AROMATIC AMINES

Abstract: Compounds of formula (I), in which Z represents O, S, SO2, CO, NR or a single bond, G represents a one or two ring, saturated or unsaturated carbocyclic or heterocyclic group optionally substituted by phenyl thrihalomethyl or at least groups selected from alkoxy C1 to 6 or halogen atoms, provided that when Z represents a single bond G does not represent phenyl, R represents hydrogen or alkyl C1-6, m and n each independently represent 2, 3 or 4, and q represents an integer from 1 to 3 inclusive, and pharmaceutically acceptable derivatives thereof. There are also described processes for producing the compounds and pharmaceutical, e.g. cardiac, compositions containing them.

Description: AROMATIC AMINES This invention relates to new compounds, processes for their preparation and compositions containing them. According to the invention we provide the compounds of formula I, in which Z represents 0, S, SO,, CO, NR or a single bond, G represents a one or two ring, saturated or unsaturated carbocyclic or heterocyclic group optionally substituted by phenyl j trihalomethy1 or at least two groups selected from alkoxy CI to 6 or halogen atoms, provided that when Z represents a single bond G does not represent phenyl, R represents hydrogen or alkyl Cl-6, and n each independently represent 2, 3 or 4, and q represents an integer from 1 to 3 inclusive, and pharmaceutically acceptable derivatives thereof. According to our invention we also provide a process for the production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises OMPI (a) selectively reducing a compound of the formula II, in which R. and R., which may be the same or different, each represent hydrogen or a protecting group, one of the pairs X 1 and X 4 , X and X , X and X~, and X. and X , each represent CO, and the remainder of X X,, X, and X each represent CH 2 , and m, n, q, G and Z are as defined above, and if necessary or desired thereafter, removing any protecting groups to give the corresponding compound of formula I, (b) producing a compound of formula I, in which Z represents SO., by selectively oxidising a compound of formula I, or a protected derivative thereof, in which Z represents S, and if necessary or desired thereafter, removing any protecting groups to give the corresponding compound of formula I, or (c) removal of a protecting group from a corresponding compound of formula I carrying one or more protected hydroxy or protected amine groups, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa. In process (a), the reducing agent may be electrophilic, for example diborane, or nucleophilic, for example a complex metal hydride, eg lithium aluminium hydride or sodium (2-raethoxyethoxy)aluminium hydride. The reaction may be carried out in a suitable solvent inert to the reaction conditions. Aprotic solvents are preferred, for example tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane. The reaction may be carried out at a temperature of from 0 to 100°C. When R- and/or R. represent a protecting group, the protecting group may be for example alkyl Cl-6, phenylalkyl C7-12, e.g. benzyl, or alkanoyl C2-6, e.g. acetyl. Removal of the protecting group depends on the nature of the protecting group; conventional techniques may generally be .employed, including acidic or basic cleavage, or hydrogenolysis. For example, protecting alkyl or phenylalkyl groups may be removed by cleavage using a protic acid, e.g. hydrochloric acid or hydrobromic acid at a temperature of 0 to 150°C, or a Lewis acid, e.g. by reacting with a boron trihalide in a halocarbon solvent. When the protecting group is alkanoyl, cleavage may be effected using a base, e.g. sodium hydroxide, in a suitable solvent, e.g. aqueous ethanol. Lewis bases, e.g. pyridine hydrochloride, may be used to cleave alkyl or phenylaklyl groups. 1-Phenylalkyl groups, e.g. benzyl, may be removed by catalytic hydrogenation using a suitable catalyst, e.g. palladium, in a suitable solvent, e.g. ethanol, or acetic acid. Oxidising agents that may be used in process (b) include hydrogen peroxide and organic peracids, eg m-chloroperbenzoic acid. The reaction may be carried out in a suitable solvent inert to the reaction conditions, eg a halogenated hydrocarbon solvent. Particular solvents that may be mentioned include dichloromethane and 1,2-dichloroethane. The reaction may be carried out at a temperature of from 0 to 100°C. The reaction may be carried out on a suitable unprotected de ivative of the compound of formula I. However we prefer the starting compound to have the nitrogen and/or oxygen groups bearing protecting groups. Suitable protecting groups for oxygen include those listed above for R- and R.; groups that may be particularly mentioned are alkyl CI to 6, eg methyl, and phenylalkyl C7. to 12, especially benzyl. Suitable protecting groups for nitrogen include alkanoyl groups, eg alkanoyl C2-6. A particular group that may be mentioned is trifluoroacetyl. The protecting groups may be removed by conventional techniques well known in the art. The removal of protecting groups, in process (c) may be carried out as described for process (a), under acidic, basic or hydrogenolytic conditions. The compound of formula I may have protected hydroxy and/or amino groups. Such groups, their application, and their removal, are well known and include those described in Protective Groups in Organic Chemistry, Ξd: J F W McOmie, Plenum Press (1973) and Protective Groups in Organic Synthesis, T W Greene, Wiley-Interscience (1981). The preparation of compounds of formula II depends on the nature of X.., X_, X_ and X.. When X, and X. both represent CO, and X. and X- both represent CH_, the compounds of formula II may be made by sequentially reacting a compound of formula III, NH Δ,-(CH.)m-Z-(CH2,)n-NHRo. Ill where R- represents hydrogen or a nitrogen protecting group removable in the presence of an amide bond, alkylene CONH alkylene, and m, n and z are as defined above, with the compounds of formulae IV and V, in any order, wherein L., and L_ represent good leaving groups, and q, G, R. and R. are as defined above. Suitable nitrogen protecting groups R 5 are well known in the art of peptide synthesis, and include for example alkoxycarbonyl groups, e.g. ethoxycarbonyl. Good leaving groups L. and L„ include, for example, halogen, e.g. chlorine or bromine; 1-imidazolyl, trifluoromethane sulphonate, alkyl carbonate, e.g. ethyl carbonate; benzyl carbonate; alkanoyloxy, e.g. acetyl; o trifluoracetoxy. The reaction may be carried out in a solvent which is inert to the reaction conditions, for example a chlorinated hydrocarbon, e.g. chloroform, in the presence of a non-nucleophilic base, e.g. triethylamine. The reaction may be carried out at a temperature of from about 0 to 100°C. The free acids corresponding to the compounds of formula IV and V, i.e. when L, and L. both equal hydroxy may be reacted, e.g. with thionyl chloride, ethyl chloroformate , or N ,N' -carbonyldiimidazole to convert the car boxy 1 groups to a group -COL, or -COL- respectively. When X, and X 3 both represent CO, and X. and X . both represent CH, , " the compounds of formula II may be prepared by sequentially reacting the groups L 3 and L . , in any order , in the compound of formula VI , ' 3 ∞- <«2> »-_-*- < αi 2> n-l- 00l 4 W in which L 3 represents a good leaving group, and L . represents either a good leaving group, or a group which may be readily converted into a good leaving group, and m, n and Z are as defined above, with the compounds of formula VII and VIII, wherein q, G, R 3 and R are as defined above. Good leaving groups that L 3 and L. may represent include those described above for L. and L 2> When h . represents a group which may be converted into a good leaving group, such convertable groups include alkoxy, e.g. ethoxy, methoxy; and hydroxy. The conversion may be effected using conventional techniques. We prefer to carry out the sequential replacement of 3 and L. as follows: with L. as a group convertable to a leaving group, L 3 may be reacted with a compound of formula VII or formula VIII. L. is then converted to a good leaving group, and reacted with the remaining compound of formula VII or formula VIII. The reactions may be carried out under conditions similar to those described above when X, and X. both l 4 represent CO. When both X, and X 3_ , or both X.2 and X 4. represent CO, and the remainder of X, , X 2 , X 3 and X. represent CH 2 , the corresponding compounds of formula II may be made by sequential reaction in any order with the nitrogen function and the carbonyl function of the compound of formula IX, R.NH (CH, 2) m -Z- (CH 2-) n— l . COL 4. IX wherein R-, L., m, n and z are as defined above, with the compounds of either formula IV and formula VIII, or the compounds of formula VII and formula V, as defined above. A typical procedure is as follows: with L. as a leaving group and R 5 as a protecting group, a compound of formula IX may be reacted with a compound of formula VIII, followed by conversion of R_ from a protecting group to a hydrogen, and the process is concluded by reacting this compound with a compound of formula IV, to give a compound of formula II in which X, and X 3 each represent CO, and X 2 and X represent CH 2 . The reactions may be carried out under conditions similar to those described above for the preparation of compounds of formula II when X, and X both represent CO. The compounds of formulae III, IV, V, VI, VII, VIII and IX are either known, or may be made from known compounds using techniques known per se. The acid addition salts of the compounds of formula I may be prepared by reaction of the free-base with an appropriate acid. The acid addition salts may be converted to the corresponding free-base by the action of a stronger base. The processes as described above may produce the compound of formula I or a derivative thereof. It is also within the scope of this invention to treat any derivative so produced to liberate the free compound of formula I, or to convert one derivative.into another. The compounds of formula I and the intermediates therefore may be isolated from their reaction mixtures using