IE47131B1

IE47131B1 - Indoles

Info

Publication number: IE47131B1
Application number: IE1448/78A
Authority: IE
Original assignee: Sandoz Ltd
Priority date: 1977-07-21
Filing date: 1978-07-19
Publication date: 1983-12-28
Also published as: IL55170A0; AU3818278A; GB2001971A; GB2001971B; CA1098909A; DE2830211A1; SE7807753L; PT68317A; NZ187909A; FI782229A; IL55170A; IE781448L; NL7807626A; IT7850299A0; FR2398058B1; DK312878A; SE435374B; BE869133A; FR2398058A1; JPS5422364A

Abstract

The compounds of formula I wherein R is a group wherein A is C2-5 alkylene, X is a bond, oxygen or sulfur, R3 is hydrogen, hydroxy, C1-4 alkoxy, halogen of atomic number of from 9 to 35, cyano, carbamoyl or a group NHCORd, wherein Rd is C1-4 alkyl, and R4 is hydrogen and, when R3 is C1-4 alkoxy, R4 additionally may be C1-4 alkoxy or, when R3 is halogen of atomic number of from 9 to 35, R4 additionally may be halogen of atomic number of from 9 to 35 either i) R1 is hydrogen or methyl and R2 is cyano, CONRaRb, COORc or CH2ORe, wherein Ra, Rb, Rc and Re independently are hydrogen or C1-4 alkyl, or ii) either R1 is methyl and R2 is Cl or Br or R1 is Cl or Br and R2 is hydrogen or methyl, with the provisos that a) X is separated from the nitrogen atom of the 3-amino-2-hydroxy-propoxy chain by at least 2 carbon atoms, b) when X is a bond, P3 is other than hydrogen and c) when R2 is cyano, R additionally may be C3-7 alkyl are useful as alpha - and beta -adrenoceptor blocking, anti-arrhythmic and anti- hypertensive agents and as inhibitors of metabolic effects of emotional stress.

Description

INDOLES The present invention relates to 1-(indol-4-yloxy)3-amino-2-propanol derivatives.

Xn accordance with the invention there are provided compounds of formula I wherein R is a A is alkylene of 2 to 5 carbon atoms, X is a bond, oxygen or sulfur.

R3 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen of atomic member of from 9 to 35.. cyano, carbamoyl or a group NHCOR^, wherein Rj is alkyl of 1 to 4 carbon atoms, and R^ is hydrogen and, when Rg is alkoxy of 1 to 4 carbon atoms, R^ additionally may be alkoxy of 1 to 4 carbon atoms or, when Rg is halogen of atomic number of from 9 to 35, R^ additionally may be halogen of atomic number of from 9 to 35 lc either i) Rg is hydrogen or methyl and Rg is cyano, CONR^P^, COORc or CH^OR^, wherein Ra,Rb,Rc and Rfi independently are hydrogen or alkyl of 1 to 4 carbon atoms, or ii) either Rg is methyl and Rg is halogen of atomic number of from 17 to 35 or Rg is halogen of atomic number of from 1? to 35 and Rg is hydrogen or methyl, with the provisos that a) X is separated from the nitrogen atom of the 3amino-2-hydroxypropoxy chain by at lec. :t 2 carbon atoms, b. when x is a bond, Rg is other than hydrogen and is c’ when Rg is cyano, R additionally may he alkyl cf to 7 carbon atoms. 7131 -3 R preferably is a group A-XX pre10 ferably is a bond or oxygen. Rg preferably is hydrogen, hydroxy or alkoxy. R^ preferably is hydrogen or alkoxy.

R^ preferably is hydrogen or halogen. Rg preferably is methyl, cyano or CONR^R^. R&, R^ and Rg preferably are hydrogen. Rc preferably is alkyl.

