GB2162182A

GB2162182A - Pharmaceutical indoloindole compounds and their preparation

Info

Publication number: GB2162182A
Application number: GB08518628A
Authority: GB
Inventors: William Hubert Hunter
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1984-07-27
Filing date: 1985-07-23
Publication date: 1986-01-29
Also published as: IL75887A0; GB2162182B; JPS6143189A; EP0176182A3; IL75887A; GB8518628D0; EP0176182B1; ATE56012T1; DE3579401D1; EP0176182A2; GB8419278D0; US4742075A; US4841056A

Abstract

There are disclosed pharmaceutical compounds of the formulain which R' is an aliphatic or aromatic function, and R2 and R3 are each hydrogen, C1-4 alkyl or a protecting group ; and salts thereof.

Description

1 GB 2 162 182 A 1

SPECIFICATION

Pharmaceutical compounds and their preparation This invention relates to novel pharmaceutical compounds and a novel process by which they may be 5 prepared.

The literature describes many compounds having the ergoline nucleus:

9 1 ,! H 2 7 H N 4 5 and compounds of this type have been found to possess a surprising variety of pharmacological activi- 20 ties.One such ergoline found in nature is agroclavine, the compound bearing a methyl substituent at po sitions 7 and 9 and an ethylenic unsaturation in the 9,10 position.

The present invention provides a new indoloindole structure derived from agroclavine and related er goline compounds.

The compounds of the invention are of the formula R' '-',q 8 H ' NR3 30 2 H 7 3 j 35 11 5 R2 4 in which R, is an aliphatic or aromatic function, and R2 and R3 are each hydrogen, C,-4 alkyl or a protect ing group; and salts thereof. The compounds having optimum biological activity are the unprotected compounds, that is, those in which R2 and R3 are hydrogen or C1-4 alkyl.

The compounds of the invention represent a novel type of structure in which the six-membered D-ring of such compounds as agroclavine, is replaced by a 5-membered ring.They have been found to affect the levels of prolactin in rats and are thus indicated for use in the treatment of disorders of the central nervous system.

In the above formula R1 can be an aliphatic or aromatic function and such groups may be chosen from 45 a wide range, of which examples are as follows:

(i) a substituent of the formula R'CO- where R' is C1-4 alkyl, especially CH,CO-, X 1 (H) a group of the formula RCH- where R' is hydrogen or C1-4 alky], X is -OH or -NH,, X 11 (iii) a group of the formula R C- where R' is hydrogen or C1-4 alkyl, X is =NOH, -SCH,Cl-1,S-, =NNH, or 55 =NNHR"where Wis C1-4 alkyl or optionally substituted phenyl, 0v) a C, alkyl group, (v) a substituent of the formula -COZ where Z can be hydrogen, -OH, halogen especially chlorine, -OC1-4 alkyl, -OC,., alkylphenyl, -N,, -NH,, -NHR', -NR', where each R' group is Cl- 4 alkyl, (vi) an -NH,, -NHR' or -NR', group or a group of the formula -NHCOR' where R' 'S C1-4 alkyl, (vii) a nitrile (-CN) group, and (viii) a group of the formula -C(OH)(CH,)R' where R' is optionally substituted phenyi.Rl is preferably an aliphatic group and especially one chosen from (i), (iv) and (v) above.

2 GB 2 162 182 A 2 Reference to such groups as C,, alkyl is intended to include both straight and branched chain groups, such as for example, methyl, ethyl, propyl, isopropyl, butyl and tert. butyl. An optionally substituted phenyl group is phenyl or phenyl substituted with one or more, preferably one to three substituents, selected from for example, C, alkyl especially methyl, C, alkoxy especially methoxy and ethoxy, nitro, cyano, hydroxy, halo and amino.

As mentioned above, R2 and R3 are each hydrogen, C, alkyl or a protecting group. A protecting group can be any group conventionally employed to protect a nitrogen on an indole nucleus. Such groups are well known and are discussed, for example, by RJ. Sundberg and H.F. Russell J.0.C. 38, 3324 (1973).

They include groups of the formula R'CO where R' is C,-, alkyl, optionally substituted phenyl or optionally substituted phenyl C,,, alkyl, particularly preferred examples being acetyl, benozyi, and especially benze- 10 nesulphonyl or toluenesulphonyl.

Salts of the compounds of this invention include pharmaceutical lyacceptable acid addition salts such as salts derived from non-toxic inorganic acids, for example, hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydriodic acid and phophorous acid, as well as salts derived fron non-toxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl -substituted alkanoic acids, 15 hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulphonic acids. As well as pharmaceutically-acceptable salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acids; they may serve as intermediates in the puri fication of the compounds or in the preparation of other, for example pharmaceutical ly-accepta ble, acid addition salts, or are useful for identification, characterisation or purification of the bases.When the com- 20 pound of the invention contains an acid group, for example when R! is - COOH, cationic salts can be pre pared such as inorganic salts formed with alkali or alkaline earth metal metals especially sodium and potassium, or organic base salts such as ammonium or tetramethylammonium. Furthermore, the zwitter ionic form of the compounds formed with an amino function and a carboxy group, is also included in the term "salt".

