DI/TETRA-HYDROQUINOLINES

Abstract: Compounds of formula (I), wherein: n is 1 or 2; R1 is chloro, bromo, C1-6 alkylcarbonyl or cyano; one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl or R3 and R4 together are C2-5 polymethylene; and either; R5 is hydroxy, C1-3 alkoxy or C1-8 acyloxy; and R2 is hydrogen and the cyclic amide moiety and R5 are trans; or R5 and R2 together form a bond; having anti-hypertensive activity, and process for their preparation and their use as pharmaceuticals.

Description: DI/TETRA-HYDROQUINOLINES The present invention relates to novel compounds having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containg them, and to their use in the treatment of mammals. Accordingly, the present invention provides a compound of formula (I) : wherein: n is 1 or 2; Rl is chloro, broirio, or cyano; one of R3 and R4 is hydrogen or C1-4 alkyl and the other is C1-4 alkyl or R3 and R4 together are C2-5 polymethylen 7 and either: R5 is hydroxy, C1-.3 alkoxy or C1-8 acyloxy; and 2 is hydrogen and the cyclic amide moiety and R5 are trans; or R5 and R2 together form a bond, n is often 1. Suitable values for Ri include chloro, bromo, acetyl, propionyl, n-, and iso-butyryl and cyano. Often R_ is rc-hnllnorrno,. hbrrnommno,. sacc-ea-tt-yvll norr- rcvysannno.. The alkyl groups or alkyl moieties of alkyl-containing groups for R^ are, preferably, methyl or ethyl. Favourably, R3 and R4 are both alkyl having from 1 to 4 carbon atoms including methyl, ethyl or n-propyl. In particular, they are both methyl or ethyl, preferably both methyl. Suitable examples for " R5 when C- j __3 alkyloxy include methoxy, ethoxy, n- and iso-propyoxy, preferably me hoxy. Suitable examples for R5 when acyloxy include carboxylic acyloxy such as acetoxy, propionyloxy and benzoyloxy. There is a group of compounds within formula ( I ) of formula ( II ) : wherein variables are as defined in formula (I). Suitable and preferred values for the variables are as described for the corresponding variables under formula (I). It will be appreciated that there is a favourable sub-group of compounds within formula (I) of formula (III): wherein the variables are as defined in formula (I). The present invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (IV): with an anion of formula (V) wherein R]_' is R^ or a group or atom convertible thereto? P-6 is hydrogen or an N-protecting group7 and the remaining variables are as defined in formula (I), and thereafter if necessary converting R- j _' to Ri and/or 6 to hydrogen,- optionally C1-3 alkylating or c l-8a.cy ating an R5 hydroxy group, or dehydrating a compound of formula (I) wherein R5 is hydroxy to form the compound of formula (I) wherein R5 and R2 together form a bond. [RE T OMPI The reaction is suitably carried out in an inert solvent such as dimethylsulphoxide in the presence of a base, such as sodium hydride. C onversions of Ri' to Ri are generally known in the art of aromatic chemistry. For example, R]_ ' , when halo, preferably bromo, may be converted to an Ri cyano group by heating with copper (I) cyanide in an inert solvent, such as N-methylpyrrolidone. This process is preferred when R]_ is cyano in formula (I) Suitable N-protecting groups Rg include acyl groups such as C2-5 alkanoyl for example acetyl and propionyl7 benzoyl, phthalolyl or readily hydrogenolysable groups such as benzyl or benzyloxycarbonyl. Preferably an R6 protecting group is C2-5 alkanoyl such as acetyl or propionyl. Such groups may be removed by conventional hydrolysis. _ - An Rβ acetyl group is particularly easily removed and may therefore under certain conditions be converted to an R6 hydrogen by chromatographic methods, such as on a silica gel column. Alkylation of R5 hydroxy may be