Alkyl (except as indicated hereunder for R and Rc) and/or alkoxy preferably are of 1 or 2, especially of 1 carbon atom. When R is alkyl, it preferably is of 3 to 5 carbon atoms and preferably is branched, especially in the position a to the nitrogen atom to which it is bound. Interesting alkyl groups R are e.g. isopropyl, tertbutyl and 3-pentyl, especially tert-butyl. When Rc is alkyl,it preferably is of 1 to 3 carbon atoms; when it is of more than 2 carbon atoms, it preferably is branched, as e.g. in isopropyl.

Halogen preferably is bromine of chlorine, especially chlorine. A preferably is branched alkylene, especially in the position a to the nitrogen atom to which it is bound, e.g, the group -CH(CHg)-CHg-, -C(CHg)g-CKgα cc or -C(CHg)(CHg)g-, or it is ethylene, a When Rg and R^ are hydrogen, X preferably is oxygen. When Rg is not hydrogen, X preferably is a bond.

When Rj is not hydrogen, it preferably is in the para position. When R^ is not hydrogen, it preferably is in the meta position. When R^ is alkoxy or halogen, it preferably is identical to R^.

A group of compounds of formula X are the compounds of formula Xx wherein Rx is a group A~XX10 defined above, either i) Xx is oxygen or sulfur and Rx to Rx have the significances indicated above for R. to R. 4 os ii) Xx is a bond and either j) RX is alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35 , Rx is hydrogen and, when Rx is alkoxy of 1 - 5 to 4 carbon atoms, R^ additionally may be alkoxy of 1 toe 4 carbon atoms or, when Rg is halogen of atomic number of from 9 to 35, R^ additionally may be halogen of atomic number of from to 35, Rg is hydrogen or methyl and R^ is CONR^R^, wherein Rfi and R^ are as defined above, or jj) Rg is hydroxy, cyano, carbamoyl or NHCOR^, wherein R. is as defined above, d X R^ is hydrogen and Rg and Rg have the significances indicated above for Rg and R2, with the proviso, that XX is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2hydroxypropoxy chain.

A group of compounds of formula Ix are the compounds of formula Ix' wherein A is as defined above, X * X ' is oxygen or sulfur and X * X 1 Rj to have the significances indicated above for Rj to , χ ι with the proviso, that X is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino2-hydroxypropoxy chain.

In accordance with the invention, a compound of formula I may be obtained by a process comprising reacting a corresponding compound of formula II I H wherein Rj and Rj are as defined above and Ro is a group capab.' of reacting with an amine to give a 2-arcino-l-hydroxyethyl group, with a corresponding compound of formula III R - NH2 III wherein R is as defined above. - 7 The present process is an amination by a primary amine. It may be effected in conventional manner for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds. For example R may be a group of ' /Os formula -CH-CHg or a reactive derivative of this group, e.g. of formula -CHiOHj-CHgY, wherein Y is halogen, preferably chlorine or bromine, or a group R -SO_r-O, wherein y z is phenyl, tolyl or lower alkyl. Y is especially chlorine. The reaction is effected preferably in an inert organic solvent, e.g. in an appropriate ether such as dioxane. Optionally an excess of a compound of formula III may be used as solvent. Alternatively the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20 to about 200°C, conveniently the reflux temperature of the reaction mixture when a solvent is present.

Free base forms of the compounds of formula I may be converted into salt forms, e.g. into acid addition salt forms, in conventional manner and vice versa.

Suitable acids for salt formation include maleic, malonic and fumarie acid. When Rg is hydroxy or Rc is hydrogen, salts may be formed with strong bases, e.g. sodium hydroxide.

In the compounds of formula I, the carbon atom to which the hydroxy group is bound is asymmetrically - 8 substituted. The compounds may thus exist in the racemic form or in individual optical isomer form.The preferred optical isomer has the S configuration at the asymmetrically substituted carbon atom of the hydroxypropoxy side chain.

Individual optical isomer forms may be obtained in conventional manner, for example by using optically active starting materials or by fractional crystallisation using optically active acids.