Preferred compounds of formula (1) are those in which R, is an aliphatic or aromatic function, R2 is hydrogen, C, alkyl or a protecting group and R3 is C,-, alkyl; and acid addition salts thereof.Of these compounds three groups are especially preferred (a) those in which R, is CH3C0-, R2 is hydrogen or a protecting group and R3 is C, alkyl especially methyl, such compounds being intermediate in the preparation of other compounds of formula (1), 30 (b) those in which R, is -CO0C,, alkyl, especially compounds in which R, is -COCH53, R2 is hydrogen or a protecting group and R3 is C, alkyl especially methyl, such compounds being of special practical use, and (c) those in which R, is ethyl, R2 is hydrogen or a protecting group and R3 is C, alkyl especially methyl.

The compounds of formula (1) are prepared by a novel method which involves the initial preparation of 35 the compound in which the substituent R, is CH,C0-, which in turn can be converted to other aliphatic or aromatic functions. Thus the invention includes a process for preparing a compound of formula (1) above, which comprises the rearrangement of a compound of the formula H0. CH3 40 Xol,", Hi Hi,, N R3 1 H 45 1 YN 1 R2' in which R2 is as defined above and R3 is C,, alkyl or a protecting group, and -OX is a leaving group, to give a compound of formula (1) in which R, is -COOH,, and optionally converting the R' group to another aliphatic or aromatic function, or removing an R2or R3 group when it is a protecting group.

The compounds of formula (11) undergo a pinacolpinacolone rearrangement as described in Compre- 55 hensive Organic Chemistry (The Synthesis and Reactions of Organic Compounds) Pergamon Press 1979 Vol. 1, p.688. The compound of formula (11) bearing a leaving group X on the 10-hydroxy substituent gives a compound of formula (1) when treated preferably with a base such as pyridine. Suitable X groups include, for example, groups of the formula R'SO, in which R, is C, alkyl or optionally substituted phenyl, for instance, methane sulphonate.

The process of the invention is preferably carried out at a temperature of from OOC to 1000C, for exam ple, from 100C to 60'C and in an inert organic solvent. When a base such as pyridine is employed which is a solvent for the reaction, excess base may be employed.

Compounds of formula (1) in which R3 is hydrogen can also be prepared by dealkylation of compounds in which R, takes an appropriate value such as for example ethyl.

3 GB 2 162 182 A 3 Compounds of formula (11), and the free 10-hydroxyl compound (X is hydrogen), are novel compounds and are included as part of the present invention.The former can be prepared simply by reaction of the free 10- hydroxyl compound with the appropriate reagent, for example RISO,Cl. In its turn the compound of formula (11) (X is hydrogen) can be prepared by oxidising a compound of the formula:

5 CH3 NR3 10 R2' N 15 This oxidation step is preferably performed in a suitable inert organic solvent such as for example diethyl ether at a temperature of from O'C to 40'C. Suitable oxidising agents include osmium tetroxide in stoichi ometric amounts in an inert atmosphere such as nitrogen, or in catalytic amounts in the presence of a 20 co-oxidant such as for example described in Comprehensive Organic Chemistry (The Synthesis and Reac tions of Organic Compounds) Pergamon Press 1979, Vol.1, P.164, for instance N-methyimorphoiine-N oxide.

It will be appreciated that the compound of formula (ill) in which R2 is hydrogen is the known clavine alkaloid, agroclavine. Other starting materials in which R2 andlor R3 is C, alkyl or a protecting group can 25 be prepared by reaction of agroclavine or noragroclavine with the appropriate C1-4 alkyl halide or with a suitable protecting group-donating compound by standard methods.

Similarly, it will be appreciated that compounds of formula (1) in which R2 is hydrogen can be prepared by removal of a protecting group from the nitrogen atom by the use, for example, of potassium hydrox ide and ethanol. R, groups can be derived from the compound in which R, is -COCH, by conventional 30 methods known in the art, as for instance illustrated in the following Examples.

As mentioned above, compounds of the invention have useful central nervous system activity and low toxicity. This activity has been confirmed by their ability to alter serum prolactin levels in rats according to the test described by Clemens J.A. Smalstig E.B. and Sawyer B.D. (1974) Psychopharmacologia Vol.40, p.123.

The following compounds significantly (p <0.05) reduced the proiactin levels in reserpinised rats, by more than 20%, at dosages of 100 KgAg i.p., R1 11,11 R, = -COCH, 40 H -CH2CH, tN -C H 3 -CONH2 H -NHCOCH, -CH20H HN -CON(C,HJ2 45 A positive result in the above test indicates that the compounds possess dopamine agonist activity which is indicative of use in the treatment of, for example, parkinsonism and hyperprolactinemia states. 50 The compounds are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall within the range of 0.05 to 10 mg/kg per day, for example in the treatment of adult human dosages of from 0.2 to 5 mg/kg may be used.

