GB2187738A - Pyrimidoindoles - Google Patents

Description

GB 187 738 A 1

SPECIFICATION

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

The novel compounds of the present invention are pyrimidoindoles of the general formula (1) R 1 RO- OH N 10 R 2 R 3 N R 4 15 and their pharmaceutical ly acceptable acid addition salts. In theformula, A represents a lower alkylene chain optionally containing one double ortriple bond, RO represents (lower)aikoxy, aryl(lower)alkoxy, hydroxy or protected hydroxy, R' and R 2 which may be the same or different each represent hydrogen, hydroxyl, lower alkyl, lower alkoxy, halo(lower)alkyl, halogen, amino or mono- or diflower)alkylamino and R 3 and R 4 each independently represent hydrogen or loweralkyl. 20 Theterm "lower" as used herein meansthatthe radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. For example, a lower alkyl group may be methyl, ethyl propyl or butyl and a lower alkoxy may be methoxy, ethoxy, propoxy, or butoxy.

When RO is an aryl(lower)alkoxy group, the aryl radical is preferably a phenyl groupwhich mayoptionally be substituted by,for example, the substituents defined above in respect of R' and R 2; for example RO may 25 represent an optionally substituted benzyloxy group. When RO is a protected hydroxy group, the group may be, for example, tetrahydropyranyloxy ortrialkylsiloxy (eg trimethylsiloxy); benzyloxy may also be used as a protecting group. Preferably RO is (lower)alkoxy.

A may be a straight or branched lower alkylene chain optionally containing a double ortriple bond.

PreferablyA is a branched orstraight chain saturated alkylene group containing 3to 5 carbon atoms. 30 Examples of suitable RO-A- groups include 3- or4- methoxybuty], 4- ethoxybutyl, 3-methoxy-2-methyl pro pyl and 3-hyd roxy-1 -pro pynyi.

Preferred examples of R' and R 2 residues includes hydrogen, lower alkyl (e.g. methyl, ethyl propyl and butyl), loweralkoxy (e.g. methoxy, ethoxy, propoxy and butoxy), halo(lower)alkyl (e.g. trifluoromethyl) and halogen (e.g. chlorine and bromine). 35 Preferably both R' and R 4 represent lower alkyl (e.g. methyl).

Examples of preferred compounds o f the invention are:

3,3-dimethyM 0-hydroxy-1 0-(4-methoxybutyi)-2,3,4,1 0tetrahydropyrimido[1,2-alindole 2,3,4,1 0-tetrahydro-l 0-hydroxy-3,3-dimethyl-l 0-(3-methoxy-2methylpropyl)pyrimido[1,2-alindole 2,3,4,1 0-tetrahydro-l 0-hydroxy-1 0-Q-meth oxybutyl)-3,3-d i methyl pyri m ido [ 1,2-a in do 1 e 40 8-chloro-l 0-hydroxy-1 0-(4-methoxybutyl)-2,3,4,1 0-tetrahydropyrimido[1, 2-alindole 10-(4-benzyloxybutyl)-2,3,4,1 0-tetrahydro-10-hydroxy-3,3dimethylpyrimido[1,2-alindole 10-(4-ethoxybutyi)-2,3,4,1 0-tetrahydro-l 0-hydroxy-3,3-di methyl pyrim ido[1,2-aindole 2,3,4,1 0-tetrahydro-l 0-hydroxy-1 0-(3-methoxybutyl)-pyrimido[1,2- alindole 1 0-hydroxy-1 0-(3-hydroxy-1 -propynyi)-2,3,4,1 0-tetrahydropyrimido[1,2- a]indole 45 and pharmaceutical ly acceptable salts thereof.

The compounds of the invention in which RO represents (lower)aikoxy, aryl (lower) alkoxy or protected hydroxy may be prepared by a process in which a ketone of general formula (11) 53 R 0 50 -N 3 N 55 2 4 R R where R', R 2, R'and R 4 havethe meanings given above is reactedwith an organometallic compound 60 containing a RO-A-residue where A is as defined above and RO is (lower)alkoxy, aryl(lower)alkoxyor protected hydroxy. The organometallic compound is preferably a lithium compound of formula RO-A.Li ora Grignard reagentof formula RO-AMgYwhereA is as defined above, RO represents (lower)alkoxy,ary] (lower)alkoxy or protected hydroxy and Yis halogen. The reaction with the organometallic compound may be carried out in an inert organic solvent. 65 2 GB 187 738 A 2 The ketones of general formula (11) are known in the literature or may be prepared by known processes,for examplethose disclosed in UKSpecification No. 1,366,133.

An alternative method of preparing the compounds of the invention in which RO represents (lower)alkoxy, aryl(iower)aikoxy, or protected hydroxy and A is a saturated lower alkylene chain comprises cyclodehydrating an indole derivative of the general formula (111) 5 R A-OR OH 10 N 0 R 2 1 3 4 Ch CR R CH-NH 2 2 2 15 wherein W, R 2, R'and R 4 havethe meanings given above,A is a saturated lower alkylene chain and RO is (lower)alkoxy, aryi(lower)alkoxy or protected hydroxy.

The compound of general formula (111) in itsfree base form or as an acid addition saitthereof may be cyclodehydrated to the compound of general formula (1) by heating itjor example, in an inertorganic solvent. It is preferred to carry out the cyclisation in the presence of a catalytic amount of an acid catalyst, e.g. 20 p-toluene sulphonic acid or benzene sulphonic acid.