IO In so far the preparation of any particular starting material is not particularly described, this may be effected in conventional manner. 4-HydroxyindoI2-carbonitrile and 4-Hydroxy-3-methylindol-2-carbonitrile may be obtained by splitting off of a water molecule from the corresponding 2-carboxamide derivative, e.g. using titanium tetrachloride.

In the following examples all temperatures are in degrees Centigrade and are uncorrected. - 9 Example 1; Ijj3-chloro22-methylindol;42yloxy)_l32 (2-ghenoxyethylamino272-nroganol g 3-chloro-4-(2,3-epoxypropoxy)-2-methylindole, 4,3 g phenoxyethylamine and 75 ml dioxane are heated at 130° for 15 hours in an autoclave. The reaction mixture is allowed to cool down, the excess dioxane is evaporated in a vacuum produced by a waterpurcp and the excess amine is distilled off under high vacuum at 80°. The reaction mixture is partitioned between aqueous tartaric acid lo solution and methylene chloride. The aqueous phase is made alkaline with cone, ammonia and extracted with methylene chloride. Evaporation of the organic phase yields the title compound (M.P. of the hydrogen malonate 135-137° after crystallization from methanol).

From the appropriate compound of formula II, wherein is-CH(OH)-CH2Cl, and the appropriate compound of formula III the following compounds of formula I may be obtained in analogous manner to Example 1: - 10 10 Example NO. RR1 r2 M.P. 2 -c(ch3)3 H CN f 259-261° 3 -CHgCHgO-^^ H CN hmi 166-169° 4 . OCHg -ch2ch2-^-°ch3 H CN hcl 88° (foam)5 CHg -HO °h ch3 H CN f 172-175° 6CH3 -c-ch2-o-<^)^-cn ch3 H CONH 2 b 198-200° 7CH3 -C-CH ,-0-^ CONHg CH3 H CONHg f 209-212° 8 -ch2ch2-o-@ II CONH hcl 111-113° 9 CH, -c-ch2>oh CH3 H CONH 2 f 170-173° 10 OCH3 -CHgCHgHj^^—OCH3 H CONH 2 hcl 94° [(foam) 11 -c-ch2-^-°h ch3 H ζ» I CON | f 157-160° 'ch.: Example No. RR1R2 M.P. 12GH3 -C-CHj-^-OH CH3 CHj CONHj f 236-238° 13 -ch2ch2-o^> II cooch(ch3)2 b 121-124° 14CH3 4-2>or ch3 H COOCH(CHj) 2 b 203-205° < 15 CHq -C-CH^OH CHj CHj COOCHjCHj f 241-243° 16 ^OCHj -CH2CH2^Q/-OCHj ch3 Cl b 129-131° 17 -CHjCHj-^^- OCHj Cl ch3 hf 99° . (sinters) 18 OCHj -CH2CH2O^0CH3 CHj Br b 126-128° 19 CHj -C-CHj^)/- 0H cn3 Cl CHj f 141-143° 20 -CH2CH2O 0CH3 H CONHCHj f 121-124° Example No. R *1R2 i·-·.? 21 τα00"3 -CH2CH2-/^2?OCH3 HCH2OCK3 22CH3 °hCH3 H CH2OCH3 b 149-151° = free form ί f - bis[base]fumarate hcl = hydrochloride ί hf = hydrogen fumarate j hmi = hydrogen maleinate - 13 The compounds of formula I exhibit pharmacological activity.

In particular, the compounds possess cardiovascular adrenergic a- and β-blocking activity, as indicated by standard tests. For example, the inhibition of α-adrenoceptors may be observed in isolated spiral strips of the Vena femoralis of dogs (E. Muller-Schweinitzer and E. Stunner, Br. J. Pharmacol. [1974] 51, 441-446) and the inhibition of β-adrenoceptors in isolated spiral strips of the Arteria coronaria of dogs (T.J. Bucher et al., Haunyn-Schmiedeberg's Arch. Pharmacol. 280 [1973] 153-160). These actions take place at a bath concentra—9 —fi tion of from about 10 to about 10 M. In the spontaneously beating guinea pig atrium (K. Saameli, Helv. Physiol. Acta 25 [1967] CR 219- CR 221) they inhibit the positive inotropic adrenaline effect at bath concentrations of from 0.005 to 2.5 mg/1.

