-3-phenylethylimino-1,2,3,4-tetrahydro-30-cyclopent [b] indol-7-ol hemihydrate

To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydro-cyclopent [b] -3-one (5.0 g) in acetonitrile (100 mL) was added phenethylamine (6.0 g) and titanium isopropoxide (14.1 g) and the resulting mixture was stirred under nitrogen at room temperature for 3 hours. The mixture of? 33107150 was poured into ice / water (200 mL) and methylene chloride (500 mL) was added. The mixture was filtered and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. Recrystallization from methylene chloride / hex-5 xane gave 4-methyl-3-phenylethylimino-1,2,3,4-tetrahydrocyclopent [b] indol-7-ol hemihydrate (3.0 g).

Analysis for C20H20N2O.1 / 2H2O

Calculated: 76.65% C 6.75% H 8.94% N

106.76% C 6.38% H 8.89% N

Example 16 4-Methyl-3-phenyl-ethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate

To a stirred solution of 4-methyl-3-phenyl-15-ethyl-ethylimino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol hemihydrate (1.43 g) in methylene chloride (25 mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.11 g). Methyl isocyanate (0.27) in methylene chloride (20 mL) was added to the reaction mixture. The reaction was monitored by TLC and after 3 hours the methylene chloride was evaporated.

The brown residue was recrystallized from acetonitrile. Analysis for C22H23N3H2: 11e

Calculated: 73.11% C 6.41% H 11.63% N

found: 73.03% C 6.35% H 11.65% N

Example 17 4-Methyl-3- (2-propynyl) imino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethyl-carbamate

To a suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent [b] indol-3 (2H) -one (5.5 g) in acetonitrile (100 mL) was added propargylamine (3.0 g). , and the solution was stirred at room temperature under nitrogen while titanium (IV) isopropoxide (15.6 g) was added dropwise. The mixture was stirred for 16 hours before ice water was added. The mixture was filtered, the solid washed with 35 methylene chloride, the layers separated and the organic layer 34107150 dried (Na 2 SO 4). After concentration, the crude product was purified by flash chromatography eluting with hexane: acetone (2: 1) to give 4-methyl-3- (2-propynyl) imino-1,2,3,4-tetrahydro-cyclopent [b] indole. -7-5 ol.

To a stirred solution of 4-methyl-3- (2-propynyl) imino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol (3.4 g) in methylene chloride (15.0 ml) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (326 mg) as well as thiopotassium methyl isocyanate (0.8 g) in methylene chloride (5.0 ml). The reaction was monitored by TLC and after 1 hour the solution was concentrated and the crude product was purified by flash chromatography eluting with hexane / acetone (2: 1). The product precipitated from the pure fractions was collected to give 4-methyl-3- (2-propynyl) imino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ylmethylcarbamate (1.2 g) and concentrated fractions to give 0.9 g more. Analysis for C 17 H 17 N 3 O 2

Calculated: 69.14% C 5.80% H 14.23% N

Found: 68.94% C, 5.81% H, 13.94% N

Example 18 4-Methyl-3- [2- (4-morpholinyl) ethyl] imino-1,2,3,4-tetrahydro-cyclopent [b] indol-7-ol

To a stirred solution of 7-hydroxy-4-me-25-methyl-1,4-dihydro-cyclopent [b] indol-3-one (8.00 g) in acetonitrile (125 mL) was added 4- (2) under nitrogen -aminoethyl) morpholine (10.35 g) and titanium isopropoxide (22.60 g). The reaction was monitored by TLC and after two hours an additional equivalent of 4- (2-aminoethyl) -30 morpholine (5.17 g) and titanium isopropoxide (11.30 g) was added.

Fourteen hours later, the reaction was quenched with water (200 mL). Ethyl acetate (200 mL) was added and the mixture was stirred for 15 minutes and filtered. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na 2 SO 4) and concentrated in vacuo. The resulting yellow solid was dried to give 6.65 g of product. A further 2 g sample of the solid was purified by crystallization from methylene chloride / hexane to give 1.2 g of 4-methyl-3- (2-5 morpholinoethyl) imino-1,2,3,4-t ethydrocyclo - pent [b] indol-7-ol.

Analysis for C 18 H 23 N 3 O 2

Calculated: 68.98% C 7.40% H 13.41% N

found: 68.78% C 7.52% H 13.26% N

• · ») ·»

Claims (3)

36 107150 A process for the preparation of therapeutically active 3-imino-substituted cyclopent [b] indole derivatives of the formula (III) 10 R 3 N Re 15 and pharmaceutically acceptable addition salts thereof, wherein R 3 is hydrogen or lower alkyl, - O, R 10 / R 4 is hydrogen, -OH, -OCN, lower alkoxy, or 20 O II -OC- (lower alkyl) wherein R 8 is lower alkyl or phenyl-lower alkyl, and R 8 is hydroxy, amino-lower alkoxy, lower alkynyl ,; Cycloalkyl, phenyl-lower alkyl, morpholino-lower alkyl, phenylcycloalkyl, lower-alkylcarbonyloxy or lower-alkylaminocarbonyloxy, characterized in that: a) a compound of formula (XV) 30 - (-) -; Wherein R3 is as defined above and R12 is hydrogen, hydroxy or lower alkoxy, is reacted with hydroxylamine hydrochloride to form a compound of formula III wherein R3 is as defined above, R4 is as defined above for R12 and Ra is hydroxy, b) optionally reacting a compound of formula III wherein R 3 is as defined above, R 4 is hydrogen, hydroxy or lower alkoxy and R 8 is hydroxy, with a compound of formula Br-R 13 -NH 2 wherein R 13 is lower alkylene, of formula III wherein R 3 is as defined above, R 4 is hydrogen, hydroxy or lower alkoxy and R 8 is amino-lower alkoxy; or c) a compound of formula XV wherein R 3 is as defined above and R 12 is hydrogen, hydroxy, lower alkoxy or chloroacetyloxy, is reacted with an amine of formula NH 2 R 14 wherein R 14 is lower alkynyl, cycloalkyl, phenyl-lower alkyl, morpholino-lower alkyl, phenylcyclo alkyl to form a compound of formula III wherein R3 is as defined above, R4 is as defined above for R12, and R8 is as defined above for R14, d) optionally providing a compound of formula III wherein R3 is as defined above, R4 is hydrogen or lower alkoxy and R e is hydroxy or phenyl-lower alkyl, with an isocyanate of formula R 17 -N = C = O, if R 17 is lower alkyl, to form a compound of formula III wherein R 3 and R 4 are as defined above and R8 is a group R17-NH-CO-O- wherein R17 is as defined above, e) optionally providing a compound of formula III wherein R3 is as defined above, R4 is hydrogen, hydroxy or lower alkoxy and R8 is hydroxy, with an acyl chloride of formula R17-CO-Cl or an acyl anhydride of formula (R17-CO0) wherein R17 is lower alkyl to form a compound of formula III wherein R3 and R4 are as defined above and R8 is -O -C0-R17, wherein R17 is as defined above. 38 107150 Process according to Claim 1, characterized in that R 4 is hydrogen or a group -O-CO + · NHRS wherein R 8 is as defined above and R 8 is hydroxy, lower alkynyl, amino-lower alkoxy, lower alkyl-carbonyloxy, lower alkyl -aminocarbonyloxy, cycloalkyl, phenylcycloalkyl or phenyl-lower alkyl. Process according to claim 1, characterized in that 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydro-cyclopent [b] indole-7-ol is prepared. «I • ·« ♦ 39 107150