The indole compounds of general formula (111) and their acid addition salts can be prepared bythe hydrogenation of a nitrile compound of general formula (IV) R A-OR 25 - OH 2,' N ^0 IV) 30 1 ' 3 4 CH 2 CR R CN wherein A, W, R 2, R', R 4 and R'0 have the meanings given above in connection with formula (111).

The hydrogenation may be carried out in the presence of a hydrogenation catalyst. Elevated temperatures 35 and pressures may be employed. However, if the compound of formula (IV) contains any substituents R' and R2 such as halogen atoms, which are liable to be effected by drastic 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. Syri. Coil. Vol. Ill, 1955,181)l can be employed, e.g. in presence of ammonia and ethanol, and the hydrogenation carried out at relatively low pressures and temperatures. 40 The compounds of general formula (111) need not be isolated from the hydrogenation reaction medium and hence the compounds of formula (1) may be prepared by hydrogenation of the nitrUe compounds of general formula OV).

The nitrile compounds of general formula ([V) can be prepared from oxindoles of general formula (V) R A-OR 45 -OH (V) 50 N ",,L 0 R 2 H wherein W, R 2 and RO have the meanings given above in connection with formula Ill. For example, a 55 compound of formula (]V) in which R'and R 4 are hydrogen can be prepared by Michael addition of the oxindole to acrylonitrile. For example, the oxindole can be reacted with acrylonitrile in an inert solvent, preferably in presence of a basic catalyst. A particularly suitable basic catalyst is benzyitrimethylammonium hydroxide (Triton B) used as a 40% solution in water. A compound of formula (]V) in which R 3 andlor R 4 are 60 independently lower alkyl or in which R'and R 4together with the carbon atom to which they are attached represent cycloalkyl can be prepared by reacting the oxindole with an appropriately 2-substituted-3-halopropionitrile in the presence of a base.

The oxindoles of general formula (V) are known compounds orthey may be prepared by known methods.

Forexample an isatin of the general formula (Vi) 65 3 GB 187 738 A 3 R 0 5 R 2 N 0 (VI) H wherein R' and R 2 havethe meanings given above may be reacted with a Grignard reagent of generalformula 10 (V11) ROAM913r (V11) or a lithium compound of formula ROA.Li wherein A and RO have the meaning given above in connection 15 with formula (111).

The indole derivatives of general formula (111) can be prepared by an alternative method which comprises removing the protecting group from a corresponding compound of formula (111) in which the amino group is protected, e.g. hydrolysing a phthalimide derivative of general formula (VIII) R -OR 20 OH A 1 2 N "_LO 25 1 1 --- ' N 1.5 - kCH 2)3_ 1 (VIII 30 0 wherein R', R 2 A and OR are as hereinbefore defined with reference toformula (111).

The hydrolysis of the phthalimide derivative of general formula (V111) can be carried out in the presence of, 35 e.g. acid, base or hydrazine as in the Gabriel synthesis.

The compound of formula (111) in which the amino group is protected may be prepared by condensing an oxindole of general formula (V) abovewith a 1 -protected amino-3-halo-propane. Forexamplethe phthalimide derivative of general formula (VIII) may be prepared by condensation of an oxindole of general formula (V) as given above, with N-(3-halopropyl)pInthalimide, e.g. N-(3- bromopropyi)phthalimide. The 40 condensation can be effected in presence of a basic catalyst such as sodium hydride in, for example, an organic solvent e.g. climethylformamide ortoluene.

The compounds of the invention in which RO represents hydroxy may be prepared by de-etherification of the compounds of formula (1) in which RO is (lower)alkoxy or aryl(lower)alkoxy or removing the protecting group, by methods known in the art,from a compound of formula 1 in which RO is a protected hydroxy group. 45 In a preferred method, a compound of formula (1) in which RO is benzyloxy is subjected to hydrogenolysis in presence of a hydrogenation catalyst.

If in the processes described abovethe 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 53 process is a free base, an acid addition salt, particularly a pharmaceutical ly acceptable acid addition salt may 50 be obtained by dissolving thefree base in a suitable organic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from base compound.

Examples of acid addition salts are thoseformed from inorganic and organic acids, such assulphuric, hydrochloric hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids. 55 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 bystandard procedures. For example resolution of a racemicfinal product or intermediate may be carried out by known procedure so asto give the product as an optically active enantiomorph.

The compounds of the present invention in which RO represents (lower)alkoxy, aryl(lower)alkoxy and 60 hydroxy possess pharmacological activity. For example, the 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 priorto administration and at various times after dosage. When 2,3,4,10-tetrahydro-10-hydroxy-10-(3-methoxybutyi)-3,3-dimethylpyrimido[1, 2-a]indole,a representative 65 4 GB 187 738 A 4 compound of the invention, was tested by this procedure at 20,50 and 100 mg/kg p.o. the plasma glucose concentration was found to be respectively 79%,73% and 54% of control animals (i.e. rats administered vehicle alone) at 2 hours after administration.

The invention further provides a compound of formula (1) in which RO represents (lower) alkoxy, aryl(lower)alkoxy or hydroxy or a pharmaceutically acceptable acid addition saitfor use as a hypoglycaemic 5 in a mammal.