conventional techniques. Pharmaceutically acceptable derivatives of the compounds of formula I include pharmaceutically acceptable acid addition salts. Suitable salts include salts of mineral acids, for example, hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid; or organic acids, e.g. formic, acetic or lactic acids. The acid may be • polybasic, for example sulphuric, fumaric or citric acid. Other pharmaceutically acceptable derivatives are compounds which will be suitable bioprecursors (prodrugs) of the compounds of formula I and will be readily apparent to those skilled in the art and may be made from the compounds of formula I using conventional processes known per se or by processes analagous to those described above. Suitable bioprecursors include amides e.g. acetamides or benzamides of compounds of formula I, and esters, for example, carboxylic acid esters, e.g. alkanoyl, such as acetyl or isobutyryl, or aroyl, e.g. benzoyl. One or two ring, saturated or unsaturated, carbocyclic or heterocyclic groups that G may represent include phenyl, cyclohexyl, cyclohexenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, decalyl, pyridyl, quinolyl, piperidinyl, pyrrolo, pyrrolidinyl, thiophenyl and furanyl. A preferred group of compounds of formula I are those in which Z represents 0, S, S0 2 , CO or NR, R represents hydrogen or alkyl CI to 6, m and n each represent 2, 3 or 4, and q represents an integer from 1 to 3 inclusive, and pharmaceutically acceptable derivatives thereof. We particularly prefer Z to represent 0, S or S0 2 - A further preferred group of compounds of formula I are those in which z represents a single bond, G represents maphthyl, thiophenyl, cyclohexenyl, cyclohexyl or phenyl, the phenyl being substituted by phenyl or trihalomethyl or by at least two alkoxy CI to 6 or by at least two halogen atoms, m and n together represent an integer from 4 to 8 inclusive, q represents an integer from 1 to 3 inclusive, and pharmaceutically acceptable derivatives thereof. We particularly prefer G to represent naphthyl, thiophenyl, or phenyl, the phenyl being substituted by phenyl or trihalomethyl or by at least two alkoxy CI to 6 or by at least two halogen atoms. Specific groups that G ma.y represent include 2-, 3- and especially 4-biphenyl; 2-, 4- and particularly 3-trihalomethyl, eg 3-trichoromethyl; 3-trifluoromethylphenyl is especially preferred; 3- and especially 2-thiophenyl; 2- and especially 1-naphth l; cyclohexyl; amd cyclohexenyl. When G represents phenyl substituted by at least two alkoxy CI to 6 groups, the alkoxy groups may be the same or different. In particular, G may represent phenyl substituted by two alkoxy CI to 6 groups in which the alkoxy groups may be in a 1,2, 1,3 or 1,4 relationship to one another. Preferably G represents 3,4-dialkoxyphenyl, particularly 3,4-dimethoxyphenyl. When G represents phenyl substituted by at least two halogen atoms, the halogen atoms may be the same, eg all chlorine atoms, or different, eg selected from fluorine, chlorine, bromine or iodine. In particular, G may represent phenyl substituted by two halogen atoms, in which the halogen atoms may be in a 1,2, 1,3 or 1,4 relationship to one another. Preferably G represents 3,4-dihalophenyl, particularly 3,4-dichlorophenyl. We prefer compounds of formula I in which m + n is an integer from 4 to 7; and preferably 5 or 6. We prefer compounds of formula I in which q is 2. Specific values of m that may be mentioned include 2 and 3 * Specific values of n that may be mentioned include 2 and 3. When R represents alkyl, groups that may be mentioned include methyl, ethyl and propyl. The compounds of formula I, and pharmaceutically acceptable derivatives thereof, are useful because they possess pharmacological activity in animals. Thus the compounds act on peripheral and/or central dopamine receptors. As such, they lower blood pressure, reduce heart rate and increase blood flow to certain vascular beds, e.g. renal beds. Some compounds also have an action on other adrenoreceptors, and these exhibit cardiac stimulant and bronchodilato effects. Activity of the compounds has been observed in the following assay systems: (a) canine renal blood flow and canine femoral blood flow, McNay and Goldberg, J. Pharmac, Exp. Ther., 151, 23-31, 1966. (b) rabbit isolated ear artery, McCullogh , Rand and Story, Br . J . Pharmac, 49 , 141-142 , 1973 , and (c) cat nictitating membrane , Gyorgy and Doda, Arch . Int. Pharmacodyn, 226 , 194-206 , 1977 . The compounds of the invention are indicated for use in the treatment of congestive heart failure, renal failure , ang ina pec tor is , ischaemic heart disease , hyper tens ion and reversible obstructive airways disease, hyperprolactinaemia and also in Parkinson ' s disease and m OMPI _ other neurological disorders. The dosage administered will naturally depend on the compound employed, the mode of administration and the desired effect. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of from 0.05 ug to 50mg per kilogram of body weight per day. For man, the indicated total daily dosage is in the range 2.5 ug to 3.5g, which may be administered in divided doses of, for example 1 ug to 750mg. The new compounds of the present invention may be used in combination with, or sequentially with, a wide variety of other pharmaceutically active substances. Where appropriate the compounds may be mixed with one or more other active substances. The particular mixture or dose regimen used, and ratio of the active ingredients will depend on a variety of factors including the condition to be treated, the mode of administration, the particular active ingredients and the patient concerned. Examples of compounds with which the present compounds may be mixed include: beta-blockers, especially cardioselective beta blockers, for example, atenolol; diuretics, for example thiazides, e.g. furosemide; angiotensin converting enzyme inhibitors, for example captopril; inotropic agents, for example, amrinone; antiemetics, for example, sulpiride, metoelopram e, or domperidone. The compounds of formula I, and pharmaceutically acceptable derivatives thereof, have the advantage that they are more efficacious or produce less undesirable side effects in certain pharmacological models, or are longer acting than compounds of similar structure to the compounds of formula I. The compounds of the invention may be administered by a wide variety of routes and may act systemically or locally. Thus the compounds may be administered by oral or nasal inhalation to the lung, to the buccal cavity, oesophageally, rectally, topically to the skin or to other available surfaces of the body, by injection, e.g. intravenously, intramuscularly, intraperitoneally, or by surgical implant. According to our invention we also provide a pharmaceutical composition comprising preferably less than 80% and more preferably less than 50% by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees; microcrystalline cellulose, calcium OMPI ^ATlO ' ≤y phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for supposito ies; natural or hardened oil or waxes; and for inhalation compositions, coarse lactose. When the compounds are to be used in aqueous solution it may be necessary to incorporate a chelating or sequestering agent, e.g. sodium edetate, an antioxidant, e.g. sodium metabisulphite or buffering agents, e.g. sodium hydrogen phosphate and sodium phosphate. Aqueous solutions typically contain up to about 10% w/w of the new compound and may be used for intravenous injections. According to the invention, we further provide a method of increasing the force of contraction of the heart in an animal, either human or non-human, which method comprises administering to the animal an effective amount of one or more compounds of the invention. The invention is illustrated, but in no way limited by the following examples, in which temperatures are in degress centrigrade. Example 1 4-(2-(2-(3-(2-Phenylethylamino)propylthio)ethylamino) ethyl-1,2-benzenediol (a) 3(Methoxycarbonylmeth lthio)propionic acid OMPI A mixture of E> -prop iolac tone (15.2ml, 0.24 mole) and ethylthioglycollate (43.3ml, 0.55 mole) was heated on a steam bath for 72 hr under nitrogen. The cooled reaction mixture was dissolved in ether and extracted with saturated aqueous sodium bicarbonate solution (2 x 250ml). The combined aqueous extracts were washed with ether (2 x 100ml) acidified with 2N hydrochloric acid (pH 3) and extracted with ethyl acetate (5 x 100ml). The combined organic extracts were washed with water and brine, dried (Na 2 SO ) and evaporated to give the sub-title compound as a colourless oil (40. lg, 94%) nmr (CDC1 3 ) «S :2.6-3.2, 4H,ra,; 3.3, 2H,s; 3.8, 3H,s; 11.55, 1H, s exchanged with D 2 0. (b) 3-(2-Oxo-2-(2-(3,4-dimethoxyphenyl)ethylamino)ethyl- thio)-N- (2-ρhenylethyl)propamamide. The product from step a (10.0g, 0.0562 mole) was dissolved in dry dichlorome thane (300ml) and N,N-carbon ldiimidazole (9.4g, 0.058 mole) added in portions under nitrogen with stirring. Stirring was continued for 4 hr and 2-phenylethylamine (7.0ml, 0.0562 mole) was added and the mixture stirred for 18 hr. The solution was washed with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water, dried (Na 2 S0 ) and evaporated to give a yellow oil (13.3g) mass spectrum M m/e 281. A portion of this oil (12.8g) was dissolved in methanol (100ml) and to this solution was added water (50ml) and saturated aqueous sodium bicarbonate (100ml) and the mixture heated to reflux for 3 hr . The major ity 5 of the methanol was removed in vacuo and the aqueous residue washed with ether (discarded) , acidified and extracted w ith ethyl acetate (4 x 100ml) . The combined extracts were washed with water, dr ied (Na 2 SO . ) and evaporated. The residue was tr iturated with ether to give 0 a solid (7.9g) , mass spectrum M + m/e 267 . . Th is solid was dissolved in dry dichlorome thane (300ml) , N ,N-carbonyldiimidazole (5 .13g) was added and the solution stirred for 3 hr under nitrogen. 