The compounds are therefore indicated for use as a- and β-blocking agents, e.g. for the prophylaxis and therapy of diseases related to an adrenergic vasoconstriction, and of coronary diseases, especially of Angina pectoris. They are also useful for the treatment of diseases related to an inhibition of bowel motility, especially of paralytic ileus. In view of their antiarrhythmic activity they are also useful as antiarrhyth47131 - 14 mi cs, The compounds of Example 1 and 19 exhibit particularly interesting activity as a- and p-blockers. The Example 10 compound exhibits particularly interesting activity as a β-blocker.

For these uses an indicated daily dose is from about 20 to about 100 mg,conveniently given in divided doses 2 to 4 times a day in unit dosage form contains..yr: from about 5 to about 50 mg, or in sustained release form .

The compounds of formula 1 also exhibit antihypertensive activity, as indicated in standard tests.

For example, this activity may be observed in the Grollman rat test [A. Grollman, Proc..Soc. Exp. 5,. c and Med. 57 (1944) 102] on s.c. administration of from 0,1 to 10 mg/kg animal body weight of the compounds, and on p.o. administration of from 10 tc 100 mg/kg* The compounds are therefore useful as antihypertensive agents. Especially interesting in thio indica20 tion is the compound of Example 1.

For this use an indicated daily dose is from about 1 to about 50 mg, conveniently given ii divided doses 2 to 4 times a day in unit dosage form containing from about 0.25 to about 25 mg, or in ΐϊ o- ITΌ t-ϊ tu form. - 15 The compounds of formula I also possess interesting metabolic activity. In particular, they inhibit glycerol release and hyperglycemia stimulated by isoproterenol in standard tests.

For example, inhibition of glycerol release stimulated by isoproterenol is observed in vitro in isolated fat cells of epididymal fat tissue of rats, the cells having been isolated in accordance with the method of M. Rodbell [J.Biol. Chem. 239, 375-380 (1964)], at a concentration of from about 0.1 to about 10 mg/ litre, and in vivo in rats at a dose of from about 0,1 to about 10 mg/kg body weight s.c.

Inhibition of hyperglycemia is e.g. observed in rats in vivo at a dose of from about 0.1 to about 10 mg/kg animal body weight s.c.

The compounds are therefore indicated for use in the treatment of lipolysis in the blood and hyperglycemia induced by emotional stress, and are useful therefore for the treatment of, or prophylaxis of, myocardial infarction and appetite induced by emotional stress.

Especially interesting in this indication are the compounds of Examples 2,5 and 19, especially the compound of Example 5.

For these uses as metabolic inhibitors an infii·47131 - 16 cated daily dose is from about 0.1 to about 200 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing from about 0.025 to about 100 mg, or in sustained release form.

One groip of compounds of formula I, i.e. the compounds of formula Iu (Wherein wherein Du RU is a group A A is as defined above, Rj, rU and rU have the significances indicated above for Rj, R2 and R^ and Rj with the exception of hydrogen has the significance indicated above for Rj, with the provisos, that a) the phenyl ring is separated by at least two carbon atoms from the nitrogen atom of the 3-aminc-2-hydrox propoxy chain and b) when ?2 is cyar.c, additionally may be alkyl of 3 7131 - 17 to 7 carbon atoms, exhibit activities that are unexpectedly more interesting than those exhibited by known compounds of similar structure.