The invention also provides a pharmaceutical composition comprising a compound of general formula (1) or a pharmaceutical ly acceptable acid addition saitthereof in association with a pharmaceutical ly acceptable carrier. Any suitable carrier known in the art can be used to preparethe pharmaceutical composition. In such a composition,the carrier is generally a solid or liquid or a mixture of a solid and a liquid. 10 Solid form compositions include powders, granules tablets, capsules (e.g. hard and soft gelatine capsules) suppositories and pessaries. A solid carriercan be for example, one or more substances which may also act asfiavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides binders ortablet disintegrating agents; it can also be an encapsulating material. In powdersthe carrier is afinely divided solid which is in admixturewith the finely divided active ingredient. In tabletsthe active ingredient is 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 0.03to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers includeJor example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, low melting waxes and ion exchange resins. 20 Theterm "compositon" is intended to include the formulation of an active ingredientwith encapsulating material as carrierto give a capsule in which the active ingredient (with orwithout other carriers) is surrounded bythe carrier, which isthus in association with it. Similarly cachets are included.

Liquid form compositions include, forexample, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredientJor example, can be dissolved orsuspended in a 25 pharmaceutical ly acceptable liquid carriersuch aswater, an organicsolvent, a mixture of both or pharmaceutical ly acceptable oils orfats. The liquid carrier can contain othersultable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples of liquid carriersfororal and parenteral administration include water (particularly containing additives as 30 above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycerol and glycols) and their derivatives, and oils (e.g.

fractionated coconutoil and arachis oil). For parenteral administration the carriercan also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. 35 Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized byfor 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 orsolid composition form.

Preferablythe pharmaceutical composition is in unitdosageform, e.g. astablets or capsules. In suchform 40 the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes orsachets containing liquids. The unit dosageform can befor example, a capsule ortablet itself, or it can bethe appropriate numberof any such composition in package form. The quantity of the active ingredient in unit dose of compositon may be varied or adjusted from 0.5 mg or less to 750 mg or more, 45 according to the particular need and the activity of the active ingredient. The invention also includesthe compounds in the absence of the carrierwherethe compounds are in unit dosageform.

Thefollowing Examples illustratethe invention; so 50 EXAMPLE 1

3,3-Dimethyl- 10-hydroxy- 10-(4-methoxybutyl)-2,3,4, 10tetrahydropyrimido[1,2-alindole Asolution of 1-bromo-4-methoxybutane (6.26g) in diethyl ether (23 mi)was added dropwise to stirred magnesium turnings (0.9g) under nitrogen, ata rate sufficientto maintain reflux. The mixture was stirred for 55 afurther45 min.,then a solution of 3,4-di hyd ro-3,3-di methyl pyri mid o [1,2-al in dol e- 1 0(2H)-one (1.6g) in 1,2-dichloroethane (75 mi)was added dropwise. The mixture was stirred for30 min.,then poured into aqueous ammonium chloride solution and extractedwith chloroform (2x 100 mi). Thechloroform extracts werecombined, dried (M9S04) and evaporated underreduced pressure giving an orange solid. Trituration from ethyl acetate, followed by recrystallisation from ethyl acetate gavethetitle compound (1.29).Addition 60 of ethereal hydrogen chlorideto a solution ofthefree base in methanol, followed by evaporation ofthe solvents and crystallisation of the resulting solidfrom propan-2-ol gavethe hydrochloride salt (0.6g), m.p.

188-1900.

Found: C63.9; H 8.2; N,8.1% C181-126N202.1---1C1 requires: C, 63.8; N, 8.0; N, 8.3% 65 GB 187 738 A 5 EXAMPLE2

2,3,4, 10-Tetrahydro- 10-hydroxy3,3-dimethyl- 10-(3-methoxy-2methylpropyl)pyrimido[1,2-alindole Approximately one quarter of a solution of 1-b ro m o-3-meth oxy-2-m ethyl propane (5.65g) in diethyl ether (10 m I) was added to stirred magnesium turnings (0.979) under nitrogen, followed by three drops of 1,2-dibromoethane. Them ixture was heated, and when the reaction commenced, the remaining solution of 5 ll-bromo-3-m ethoxy-2-m ethyl propane in ether was added at such a rate as to maintain reflux. The mixture was heated to ref lux fora further 15 min., cooled to room temperature, and a solution of 3,4-dihydro-3,3-di methyl primido[1,2-alindol-10(2H)-one (2.91 g) in 11,2- dichloroethane (50 m I) added dropwise.Afterl hourthe reaction mixture was poured into water (200 ml), extracted with chloroform (2x 100 ml) the chloroform extracts combined, dried (M9S04) and the solvents evaporated under reduced 10 pressure to give a solid (2.3g). The solid was crystallised from ethyl acetate, giving the title compound (1.1 g).

The mother liquor was evaporated under reduced pressure giving a crude solid which was triturated from ethyl acetate, giving more of the title compound (0.45g). Ethereal hydrogen chloride was added to a solution of the combined solids (1.55g) in methanol. The solvents were removed under reduced pressureto givethe title compound as the hydrochloride salt (1.58g), m.p. 154.5-155.5'. 15 Found: C, 63.3; H, 8.0; N, 8.3%.

C,8H2,N202.HC'/4H20 requires: C,610; H,8.1; N,8.2%.