The compounds and pharmaceutical ly-acceptabie salts of the invention will normally be administered orally or by injection and, for this purpose, said compounds and salts will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the phar maceutical art and normally comprise at least one active compound or pharmaceutically-acceptable salt of the invention associated with a pharmaceutical ly-acceptable carrier therefor. In making the composi- 60 tions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other con tainer. When the carrie serves as a diluent, it may be a solid, semi- solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, stargesh, gum acacia, calcium phosphate, alginates, tragacanth, 65 4 GB 2 162 182 A 4 gelatin, syrup, methyl cellulose, methyl and pro pyl hydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, as is well-known in the art, be formulation so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Depending on the route of administration, the foregoing compositions may be formulation as tablets, capsules or suspensions for oral use and injection solutions for parenteral use. Preferably the composi- 5 tions are formulated in a dosage unit form, each dosage containing from 1 to 200 mg more usually 5 to mg, of the active ingredient.

The invention is illustrated by the following Examples.

Example 1 4-Benzenesulphonyl-7,9-dimethyl-4,6.6a.7.8,9. 10, 10aoctahydroindole [4,3-fgl quinoline To a solution of agroclavine (9.0 g) in dichforomethane (150cm3) at O'C under nitrogen was added with stirring aqueous sodium hydroxide (45 cm3, 50% wiw) and a solution of tetra-N-butylammonium hydrogen sulphate (1.462 g) in dichloromethane (50cm3). After 0.5 hours a solution of benzenesulphonyl chlo- ride (6.2CM3) in dichloromethane (25cm3) was added over a period of 15 minutes, the temperature being maintained at O'C. The mixture was allowed to warm to room temperature and stirred for 16 hours.

To the reaction was added water (500cm3) and dichforomethane (500cm3), the phases separated and the aqueous layer was re-extracted with dichloromethane (2 x 125cm3). The combined extracts were washed with aqueous sodium hydroxide (2 x 500cm3, M), water (2 x 250CM3) and dried before evapora- ting under vacuum. Trituration of the resultant brown oil with diethyl ether yielded the title compound as 20 an off-white foam, m.p. 80-8VC (dec).

Example 2

9, 10Dihydroxy-7,9-dimethyl-4,6,6a,7,8,9, 10, 10a-octahydroindolo [4,3fgj quinoline To a stirred solution of agroclavine (0.90 g) in dry ethanol-pyridine (20cm3, 1:3) under nitrogen was 25 added a solution of osmium tetroxide (1.00 g) in dry diethyl ether (50cm:l). The solution immediately be came dark brown in colour and after 5 hours reaction was indicated to be complete.Hydrogen sulphide was bubbled through the stirred solution causing complete precipitation of a black solid (osmium W salt) in 4 hours. The precipitate was removed on a Kieselguhr bed filter and washed with ethanol (2 x 20cm3); evaporation under vacuum of the combined filtrate gave a dark red solid.

Purification on silica gel 60 eluted with chloroform-methanol (4:1), yielded the title compound as an off-white solid, m.p. 148-152'C (dec).

Example 3

4-Benzenesulphonyl-9, 10-dihydroxy-7,9dimethyl-4,6,6a, 7,8,9, 10, 10aoctahydroindolo [4,3,-fgl quinoline 35 N-Benzenesulphonyl agroclavine (1.48 g) was dissolved under nitrogen in dry, degassed pyridine (10cm3). Diethyl ether (75cm3) was added with stirring followed by a solution of osmium tetroxide (1.0 9) in diethyl ether (20cm3). A copious brown precipitate formed and the mixture was left to stir for 16 hours.

Addition of a solution of sodium hydrogen sulphite (1.628 9) in ethanolwater (40cM3, 1:11) gave a clear orange coloured solution containing a heavy brown precipitate of osmium (N) oxide.

After 5 hours the solution was filtered, the solvents evaporated under vacuum and the orange residue partitioned between chloroform (150cm3) and water (150cm;'). The separated aqueous layer was re-ex tracted with chloroform (4 x 40cm3) and the combined extracts washed with water (50cm3), dried and evaporated under vacuum to give an orange gum. Trituration with diethyl ether gave an impure product as a dark yellow foam.

Purification on silica gel 60 eluted with chloroform-methanol (12:1) yielded the title compound as a pale cream foam m.p. 120-122'C.

Example 4

9-Acetyl-4-benzenesulphonyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indoloffi, 5, 4-cdlindole The diol of Example 3 (1.00 9) was dissolved in dry pyridine (4cM3), an excess of 4A molecular sieve (0.5 9) added and stirred solution cooled to O'C. After 10 minutes, methanesul phony] chloride (0.097CM3) was added and stirring continued for 16 hours.

Chloroform (100CM3) and water (200cm3) were added and the mixture partitioned. The separated aqueous layer was re-extracted with chloroform (3 X 50CM3) and the combined extracts washed with 55 aqueous sodium hydroxide (2 x 50cm3, M) and water (100cm3) before drying. Evaporation of the filtrate under vacuum gave a tan coloured foam.

Purification on silica gel 60 eluted with chloroform-methanol (20:1) yielded the title compound as a white foam, m.p. 76-79'C.

GB 2 162 182 A 5 Example 5 9-Acetyl-4-benzenesulphonyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H- indolo [6,5,4-cd] indole-9-dithioketal The 9-acetyl compound of Example 4 (0.211 g) was dissolved with stirring into ethanedithiol (0.25cm3) and boron trifluoride diethyletherate (0. 25cm3) added causing gaseous evolution. After stirring for 12 5 hours the reaction was indicated to be complete, and all solvents were removed under vacuum. Repeated high vacuum trituration with methanol gave impure product (0.415 9) as a sticky white solid.