A preferred group of compounds of formula Iu are the compounds of formula Iu* OH Wherein RU' is A „u a group Ais as defined above, either , wherein is alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, u * is hydrogen and, when R^ is alkoxy of 1 to 4 u1 carbon atoms, R^ additionally may be alkoxy u1 of 1 to 4 carbon atoms or, when R^ is halogen u * of atomic number of from 9 to 35, R^ additionally may be halogen of atomic number of from 9 to 35, - 18 u1 1) Rg is hydrogen or methyl and u1 R? is cyano, COOR„ or CH-OR , wherein R and R are * c 2 e c c as defined above, or u ’ u' o ii) either Rg is methyl and Rg is halogen of atomic number of from 17 to 35 u1 or Rg is halogen of atomic number of from 17 u * to 35 and Rg is hydrogen or methyl, with the provisos, that ±0 a) the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2~ hydroxypropoxy chain and u ’ u1 b) when Rg is cyano, R additionally may be alkyl of 3 to 7 carbon atoms.

In general, the 2(S) optical isomers are more active than the 2(R) optical isomers in the cardiovascular β-blocking, metabolic and blood pressure lowering tests.

The compounds of formula I may be administered 20 in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as tha free forms and are readilly prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula f, in free = 13 form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Further groups of compounds of formula I are the following: a) Compounds of formula Ipa wherein RP is alkyl of 3 to 7 carbon atoms and rP is hydrogen or methyl; b) compounds of formula Ipb H wherein 7131 - 20 rP and A are as defined above is hydroxy, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35, cyano, carbamoyl or acetamido and R^ is hydrogen and, when is alkoxy of 1 to 4 carbon atoms, R^ additionally may be alkoxy of 1 to 4 carbon atoms, or when R^ is halogen of atomic number of from 9 to 35, R4 additionally may be halogen of atomic number of from 9 to 35, with the proviso that the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2-hydroxypropoxy moiety; c) compounds of formula Ipc wherein A, Rp R?j, R4, Ra and Rfc are as defined above, with the proviso tnat the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3amino-2-hydroxypropoxy moiety; " 21 ~ d) compounds of formula Ipd A is as defined above, either i) R^d is halogen of atomic number of from 17 to 35 and R^d is hydrogen or methyl or ii) R^d is methyl and R2d is halogen of atomic number of from 17 to , Rjd is hydrogen or has the significances indicated above for Rj has the significances indicated above for S^and is oxygen or sulfur, with the proviso that is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2hydroxypropoxy moiety.·

Claims

1., A process for the production of a compound of wherein R is a group A-X- 1 wherein A is alkylene of 2 to 5 carbon atoms, X is a bond, oxygen or sulfur. Rg is hydrogen, hydroxy, alkoxy of 1 to 4 carbcn atoms, halogen of atomic member of from 9 to 35 10 cyano, carbamoyl or a group NHCOR , wherein R a $ is alkyl of 1 to 4 carbon atoms, and R^ ia hydrogen and, when Rg is alkoxy of I to 4 carbon atoms, R^ additionally may be alkoxy of 1 to 4 carbon atoms or, when Rg is halogen of 15 atomic number of from 9 to 35, additionally may be halogen of atomic number of from 9 to 35 e- ! ther i) Rg Is hydrogen or methyl and R is cyano, CONR Ρ, C00R or CH.OR , wherein 2 d 0 C 2 6 R a ,Rj 5 ,R c and R g independently are hydrogen or alkyl of 1 to 4 carbon atoms, or ii) either is methyl and R 2 is halogen of atomic 5 number of from 17 to 35 or R^ is halogen of atomic number of from 17 to 35 and P 2 is hydrogen or methyl, with the provisos that a) X is separated from the nitrogen atom of the 3 3o amino-2-hydroxypropoxy chain by at least 2 carbon atoms, b) when X is a bond, R^ is other than hydrogen and c) when R 2 is cyano, R additionally may be alkyl of 3 to 7 carbon atoms, 15 which comprises reacting a corresponding compound of formula II H wherein Rj and Rg are as defined above and R q is a group capable of reacting with an amine to give a 2-amino-lhydroxyethyl group, with a corresponding compound of formula III R - NH III wherein R is as defined above.