EXAMPLE3

2,3,4, 10- Tetrahydro- 10-hydroxy- 10-(3-methoxybutyl)-3,3dimethylpyrimido[1,2-alin dole 20 A solution of 1 -bromo-3-methoxybutane (4.75g) in diethyl ether (10 mi) was added to magnesium turnings (1.03g) in diethyl ether (10 ml) under nitrogen at such a rate asto maintain reflux. After45 minutes at reflux temperature the solution was cooled to Wand a solution of 3,4-dihydro-3,3-dimethylpyrimido[1,2-a]-indol-10(2H)-one (3.03g) in 1,2dichloroethane (50 mi) added dropwise. The cooling bath was removed and after 0.5 hourthe solution was poured into saturated aqueous 25 NH4C1 (100 ml) and the mixture extracted with chloroform (3 x 100 mi). The chloroform extracts were dried (M9S04) and evaporated under reduced pressure to give a solid (3.7g). The solid was washed with a small quantity of ethyl acetate then crystallised from ethyl acetate, giving the title compound (2.29g). A solution of the free base in methanol was treated with ethereal HCI, the solvents evaporated under reduced pressure and the gum triturated with etherto give the title compound hydrochloride, m. p. 179-186'. 30 Found: C, 62.9; H, 8.2; N, 8.0% C18N26N2O.HCI.1/4H20 requires: C, 63.0; H, 8.11; N, 8.2% EXAMPLE4

8-Chloro- 10-hydroxy- 10-(4-methoxybutyl)-2,3,4, 10-tetrahydropyrimido[1, 2-alindole 35 A G rig nard reagent was prepared from 4-methoxybutyl bromide (5g) and mag nesiu m (0.72g) in dry ether (25m1). After cooling with an ice-bath under a blanket of nitrogen a solution of 8-chloro-3,4-dihydropyrimido[1,2-a]indol-1 0(2H)-one(2.2g) in dichloromethane (25 mi) was added slowly.

When addition was complete the mixture was stirred at room temperature for 3 hours. It was poured onto saturated aqueous NH4C1 the layers were separated and the aqueous phase extracted with dichloromethane. 40 The combined organic phases were washed with water and dried (M9S04). Filtration and evaporation gave an orange solid, which was triturated with boiling ethyl acetate, cooled, filtered and the crystals were washed with hexane. The crystals were suspended in boiling ethanol and acidified with ethanolic HCL Evaporation of the solution gave a solid which crystallised from isopropanol. Two crops were combined and dried at5T/1 mm to give pure 8-chloro-l 0-hydroxy-1 0-(4-methoxybutyl)-2,3,4,1 0tetrahydropyrimido[1,2-alinole, 45 hydrochloride quarter hydrate (2.289) as buff-cream crystals, m.p. 218- 221'(dec.) Found: C, 55.2; H, 6.5; N, 7.8% C16H21C1 N202MC1.1141-120 requires:C, 54.9; H 6.5; N,8.0%.

EXAMPLE5 50

10-(4-Benzyloxybutyl)-2,3,4, 10tetrahydro- 10-hydroxy-3,3dimethylpyrimido[1,2-alindole 1-Benzyioxy-4-bromobutane (6.77g) was added to magnesium turnings (0.90g) in diethyl ether (15 mi) under nitrogen. Addition of a small volume of 1,2-dibromoethane followed by gentle warming initiated the reaction. The mixture was heated at refluxfor a further 0.5 hour, cooled in an ice bath, then a solution of 3,4-dihydro-3,3-dimethylpyrimido[l.2-alindol-10(2H)-one (3.0g) in dry 1,2dichloroethane (50 m]) added 55 dropwisetothe stirred solution. The ice-bath was removed and afterO.5 hourthesolution was poured into aqueous NH4C1 and extracted with chloroform (3x 100 mi).The chloroform extractswere dried (M9S04) and evaporated under reduced pressureto give an oil. Trituration of the oil with ethyl acetate gave ayellowsolid (3.78g),which was recrystallised from ethyl acetateto give the title compound asthefree base (2.3g).

Ethereal HCI was addedto a solution of thefree base in methanol,the solvents removed underreduced 60 pressure and the resulting oil triturated with etherto givethetitle compound asthe hydrochloride (2.15g) m.p. 147-150'.

Found: C, 69.4; H, 7.5; N, 6.75%.

C24H3ON202HCI requires:C,69.5; H 7.5; N,635%.

6 GB 187 738 A 6 EXAMPLE6

10-(4-Ethoxybutyl)-2,3,4, 10-tetrahydro- 10-hydroxy-3,3dimethylpyrimido[1,2-alindole 1-Bromo-4-ethoxybutane (9,05g) was added to a stirred mixture of magnesium turnings (1.22g) in diethyl ether (20m I) under nitrogen. Them ixture was heated to ref I ux fora further O.5hour, cooled in an ice bath and a solution of 3,4-dihydro-3,3-dimethyi-pyrimido[1,2-alindol-10(2H)-one (4. 28g) in dry 11,2-clichloroethane 5 (100 mi) added dropwise. The cooling bath was removed and after 1 hourthe solution was poured into saturated aqueous NH4C1 (200 mi) and extracted with chloroform (3 x 100 mf). The extracts were dried (M9S04) and evaporated under reduced pressureto give an oil. Trituration with ethyl acetate gave a solid (6.0g) which was recrystallised from ethyl acetate and washed with etherto give thetitle compound asthe free base, yellow crystals (4.869). Ethereal HCI was addedto a solution of thefree base in methanol,the 10 solvents removed under reduced pressure and the gum triturated with etherto give the title compound asthe hydrochloride (3.96g), m.p. 155-6'.

Found: C, 64.4; H, 8.6; N, 7.9%.

C19H28N202HCI requires: C, 643; H, 83; N, 7.9%.

15 EXAMPLE7

2,3,4, 10-Tetrahydro-10-hydroxy-10-(3-methoxybutyl)-pyrimido[1,2alindole A Grignard reagent prepared from magnesium (1.1 5g) and 1 -bromo-3methoxybutane (7.93g) in dry ether (35 mO was treated dropwise over30 minutes with a solution of 3,4- dihydropyrimdio[1,2-alindol-1 0(2F1)-one (4.27g) in dry dichforoethane (20 mi) at O'under an atmosphere of N2. Afterwarming to room temperaturethe 20 solution was poured into a mixture of saturated aqueous NH4C1 (100 mi) and ice (1 00g), and extracted with chloroform (3 x 130 ml). The extracts were washed with water (300 mi), dried (M9S04), and evaporated in vacuo to give an orange solid (6.64g) which was triturated with ethyl acetate (5 mi) to givethe productfree base as pale yellow crystals (4.27g). The solid was suspended in methanol (10 mi), acidified with R20-HCl (ca.

8 m]), and the resulting solution evaporated in vacuo to give the title compound as the hydrochloride (4.85g), 25 pale yellow crystals, m.p. 200-204'(dec.) Found: C, 613; H, 73; N, 8.7% C16H22K1202MC1 requires C, 61.8; H, 7.5; N, 9.0%.

EXAMPLE8 30

10-Hydroxy- 10-(3-methoxy-2-methylpropyl)-2,3,4, 10-tetrahydropyrimido[1, 2-a.lindole 1-Bromo-3-methoxy-2-methylpropane (1 0.02g) in ether (50 mi) was added dropwise over 20 minutesto magnesium turnings (1.46g) in ether (1 Orni). The mixture was stirred under argon at room temperature for30 minutes, cooled to Wand 3,4-dihydropyrimido[1,2-alindol-1 O(M)-one (3. 729) in dry 1,2-dichloroethane (20 mi) was dropwise over 20 minutes. The solution was stirred under argon at O'for 1 hour, poured onto a 35 swirling mixture of ice (100 m]) and saturated aqueous ammonium chloride (60 mi). The mixture was stirred for 20 minutes and concentrated in vacuo. The aqueous residue was extracted with chloroform (3 x 100 mi).

The extracts were dried (Na2S04) and concentrated in vacuo. Ether (20 mi) was added and the productwas filtered and recrystailised from ethyl acetate to give the title compound as the free base (2.85g) m.p.

162-1670C. Thefree base was acidified with ethereal HCI to give the title compound as the hydrochloride, m.p. 40 244'(dec.) Found: C61.70; H,730; IM,8.80% C161122N202MC1 requires:C, 61.85; H 7.45; N, 9.0%.

EXAMPLE9 45

10-Hydroxy-10-(4-ethoxybutyl)-2,3,410-tetrahydropyrimido[1,2-alindole Ether (10 mi) and a few drops 4-bromo-l-ethoxy-butane were added to magnesium turnings (1.46g). After the reaction started, the remainder of the 4-bromo-1 -ethoxybutane (total 10.869) in ether (50mi) was added dropwise over 20 minutes. The mixture was stirred under argon at room temperature for 30 minutes, cooled 5,3 to O'C over 30 minutes and 3,4-dihydropyrimido[1,2-alindol-1 0(2F1)- one (3.72g) in dry 1,2-dichloroethane (20 50 mi) added dropwise over 20 minutes. The solution was stirred under argon at O'Cfor 1 hour, poured onto a swirling mixture of ice (100 mi) and saturated aqueous ammonium chloride (60 mi), and the mixture stirred for afurther20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3 x 100 mi). The extracts were dried (Na2S04) and concentrated in vacuo. Ether (20 mi) was added and the productwas filtered and recrystallised from ethyl acetate to give the title compound as the free base 55 (2.99g), m.p. 123'-1 24C. The free base was acidified with ethereal HCl to give the title compound asthe hydrochloride, m.p. 189-190'C.

Found. C, 63.25; H 7.5; N, 8.6% C17H24N202.1HIC1 requires:Q 62.85; H, 7.75; N, 8.6%.

7 GB 187 738 A 7 EXAMPLE 10

10-Hydroxy- 10-(4-methoxybutyl)-2,3,4, 10-tetrahydropyrimido[1,2-alindole Ether (60 mi) and 4-bromo-l-methoxy-butane (10.2 9) were added to magnesium turnings (1.46 g).After formation of the Grignard reagent,the mixturewas cooled to 0'and3,4- dihydropyrimido[1,2-a]indol-10(2H)- one (3.72 g) in dry 1,2-dichloroethane (20 m]) added dropwise over20 minutes. The solution wasstirred 5 underargon at O'Cfor 1 hour, poured onto a swirling mixture of ice (100 mi) and saturated aqueous ammonium chloride (60 mi) and the mixturewas stirred fora further20 minutes. The mixturewas concentrated in vacuo andthe aqueous residue extracted with chloroform (3x 100 mi). The extractswere dried (Na2S04) and concentrated in vacuo. Ether (20 mi) was added and the product was filtered and recrystallised from ethyl acetateto givethetitle compound orthefree base (3.55 g), m.p. 128M39'C. Thefree 10 basewas acidifiedwith etheral HCl to givethetitle compound asthe hydrochloride, m.p. 178-179'C.

Found: C, 61.55; H, 7.55; N,8.80% C16H22N202.W requires:C, 61.85; H, 7.45; N, 9.0%.

