GB2187739A - Substituted spiro-pyrimidoindoles - Google Patents

Description

GB2187739A 1

SPECIFICATION

Substituted pyrimidoindoles This invention relates to substituted pyrimidoindoles, to processes for their preparation, to their 5 use and to pharmaceutical compositions containing them.

The novel compounds of the present invention are pyrimidoindoles of the general formula (1) R1 R OH v N 10 R2 N 1A 15 and their pharmaceutically acceptable acid addition salts. In the- formula, R represents lower alkyl, a mono- or bi-cyclic aryl radical or a group of formula R30-13- [where R30 is (lower)alkoxy, aryi(iower)aikoxy or hydroxy and B is a lower alkylene chain optionally containing one double or triple bond], R' and R 2 which may be the same or different each represent hydrogeri, hydroxy], 20 lower alkyl, lower alkoxy, halo(lower)aikyi, halogen, amino or mono- or di(lower)alkylamino and A, together with the carbon atom to which it is attached, represents 5, 6 or 7 membered saturated carbocyclic or heterocyclic ring.

The term -lower- as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. For example, a lower alkyl group 25 may be methyl, ethyl, propyl or butyl and a lower alkoxy may be methoxy, ethoxy, propoxy or butoxy.

The term ---ary]- is used herein to denote a radical having an aromatic character. Such radicals include phenyl, naphthyl and heterocyclic radicals having an aromatic character. For example, when R is an aryl radical it may be a radical such as phenyl, naphthyl, furyl, thienyl, pyridyl, 30 indolyl and benzothienyl, each of which may be substituted or unsubstituted. Suitable substitu ents include those mentioned herein for the definitions of R' and R2; preferable substituents are halogen (for example fluorine, chlorine or bromine), lower alkyl (for example methyl, ethyl, propyl or butyl), lower alkoxy (for example methoxy, ethoxy, propoxy or butoxy) and halo (lower)alkyl (for example trifluoromethyl). Preferably R is phenyl optionally substituted as mentioned above or 35 lower alkyl (e.g. butyl).

Preferred examples of R' and R 2 residues include hydrogen, lower alkyl (e.g. methyl, ethyl, propyl and butyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy and butoxy), halo(lower)aikyl (e.g.

trifluoromethyl) and halogen (e.g. chlorine and bromine).

When R30 is an aryl(lower)alkoxy group, the aryl radical is preferably a phenyl group which 40 may optionally be substituted by, for example, the substituents defined above in respect of R' and R2. For example R30 may be an optionally substituted benzyloxy group. Examples of suitable R30-13 groups include 3- or 4-methoxybutyl, 4-ethoxybutyl, 3- methoxypropyl and 3-hydrox y-l-propyny].

When A, together with the carbon atom to which it is attached, represents a carbocyclic ring, 45 the radical A is an alkylene chain; one or more carbon atoms in the claim may be substituted by, for example, one or two lower alkyl groups. Preferably A represents - (CH2),- where n is 4, or 6. When A, together with the carbon atom to which it is attached, represents a saturated heterocyclic ring, the heterocylic ring may contain one or more hetero atoms such as oxygen or nitrogen. Examples of heterocyclic rings include piperidine, pyrolidine, tetrahydropyran and tetrahydrofuran. A nitrogen heteroatom may, if desired, be substituted by, for example, a lower alkyl group or a protecting group (such as 1,1-dimethylethoxycarbonyi, benzyl or trimethylsilyl) which can be removed to give a compound in which the nitrogen atom is unsubstituted.

Examples of preferred compounds of the invention are:

2', X, 4', 10'-tetrahydro-10'-hydroxy-10'-phenyi-spiro[cyclohexane-1,3'pyrimido(1,2-a) in- 55 dole] 2',3',4',10'-tetrahydro-10'-hydroxy-10'-phenyl-spiro[cycloheptane-1,3'pyrim ido(1,2-a)indole] 2',XA', 1 O'-tetra hydro- 1 U-hydroxy-spi ro[eyclohexane- 1,X-pyrim ido(l, 2-a) i ndole] 2',3',4',10'-tetrahydro-10'-hydroxy-10'-phenyi-spiro[cyclopentane-1,3'pyrim ido(1,2-a)indole] 2% 3%4% 1 O'-tetrahydro- 1 U-hyd roxy- 1 U-phenyl-spi ro[piperidi ne-4,X- pyri mid o (1 2-a) i ndolel 60 and the pharmaceutically acceptable salts thereof.