2- (3 ,4-Dimethoxyphenyl) ethylamine (5.13g) was added and 5 the solution stirred for 18 hr , washed with 2M hydrochlor ic acid, water , saturated sodium bicarbonate solution and water, dr ied (Na 2 S0 . ) and evaporated . The residue was recrystallised from methanol to give the sub title compound as a cream solid (10 .9g, 38%) ; mp 20 156-8°. (c) 3-(2-(2-(3,4-Dimethoχyρhenyl)ethylamino)ethylthio)-N- (2-phenylethyl)propanamime dihydrochloride A mixture of the product from step b (5.2g - 0.012 mole) and diborane (70ml of 1M solution in 25tetrahydrofuran) in tetrahydrofuran (200ml) was heated to reflux for 5 hr with stirr ing under nitrogen. Methanol was added to the cooled reaction mixture and the solution stirred for 18 hr . The solvents were evaporated and the residue treated wth a saturated solution of hydrogen chlor ide gas in methanol. The mixture was heated to reflux for 1 hr , the solvents evaporated and the residue recrystallised from methanol to give the sub t itle compound as a wh ite solid (4.75g , 83%) ; mp 241-4°. (d) 4- (2- (2- (3- (2-Phenylethylamino) propylthio) ethylamino) eth l-l f 2-benzened iol dihydrobromide The product from step (c) (3.5g - 0 .0074 mole) was suspended in dry dichlorome thane (200ml) and the mixture cooled to -70°. Boron tr ibromide (4 .0ml, 0.042 mole) was added and the mixture stirred for 5 hr under nitrogen wh ilst warming to room temperature . Methanol was added and the mixture stirred for 18 hr . The solvents were evaporated and the residue recrystallised twice from ethanol to give the dihydrobromide of the t itle compound as a wh ite solid (3.2g, 81% ) ; mp 157-9 . Example 2 4- (2- (2- (3- (2-Phenylethylamino) ethylthio) propylamino) e thyl-1 , 2-benzened iol (a) N- (2- (3 ,4-Dimethoxyphenyl) ethyl-3- (2-oxo-2- (2 -phenyl - ethylamino) ethylth iopropanamide The subtitle compound was prepared by the method of OMPI o Example 1 (b) , mp 153-5 . (b) N- (2- (3 r4-Dimethoχyphenyl) ethyl-3- (2- (2-phenyl- ethylamino) ethylthiopropanamine dihydrochlor ide The subtitle compound was prepared by the method of Example 1 (c) , mp 242-5 . (c) 4- (2-(3- (2- (2-Phenylethylamino) ethylth io) ropylamino) ethyl-l ,2-benzenediol dihydrobromide The title compound was prepared as a dihydrobromide, by the method of Example 1 (d) , mp 156-9° Example 3 4- (2- (2- (3- (2-Phenylethylamino) propoxy) ethylamino) ethyl) -1 ,2-benzenediol (a) 3- (2-0x0-2- (2- (3 ,4-dimethoxyρhenyl) ethylamino) ethoxy) -N - (2-phenylethyl) ropanamide The sub title compound was prepared by the method of Example 1 (b) , mp 108-10°. (b) 3- (2- (2- (3 ,4-Dimethoxyphenyl) ethylamino) ethoxy) -N- (2- phenylethyl) propanamine dihydrochlor ide The subtitle compound was prepared by the method of Example 1 (c) , mp 207-10°. (c) 4- (2- (2- (3- (2-Phenylethylamino) propoxy) ethylamino) ethyl) -1 ,2-benzenediol The title compound was prepared as a dioxalate , by the method of Example 1 (d) , mp 149-51°. Example 4 • 4- (2- (3- (2- (2-Phenylethylamino) ethoxy) propylamino) ethy 1 ) -1 , 2 -ben z ened io 1 (a) 3- (2-OXQ-2- (2-phenylethylamino) ethoxy) -N- (2- (3 , 4- dimethoxyphenyl ethylpropanamide mp 107-110° 5 (b) N- (2- (3 ,4-dimethoxyphenyl) ethyl) -3- (2- (2-phenyl ethylamino) ethyl) propanamine dihydrochlor ide The subtitle compound was prepared by the method of Example 1(c), mp 194-7° (c) 4- (2- (3- (2- (2-Phenylethylamino) ethoxy) propylamino) 0 ethyl) -1 , 2-benzened iol The title compound was prepared by the method of Example 1(d), as a dihydrobromide, mp Example 5 4-(2-(2-(3-(2-Phenylethylamino)propanesulphonyl) 5 -ethylamino)ethyl)-l,2-benzenediol (a) 3,4-Dimethoxy-N-(2-(3-(2-phenylethylamino) propylsulphonyl) ethyl) -benzeneethanamine dihydrochlor ide A solution of tr ifluoroacetic anhydride (2.0ml, 2.97g, 14.1 moles) in dry dichlorome thane (20ml) was added 0 dropwise with stirring to the product from Ex 1(c) (1.8g, 3.8 mmoles) and triethylamine (1.6ml, 11.5 mmoles) in dry dichlorome thane (100ml). The mixture was stirred for 3 hours, then washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and water and dried 5 (Na 2 so 4 ) . This solution of the bis tr if luoroacetyl der ivative was cooled to 0 and treated with stirr ing with m-chloroperoxybenzoic acid (1.38g, 8.0 mmoles) . The solution was allowed to warm to room temperature and stirred for 1.5 hours , then washed w ith 2% w/v sodium bisulphite solution and saturated sodium bicarbonate solution, dr ied and evaporated to give the N ,N' -bis tr if luoroacetyl der ivative of the sub-title product as a glassy semi-solid (2.3g) . Th is crude mater ial was dissolved in methanol (30ml) and potass ium carbonate (1.04g, 7 .5 mmoles) in water added . The dark mixture was boiled under reflux for 2.5 hr , then the bulk of the methanol was removed by distillation under vacuum. The aqueous residue was extracted with ethyl acetate and the extracts were dr ied and evaporated to an oil, which was dissolved in ethanol (20ml) and treated with concentrated hydrochlor ic acid (1ml) .. The white precipitate was collected and recrystallised from ethanol-water giving sub-t itle compound (1.31g) as colourless crystals mp 246-8° (decomp) . ( ) 4- (2- (2- ( 3- (2-Phenylethylamino) propane sulphonyl) - ethylamino) ethyl) - ,2-benzenediol dihydrobromide The product of step (a) above (1.5g) in 48% aqueous hydrobromic acid (15ml) containing aqueous hypophosphorous acid (5 drops) was heated at reflux under nitrogen for 4 hr . The soluton was cooled and crystals which separated . were filtered and washed with cold ethanol and ether to give the dihydrobromide as the title compound (1.2g) m.p. 190 - 191° (from 2-propanol-methanol) . Example 6 5 The following compound was made by methods analogous to those described in Example 5: 4- (2- (3- (2- (2-Phenylethylamino) ethane sulphonyl) ethylamino) ethyl) -1,2-benzenediol dihydrobromide m.p. 191.5 - 193.5°. 