carried out using R5I L2 wherein L2 is a leaving group. L2 ^ s group readily displaceable by a nucleophile, preferably halo such as iodo. The reaction is carried out in an inert solvent, such as toluene, in the presence of a base, such as potassium t-butoxide. OMPI Acylation of an R5 hydroxy group may be carried out using a carboxylic acid or a derivative thereof, such as an anhydride, the reaction being carried out in a non-hydroxylic solvent in the presence of a condensation promoting agent, such as dicyclohexyl-carbodiimide. It will be appreciated that the above acylations/alkylations at R5 may affect the substitution at the hydroquinoline nitrogen atom and appropriate modifications of reaction conditions and/or appropriate protection of should be carried out during the reaction. It will also be appreciated that such conversions may take place in any desired or necessary order. Compounds of formula (V) may be prepared by reacting a compound of formula (VI): wherein the variables are as hereinbefore defined 7 with a base, such as potassium hydroxide, in ether or aqueous dioxan. Compounds of the formula (VI) may be prepared in accordance with known processes, for example as described in the following Scheme: Scheme a) Room temperature? triethylamine? copper (I)chloride, copper bronze? water? ether. b) Heat to 80O-C? copper (I) chloride in dioxan under N 2 . c) Optional N-protection eg. acetylation with acetyl chloride in N,N-dimethylaniline in dichloromethane? then N-bromo succinimide/dimethylsulphoxide/water. The above process can produce mixtures of compounds during reaction b) owing to the two sites available for ring formation. It is therefore advisable to remove any of the undesired compound by, for example, chro atography, before reaction c) . Instead of carrying out the conversion of R-j when a group or atom convertible into Ri after reacting a compound of formula (IV) with an anion of formula (V) , it is greatly preferred that any such conversions are carried out at an earlier stage, preferably on the dihydroquinoline produced after reaction b) above. In other words, it is preferred that, for the process of the invention Ri' is Ri, except when R± is cyano as hereinbefore described. As mentioned previously, the compounds of formula (I) exist in optically active forms, and the processes of the present invention produce mixtures of such forms. The individual isomers may be separated one from another by chromatography using a chiral phase. Alternatively, an asymmetric synthesis would offer a route to the individual form. The intermediates of formulae (IV) and (VI) are novel and form an aspect of the present invention. As mentioned previously, the compounds of formula (I) have been found to have blood-pressure lov/ering activity. They are therefore useful in the treatment of hypertension. The present invention accordingly provides a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier. In particular, the .present invention provides an anti-hypertensive pharmaceutical composition which comprises an anti-hypertensive effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration for patients suffering from heart failure. In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit-dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 1 to 100 mg of a compound of the invention and more usually from 2 to 50 mg, for example 5 to 25 mg such as 6, 10, 15 or 20 mg. Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 5 to 200 mg for a 70 kg human adult and more particularly from 10 to 100 mg. The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavouring agent. They are formulated in conventional manner, for example in a manner similar to that used for known anti-hypertensive agents, diuretics and P-blocking agents. The present invention further provides a compound of formula (I) for use in the treatment of hypertension. -$JRE OMPI The present invention yet further provides a method of treating hypertension in mammals including man, which comprises administering to the suffering mammal an anti-hypertensive effective amount of a compound of formula (I) or a pharmaceutical composition The following examples illustrate the preparation of compounds of formula (I); The following descriptions relate to the preparation oi intermediates. 1 ϊ ' rli^ lT}. ' ? . l N -.1 4-Chloro-N-(1 ,1-dimethy1-2-propynyl)-aniline 3-Chloro-3-methyl-l-butyne (24.Og) was added dropwise t vigorously stirred mixture of 4-chloroaniline (25.6g), triethylamine (20.5g), copper (1) chloride (0.4g), copp bronze (0.4g), water (20 ml) and ether (100 ml), while maintaining a temperature of 15-22 C. After stirring f 2.5 hours at room temperature, the mixture was poured i ether (200 ml) and water (100 ml). The ethereal layer separated, and washed with water, and then brine before drying over potassium carbonate and potassium hydroxide. Removal of drying agent and solvent gave a brown oil wh was distilled to give the title compound (30.0g) which b.pt. 68-74°C at 0.06 mm Hg (G.F. Hennion and R.S. Hanz J.A.C.S., 82^ 4908, (1960) quote b.pt. 98-99°C at 0.4 m Hg); N r (CDC1 3 ) 1.55 (s, 6H) 2.30 (2, 1H) 3.45 (NH) , 6.80 (d, J=9,2H) 7.20 (d, J=9, 2H) M + 193.660 (C H C1N requires M + 193.0658). ΪRE DESCRIPTION 2 C-Chloro-2,2-dimethyl-l,2-dihydroquinoline A mixture of 4-chloro-N-(2,2-dimethyl-2-propynyl)-aniline (32.5g) and copper (1) chloride (17.Og) " in dioxan (200 ml was stirred at 80 C for 2 hours, under nitrogen. The mixture was cooled, diluted with ether, and filtered. Th organic phase was washed with water, then brine before drying over magnesium sulphate. Removal of drying agent and solvent, followed by distillation of the residue, gav tthhee ddiihhyyddrrooquinoline (18.Og) which had b.pt 85-100°C ' at 0.06 mm Hg; N r (CDC1 3 ) 1.25 (s, 6H) 3.45 (NH) 5.35 (d, J=9, 1H) 6.10 (d, J=9, 1H) 6.20 (d, J=10, 1H) 6.70 (m, 2H) M ÷ 193.0658 (C H. -NC1 requires M + 193.0658) ? TRE T/GB84/00252 -13- Dl-aSC RH TJON 3 l--Acetyl-G-chloro-2,2-dimethyl-l ,2-dihydro uinoline Acetyl chloride (12 ml) was added dropwise to a stirred solution of 6-chloro-2,2-dimethyl-l,2-dihydroquinoline (I6.0g) and N.N-dimethylaniline (24 ml) in dichloro- methane (200 ml) at 0°C. The solution was stirred for further 24 hours at room temperature, then poured into water and the organic layer separated, and washed successively with IN hydrochloric acid, 5% sodium bicarbonate solution, water, brine and then dried over sodium sulphate. Removal of drying agent and solvent g the crude N-acetyl derivative as a gum (I8.9g) having Nmr (CDC1 ) 1.50 (s, 6H) - 2.10 (s, 3H) 5.60 (d, J=10, 1H) 6.15 (d, J=10, 1H) 6.60 (d, J=8, 1H) 6.90 ( , 2H) M + 235.0766 (C^H C1NO requires M + 235.0764). DESCRIPTI ON 4 l-Acetyl-3~bromo-S-chloro-2 , 2-dimethyl-l , 2 , 3 , 4- tetrahydroguinolin-4-ol N-Bromosuccininide (16.Og) was added to a vigorously stirred solution of l-acetyl-6-chloro-2,2-dimethyl-l,2- dihydroquinoline (18.9g) in dimethyl sulphoxide (150 ml containing water (15 ml) . The mixture was stirred for hour at room temperature, then diluted with water and extracted into ethyl acetate. The organic extracts wer washed with water and brine, then dried over sodium sulphate. Removal of drying agent and solvent gave the bromohydrin as a gum (26.5g) which had Nmr (CDC1 3 )' 1.70 (s, 6H) 2.10 (s, 3H) 3.30 (OH) .3.80 (d, J=9, 1H) 4.70 (d, J=9, 1H) 6.75 (ά, J=8, 1H) 7.10 (dd, J=8, 2, 1H) 7.45 (d, J=2, 1H) M + 330.9972 (C l3 H 1 ^BrClN0 2 requires M * * " 330.9975). DESCRI TION 5 l-Acetyl-6-chloro-2 , 2-dimc hyl-3 , 4-epoxy-l ,2,3,4- i-etrahydroquinoline CH. A mixture of l-acetyl-3-bromo-6-chloro-2,2-dimethyl-l ,2, 4-tetrahydroquinolin -4-ol (26.5g) and potassium hydroxi pellets (25.Og) in dry ether (500 ml) was vigorously stirred at room temperature for 48 hours. The solution was filtered and evaporated in vacuo to give the epoxide (I8.5g) as a gum having Nmr (CDC1-) 1.20 (s, 3H) 1.85 (s, 3H) 2.10 (s, 3H) 3.35 (d, J=4, 1H) 3.75 (d, J=4, 1H) 6.65 (d, J=9, 1H) 7.15 (m, 2H) EXz- -iPL-E 1 Tr ns-2 , 2-dimethyl-C-chloro-4- ( 2-oxo-pyrrolidinyl) -1 , 2 , 3 , -tetrahvdχ-oαuinol in-3-ol To a suspension of sodium hydride (450 mg of 80% dispersi in oil) in dry di ethylsulphoxide (20 ml) was added 2-pyrrolidinone (1.2g) in dimethylsulphoxide (20 ml) and the mixture was then stirred at room temperature, under nitrogen, for 1 hour.. A solution of.1-acetyl 6-chloro-2 / 2-dinethyl . 3,4-epoxy-l,2,3,4-tetrahydroσuinoline (2.5g) in dimethyl sulphoxide was then added dropwise, and the solution stirred for 24 hours at room temperature. The mixture wa then poured into water and extracted into ethyl acetate. The combined organic layers were washed with water, then brine, and dried over sodium sulphate. Removal of solven and drying agent, followed by chromatography of the resid on a silica gel column eluted with mixtures of chloroform and ethanol, gave the title compound as a yellow foam ( 1-lg ) which recrystallised from 60-80 petrol-ethyl aceta ( 9:1 ) as colourless micropris s (0.24g) having m.pt. 82-85°C; Nmr (CDC1 3 ) 1.20 (s, 3H) 1.30 (s, 3H) 2.10 ( , 2H) 2.55 (m, 2H) 2.80 (OH) 3.20 (HI, 2H) 3.65 (d, J=10 " , 1H) ! ' 3.75 (HH) 5.25 (d, J=10, IH) 6.45 (d, J=8, IH) 6.95 (m, 2H) M 294.1134 (C 15 H 19 N 2°2 C1 requires M 294.1134) ι a i;>!7-.N.i J E 2 6-Ch]oro-2,2- imethyl-4-(2ρoxo-pyrrolidinyl)-l ,2- dihydroquinoline From the reaction between 2-pyrrolidinone and 6-chloro-2, 2-dimethyl-3,4-epoxy-l,2,3,4-tetrahydroquinoline describe in Example 1, investigation of the earlier chromatographi fractions gave the title compound as a yellow foam, which recrystallised from 60-80 petrol-ethyl acetate (9:1) as yellow plates (0.8g) ' having " m.pt. 158-9 C; Nmr (CDC1 3 ) 1.35 (s, 6H) 2.20 (m, 2H) 2.50 (m, 2H) 3.60 (t, J=6, 2H) 3.75 (NH) - 5.50 (s, IH) 6.40 (d, J=8, IH) 6.75 (d, J=2, IH) 6.95 (dd, J=8, 2, IH) M + 276.1008 (C 15 H 17 N OCl requires M + 276.1010); Anal. Found: C, 65.09; H, 6.18; N, 10.14; C J OCl requir C, 65.10; H, 6.19; N, 10.12. Example 3 Trans-2,2-dimethyl-6-bromo-4-(2-oxo-pyrrolidinyl)-1,2,3,4- tetrahydroquinolin-3-ol By an analogous procedure to that found in Example 1, reaction between 2-pyrrolidinone (3,4g) and l-acet l-6- bromo-2,2-dimethyl-3, -epoxy-l,2,3,4-tetrahydroquinoline (12.0g) using sodium hydride (1.5g) as base in dimethyl¬ sulphoxide (70. ml) gave the title compound, after chromato¬ graphy, as an off-white foam (0.7g) having m.pt. 93-102°C. N r (CDC1 3 ) 1.20 (s, 3H) 1.35 (s, 3H) 2.20 (m ; 2H) 2.60 (m, 2H) 3.20 ( , 2H) 3.60 (OH, H) 3.70 (d, J=10,1H) 5.20 (d, J=10,1H) 6.40 (d, J=8,1H) 7.10 ( , 2H) M+ 338.0639 (C H N O Br requires M + 338.0630). v i§_\\ 2 fs Example 4 Trans-2 , 2-dimethyl-6-cyano-4- ( 2-oxo-pyrrolidinyl) -1 , 2 , 3 , 4* tetrahydroquinorin-3-ol ^ • NN ^^ -CO A solution of trans-2,2-dimethyl-6-bromo-4-(2-oxo-pyrroli- dinyl)-1,2,3, -tetrahydroquinolin-3-ol (0.37g), and copper (1) cyanide (0.2g) in N-methylpyrrolidone (10 ml) was heated under reflux for 4h. After cooling, the mixture was poured into 10% aqueous ethylenediamine (50 mi) and extracted into ethyl acetate. The combined extracts were washed with water and dried over magnesium sulphate. Removal of solvent and drying agent, followed by crystallisation of the residue from ethyl acetate gave the title compound as off-white microcrystals (76 mg) having m.pt. 297-298°C; Nmr (DMSO-d e ) 1.10 (s, 3H) 1.30 (s, 3H). 2.00 (m, 2H) 2.35 ( , 2H) 3.00-3.75 (m, hidden by H 2 0, 3H) 4.90 (d, J=10, IH) 5.35 (d, J=4, IH, exchangeable with D O) 6.65 (d, J=8, IH) 6.80 (s, IH, exchangeable with D~0) 7.05 (m, IH) 7.36 (dd, J=8, 2, IH) + M ' 285.1481 ( C 16 H 19 N 3°2 requires M ÷ 285.1477); Anal. Found: C, 67.35; H, 6.74; K, 14.64; C 1 6 H 19 N 3°2 e -Ji-es C, 67.35; K, 6.71; N, 14.73. Pharmacological Da a Systolic blood • pressures were recorded by a modification of the tail cuff method described by I M Claxton, M G Palfrey an, R H Poyser, R L Whiting, European Journal of Pharmacology, .3_2, 179 (1976) . A W+W BP recorder, model 8005, was used to display pulses prior to all measurements rats were placed in a heated environment (33.5±0.5 C) before transfer to a restraining cage. Each determination of blood pressure was the mean of at least 6 readings- Spontaneously hypertensive rats (ages 12-18 weeks) with systolic blood pressures >170 mmHg were considered hypertensive.- Compound of Time Post % Change in % Change in Example 4 Dose Hours Systolic Blood Blood Heart Rate 6 rats Dose 3 g/kg 1 - 2 ± 6 r- " 4± p.o. 2 -.8 ± 6 -11 + Initial Blood Pressure 4 -26 ± 5 _ 6± 09 ± 6 mmHg 6 -19 ± 4 _ 7+ Initial Heart Rate 24 - 3 ± 9 5+ 6 65 ± 16 beats/ min Compound of Time Post % Change in Systolic Blood % Change in Example l Dose Hours Blood Heart Rate 6 rats Dose 10 mg/kg 1 _ 25 +1 3 ± 2 p.o. 2* - 18 ±3 1 ± 3 Initial Blood Pressure 4 - 16± 4 6 ± 2 246± 8 mmHg 6 - 10 + 4 4 + 3 Initial Heart Rate

Claims: CLAIMS 1. A compound of formula (I) Rl is chloro, bromo, C _6 alkylcarbonyl or cyano; one of R3 and R4 is hydrogen or C j __ alkyl and the other is Cχ_4 alkyl or R3 and R4 together are 02-5 polymethylene; and either; R5 is hydroxy, Cι_3 alkoxy or Cχ_8 acyloxy; and R2 is hydrogen and the cyclic amide moiety and R5 are trans 7 or R5 and R2 together form a bond. 2. A compound according to claim 1 wherein R3 and R4 are both methyl. 3. A compound according to claim 1 or 2 of formula (III): (III) wherein R-_ and n are as defined in formula (I). 4. A compound according to any one of claims 1, 2 or 3 wherein n is 1. 5. A compound according to any one of claims 1 to 4 wherein R^ is chloro, bromo, acetyl or cyano. 6. Trans-2,2-dimethyl-6-chloro-4-(2-oxo-pyrrolidinyl)-1, 2, 3,4,-tetrahydroquinolin-3-ol, 6-chloro-2,2-dimethyl-4-(2-oxo-pyrrolidinyl)-1, 2- dihydroquinoline, trans-2,2-dimethyl-6-bromo-4-(2-oxo-pyrrolidinyl)-1, 2, 3,4-tetrahydroquinolin-3-ol or trans-2,2-dimethyl-6-cyano-4-(2-oxo-ρyrrolidinyl)-1, 2, 3, 4-tetrahydroquinolin-3-ol 7. A process for the preparation of a compound according to any one of claims 1 to 5 which process comprises reacting a compound of formula (IV): OMPI with an anion of formula (V) : wherein Ri'is Ri or a group or atom convertible thereto; Rg is hydrogen or an N-protecting group; . and the remaining variables are as defined in claim 1 and thereafter if necessary converting Ri'to Ri and/or Rg to hydrogen; optionally C-__2 alkylating or C^_g acylating an R5 hydroxy group, or dehydrating a compound of formula (I) wherein R5 is hydroxy to form the compound of formula (I) wherein R5 and R2 together form a bond. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 9. A method of treating hypertension in mammals including man, which comprises administering to the suffering mammal an anti-hypertensive effective amount of a compound according to any of claims 1 to 6. f ' -

Inventors: EVANS JOHN MORRIS, STEMP GEOFFREY, EVANS, JOHN, MORRIS, STEMP, GEOFFREY
Applicants: BEECHAM GROUP PLC, BEECHAM GROUP P.L.C.
Application year: 1984
Main classification: C07D401
IPC codes: C07D215, C07D401, C07D491