The compounds of the invention may be prepared by a process in which a ketone of general formula (11) 2 GB2187739A 2 0 R1 N Y G 1) 5 N R23D: A 10 where W, R2 and A have the meanings given above is reacted with an organometallic compound containing a R4 residue where R4 represents lower alkyl, a mono- or bicyclic aryl radical or a group of formula0293'-0-B[where." is (lower)aikoxy, aryi(lower)aikoxy or protected hydroxy such as tetrahydropyranyloxy, trialkylsiloxy or benzyloxy and B is as defined above] and whereX-0- is a protected hydroxy group removing the protecting group to give a product in which3'0 is 15 hydroxy. The organometallic compound can be, for example, a Grignard reagent of formula R4M9Y where R4 has the meaning given above and Y is halogen or an alkalimetal compound such as a lithium derivative of formula R4Li (e.g. phenyl lithium). The reaction with the organometallic compound is generally carried out in an inert organic solvent.

The ketones of general formula (11) may be prepared by known processes, for example those 20 disclosed in UK Specification No. 1,366,133. For example, a substituted isatin of general formula (111)

R1 25 X N 0 R2 LH2. L Y CN 30 where W, R2 and A are defined above and X is a protected oxo group, such as a ketalized oxo group (e.g. ethyleneketal, propyleneketal or dimethoxy) may be hydrogenated e.g. in presence of a hydrogenation catalyst to give an amine of general formula (R) 35 R1 X R2j 1 "N 0 OV) 40 1 CH CCH2NH2 2W 45 where W, R2, A and X have the meanings given above.. The amine may be cyclodehydrated to a compound of general formula (V) R' X 50 N N (V) R2:: A 55 where W, R2, A and X have the meanings given above. The amine may be cyclodehydrated by, for example, heating in an inert organic solvent. In general, the substituted isatin of general formula (111) may be hydrogenated to the compound of formula (V) without isolation of the intermediate amine of general formula (IV). 60 The compound of formula (V) can be converted to the ketone of formula (11) by deprotecting the protected keto group, e.g. by hydrolysis of a ketalised oxo group.

The starting substituted isatin of formula (111) may be prepared by, for example, condensing a 3-halopropanenitrile of general formula (V1) 3 GB2187739A 3 NC CH2Hal (VI) (A) 5 where A has the meaning given above and Hal is chloro or bromo with a compound of general formula (VII) 10 R1 Y (V1 D R2:: N 0 15 where R' and R2 have the meanings given above and Y is oxo or protected oxo and, where Y is oxo, protecting the oxe, group in the resulting product. The condensation may be carried out in 20 presence of a base, e.g. potassium tertiary butoxide or sodium or potassium hydride in a solvent such as dimethyisulphoxide, dimethylfuranamide or N-methyl-2-pyrroliclone. The 3-halopropan enitriles can be prepared by known methods or by condensing a corresponding 2-substituted-e thanenitrile with bromochloromethane, dibromomethane or dichloromethane in presence of a non nucleophilic strong base such as lithium diisopropylamide. 25 An alternative method of preparing the compounds of the invention comprises cyclodehydrat ing an indole derivative of the general formula (VIII) R1 R 30 OH (V1 1 D N to R 2 4 CH2-C7C142NH2 35 wherein R, W, R2 and A have the meanings given above.

The compound of general formula (VIII) in its free base form or as an acid addition salt thereof may be cyclodehydrated to the compound of general formula (1) by heating it, for example, in an 40 inert organic solvent. The solvent can be, e.g. xylene or o- clichlorobenzene, and the heating can be carried out at the reflux temperature. It is preferred to carry out the cyclisation in the presence of a catalytic amount of an acid catalyst, e.g. p-toluene sulphonic acid or benzene sulphonic acid.

The indole compounds of general formula (VIII) and their acid addition salts can be prepared 45 by the hydrogenation of a nitrile compound of general formula (IX) R1 R OH OX) 50 R2 CH C CN A 55 wherein R, W, R2 and A have the meanings given above.