10 Example 7 4-(2-(6-(2-(3,4-Dimethoxyphenyl)ethylamino)hexylamino) ethyl) -1,2-benzenediol - (a) N (2- (3 ,4-bis (Phenylmethoxy) ethyl) -N ' -2- (3 ,4- dimethoxyphenyl) ethyl) hexan-1 , 6-diamide. 15 To a solution of 6- (2- (3 ,4-dimethoxyphenyl) ethylamino -6-oxohexanoic acid (3.93g, 0.0127 mole) in dry dichloromethane (100ml) was added triethylamine (3.22g, 4.4ml, 0.032 mole) and ethylchloroformate (1.38g, 1.21ml, 0.0127 mole) with stirring and cooling. The solution was 20 stirred at room temperature for 1 hour and 2-(3,4-bis (phenylmethoxy) phenyl) ethylamine hydrochloride (4.71g - 0.0127 mole) added and the solution stirred at room temperature for 20 hours. The reaction mixture was washed with 2 N hydrochloric acid (3 x 100ml), 5% w/v sodium 25hydroxide solution (2 x 100ml) and water (2 x 100ml), dried (Na 2 SO ) and evaporated. The residue was recrystallised from 2-propanol to give a white solid (6.23g, 77%); mp 151-2°. (b) N-(2-(3,4-Bis (phenylmethoxy) ethy 1-^-2- (3 ,4- dimethylphenyl) ethyl) hexane-1 , 6-diamine dihydrochlor ide The product from step (a) (5.5g, 0.0086 mole) was dissolved in dichlorome thane (100ml) and to this solution was added a solution of lithium aluminium hydride (34ml of 1M solution, 0.034 mole) and the mixture heated to reflux for 18 hours. 10% w/v sodium hydroxide solution was added cautiously, the organic layer separated and the aqueous layer extracted with dichloromethane (2 x 20ml). The combined organic extracts were washed with water, dried (Na-SO.) and evaporated. The residue was dissolved in warm methanol saturated with hydrogen chloride gas and then the solvents were evaporated. The residue was recrystallised from methanol to give a white solid (2.51g 42%) ? mp 238-40°. (c) 4-(2-(6-(2-(3,4-Dimethoxyphenyl)ethylamino)hexylamino) ethyl) -1,2-benzenediol dihydrochlor ide The product from step (b) (2.41g, 0.0036 mole) was dissolved in methanol (200ml) and hydrogenated at room temperature and pressure in the presence of 10% palladium on carbon (0.4g). The catalyst was removed by filtration, the filtrate evaporated and the residue triturated with hot 2-propanol to induce crystallisation. The solvent was removed in vacuo and the residue recrystallised from ethanol to give the dihydrochlor ide of the title compound as a white solid (1.30g, 73%); mp 188-91°. Example 8 4- (2- (6- (2- (2-Thienyl) ethylamino) hexylamino) ethyl) -1.2 -benzenediol a) N- (2- (3 ,4-Dimethoxyphenyl) ethyl) -N ' - (2- (2-th ienyl) ethyl hexane-1 , 6-diamide This was prepared from 6-(2-(3,4-dimethoxyphenyl)ethyl amino-6-oxohexanoic acid and 2-thiopheneethanamine by the method of Example 7 (a) above. (b) N- (2- (3 , 4-Dimethoxyphenyl) ethyl-N' -2- (2-thienyl) ethyl hexane-1 , 6-diamine Boron trifluoride etherate (8.5g) in dry tetrahydrof uran (50ml) was added dropwise with stirring to the product from step a) (4.3g) and sodium borohydride (1.75g) in dry tetrahydrof uran (200ml). The resulting suspension was heated at reflux for 8 hours under Chitrogen. Methanol was then added cautiously and the solution evaporated to dryness. The residue was heated at reflux for 30 minutes in methanol (100ml) saturated with hydrogen chloride gas. The solution was cooled, to give on filtration, the dihydrochlor ide of the sub title 3ompound, (2.2g), mp 269.5-271.5 (from methanol) . (c) 4- (2- (6- (2- (2-Thienyl) ethylamino) hexylami no) ethyl) -1,2-benzed iol The product of step (b) (2.2g) in dry tr iethylamine (l . Oβg) in dry dichlorome thane (100ml) was cooled to -70° and boron tr ibromide (4.76g) was added under nitrogen. The resulting suspension was stirred at -70° for 1 hour and then allowed to warm to ambient temperature overnight. Excess methanol was added cautiously, the solution taken to dryness and the residue crystallised by tr ituration with dry ethanol and dry ether . The result ing deliquescent solid was dissolved in water and neutralised with saturated aqueous sodium bicarbonate solution . The precipitated, air-sens itive base was filtered, washed w ith water , ethanol and ether and was then dissolved in boiling methanol ( 50ml) and treated with a solution of oxalic acid (Ig) in methanol (10ml) . The crystals which separated on cooling (0 .5g) we re filtered and washed thoroughly with hot methanol giving the title compound as a dioxalate salt conta ining 1.5 moles water of crystallisation mp 213-5 . Example 9 4- (2- (6- (2- ( (l ,l ' -Biphenyl) -4-yl) ethylamino) hexylamino) ethyl -1 ,2-benzenediol (a) N' (2- ( (1 ,1' -Biphenyl) -4-yl) ethyl) -N' - (2- (3 ,4- dimethoxyphenyl) ethyl) hexane-1 , 6-diamide Tr ie thy leonine (5 .6ml, 0.04 mole) was added to a solution of 6-oxo-6-(2-(3,4-dimethoxyphenyl)ethyl) aminohexamoic acid (5.56g, 0.018 mole) in dry dichlorome thane (200ml) . This solution was cooled to 0° and ethylchloroformate (1.8ml, 0.019 mole) added and the solution stirred for 2 hours at room temperature. 2-( (l,l'-Biphenyl)-4-yl)ethylamine hydrochlor ide (4.4g, 0.019 mole) was added and the mixture stirred at room temperature overnight. A solid was isolated by filtration washed well with dichlorome thane, 2M aqueous hydrochloric acid and water and dried in vacuo. The dichlorome thane layer from the filtrate was separated, washed with 2M aqueous hydrochloric acid and water, dried (Na 2 SO.) and evaporated to give a total yield of 8 ** .8g. This solid was recrystallised twice from ethanol to give the sub title compound as a white solid (7.3g, 83%) mp 177-9°. (b) N-(2-((l,l , -Biphenyl)-4-yl)ethyl-N' (2- (3 ,4-dimethoxy phenyl) ethyl) hexane-1 , 6-diamine The product from step (a) (6.5g, 0.013 mole) was suspended in dry tetrahydrofuran (200ml), a solution of diborane in tetrahydrofuran (0.065 mole, 65ml of 1 molar solution) added and the mixture heated to reflux with stirring under nitrogen for 5 hours after which time the suspended solid had dissolved. Methanol was added cautiously to the cooled reaction mixture and the solution stirred at room temperature for 16 hours. The solvents were removed in vacuo and the residue dissolved in methanol, treated with a solution of hydrogen chloride gas in methanol and the mixture heated to reflux for 2 hours. After cooling the precipitate was isolated by filtration and recrystallised twice from methanol giving the dihydrochlor ide of the sub title compound as a white solid (5.6g, 79%, mp 231-4°). (c) 4- (2- (6- ( (1 ,1 ' -Biphenyl) -4-yl) ethylamino) hexylamino) ethyl-l,2-benzenediol dihydrobromide The product from step (b) (5.0g, 0.0094 mole) was heated to reflux with stirring under nitrogen with 48% aqueous hydrobromic acid (100ml) and hypophosphorous acid (0.1ml) for 4 hours. The solid precipitated on cooling was isolated, washed with water, dried in vacuo at 80° and recrystallied twice from methanol affording the dihydrobromide of the title product as a white solid (2.6g, 47%), mp 248-51°. Example 10 4- (2- (6- (2- (3 ,4-Dichlorophenyl) ethylamino) hexylamino) ethyl) -1,2-benzenediol (a) N-(2-(3,4-Dichlorophenyl)ethyl)-N'-(2-(3.4-dimethoxy- phenyl) ethyl) hexane-1 , 6-diamide This was made by the method of Example 7 (a) mp (b) N-(2-(3,4-dichlorophenyl)ethyl)-N'-(2-(3,4-dimethoxy- phenyl) ethyl) hexane-1 , 6-diamine dih drochlor ide . The product of step (a) was treated by the method of Example 8 (b) to give the sub title compound, mp 275-277°. (c) 4- (2- (6- (2- (3 ,4-dichlorophenyl) ethylamino] ) exylamino) 5 ethyl) -1 ,2-benzenediol dihydrobromide The product of step (b) was treated by the method of Example 9 (c) to give the dihydrobromide salt of the title compound, mp 169.5-171°. Example 11 10 4-(2-(6-(2-(3-(trifluoromethyl)ρhenyl)ethylamino) hexylamino) ethyl) -1 , 2-benzened iol (a) N- (2- (3 ,4-Dimethoχyphenyl) ethyl) -N- (2-(3- ( tr if luoromethyl) phenyl) ethyl) hexane-1 , 6-diamide This was made by the method of Example 7 (a), mp 15125-6.5° (b) N- (2- (3 ,4-Dimethoχyphenyl) ethyl) -N- (2- (3- (tr if luoro methyl) phenyl) ethyl) hexane-1 , 6-diamine dihydrochlor ide This was made by the method of Example 8 (b) , mp 239-241°. 20 (c) 4-(2-(6-(2-(3-(Trifluoromethyl)phenyl)ethylamino) hexylamino) ethyl) -1,2-benzenediol This was made by the method of Example 9 (c) to give the dihydrobromide of the title compound, mp 235-237 . Example 12 4- (2- (6- (2- (1-Naphthalenyl) ethylamino) hexylamino) OMPI ethyl) -1 ,2-benzenediol (a) N- (2- (3 ,4-Dimethoxyρhenyl) ethyl) -N ' - (2- (1- naphthalenyl) ethyl) -hexane-l,6-diamide This sub title compound, mp 155.5-156.7° was prepared from 6-(2-(3,4-dimethoxyphenyl)ethylamino-6-oxo -hexanoic acid and 2-(l-naphthyl)ethylamine hydrochlor ide by the method of Example 7 (a) . (b) N- (2- (3 ,4-Dimethoχyphenyl) ethyl) -N' - (2- (1-naphthalenyl) ethyl) -hexane-1 , 6-diamine dihydrochlor ide The product of step (a) was treated by the methof of Example 8 (b) to give the sub title compound, mp 224.8-226.6°. (c) 4- (2- (6- (2- (1-Naphthalenyl) ethylamino) hexylamino) ethyl) -1,2-benzenediol dihydrobromide The product of step (b) was treated by the method of Example 9 (c) to give the dihydrobromide of the title compound, mp 183.5-185.5°. Example 13 4- (2- (6- (2-Cyclohexyl thylamino) hexylamino) ethyl) - benzene-l , 2-d iol The title compound and the following intermediates were made by the method of Example 8. (a) N-(2-(3,4-Dimethoxyphenyl)ethyl)-N 1 -(2-cyclohexyl ethyl)hexane-1,6-diamide Colourless needles from aqueous ethanol, mp 158-160°. (b) N-(2-(3,4-Dimethoχyphenyl)ethyl)-N 1 -(2-cyclohexyl eth l)hexane-1,6-diamine dih drochloride, mp 255-7 (dec). (°) 4-(2-6-(2-Cyclohexylethylamine)hexylamino)ethyl)- benzene-l,2-diol dihydrobromide, mp 182.5-183.5°.