EXAMPLE 11 15

10-Hydroxy-10-(3-hydroxy- 1-propynyl)-2,3,4, 10-tetrahydropyrimido[1,2alindole (1) 2-(3-Propynloxy) -3,4,5,6-tetrahydropyran (9.25 g) in ether (100 ml) was added dropwise to a solution of ethyl magnesium bromide (from bromoethane 5.99 g and magnesium 1.6 g) in ether (60 mi) with stirring under an argon atmosphere. Afterstirring for30 minutes,the reaction was cooled to O'C and 3,4-dihydropyrimido[1,2-alindol -1 0(2H)-one (9.31 g) in dry 1,2- clichloroethane (40 mi) was added over 50 20 minutes. The mixture was stirred under argon at O'C for 1 hour and at room temperature for 17 hours. Dry THF (160 mO was added and the mixture was refluxed for 2 hours.After cooling the mixture was poured onto a mixture of ice (600 mi) and saturated aqueous ammonium chloride (65 mi) and concentrated to a small volume in vacuo. The residue was extracted with chloroform (3 x 200 mi), washed with brine (100 mi), dried (Na2S04) and concentrated in vacuoto give crude 25 1 0-hydroxy-1 0-[3-(2-(3,4,5,6-tetra hyd ro-2 H-pyra nyl oxy)) pro p- 1 - ynyl 1-2,3,4,1 0-tetrahyd ro pyrim ido [ 1,2 alindole. The produetwas purified by chromatography on silica eluting with methanollchloroform (1:20 1: 10). The addition of ether (30 m[) induced crystallisation. Recrystallisation from ethyl acetate gave the pure product as the free base (6.16 9) m.p. 173'-1 7WC.

Found: C 69.85; H, 7.10; N, 8.40% 30 C19H22N203 requires: C, 69.90; H 6.80; N, 8.60%.

(2) Ethanolic hydrogen chloride (5 mi) was added to a suspension of 1 0-hydroxy-1 0-[3-(2-(3.4.5.6-tetrahydro-2H-pyranyloxy))prop-1 -ynyll-2, 3,4,1 0-tetrahydropyrimido[1,2-al indole (3.0 g) in ethanol (30 mi). The solution was concentrated in vacuo and the product was recrystallised 35 from ethanol to give the title compound as the hydrochloride (2.0 g) m.p. 194'C dec.

Found: C, 60.55; H, 5.50; N, 10.00% C14H14N202.W requires: C, 60.35; H 5.40; N 10.05%.

EXAMPLE 12 40

7-Chloro- 10-hydroxy- 10-(3-methoxybutyl)-2,3,4, 10-tetrahydropyrimido[1, 2-alindole (1)7'-Chloro-2',3',4',10'-tetrahydrospiro[l,3-dioxolane-2,10'-pyrimido(1, 2-a)indolej (5.71 g)wasaddedto cooled 98% sulphuric acid (30 mi) with stirring. The solution was then pouredonto ice(300mi)andbasified to pH9with conc. ammonia solution. The resulting suspension was stirred with chloroform (100m1)and, after separation, the aqueous phase was exhaustively extracted with further chloroform. Evaporation of the 45 combined,dried (M9S04)extracts lefta brownish orange solid which was crystallised from benzene-cyclohexane, giving 7-chloro-3,4-dihydropyrimido[1,2-alindol- 10(2H)-one as orange crystals (3.06 g),darkening above 160'and meltingfrom 168170'withdecompositon.

Found: C, 59.6; H 4.2; N, 12.5%.

C11H9CIN20 requires:C, 59.9; H, 4.1; N 12.7% 50 (2) A solution of 1-bromo-3-methoxybutane (2.0 g) in dry ether (20 mi) was added dropwise undera nitrogen atmosphereto magnesium turnings (0.3 g) at such a rate as to maintain gentle reflux. AfterO.5 hour the reaction mixturewas cooled and a solution of 7-chloro-3,4- dihydropyrimido[1,2-alindol-1 0(2H)-one (1.0 g) in dry 1,2-dichloroethane (50 mi) was added dropwise. Afterstirring the reaction mixturefor one hourat 55 room temperature itwas cooled and excess saturated ammonium chloride solution was added dropwise.

The organic phase was separated and the aqueous phase was extracted with chloroform. The extractswere combined with the organic phase, dried (M9S04) and the solution evaporated in vacuoto leave an oil which wastriturated with etherto give a solid. Recrystallisation from ethyl acetate gave the title compound as crystals m.p. 146.5-148'. A solution of these crystals in warm propan-2- ol was treated with etheral hydrogen 60 chloride. Evaporation in vacuo followed by recrystallisation from propan2-ol gave the title compound asthe hydrochloride colourless needles, m.p. 226-8'.

Found: C, 55.84; H, 6.10; N, 8.02 % C16H21CIN202HCl requires:C, 55.65; H, 6.38; N, 8.12%.

8 GB 187 738 A 8 EXAMPLE 13

9-Chloro-10-hydroxy- 10-(3-methoxybutyl)-2,3,4, 10-tetrahydropyrimidofl,2alindole (1) 9'-Chloro-2',3',4',10'-tetrahydrospiro[1,3-dioxolane-2,10'-pyrimido(l, 2-a)in dolej (6.58 g) was added to cooled 98%sulphuric acid (35 m I) with stirring until complete solution was achieved (approx. 2 hours). The 5 solution was poured onto ice (400 mi) and basified to pH9 with conc. ammonia solution. The resulting suspension of the product was stirred with chloroform (100 m I), and after separation, the aqueous phase was exhaustively extracted with further chloroform. Evaporation of the combined, dried (M9S04) extracts left a brownish orange solid (4.84 g) which was crystal I ised from benzene to give 9-chloro-3,4-dihydropyrimido[1,2-alindol-10(2H)-one as dark orange prisms (3.16 g) darkening above 165' 10 and melting at 170'with decomposition.