Purification on silica gel 60 eluted with chloroform-methanol (M) gave, after trituration with diethyl ether, the title compound as a white solid, m.p. 89-91'C (dec).

Example 6 4-Benzenesulphonyl-9-ethyl-7-methyl-6,6a, 7,8,9,9a-hexahydro4Hindolo [6,5,4-cd] indole To the dithioketal of Example 5 (0.259 g) and Raney nickel catalyst, 50 micron grade, (3.5 g) was added ethanol (20cm3) the resultant stirred suspension was heated to reflux. After 5 hours all starting material was indicated to have been consumed. To the cooled reaction was added chloroform (20Cm 3) and the mixture vigorously shaken and filtered. The residue was further extracted with chloroform-methanol (2 x 15 20cm3, 5:1) and the combined extracts evaporated under vacuum to give a dark green solid.

Purification on silica gel 60 eluted with chloroform-methanol (5:11) gave the title compound as a yellowwhite smear which could not be crystallised.

Example 7 9-Ethyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4cd] indole To a stirred solution of the compound of Example 6 (0.0965 g) in ethanol (3cm3) was added potassium hydroxide (0.036 g) and the reaction heated to reflux. After 3 hours reaction was indicated to be cornplete, and the product was isolated as described in Example 6.

Purification on silica gel 60 eluted with chloroform-methanol (M) gave, after trituration with dichloro- 25 methane, the title compound as a white solid, m.p. 137-139'C (dec).

Example 8

4-Benzenesulphonyl-7-methyl9-methyloximino-6,6a,7,8,9,9a-hexa- hydro-4Hindolo [6,5,4-cd] indole To a stirred solution of the 9-acetyl compound of Example 4 (0.25 g) in methanol (12cm3) was added 30 anhydrous sodium acetate (0.078 g) and hydroxylamine hydrochloride (0. 0615 9) and the orange solution heated to reflux. After 5 hours reaction was indicated to be complete, all solvents were removed under vacuum. Chloroform (40cm3) and water (40cm3) was added and the residue partitioned. The organic layer was re-washed with water (25CM3), dried and evaporated under vacuum to give a yellow-white solid.

Purification on silica gel 60 eluted with chloroform-methanol yielded the syn ketoxime as an off-white 35 foam, m.p. 160-162'C (dec), and the anti ketoxime as a cream coloured solid, m.p. 129-1320C (dec).

Example 9 4-Benzenesulphonyl-7-methyl-9-methyloximino-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4-cd] indole-9-p- toluenesulphonate The 9-acetyl compound of Example 4 (0.15 9) was converted into the impure ketoximes of Example 8 by the procedure previously described.

To a vigorously stirred solution of the ketoximes (0.181 g) in chloroform (5cm3) was added 3.75 M aqueous sodium hydroxide (0.305cml). After 5 minutes, to the slowly clearing solution was added p-tolu enesulphonyl chloride (0.127 g) and the reaction left to stir. After 2 days the reaction was indicated to be 45 complete. Water (20cM3) and chloroform (30CM3) were added and the mixture partitioned, the aqueous layer was re-extracted with chloroform (20cm3) and the combined extracts washed with saturated aqueous sodium hydrogen carbonate (2 x 25CM3) and water (25CM3), and dried.Evaporation under vac uum of the yellow filtrate yielded the title compound, after trituration with diethyl ether, as an off-white foam, m.p. 95-99'C (dec).

Example 10

9-Acetamido-4-benzenesulphonyl-7-methyl-6,6a, 7,8,9,9ahexahydro- 4Hindolo [6,5,4-cd] indole -Beck mann Rearrangement To a stirred solution of the syn ketoxime of Example 8 (0.141 g) in dry pyridine (3cm3) at O'C was added phosphorus oxychloride (0.32CM3). The reaction was left to stir at O'C for 1 hour at room tempera ture for 16 hours before being acidified to pH 1 with concentrated hydrochloric acid. Water (50cm3) was added and the solution extracted with chloroform (3 x 30cm3), the combined extract was washed with saturated aqueous sodium hydrogen carbonate (2 x 25crn'), water (2 x 25cm3) and dried. The aqueous washings were neutralized with saturated aqueous sodium hydrogen carbonate and treated as before 60 and further extracted. Evaporation under vacuum of the combined filtrate gave, after trituration with die thyl ether, the title compound as a white solid, m.p. 165-167'C (dec).

6 GB 2 162 182 A 6 Example 11 9-Acetamido-7-methyl-6,6a, 7,8,9,9a-hexahydro-4H-indo1o [6,5,4, - cd] indole The N-benzenesulphonyl-9-acetamide of Example 10 (0.131 g) was debenzenesulphonylated with potassium hydroxide in refluxing ethanol by the procedure of Example 7.

Purification on silica gel 60 eluted with chloroform-methanol (5:1) yielded the title compound as an off- 5 white solid, m.p. 174-178'C (dec).

Example 12 Haloform oxidation of the 9-acetyl compound of Example 4 The aqueous sodium hypochforite solution was assayed prior to use in the reaction.