The hydrogenation may be carried out in the presence of a hydrogenation catalyst. Elevated temperatures and pressure may be employed. However, if the compound of formula (IX) contains any substituents R' and R2, such as halogen atoms, which are liable to be effected by drastic 60 hydrogenation conditions, the hydrogenation should be carried out under mild conditions. For example, a nickel catalyst [such as Raney nickel, e.g. Raney nickel W2 (Org.Syn.Coll.Vol.i 11,1955),181)1 can be employed, e.g. in presence of ammonia and ethanol, and the hydrogena tion carried out at relatively low pressures (e.g. about 40 p.s.i.) and temperatures (e.g. about 40' to WC). 65 4 GB2187739A 4 In general, the intermediate of formula (V111) is not isolated from the reaction medium and hydrogenation of the nitrile or formula (R) gives the compounds of the invention directly.

The nitrile compounds of general formula (R) can be prepared by condensing an oxindole of general formula (X) 5 R1 R OH N 0 10 R2 H wherein R, R' and R2 have the meanings given above with a chloropropanenitrile of general formula (V1) given above in the presence of a base. 15 A further process for preparing the compounds of the invention comprises cyclising a compound of general formula (Xl) R1 R 20 OH (M) N 2: WC112.(C 1 CH2Z R A 25 or an acid addition salt thereof, wherein R, R', R2 and A are as defined above and Z is a halogen atom, preferably chlorine. The process may be carried out as described in UK Specifica tion No. 1,450,543.

In yet another process for preparing the compounds of the invention in indole of general 30 formula (X11) R R' OH 35 (xl 1) R2 40 where R, R' and R2 have the meanings given above, is condensed with a dihaloalkane of general formula Hal.CH 2 C.CH 2 ' Hal 45 ( _) -11 A where A has the meaning given above and Hal and Hall are each chlorine, bromine or iodine. 50 The process may be carried out as described in UK Specification 1,427,066.

If in the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt.

Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a 55 suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compound.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric tartaric, fumaric, maleic, citric, acetic, formic, methane-sulphonic and p-toluenesulphonic acids. 60 The compounds of the invention possess at least one asymmetric carbon atom and hence can exist in various stereochemical forms. The stereochemical forms can be separated or isolated by standard procedures. For example resolution of a racemic final product or intermediate may be carried out by known procedures so as to give the product as an optically active enantiomorph.

The compounds of the present invention possess pharmacological activity. For example, the 65 GB2187739A 5 compounds in general possess hypoglycaemic activity and hence are of value in the treatment of diabetes. The compounds of the invention are tested for hypoglycaemic activity by a standard procedure in which the compounds are administered to rats and the blood glucose concentration is determined prior to administration and at various times after dosage. When 2',3',4',10-tet rahydro-10-hydroxy-10-phenyispiro[cyclohexane-1,3-pyrimido[1,2-alindole], a representative 5 compound of the invention, was tested by this procedure at 100mg/kg p.o. the blood glucose concentration was found to be 76% and 65% of the control animals (i.e. rats administered vehicle alone) at 2 hours and 4 hours respectively after administration.

The invention further provides a compound of formula (1) or a pharmaceutically acceptable acid addition salt for use as a hypoglycaemic in a mammal. 10 The invention also provides a pharmaceutical composition comprising a compound of general formula (1) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid. 15 Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with 20 the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl 25 cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion ex change resins.

The term -composition- is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets 30 are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other 35 suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweet ners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, sta bilisers or osmo-regulators. Suitable examples of liquid carriers for oral and parental administra tion include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohdric alcohols and polyhydric 40 alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parental administration the carrier can also be an oily ester such a ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parental administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized 45 by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.

In such form the composition is sub-divided in unit dose containing appropriate quantities of the 50 active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in unit dose of composition may be varied or adjusted frm 0.5mg or less to1750mg or more, according to the particular 55 need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention:

EXAMPLE 1 60

3',4-Dihydro spiro[cyclohexane-1,3-pyrimido(1,2-a)indol-10'(2H)-oneJ (a) 1-[1-[2(3H)-oxospiro(1,3-dioxotane)-2,3-indolylllmethy1 cyclohexane carbonitrile Spiro[1,3-dioxolane)-2,3'-indol-2'(3'M-oneJ (1.91g) was added portionwise to a stirred solu tion of potassium t-butoxide (1.349) in dry DMSO (20mi) under nitrogen. After 10 min, 1-chloromethylcyclohexanecarbonitrile (1.969) was added dropwise and the solution heated at 130' for 65 6 GB2187739A 6 24h. The solution was cooled, poured into ice-water (100mi), and stirred vigorously for 18h. The solid was separated, dried, and recrystallised from propan-2-ol to give the title compound (1.49), m.p. 130-130.5'.

Found: C, 69.0; H, 63; N, 8.8% C,H20N,0, requires: C, 69.2; H, 6.45; N, 9.0% 5 (b) 2',Y,4', 10-Tetrahydro(1,3-doxolane)-2-spiro- 10-pyrimido[1,2alindole-31--spirocyclohex- ane Ethanolic ammonia (100mi) and one spatula Raney nickel were added to a solution of 1-[1'-[2'(3'H)-oxospiro(1,3-dioxolane)2,3-indolylllmethylcyclohexane carbonitrile(l.259) in etha no[ (1 00mi). The mixture was hydrogenated at 5Wc at 4-5 atm. (about 3.9 x 105-4.9 x 1 05Pa) 10 for 2 hours. After cooling to room temperature it was filtered through Kieselguhr, and the solution was concentrated in vacuo to give the crude product (1.23g). The product was re dissolved in ether(60mi), filtered through Kieselguhr, and concentrated in vacuo. The product was recrystallised from hexane to give a first crop of the title compound as the free base (0.36g) m.p. 71'-107'C. 15 Found: C, 72.30; H, 7.55; N, 9.56% c18H22N202 requires C, 72.45; H, 7.45; N, 9.40%.

Further material was obtained by chromatography of the mother liquors on Si02 eluting with EtOAc.

(c) 3'4-Dihydrospiro[cyclohexane-1,3-pyrimido[1,2-alindol-10'(2H)-onej 20 A soiution of the compound of Example 1(b) (4.4g) in hexane (3m]) was added dropwise to concentrated H2S01 (25m1) at 30'. The solution was kept at room temperature and after 1 hour poured onto ice. The solution was basified with concentrated aqueous ammonia and at pH7 a brown precipitate formed. The solution was decanted and further basified with concentrated aqueous ammonia to pH9. The precipitate was filtered, washed with aqueous ammonia and dried 25 in vacuo. A solution of the solid in EtOAc was passed down a silica column and the solvent evaporated to give crystals of the title compound (1.49), m.p. 138-143'.

Found: C, 74.5; H, 7.3; N, 10.8% Cl,H,,N,OIH,0 requires: C, 75.6; H, 7. 1; N, 11.0% 4 30 EXAMPLE 2

2',Y,4', 10-Tetrahydro-10'-hydroxy-10-phenylspiro[cyclohexane-1,3pyrimido(1,2-a)i ndolej Bromobenzene (10 drops; from 2.69) was added dropwise to stirred magnesium turnings (0.389) in diethyl ether (10mi) under nitrogen. When the reaction commenced a solution of the remaining bromobenzene in diethyl ether (3mi) was added dropwise to maintain reflux. The mixture was 35 heated under reflux until little magnesium remained, then cooled and a solution of X,4'-dihydros piro-[cyclohexane-1,3'-pyrimido(1,2-a)indol-10(2H)-onel(l.49) in dichloroethane (20mi) added dropwise. After 1 hour the reaction mixture was pourdi onto water (100mi), extracted with chloroform (2 x 1 00mi), the chloroform extracts combined, dried (M9S04) and evaporated under reduced pressure to give a solid. Trituration of the solid with diethyl ether, followed by reerystal- 40 lisation from ethyl acetate gave the title compound (0.859). Ethereal hydrogen chloride was added to a solution of the title compound in propan-2-ol, giving the title compound in the form of the hydrochloride as a precipitate of white crystals (0.559), m.p. 273274'(dec).

Found: C, 71.3; H, 7.1; N, 7.5% C,,H,^OMC1 requires: C, 71.6; H, 6.8; N, 7.6% 45 EXAMPLE 3

2',Y,4', 10'_Tetrahydro- 10-hydroxy- 10-phenyispiro[cycloheptane- 1,3pyrimido(1,2-a)indolel (a) 1-[1-(3-Hydroxy-2(3H)-oxo-3phenylindolyl)methyllcycloheptanecarbonitrile 3-Hydroxy-3-phenylindol-2(1 Fn one (9.0g), was added portionwise to a stirred solution of potassium tert-butoxide (4.9g) in dimethyl sulphoxide (100mi) under an atmosphere of nitrogen.

After 10 min, 1-chloromethylcycloheptanecarbonitrile (6.99) was added rapidly. The solution was heated to 130' for 18h, cooled, and poured into water (500mi). The aqueous mixture was extracted with diethyl ether (3x200mi; the organic extracts dried (M9SOJ and evaporated in vacuo to ca. half volume to give a white precipitate of the title compound (1.94g). Further 55 washing of the drying agent with chloroform and evaporation in vacuo gave more of the title compound (1.89). A small sample was recrystallised frm propan-2-ol; m.p. 202.5-203.5'.

Found: C, 76.1; H, 6.8; N, 7.5% C231-124N402,14H20 requires: C, 75.7; H, 6.8; N, 7.7% (b) 2,3A, 10-Tetrahydro- 10'1-hydroxy10-phenyl-spiro[cycloheptane- 1,3- pyrimido(1,2-a)in- 60 dole] A mixture of the compound of Example 3(a) (4.09) and Raney nickel (1 small spoonful) in 50% saturated ethanolic ammonia (200mi) was heated at 50' under an hydrogen atmosphere (approx.

psi, about 3 x 105Pa) for 7 hours. The mixture was cooled, filtered through Kieselguhr, and 7 GB 2 187 739A 7 the filtrate evaporated under reduced pressure to give a gum (3.6g). Trituration of the gum with EtOAc gave a solid (2.439). The filtrate was evaporated under reduced pressure to give an oil which was triturated with EtOAc to give a solid (0.439). The solid from the first trituration (2.439) was chromatographed (basic A1203; CHC13) and the gum triturated with EtOAc to give a solid (1.459). A solution of the combined solids (1.88g) in MeOH was treated with etheral 5 hydrogen chloride and evaporated under reduced pressure to give an oil which was triturated with Et20 to give the title compound as the hydrochloride (1.939), m.p. 267' (dec).

Found: C, 72.2; H, 6.9; N, 7.5% C22H2,N2O.HCI requires: C, 71.8; H, 6.8; N, 7.3% 10 EXAMPLE 4

2',3'4' 10'-Tetrahydro- 10butyl- 101--hydroxyspiro[cyclohexane- 1,3'pyrimido(1,2-a)indolel (a) 3-butyi-3-hydroxyindole-2(3H)-one (3.4g) was added portionwise to a solution of potas sium t-butoxide (1.99) in dry, deoxygenated dimethyl sulphoxide (30mi). To this was added 1-chloromethylcyclohexanecarbonitrile (3.29). The mixture was heated to 130' for four days. and 15 then poured onto ice. Extraction with ethyl acetate, washing with water, drying (MgSOJ and evaporation in vacuo gave an impure oil which was purified by chromatography on silica eluting with ether. Crystallisation from ethyl acetate/hexane and recrystallisation from cyclohexane gave 1-[1-(3-butyl-3-hydroxy-2(3H)-oxo-indoiyl)methyi]cyclohexanecarbonitrile as crystals (5.4g) m.p. 124-5'. 20 (b) The crystals from Example 4(a) were hydrogenated in saturated ethanolic ammonia (200mi) with Raney nickel under a hydrogen atmosphere (40p.s.i.; about 2.7 X 1 01Pa). After removal of the catalyst, evaporation in vacuo and trituration with ethyl acetate gave the title compound as colourless crystals (2.0g) m.p. 192-5'.

Found: C, 67.9; H, 93; N, 7.2% 25 C2,H2,N2O.HCI.2/3C3H,0 requires: C, 67.9; H, 8.9; N, 7.2%.

EXAMPLE 5

2',3',4', 10'-Tetrahydro-10hydroxy-10-phenyispiro[cyclopentane-1,3pyrimido(1,2-a)indolej (a) 3-Hydroxy-3-phenylindol-2(3H)-one (11.509) was added portionwise to a stirred solution 30 of potassium tert-butoxide (6.309) in dry, deoxygenated dimethyisulphoxide (125m1) under nitro gen. After 0.5 hour 1-chloromethylcyclopentanecarbonitrile (7.189) was added and the solution heated at 120' for 17 hours, cooled to room temperature, and poured into water (500mi). The mixture was extracted with ethylacetate (3x250mi). The extracts were washed with water (100mi), dried (M9SOJ and evaporated under reduced pressure to give a gum which was 35 triturated with diethyl ether to give 1-[1-(3-Hydroxy-2(3H)-oxo-3phenylindoiyi)methyllcyclo- pentane carbonitrile as a crystalline solid (9.49g), m.p. 155-157'.

Found: C, 75.6; H, 6.25; N, 8.2%.

C21H2ON202 requires: C, 75.9; H, 6.1; N, 8.4%.

(b) A mixture of 1-[1-(3-hydroxy-2(3H)-oxo-3-phenylindolyl)methyllcyclopentanecarbonitrile 40 (8.39) and Raney nickel (2 spatula spoons) in 50% saturated ethanolic ammonia (200mi) was heated at 50' under a hydrogen atmosphere (50p.s.i.; about 3 x 105Pa) for 18 hours. The mixture was cooled, filtered through Keiselguhr, and evaporated under reduced pressure to give a solid which was purified by trituration with ethylacetate, chromatography (basic A1201; chloro- form), and trituration with ethyl acetate to give the title compound (5. 9g). 45 A solution of the title compound in methanol was treated with ethereal hydrogen chloride and evaporated under reduced pressure to give a solid which was washed with diethyl ether and air dried to give the title compound as the hydrochloride (6.2g), m.p. 263- 264' (dec).

Found: C, 703; H, 6.7; N, 7.9% C2,H2,N2O.HCI requires: C, 71.1; H, 6.5; N, 7.9%. 50 EXAMPLE 6

2',3A', 10-Tetrahydro- 10-hydroxy- 10-phenyl-spiro(piperidine-4,3pyrimido[ 1,2-alindole) (a) 3-Hydroxy-3-phenylindol-2(3M-one (5.059) was added portionwise to a stirred solution of potassium tertbutoxide (2.77g) in dry deoxygenated dimethyisulphoxide (60mi) at room 55 temperature under nitrogen. After 0.5 hour tertbutyi-4-chloromethy]-4- cyano-piperidine-l-carboxylate (5.79) was added portionwise and the solution heated at 120' for 17 hours, cooled to room temperature, poured into water (250mi), and extracted with ethylacetate (3x250mi).

The organic phase was dried (M9SOJ and evaporated under reduced pressure to give an oil.

Purification by chromatography [SiO,; methanol-chloroform (2:98)l gave a solid which was tritu- 60 rated with hot cyclohexane to give 1,1-dimethylethyi-4-[1-(3-hydroxy-2(3M- oxo-3-phenylindoyi)methyll-4-cyanopiperidine-l-carboxylate (5.5g), m.p. 197.5-198' (dec) (from ethyl ace tate).

Found: C, 70.0; H, 6.6; N, 9.75%.

C2.HA30, requires: C, 69.8; H, 6.5; N, 9.4%. 65 8 GB2187739A 8 (b) A mixture of 1,1-dimethylethyi-4-[1-(3-hydroxy-2(3M-oxo-3phenylindolyi)methyll-4-cy- anopiperidine-l-carboxylate (4.8g) and Raney nickel (1 spatula spoon) in 50% saturated etha nolic ammonia (200mi) was heated to 50' under a hydrogen atmosphere (50p. s.i.; about 3 x 105Pa) for 17 hours. The mixture was cooled, filtered through Kieseffluhr, and the solution evaporated under reduced pressure. The residue was purified by chromatography (basic A1103; 5 chloroform) to give a solid which was triturated with ethyl acetate to give 2',3',4',10'-tetrahy dro-10-hydroxy-10'-phenyi-l-(1,1-dimethyi)ethoxycarbonyispiro(piperidine4, 3'-pyrimi- do[1,2-a]indole) (2.8g), m.p. 209-210' (dec).

Found: C, 72.2; H, 7.5; N, 9.3% C,^,N30, requires: C, 72.0; H, 7.2; N, 9.7%. 10 (c) A suspension of the product of example 6(b) (2.8g) in ethanolic hydrogen chloride (50mi) was warmed to effect solution. After 10 min, the solvent was evaporated in vacuo and the residual gum dissolved in a small quantity of methanol. Toluene was added and the solvents evaporated in vacuo to leave a white solid (2.89). Recrystallisation from ethanol gave the title compound dihydrochloride (2.4g) m.p. > 300' (dec). 15 Found: C, 58.9; H, 6.7; N, 9.6.

C,H,^0.2HCL1.25H20 requires: C, 58.9; H, 6.4; N, 9.8%.

EXAMPLE 7 (-) and (+)-2,3,4', 10-Tetrahydro- 10-hydroxy- 10'phenyispiro[cyclohexane- 1,3-pyrimi- 20 do(1,2-a)indolel (-)-Di-p-toluoy]-L-tartaric acid (40.44g, 100.Ommol) was added rapidly, portionwise to a stirred suspension of the compound of Example 2 (33.25g) in acetone (1L). The clear solution was stirred at room temperature for 15h and the crystalline precipitate was filtered off, washed with acetone (2x50mi) and dried to give (-)-2',3',4',10'-tetrahydro-10'hydroxy-10'-phenyispi- 25 ro[cyclohexa ne- 1,3'-pyrimido(l, 2-a) in dole] as the (-)-di-p- toluoyltartrate (31.64g) m.p. 149' dec [ald-93'(ca 0.2%in ROH). The combined filtrate and washings were concentrated in vacuo to give a pale brown crystalline residue, which was converted to the free base.

(+)-di-p-toluoyl-D-tartaric acid (23.059), 570mmol) was added portionwise and rapidly to a stirred suspension of the free base enriched in the (+) enantiomer, in acetone (570mi). The 30 solution was stirred at room temperature for 15h and the crystalline precipitate was filtered off, washed with acetone (2x50mi) and dried to give (+)-2',3',4',10'tetrahydro-10'-hydroxy-10'phenyispiro[cyclohexane-1,3'-pyrimido-(1,2-a)indolej as the (+)-di-ptoluoyl tartrate (33.609) m.p. 149'C dec., [a],,+95' (ca 0.2% in ROH).

35 Preparation of the hydrochlorides The hydrochloride of each enantiomer was prepared by conversion of each di-p-toluoyltartrate to the free base. The resolved free bases were each suspended in absolute ethanol (200mi), and the suspension was acidified with ethereal hydrogen chloride. The solution of each hydrochloride was concentrated in vacuo and the crystalline product was filtered off, washed with ethanol 40 (2x20mi) and dried under high vacuum at Wc for 15h to give, in two crops, the hydrochloride of the (-)-enantiomer (1 1.57g), m.p. 27 VC dec., [cú],-225' (ca 0.2% in CI-ICI,) (Found: C, 71.30; H, 6.85; N, 7.40; C22H24N2OMC1 requires: C, 71.65; H, 6.85; N, 7.60%), and the hydrochloride of the (+)-enan- tiomer (13.519), m.p. 269'C dec., [al,+220' (ca 0.2% in CHClj 45 Found: C, 71.70; H, 6.75; N, 7.45; C22H24N2OMC1 requires: C, 71.65; H, 6.85; N, 7.60%) A second quantity (about 10%) of each enantiomer was obtained by reworking the mother liquors from the initial resolutions. 50

Claims (22)

1. A pyrimidoindole of the general formula (1) R1 OH 55 N N R2 1A 60 or a pharmaceuticaliy acceptable acid addition salt thereof wherein R represents lower alkyl, a mono- or bi-cyclic aryl radical or a group of formula R30-13-[where R30 is (lower)aikoxy, aryi(lower)alkoxy or hydroxy and B is lower alkylene chain optionally containing one double or triple 9 GB2187739A 9 bond], R' and R2 which may be the same or different each represent hydrogen, hydroxyl, lower alkyl, lower alkoxy, halo(lower)alkyi, halogen, amino or mono- or di(lower)aikylamino and A, together with the carbon atom to which it is attached, represents 5, 6 or 7 membered saturated carbocyclic or heterocyclic ring.

2. A compound as claimed in claim 1 wherein R is lower alkyl or a mono- or bi- cyclic aryl 5 radical.

3. A compound as claimed in claim 1 wherein R is phenyl or halophenyl.

4. A compound as claimed in any one of claims 1 to 3 wherein A is -(CHA,where n is 4, or 6.

5. 2',3',4',10'-Tetrahydro-10'-hydroxy-10-phenyi-spiro[cyclohexane-1,3pyrimi do(1,2-a)in- 10 dole] or a pharmaceutically acceptable acid addition salt thereof.

6. 2',3',4',10-Tetrahydro-10'-hydroxy-10'--phenyi-spiro[cycloheptane-1,3'pyri mido(1,2-a)indole] or a pharmaceutically acceptable acid addition salt thereof.

7. 2',3',4',10'-Tetrahydro-10-butyi-10'-hydroxyspiro[cyclohexane-1,3'pyrimido (l,2-a)indo- lel or a pharmaceutically acceptable acid addition salt thereof. 15

8. 2',3',4',10'-Tetrahydro-10'-hydroxy-10'-phenyi-spiro[cyclopentane-1,3pyrim ido(1,2-a)indolel or a pharmaceutically acceptable acid addition salt thereof.

9. 2',3',4',10-Tetrahydro-10'-hydroxy-10'-phenyl-spiro(piperidine-4,3'pyrimid o[1,2-a]indole) or a pharmaceutically acceptable acid addition salt thereof.

10. (-)-2',3',4',10'-Tetrahydro-10-hydroxy-10-phenyi-spiro[cyclohexane-1, 3'-py rimi- 20 do(1,2-a)indolel or a pharmaceutically acceptable acid addition salt thereof.

11. (+)-2',3',4',10'-Tetrahydro-10'-hydroxy-10'-phenyl-spiro[cyclohexane1,3-py rimi- do(1,2-a)indole] or a pharmaceutically acceptable acid addition salt thereof.

12. A process for preparing a compound claimed in claim 1 which comprises reacting a ketone of general formula (11) 25 0 R1 N 1 (11) 30 N A R2:

35 where W, R2 and A are as defined in claim 1, with an organometallic compound containing a R4 radical, where R4 represents lower alkyl, a monoor bi-cyclic aryl radical or a group of formula W-0-13- [where R3' is (lower)alkoxy, aryl(lower)alkoxy or protected hydroxy and B is as defined in claim 1] and, where R 31 -0- is a protected hydroxy group, removing the protecting group to give a product in which R3 -0- is hydroxy and, if desired, converting a resulting base into a 40 pharmaceutically acceptable acid addition salt thereof and/or resolving a racemic product.

13. A process as claimed in claim 12 wherein the organometallic compound has the formula R4M9Y or R4Li (where R 4 is as defined in claim 12 and Y is halogen).

14. A process for preparing a compound claimed in claim 1 which comprises cyclodehydrat- ing an indole derivative of general formula (V111) 45 R1 R tNo OH (V1 11) 50 R2 C1-12( C CH2NH2 A 55 wherein R, R', R2 and A have the meanings given in claim 1 and, if desired, converting a resulting base into a pharmaceutically acceptable acid addition salt thereof and/or resolving a racemic product.

15. A process for preparing a compound claimed in claim 1 which comprises hydrogenating a nitrile of general formula (IX) 60 GB2187739A 10 R' R 1 ON R2 0 CH c CN A 10 wherein R, W, R2 and A have the meanings given in claim 1 and, if desired, converting a resulting base into a pharmaceutically acceptable acid addition salt thereof and/or resolving a racemic product.

16. A process for preparing a compound claimed in claim 1 which comprises cyclising a compound of general formula (Xl) 15 R' R ON (Xl) 20 kN MCH2 C, CH2Z R2 A or an acid addition salt therein, wherein R, R', R2 and A are as defined in claim 1 and Z is a 25 halogen atom and, if desired, converting a resulting base into a pharmaceutically acceptable acid addition salt thereof and/or resolving a racemic product.

17. A process for preparing a compound claimed in claim 1 which comprises condensing an indole of general formula (X11) 30 R R1 ON R2 IN NH2 (Xl 1) 35 where R, R' and R2 are as defined in claim 1 with a dihaloalkane of general formula 40 Hal.CH 2 C.CH 2 Hal' (A) 45 where A has the meaning given in claim 1 and Hal and Hal' are each chlorine, bromine or iodine and, if desired, converting a resulting base into a pharmaceutically acceptable acid addition salt thereof and/or resolving a racemic product.

18. A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to any one of Examples 2 to 7. 50

19. A compound as claimed in claim 1 whenever prepared by the process claimed in any one of claims 12 to 18.

20. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 11 and 19 in association with a pharmaceutical ly acceptable carrier.

21. A compound as claimed in any one of claims 1 to 11 and 19 for use as a pharmaceuti- 55 cal.

22. A compound as claimed in any one of claims 1 to 11 and 19 for use as a hypoglycae mic.

Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685, 1987.

Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.