Found: C, 59.75; H, 4. 1; N, 12.0% C11H9CIN20 requires:C, 59.9; H, 4.1; N, 12.7% (2) Asolution of 1 -bromo-3-methoxybutane (6.0 g) in dry ether (20 m]) was added dropwise under a nit- 15 rogen atmosphereto magnesium turnings (0.9 g) atsuch a rate as to maintain gentle reflux. Afterstirring at refluxfor 0.5 hourthe reaction mixture was chilled in ice and a solution of g-chloro-3,4- dihydropyrimido[1,2alindol-1 0(21H)-one (3.5 g) in dry 1,2- clichloroethane (100 m]) was added dropwise. Afterstirring the reaction mixturefor one hour at room temperature itwas cooled and excess saturated ammonium chloride solution was added dropwise. The organic phasewas separated and the aqueous phase was extracted with chloroform. The extractswere combined with the organic phase, dried (M9S04) and the solution evaporated under reduced pressureto leave an oil which wastriturated with etherto give a solid. Recrystallisation from ethyl acetate gavethetitle compound as colourless needles m.p. 164-5'. Treatment of a solution of these needles in methanol with ethereal hydrogen chloride, followed by evaporation in vacuo gave a solid which was re crystallised from propan-2-ol to givethetitle compound asthe hydrochloride, colourless crystals (2.819) 25 m.p. 264-5'.

Found: C, 55.29; H, 6.71; N, 7.63% C16H21C1 N20MC1 requires:C, 55.65; H, 6.38; N, 8.12% EXAMPLE 14 30

10-Hydroxy- 10-(3-hydroxypropyl)-2,3,4, 10-tetrahydropyrimido[1,2alindole (1) A suspension of 1 0-hydroxy-1 0-[3-[2-[3,4,5,6-tetrahydro-2Hpyranoxyllprop-1 -ynyll-2,3,4,1 0 tetrahydropyrimido[1,2-aindole (3.14g) in ethyl acetate (1 60mi) was hydrogenated at 2-4atm over 5% Pd/C (1.063g) at room temperature for 6h. The mixture was filtered through Kieselguhr and the filtrate was con centrated in vacuo to give a yellow orange foam. Ether (30mi) was added and the crystalline productwas 35 collected to give 1 0-hyd roxy- 1 0-[3-[2-(3,4,5,6-tetra hyd ro-2H-pyra nyl oxy)l pro pyl 1 -2,3,4,10 tetrahydropyrimido[1,2-alindoie (2.44g), m.p. 105'- 12WC.

Found: C, 68.75; H, 8.30; N1,8.85; C19H26N203 requires: C, 69.05; N, 7.95; N, 8.50%.

40 (2) Asuspension of 1 0-hydroxy-1 0-[3-[2-(3,4,5,6-tetra hyd ro-2H-pyra nyl oxy)l pro pyl I 2,3,4,1 0,tetrahydropyrimido[1,2-alindole (2.4g) in ethanoi (25mi) wastreated with ethanolic hydrogen chloride (5mi) and the solution was concentrated in vacuo to give a white foam. The productwas crystallised from 20% ethanoi/ethyl acetate (20mi) at-78'C and the productwas collected to give crude title compound as the hydrochloride. The productwas dissolved in 2N-HU (1 00mi) and ice (1 00mi) and the mixture was basified 45 with concentrated aqueous ammonia atO'C. The mixture was extracted with chloroform (3 x 50mi) and the extracts were dried (N a2S04) and concentrated in vacuo. The product was recrysta 11 ised from aceton itri 1 e/ ethyl acetate to give the title compound as the free base (0.30g) m.p. 1 90'CA 93'C. The product was dissolved in ethanolic hydrogen chloride and the solution was concentrated in vacuo. The product was recrystallised 5C) from ethanol/ethyl acetateto givethe hydrochloride, m.p. MC-1149'C. 50 Found: C, 58.30; H 6.65; N, 9.65 Cl,Hl,N202.HCI 0.251-120 requires: C, 58.55; H,6.85; N,935%.

9 GB 187 738 A

Claims (25)

1. A pyrimidoindole of the general formula (1) R RO- OH N 0 R 3 N 4 10 R or a pharmaceutical ly acceptable acid addition salt thereof, wherein A represents a lower al kylene chain optionally containing one double ortriple bond, RO represents (lower)aikoxy, aryl(iower)aikoxy, hydroxyor protected hydroxy, R' and R' which maybe the same or different each represent hydrogen, hydroxyl, lower 15 alkyl, lower alkoxy halo(lower)alkyl, halogen, amino or mono- or di (lower)alkylamino and R 3 and R 4 each independently represent hydrogen or loweralkyl.

2. A compound as claimed in claim 1 wherein RO represents (lower)aikoxy, aryl(lower)alkoxy or hydroxy.

3. A compound as claimed in claim 1 or 2 wherein A is a branched or straight chain saturated alkylene group containing 3to 5 carbon atoms. 20

4. 3,3-Di m ethyl- 1 0-hyd roxy-1 0-(4-m eth oxybutyi)-2,3,4,1 0-tetra hydro pyri m ido [ 1,2-al indo 1 e or a p ha rmac etu ical ly acceptable acid addition salt thereof.

5. 2,3,4,1 O-Tetra hyd ro-1 0-hyd roxy-3,3-di methyl - 1 0-(3-m eth oxy-2m ethyl pro pyl) pyri m ido [1,2-al i ndo 1 e or a pharmaceutically acceptable acid addition saItthereof.