2. A process for the production of a compound of formula I, as stated in claim 1, substantially as 10 hereinbefore described with reference to any one of th Examples.

3. A compound of formula I, whenever produced by a process according to claim 1 or 2.

4. A compound of formula I, as defined in claim 1.

5. A compound of claim 1 of formula lx OCHgCHCH NH-R‘ ,x lx II - 25 wherein R x is a group A-X x defined in claim 1, „x r 4 , wherein A is as either JF 5 i) X is oxygen or sulfur and Rg to have the significances indicated in claim 1 for P-g to R^ or ii)X is a bond and 10 either j) Rg is alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, X X R^ is hydrogen and, when Rg is alkoxy of 1 to 4 carbon atoms, R X additionally may be alkoxy of 1 to 4 carbon atoms or, when R X is halogen of atomic number of from 9 to 35, R X additionally may be halogen of atomic number of from 9 to 35, Rg is hydrogen or methyl and R X is CONR R, , wherein R, and R, are as 2 a o a d defined in claim 1, or jj) R x is hydroxy, cyano, carbamoyl or KHCOR^, wherein is as defined in claim 1, 131 - 26 is hydrogen and Rj and F. x have the significances indicat in claim 1 for Rj and , with the proviso, that X x is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2hydroxypropoxy chain.

6. A compound of formula lx' wherein A is as defined in claim 1, X is oxygen or sulfur and Rj' to R x have the significances indicated in claim : fcr Rj to R^, x i with the proviso, that X is separated by at least 2 carbon atoms from the nitrogen atom of the 3-smino-2hydroxypropoxy chain.

7. A compound of formula lu, Xu - 27 10 wherein R U is a group A 1 - R 3 ,wherein A is as defined in claim χ, S l' R 2 and R 4 have the significances indicated in claim 1 for Rj, R 2 and R^ and u Rj with the exception of hydrogen has the significances indicated in claim 1 for Rj, with the provisos, that a) the phenyl ring is separated by at least two carbon •atoms from the nitrogen atom of the 3-amino-2-hydroxy·propoxy chain and b) when is cyano, R U additionally may be alkyl of 3 to 7 carbon atoms .

8. A compound of formula Xu’, OH - 28 1C wherein a group A-‘ , wherein is as defined in claim 1, is alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, r» I is hydrogen and, when Rg is alkoxy of 1 to 4 u ’ carbon atoms, R^ additionally may be alkoxy u * of 1 to 4 carbon atoms or, when Rg is halogen ll ’ of atomic number of from 9 to 35, R^ additionally may be halogen of atomic number of frcm 9 to 35, either i) R“' is u 1 K 2 is as hydrogen or methyl and cyano, COOR c or CHgOR e , wherein R c and R e are defined in claim 1, or u * U * ii) either P.g is methyl and Rg is halogen cf atomic number of from 17 to 35 or r” is halogen of atomic number of from 17 ll ’ 20 to 35 and Rg is hydrogen or methyl, B?ith the provisos, that a) the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2hydroxypropoxy chain and - 29 12 ΐ υ l b) when R 2 is cyano, R additionally may be alkyl of 3 to 7 carbon atoms.

9. A compound of formula Ipa H 5 wherein R P is alkyl of 3 to 7 carbon atoms and rP is hydrogen or methyl.

10. A compound of formula Ipb, 10 wherein R^ is as defined in claim 9 and A is as defined in claim. 1, rP is hydroxy, alkoxy of 1 to 4 carbon atoms, halogen of atomic number of from 9 to 35, cyano, carbamoyl or 15 acetamido and - 30 “ is hydrogen and, when Rg is alkoxy of 1 to 4 carbon atoms, rP additionally may be alkoxy of 1 to 4 carbon atoms, or when is halogen of atomic number of from 9 to 35, R^ additionally nay be halogen of atomic number of from 9 to 35, with the proviso that the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3-ami no-2-hydroxypropoxy moiety.