To a stirred solution of the 9-acetyl compound (0.919 g) in methanol (25CM3) at O'C was added 3 M aqueous sodium hydroxide (0.78CM3) and 2.23 M aqueous sodium hypochlorite (2.089cm3), dropwise causing a lightening of reaction colour. The reaction was allowed to warm slowly to room temperature and after 2.5 hours further 2.23 M aqueous sodium hypochlorite (1.55cm:I) added. After 20 hours reaction was indicated to be complete.

All solvents were removed under vacuum to give a yellow-orange solid to which water (20cM3) was added and the mixture then vigorously stirred. After 10 minutes the resultant orange slurry was cooled to O'C and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid. Evaporation under vacuum of the acidified mixture gave an orange gum which on trituration with acetone yielded the crude acid contaminated with inorganic material as an orange-brown foam.

Purification on silica gel 60 eluted with chloroform-methanol (M) followed by methanol gave, on evaporation under vacuum, a product contaminated by silica gel. Dissolution into chloroform-methanol (10cm3, M), filtration and evaporation under vacuum yielded 4-benzenesulphonyi-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indole [6,5,4-ed] indole-9-carboxylic acid in the zwitterionic form as a light tan coloured solid, m.p. 188-19VC (dec), and 4-benzenesulphonyl-7-methyl6,6a,7,8,-tetrahydro-4H-indolo [6.5.4-cd] indole-9-carboxylic acid in its zwitterionic form as a yellow solid, m.p. 195-199'C (dec).

is Example 13

7-Methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6.5.4-cd/ indole-9- carboxylic acid To a stirred solution of the 9-acetyl compound of Example 4 (1.00 g) in methanol (30cm3) at O'C was added 3 M aqueous sodium hydroxide (0.085cm3) and 2.2 M aqueous sodium hypochlorite (2.3OcM3) causing a visible lightening of reaction colour. The reaction was allowed to warm slowly to room temper ature and after 2 hours further 2.2 M aqueous sodium hypochlorite (2. 30CM3) added. After 20 hours reac tion was indicated to be complete, all solvents were removed under high vacuum to give a yellow35 orange residue.

Ethanol (20cm3) was added with stirring and into the resultant slurry was introduced potassium hy droxide (0.284 g) and the mixture heated to reflux. After 5 hours reaction was indicated to be complete, all solvent was removed under vacuum to give an orange residue. Water (30cm3) was added with stirring and the orange coloured solution cooled to OOC, careful dropwise addition of concentrated hydrochloric 40 acid was made to pH 1. All solvents were removed under high vacuum to give, after trituration with acetone, a dark yellow solid.

Purification on silica gel 60 eluted with methanol yielded the title compound in its zwitterionic form as a tan coloured solid, m.p. 160-1620C (dec).

Example 14

4-Benzenesulphonyl-9-carbomethoxy-7-methyl-6,6a,7,8,9,9a-hexahydro- 4Hindolo [65.4-cd/ indole To a stirred solution of the sodium salts of the products of Example 12 (0.203 g) in methanol (5cM3) was added concentrated sulphuric acid (0.1cm3) and the solution heated to reflux. After 2 hours further concentrated sulphuric acid (0.35CM3) was added and the reaction left to reflux for 20 hours. Evaporation 50 under vacuum of the reaction mixture gave an orange residue. Chloroform (40cM3) and water (40cm3) were added and the residue partitioned. The separated aqueous layer was re-extracted with chloroform (20Cm3) and worked up in the usual way to give, after trituration with diethyl ether, the title compound as a pale orange-white foam, m.p. 63-66'C (dec). 55 Example 15 4-Benzenesulphonyl-9-carbobenzyloxy-7-methyl-6,6a,7,8,9,9a- hexahydro-4H-indolo [6,5,4,-cd] indole Similarly 4-benzenesu 1 phony] -9-ca rbo benzyl oxy-7-m ethyl- 6,6a,7,8,9, 9a-hexahydro-4H-indolo [6,5,4,-cd] indole was prepared by acid-catalysed esterification of the products of Example 12 as a yellow gum.

7 GB 2 162 182 A 7 Example 16 9-Carbomethoxy-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5, 4- cd] indole To a solution of the free indole 9-carboxylic acid (Example 13) (0.203 g) in methanol (5cm3) was added with stirring concentrated sulphuric acid (0. 15cm) and the reaction heated to reflux. After 2 hours further 5 concentrated sulphuric acid (0.1CM3) was added, reaction was indicated to be complete after 15 hours,The resultant solution was allowed to cool to room temperature to give after evaporation under vacuum and trituration with chloroform a dark orange solid (0.329 g).

Purification on silica gel 60 eluted with chloroform-methanol OA) yielded the title compound as an offwhite solid, m.p. 181-1830C.

Example 17 9-Carboethoxy-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6.5. 4- cd] indole To a solution of the free indole 9-carboxylic acid (Example 13) (0.12 g) in ethanol (6cm3) was added with stirring fused p-toluenesulphonic acid (0.081 9) and the reaction heated to WC. After 15 hours fur- ther fused p-toluenesulphonic acid (0.081 g) was added and the temperature raised to WC. After 3 days 15 reaction was indicated to be complete. All solvent was removed under vacuum.

Dichloromethane-methanol (25cm:3, 5:1) and water (25CM3) were added and the residue partitioned. The separated aqueous layer was worked up in the usual way to yield the title compound as a dark yellow smear.

A sample was further purified on silica gel 60 eluted with chloroformmethanol (10:1) to give a tan 20 coloured solid, m.p. 100-104'C (dec).

Example 18 4-Benzenesulphonyl-7-methyl6,6a,7,8,9,9a-hexahydro-4H-indolo [65.4-cd/ indole-9-carboxamide 25 (a) Method A - With 0. 880 ammonia solution The 9-carboxylic acid (0.142 g) was dissolved in thionyl chloride (0.3cm:l) and stirred for 15 minutes, at O'C. The excess thionyl chloride was removed under vacuum (<30'C) and the residue triturated with dry benzene (2CM3) to give the 9-acid chloride as an orange solid. Concentrated ammonia solution (0.5cm3) was added at O'C with stirring. After 15 minutes, dichlorome- thane (0.5cm:l) was added and the remaining solid dissolved. After stirring for 2 hours the solvents were 30 evaporated under vacuum. The resultant orange residue was extracted with chloroform-methanol (3 x 20cm3, 5: 1) to give a yellow solid.

Purification on silica gel 60 eluted with chloroform-methanol (IIA) yielded the title compound as a Vel low- white solid.

(b) Method 8 - With anhydrous ammonia The 9-carboxylic acid (0.50 g) was dissolved in thionyl chloride (1. 245cM3) and stirred for 20 minutes at O'C. The excess thionyl chloride was removed under vacuum (<30'C) to yield after trituration with dry benzene (5CM3) the 9-acid chloride as an orange solid.

Into a stirred solution of the acid chloride in dry dichloromethane (7CM3) at O'C under anhydrous condi- 40 tions was bubbled anhydrous ammonia, causing immediate solid precipitation. After 30 minutes the ammonia flow was stopped and the mixture evaporated to dryness. Dissolution into dichloromethanemethanol (100cm:l, IIA), filtration and evaporation under vacuum gave the product contaminated with inorganic salts as an orange solid. Purification on silica gel 60 eluted with chloroform-methanol OA) yielded

the title compound as a light 45 brown solid.

Example 19 4-Benzenesulphonyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6.5.4-cd] indole-9-NN-diethylearboxam- ide Using method A as described in the preparation of Example 18, 4benzenesulphonyi-7-methyi6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4,-cd] indole-9-N,N-diethylcarboxamide was prepared as an orange-white foam, m.p. 87-90'C.

Example 20 7Methyl-6,6a, 7,8,9,9a-hexahydro-4H-indolo [6.5.4,-cdl indole9- carboxamide The N-benzenesulphonyl 9-carboxamide (Example 18) (0.30 g) was added with stirring to anhydrous ammonia at -45'C. Freshly cut sodium was added in small pieces until the blue colour persisted. After 15 minutes, the ammonia was allowed to evaporate leaving an orange residue. Ethanol (10cm3) was added to destroy residual sodium and the solution evaporated to dryness. The residue was extracted with chloroform-methanol (2 x 20cm3, 2:1), filtered and evaporated to give a product contaminated with inorganic salts as an orange solid.

Purification on silica gel 60 eluted with chloroform-methanol (1:11) yielded the title compound as a light tan- coloured solid, m.p. 163-166'C (dec).

8 GB 2 162 182 A 8 Example 21 7-Methyl-6-6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4-cdl-indole-9- NN-diethylcarboxamide (a) Method A - Sodium-liquid ammonia at -45C The 4-benzen esu 1 phonyl-9-N, N-d i ethyl a mi de (Example 19) (0.27 g) was added with stirring to anhy- drous ammonia at -45'C. Total solution was not achieved. Freshly cut sodium was added in small pieces 5 until the blue colour persisted. After 20 minutes the ammonia was allowed to evaporate leaving an orange residue, which was worked up as before to give an orange smear.

Purification on silica gel 60 eluted with chloroform-methanol (3:1) yielded the title compound as a light tan coloured solid and 7-m ethyl -4, 6,6a,7,8,9a-h exa hyd ro-i n do 1 o [6,5,4- cd] indole-9-carboxamide.

(b) Method 8 - Sodium-dry diethylamine at 20'C The 4-benze nesu 1 pho nyl-9-N,N-cli ethyl am ide (0.115 9) was added with stirring to anhydrous diethylam ine (3CM3) at room temperature. Freshly cut sodium (0.059 9) was added causing no change in coloura tion.After 60 hours t.l.c. indicated no further changes in reaction composition, all solvents were removed under vacuum. The residue was partitioned between chloroform (25cm3) and water (25cm3) and worked up as before to give on evaporation under high vacuum a dark yellow smear.

Purification on silica gel 60 eluted with chloroform-methanol (10:1) yielded slightly impure compound as a light orange solid and starting material.

c) Method C - Raney-nickel alloy in refluxing ethanol The 4-benzenesulphonyl-9-N,N-diethylamide (0.072 g) in ethanol (5cM3) was added to a stirred slurry of Raney nickel alloy (0.75 g, 50t grade).The orange suspension was heated to reflux for 4 hours and a further portion of alloy (0.37 g) added. After 24 hours the mixture was allowed to cool before dilution with dichloromethane-methanol (50cm:I, 1:1) and filtration under pressure through a Kieselguhr filter bed.

The residue was further washed with methanol (2 x 20cm3) and the combined filtrate evaporated under vacuum to give a dark orange smear.

Purification on silica gel 60 eluted with chloroform-methanol Q:1) yielded starting material and title 25 compound as a yellow-white solid, mp. 1142-144'C (dec).

Example 22

4-Benzenesulphonyl-9-hydroxymethyl-7-methyl-6 6a, 7,8,9,9a-hexa- hydro-4Hindolo [6,5,4-cd[ indole To a stirred solution of the 9-methyl ester (Example 14) (0.365 g) in dry methanol (4CM3) under anhy- 30 drous conditions was added sodium borohydride (0.252 g) causing vigorous effervescence. After 2 hours further sodium borohydride (0.067 g) was added. After the initial effervescence had subsided the reaction was heated to 60'C. Reaction was indicated to be complete and after 4 hours water (4cm3) was carefully added and the cloudy mixture allowed to cool to room temperature. The product was extracted from the aqueous solution with chloroform, the combined extract washed with water (50cM3), dried and evapo- 35 rated under vacuum to yield the title compound as a yellow-white foam, m. p. 124-127'C.

Example 23 9-Hydroxymethyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6, 5,4- cd] indole LAH reduction and debenzensulphonylation To a stirred solution of the 9-methyl ester (Example 14) (0.25 g) in dry diethyl ether (10CM3) under anhydrous conditions was added lithium aluminium hydride (LAH) (0.046 g). After 2 hours further LAH (0.046 g) was added and the reaction heated to reflux, reaction was indicated to be complete after 5 hours. Water (10CM3) was carefully added causing immediate precipitation of a flocculent solid; evapora- tion under vacuum of the mixture gave a yellow-white residue.

The residue was dissolved with difficulty into ethanol (6cm3) and potassium hydroxide (0.171 g) added with stirring.

After refluxing for 15 hours all solvents were removed under vacuum to give an orange-white solid.

Purification on silica gel 60 eluted with chloroform-methanol (1:1) yielded the title compound as a tan coloured solid, m.p. 121-125'C (dec).

Example 24

9-Hydroxymethyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4- cd] indole Using the debenzenesulphonylation procedure previously described (Example 22) (0.238 g), reaction with potassium hydroxide in refluxing ethanol yielded the title compound after purification on silica gel 55 eluted with chloroform-methanol Q:1) as a tan coloured solid, m.p. 121125'C (dec).

9 GB 2 162 182 A 9 Example 25 4-Benzenesulphonyl-9-cyano-7methyl-6,6a,7,8,9,9a-hexahydro-4H- indolo [6.5.4-cd] indole To a stirred solution of the N-benzenesulphonyl-9carboxamide (Example 18) (0.067 g) in pyridine (2CM3) was added p-tol uenesu 1 phony] chloride (0.161 g) and the reaction heated to 90-1000C. After 4 hours reaction was indicated to be complete, all solvents were removed under vacuum to give a brown smear. Chloroform (25cM3) and water (25cM3) were added and the residue partitioned; from the extract was isolated an impure product as a dark yellow solid.

Purification on silica gel 60 eluted with chloroform-methanol (10: 1) yielded, after trituration with diethyl ether, the title compound as a light orange solid, m.p. 136-139'C (dec).

Example 26 9-Cyano-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6.5.4-cd] indole To a stirred solution of the free indole-9-carboxamide (Example 20) (0. 031 g) in dry dimethylformamide (1 CM3) under anhdyrous conditions at O'C was added thionyl chloride (0.02cm:I) with visible reac- tion.Reaction was indicated to be complete after 20 minutes. Water (5CM3) was added and all solvent 15 removed under high vacuum (<30'C) to give an orange smear.

Purification on silica gel 60 eluted with chloroform-methanol (M) yielded, after trituration with 40-60 degree petroleum ether, the title compound as a tan coloured solid, m.p. 77-80'C (dec).

Example 27 9Amino-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5.4-cd] indole To the N-benzenesulphonyl-9-acetamide (Example 10) (0.15 g) was added with stirring hydrazine hydrate (4cm3) and the mixture heated to reflux under anhydrous conditions. After 24 hours all solid had dissolved to give a clear orange solution. All solvents were removed under high vacuum (<30'C) to give after trituration with water (1 Ocm3) and acetone (2 x 1 OCM3) an orange solid.

Purification on silica gel GF254 preparative plates eluted with chloroform-methanol-concentrated ammonia (20:2A) gave the title compound as a yellow-orange solid, m.p. 95-97'C (dec).

Example 28

4-Benzenesulphonyl-9-(1-hydroxyethyl)-7-methyl-6,6a,7,8,9,9a- hexahydro4H-indolo [6,5,4-cd] indole To a stirred solution of the 9-acetyl compound (Example 4) (0.10 g) in ethanol (2cm3) was added sodium borohydride (0.0075 g) with visible reaction. After 2 hours reaction was indicated to be complete. Water (20cm3) and dichloromethane (20CM3) were added and the mixture partitioned, the separated aqueous layer was re-extracted with dichloromethane (20CM3) to give, after evaporation under vacuum, a yellow-white solid.

Purification on silica gel 60 eluted with chloroform-methanol (4:1) gave the title compound as a white solid (0.090 g), m.p. 90-92'C.

Example 29

9-Acetyl-4-benzenesulphonyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H- indolo [6,5,4-cd] indole 2,4'1-dinitro- 40 phenylhydrazone To a stirred solution of the 9-acetyl compound (0.051 g) in ethanol (lcm:l) was added a solution of 2,4 dinitrophenyl- hydrazine (0.0375 g) in ethanol (4CM3) and 98% sulphuric acid (0.15cm3, the latter causing precipitation of solid.The reaction was heated to 60'C and after 1 hour further 2,4-dinitrophenylhydrazine (0.0375 g) added. The product was isolated by extraction with chloroform (20cM3) as a dark yellow-or- 45 ange solid.

Purification on silica gel 60 eluted with chloroform-methanol (20:1) yielded the title compound as a bright yellow solid, m.p. 135-137'C (dec).

Example 30

9-Acetyl4-benzenesulphonyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H- indolo [6, 5,4cd] indole ethylene ketal Ethane-1,2-cliol (0.07 cm3) and dry benzene (2cM3) were heated in a Dean and Stark azeotropic distilla tion apparatus to remove all water. To the cooled anhydrous solution was added the 9-acetyl compound (Example 4) (0.05 g) and fused p-toluenesulphonic acid (0.0025 g) and the mixture heated to reflux for 4 hours.

Dichloromethane (20CM3) and water (20CM3) were added and the product isolated as a yellow-white smear.

GB 2 162 182 A Example 31

9-Acetyl-7-methyl-6,6a,7,8,9,9a-hexahydro-4H-indolo [6,5,4-cd] indole Debenzenesulphonylation of the 9-acetyl compound (Example 4) (0.20 g) was achieved with potassium hydroxide in refluxing ethanol by the procedure previously described.

Purification on silica gel 60 eluted with chloroform-methanol (2:1) yielded the title compound as a 5 white solid, m.p. 195-198'C (dec).

The compounds of the invention can be prepared in typical formulations, and for example the follow ing are representative, the active ingredient being one of the pharmacologically active compounds.

Example 32

Tablet

Active in- 10Orng gredient Dried 40Orng starch Polyvinyl 50rng pyrroli done Sodium 50rng carboxy methyl starch Stearic 20mg acid The active ingredient and starch are mixted together and massed with a solution of polyvinyl pyrrolidone in alcohol. The mass is extruded through a screen, dried, sized and mixed with sodium carboxymethyl starch and stearic acid prior to compression on a tablet machine. Tablets weighing 620 mg are obtained.

Example 33 Capsules Active in- 50rng gredient Starch 30Orng flowable Silicone 5mg fluid A portion of the starch is mixed with the silicone fluid.To the powder is added the active ingredient 40 and the remainder of the starch. This blended mixture is filled into hard gelatin capsules.

Claims

1. A compound of the formula 1 R1 ",,9 8 H0/ m z>3 2 7 50 3 IN 5 55 R2 4 in which R, is an aliphatic or aromatic function, and R2 and R3 are each hydrogen, C, alkyl or a protect ing group; and salts thereof.

2. A compound of the formula (1) as defined in claim 1, in which R, is an aliphatic or aromatic func- 60 tion, R2 is hydrogen, C, alkyl or a protecting group and R3 is C, alkyl.

3. A compound according to claim 2 in which R2 is hydrogen or C, alkyl.

4. A compound according to claim 2 in which R, is CH3C0-, R2 is hydrogen or a protecting group and R3 is C, alkyl.

11 GB 2 162 182 A 11

5. A compound according to claim 2 in which R, is -COOC,-,, alkyl, R2 is hydrogen or a protecting group and R3 is C, alkyl.

6. A compound of formula (1) as defined in claim 1, for use as a pharmaceutical.

7. A pharmaceutical formulations comprising a compound according to any of claims 1 to 5 in admix5 ture with a pharmaceutical ly-acceptable carrier therefor.

8. A pharmaceutical formulation comprising a compound according to claim 3 in admixture with a pharmaceutical ly-acceptable carrier therefor.

9. A process for preparing a compound of formula (1) as defined in claim 1, which comprise rearrangement of a compound of the formula 10 X H0/,,pCH3 jJ, H i N R 3 15 H R2' N 20 in which R2 is hydrogen, C,-, alkyl or a protecting group, R3 is C,, alkyl or a protecting group and -OX is a leaving group, to give a compound of formula (1) in which R, is -COCH, and optionally converting the R, group to another aliphatic or aromatic function, or removing an R2 or R3 group when it is a protecting 25 group.

10. A compound of formula:

H 0,, X 0.&C H 3 H /i, 1 p R 3 1 H 1 ZZ.1 101 R2' N in which R2 is hydrogen, C,-, alkyl or a protecting group, R3 is C,, alkyl or a protecting group, and X is 40 hydrogen or -OX is a leaving group.

Printed in the UK for HMSO, D8818935, 12'85, 7102.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.