6. 2,3,4,1 O-Tetra hyd ro-1 0-hyd roxy- 1 0-(3-methoxybutyi)-3,3-d i methyl pyri m ido [ 1,2-al i ndo 1 e or a pha rm a- 25 ceutical ly acceptable acid addition salt thereof.

7. 8-Chloro-10-hydroxy-10-(4-methoxybutyl)-2,3,4,10-tetrahydropyrimido[1, 2-alin doleorapharmaceu- tical ly acceptable acid addition salt thereof.

8. 10-(4-Benzyl oxybutyl)-2,3,4,1 0-tetra hyd ro- 1 0-hyd roxy-3,3-d i methyl pyri m ido [ 1,2-al in d ol e or a ph a rm aceutical ly acceptable acid addition salt thereof. 30

9. 10-(4-IEth oxybutyi)-2,3,4,1 0-tetra hyd ro- 1 0-hyd roxy-3,3-d i methyl pyri m ido [1,2-al i ndo 1 e or a ph arm ac eutically acceptable salt addition salt thereof.

10. 2,3,4,1 O-Tetrahyd ro-1 0-hyd roxy-1 0-(3-methoxybutyl)-pyrimido[1,2aindole or a pharmaceutical ly ac ceptable acid addition salt thereof.

11. 10-Hydroxy-10-(3-methoxy-2-methylpropyl)-2,3,4,10tetrahydropyrimido[l,2-ain doleorapharmac- 35 eutically acceptable acid addition saitthereof.

12. 1 0-Hydroxy-1 0-(4-ethoxybutyi)-2,3,4,1 0-tetrahydropyrim ido[ 1,2alindole or a pharmaceutical ly ac ceptabie acid addition saitthereof.

13. 10-Hydroxy-10-(4-methoxybutyi)-2,3,4,10-tetrahydropyrimido[l,2aindoleorapha rmaceuticallyac- ceptable acid addition salt thereof. 40

14. 10-Hydroxy-10-(3-hydroxy-l-propynyi)-2,3,4,10-tetrahydropyrimido[1,2a]indol eora pharmaceutic ally acceptable acid addition salt thereof.

15. 7-Chloro-10-hydroxy-10-(3-methoxybutyl)-2,3,4,10-tetrahydropyrimido[1, 2-a]in doleorapharmaceu- tical ly acceptable acid addition salt thereof.

16. 9-Chloro-10-hydroxy-10-(3-methoxybutyi)-2,3,4,10-tetrahydropyrimido[1, 2-aind oleorapharmaceu- 45 tically acceptable acid addition salt thereof.

17. 1 0-Hydroxy-1 0-(3-hydroxypropyl)-2,3,4,1 0-tetra hyd ropyrimido [1,2al indole or a pharmaceutical ly ac ceptable acid addition salt thereof.

18. A process for preparing a compound claimed in claim 1 in which RO represents (lower)aikoxy, 8,:3 aryl(lower) alkoxy or protected hydroxywhich comprises reacting a ketone of general formula (11) 50 R 0 N 3 R 4 R 55 N R 2 (where R', R', R 3 and R 4 havethe meanings given in claim 1)with an organometallic compound containing a 60 RO-A- residue (whereA is as defined in claim 1 and RO is loweralkoxy, aryl(lower)alkoxy or protected hydroxy) and, if desired converting a base of formula (1) into a pharmaceutical ly acceptable acid addition salt thereof.

GB 187 738 A 10

19. A process for preparing a compound claimed in claim 1 in which RO represents (lower)alkoxy, aryl(lower) alkoxy or protected hydroxy and A is a saturated lower alkylene chain which comprises cyclodehydrating an indole derivative of general formula (111) R A-OR -OH 2 N --" -0 10 R 1 3 4 CH 2 CR R CH 2 NH 2 wherein W, R 2 R 3 and R 4 havethe meanings given in claim 1,A is a saturated lower alkylene chain and RO is (lower) alkoxy, aryl(lower)alkoxy or protected hydroxy, and, if desired, converting a base of formula (1) into a 15 pharmaceutical ly acceptable acid addition saitthereof.

20. A process for preparing a compound claimed in claim 1 in which RO represents (lower)aikoxy, aryl(lower) alkoxy or protected hydroxy and A is a saturated lower alkylene chain which comprises hydro- genating a nitrile of general formula (IV) R -OR OH 20 IV) N LO 25 1 4 4 R CH 2 CR R CNI wherein W, R 2, R 3 and R 4 havethe meanings given in claim 1, A is a saturated lower alkylene chain and RO is (lower)aikoxy, aryl(lower)alkoxy or protected hydroxy, and, if desired, converting a base of formula (1) into a 30 pharmaceutical ly acceptable acid addition saitthereof.

21. A process for preparing a compound claimed in claim 1 in which RO represents hydroxy which com prises de-etherifying a compound in which RO represents (lower)alkoxy or aryl(lower)alkoxy or removing the protecting group from a compound in which RO is a protected hydroxy group and, if desired, converting a resulting base of formula([) into a pharmaceutical ly acceptable acid addition saitthereof. 35

22. A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to anyone of the Examples.

23. A compound as claimed in claim 1 whenever prepared by a process claimed in anyone of claims 18to 22.

24. A pharmaceutical composition comprising a compound as claimed in anyone of claims 2 and 4to 17 40 in association with a pharmaceutical ly acceptable carrier.

25. A compound as claimed in anyone of claims 2 and 4to 17 for use as a pharmaceutical.

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Published by The Patent Office, 25Southampton Buildings, London WC2AlAY, from which copies maybe obtained.