Claims: • What we claim is 1. A compound of formula I, in which Z represents 0, S, S0 2 , CO, NR or a single bond, G represents a one or two ring, saturated or 10 unsaturated carbocyclic or heterocyclic group, optionally substituted by phenyl, trihalomethyl or at least two groups selected from alkoxy CI to 6 or halogen, provided that when Z represents a single bond G does not represent phenyl, 15 R represents hydrogen or alkyl CI to 6, m and n each independently represent 2, 3 or 4, and q represents an integer from 1 to 3 inclusive, and pharmaceutically acceptable derivatives thereof. 2. ' A compound according to Claim 1, wherein G represents 20 naphthyl, a 6-membered saturated or unsaturated carbocylic group or a ring \ A ^ t where A represents NH, 0 or S, optionally substituted by phenyl, trihalomethyl or at least two groups selected from alkoxy CI to 6 or halogen. 3. A compound according to Claim 1, wherein G represents 25 naphthyl, thiophenyl, cyclohexenyl, cyclohexyl, phenyl; or _ OMPI j phenyl substituted by phenyl, trihalomethyl or at least two groups selected from alkoxy CI to 6 or halogen. 4. A compound according to Claim 1, wherein Z represents 0, S or S0 2 » 5. A compound according to Claim 1, wherein m and n together represent an integer from 4 inclusive. 6. A compound according to Claim 1, wherein q is 2. 7. 4-(2-(2-(3-(2-Phenylethylaraino)propylthio)ethylamino) e thy 1-1 , 2 -benzened iol, 4- (2- (2- (3- (2-Phenylethylamino) ethylthio) ropylamino) e thyl-1.2-benzened iol, 4- (2- (2- (3- (2-Phenylethylamino) ropoxy) ethylamino) ethyl) -1 , 2-benzened iol, 4- (2- (3- (2- (2-Phenylethylamino) ethoxy) propylamino) ethyl) -1.2-benzened iol, 4- (2- (.2- (3- (2-Phenylethylamino) propane sulphonyl) -ethylamino) ethyl) -1 , 2-benzene iol, 4- (2- (3- (2- (2-Phenylethylamino) ethane sulphonyl) ethylamino) ethyl) -1 . 2-benzene iol, 4- (2- (6- (2- (.3 ,4-Dimethoxyphenyl) ethylamino) hexylamino) ethyl) -1 , 2-benzened iol, 4- (2- (6- (2- (2-Thienyl) ethylamino) hexylamino) eth l) -1,2 -benzened iol, 4-(2-(6-(2-( k (l,l'-Biphenyl)-4-yl)ethylaraino) hexylamino) e thyl-1 ,2-benzened iol # 4- (2- (6- (2- (3 , -Dichlorophenyl) ethylamino) hexylamino) ethyl) -1 ,2 -benzened iol, 4- (2- (6- (2- (3- (tr if luoromethyl) phenyl) ethylamino) hexylamino) ethyl) -1 ,2-benzenediol 5 4- (2- (6- (2- (l-Naphthalenyl) ethylamino) hexylamino) . ethvl) -l ,2-benzenediol ; 4- (2- (6- (2-Cyclohexylethylamino) hexylamino) ethyl) - benzene-1.2-d iol, and pharmaceutically acceptable acid addit ion salts 10 thereof . 8 . A pharmaceutically composit ion compr is ing a compound according to Claim 1, in admixture w ith a pharmaceutically acceptable adjuvant, diluent or carr ier . 9. A process for the production of a compound according 15 to Claim 1 , wh ich compr ises (a) selectively reducing a compound of the formula II , in which R 3 and R., which may be the same or different, each represent hydrogen or a protecting group, one of the pairs X. and X., X 2 and X 3 , X. and m X , and X 2 and X 4 , each represent CO, and the remainder of X,, X 2 , X 3 and X each represent CH 2 , and m, n, q, G and Z are as defined in Claim 1, and if necessary or desired thereafter, removing any protecting groups to give the corresponding compound of formula I, (b) producing a compound of formula I, in which Z represents S0 2 , by selectively oxidising a compound of formula I, or a protected derivative thereof, in which Z represents S, and if necessary or desired thereafter, removing any protecting groups to give the corresponding compound of formula I, or (c) removal of a protecting group from a corresponding compound of formula I carrying one or more protected hydroxy or protected amine groups, and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof, or vice versa. 10. A compound of formula II as defined in Claim 9. 11. A method of treatment of a cardiovascular condition, which comprises administration of an effective amount of a compound according to Claim 1 to a patient suffering from such a condition.

Inventors: DIXON JOHN, INCE FRANCIS, DIXON, JOHN, INCE, FRANCIS
Applicants: FISONS PLC
Application year: 1984
Main classification: C07C91
IPC codes: A61K31, C07C317, C07C323, C07D333