11. A compound of formula Ipc, wherein A, R fl and R^ are as defined in claim 1 R^ is as defined in claim 9 and R? and R? are as defined in claim 10, 3 4 5 with the proviso that the phenyl ring is separated by at least 2 carbon atoms from the nitrogen atom of the 3amino-2-hydroxypropoxy moiety.

12. A compound of formula Ipd, wherein A is as defined in claim 1 either i) R pfl R 1 is halogen of atomic number of from 17 to 35 and is hydrogen or methyl or ii) »r is methyl and a? is halogen of atomic number of from 17 to 35, r 10 is hydrogen or has the significances indicated in claim 10 for rP rP^ has the significances indicated in claim 10 for rP and 4 X p is oxygen or sulfur, 15 with the proviso that χΡ is separated by at least 2 carbon atoms from the nitrogen atom of the 3-amino-2hydroxypropoxy moiety.

13. The compound of claim 4, which is 1-(3-chloro-2methylindol-4-yloxy)-3-(2-phenoxyethylamino)-2-prcpsnol. 20

14. A compound of claim 4, wherein R 1 is hydrogen. - 32

15. A compound of claim 14, wherein Rg is CN.

16. The compound of claim 15, wherein R is-C(CHg)g.

17. The compound of claim 15, wherein R is-CHgCHgO-^V·

18. The compomd of claim 15, wherein R is - CHgCHg-^j^-OCHg.

19. The compound of claim 15, wherein R is -C (CHg) g-CHg-Z^-OH.

20. A compound of claim 14, wherein Rg is CONHg.

21. The compound of claim 20, wherein R is -C(CHg) 2 -CHg-O-^5)-CN.

22. The compound of claim 20, wherein R is -C (CHg) g-CIig-O·^-CONHg,

23. The compound of claim 20, wherein R is

24. The compound of claim 20, wherein R is -CCCHgJg-CHg-^OH.

25. The compound of claim 20, wherein R is -CHgCHg-^-OCHg OCHg

26. The compound of claim 14, wherein Rg is CONHCH, and R is -C(CHg)g-CHg OH.

27. The compound of claim 14, wherein Rg is CONHCIE and R is -CHgCHg OCH. 0CH r - 33

28. The compound of claim 14, wherein R^ i s COOCH(CHj) 2 and R is -CH 2 CH 2 -O-<^5) ·

29. The compound of claim 14,wherein R 2 is COOCH(CHj) 2 and R is -C(CH 3 ) 2 -CH 2 OH. 5

30. . The compound of claim 14, wherein R, is CH_OCH_ and R is -CH 2 CH 2 -^)-oCH 3 .

31. The compound of claim 14, wherein Rj is CHjOCHj and R is -C (CHj) j-CHj-^h-OH.

32. A compound of claim 4, wherein Rj is CHj.

33. The compound of claim 32, wherein R 2 is CONHj and R is -CCCHj) 2 -CH 2 -^5yQH.

34. The compound of claim 32, wherein R 2 is COOCHjCHj and R is -C(CH 3 ) 2 -CH 2 OH.

35. The compound of claim 32, wherein R 2 is Cl and R 15 is -CH 2 CH 2 -<^-OCH 3 . och 3

36. The compound of claim 32, wherein Rj is Br and R is -CH 2 CH 2 -^5^~ OCHj. och 3

37. A compound of claim 4, wherein Rj is Cl.

38. The compound of claim 37, wherein R 2 is CHj and R 20 is -CH 2 CH 2 -<^-OCH 3 . och 3

39. The compound of claim 37, wherein R_ is CH., and R it Ji ±S -C(CH 3 ) 2 -CH 2 -^H oh. 131 - 34

40. A compound according to any one of claims 3 to 39, in free form.

41. A compound according to any one of claims 3 to 39, in salt form.

42. A compound according to any one of claims 3 to 39 and 41, in acid addition salt form.

43. A pharmaceutical composition comprising a compound according to any one of claims 3 to 39 in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluen