NOVEL COMPOUNDS

PATENTS ACT 19 5 2 COMPLETE SPECIFICATION (Original) FOR OFFICE USE Class Int. Class •plication Number:

Lodged:

»mplete Specification Lodged:

Accepted:

Published:

r iority:

-lated Art:

<- ' i ;,3 :

M it | aid i, w LL ., of Applicant:

BEECHAM GROUP P.L.C.

.ddress of Applicant: Beecham House, Great West Road, Brentford, middlesex TW8 9BD, England actual Inventor(s) Francis David KING Karen Anne JOINER Address for Service: DAVIES & COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Complete specification for the invention entitled:

"NOVEL COMPOUNDS" The following statement is a full description of this invention, including the best method of performing it known to us :- - la NOVEL COMPOUNDS This invention relates to novel compounds useful as intermediates for the preparation of compounds having pharmaceutical properties.

GB 2100259A and 2125398A, and EP-A-158265 describe benzoates and benzamides having an azabicyclic side chain and possessing 5-HT antagonist activity.

In Australian Patent Application No.67121/87 (from which the subject matter of the present invention has been divided), we describe a class of novel, structurally distinct compounds which have 5-HT M-receptor antagonist activity, anti-emetic activity and/or gastric motility enhancing activity. These compounds are represented by the formula (I):

CO-L-Z (I) 900517,cS »»pe.03?,eonipoune!«.l,l wherein L is NH or 0; X and Y are independently selected from hydrogen or Ci_4 alkyl, or together are a bond; Rl and R2 are independently selected from hydrogen, Ci_q alkyl, C2_6 alkenyl-C2_4 alkyl, or together are C2_4 polymethylene; R3 and R4 are independently selected from hydrogen; halogen; CF3; Ci_5 alkyl; Ci_q alkoxy; Ci_q alkylthio; Ci_7 acyl; C.y acylamino; C_ alkylsulphonylamino; N-(C2_6 alkylsulphonyl)- N-Ci_4 alkylamino; C±_q alkylsulphinyl; hydroxy; nitro; and amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-Ci_4 alkylamino optionally N-substituted by one or two groups selected from C_g alkyl, C3-8 cycloalkyl, C3_8 cycloalkyl Ci_ alkyl, phenyl or phenyl Cj__:

alkyl groups or optionally N-disubstituted by £4.5 polymethylene; Z is a group of formula (a), (b) or (c) (CH2)nR5 2 (a) (b) - C tuj (M,) (o) 930nZp:\op«\dabJS147jpe wherein n is 1 or 3; p is 1 or 2; q is 1 to 3; r is 1 -to 3; and R5 or Rg is C-j alkyl, C3_3 cycloalkyl, 03.3 cycloalkyl-C1_2 alkyl or C2-7 alkenyl-Ci_4 alkyl.

This invention provides compounds of the formula (V):

(V) wherein G is COQ, where Q is a leaving group selected from halogen, C2_4 alkoxy, phenoxy, activated hydrocarbyloxy, succinimidyloxy and imidazolyloxy; and Rl' R2' R3' R4' x and Y have the same designation as for compounds of the formula (I) defined previously; with the proviso that l-( 2, 3-dihydro )-indolylcarbonyl chloride is specifically excluded.

Examples of leaving groups Q, displaceable by a nucleophile, include halogen such as chloro and bromo; C2_4 alkoxy, such as CH3O and C2H5O-; PhO-; activated hydrocarbyloxy, such as CI5C5O- or CI3CO-; succinimidyloxy; and imidazolyloxy.

Preferably Q is halogen, most preferably chloro.

930112,p:\oper\dab,55147-speF3 2 Suitable values for X and Y include hydrogen, methyl, 3 ethyl, n- and iso-propyl ,• or together are a bond.

Often X and Y are both hydrogen.

7 Suitable values for R or R2 include hydrogen, methyl, 8 ethyl, n- and iso-propyl; prop-2-enyl, but-2-enyl, 9 but-3-enyl, 1-methylenepropyl and l-methylprop-2-yl in their E and 'L forms where stereoisomerism exists; or Rj 3-1 and R2 together are as defined in formula (I). Often 12 r and R2 are both hydrogen.

• Values for R3 and/or R4 include hydrogen, fluoro, chloro, bromo, CF3, methyl, ethyl, methoxy, ethoxy, 1° methylthio, ethyltnio, acetyl, propionyl, acetylamino, methylsulphonylamino, methylsulphinyl, hydroxy, nitro; and amino, aminoca'rbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-methylamino any of which may be optionally substituted by one or two methyl groups or by a cyclopentyl or cyclohexyl 900517.c »spe.037,compound*.1,4 - group or disuostituted by C4 or C5 polymetny1ene; K3 is otten hydrogen and R4 is hydrogen or a JT-subst 1 tuent, such as halo or methoxy.

Preferably n is 2 or 3 and p, q and r are 1 or 2.

Examples of R5/R6 when Ci--p alkyl include as groups of interest C1-3 alkyl such as methyl, ethyl and n- and iso-propyl. Within C.y alkyl, €4-7 alkyl are also of interest, especially those of the formula (GH2)uR9 wherein u is 1 or 2 and Rg is a secondary or tertiary C3_6 alkyl group. Examples of Cj alkyl include n-, sec- and tert-butyl, n-pentyl, n-heptyl, ana iso-butyl, 3-methylDutyl, and tert-butylmethyl.

Examples of R5/R6 when C-q cycloalkyl-Ci_2 alkyl include in particular those wherein the cycloalkyl moiety is cyclohexyl or cyclopropyl. Examples srf include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethy1, cyclopropylethy1, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, tert-butylmethyl, iso-propylmethy1, iso-propylethyl and tejrt-butylethyl.

R5/R5 may in particular be cyclopropylmethyl, cyclohexylmethyl, iso-propyImethy1, tert-butylmethyl or iso-propylethyl, preferably tert-butylmethyl.

Examples of R5/R6 when C2-7 alkenyl-Ci_4 alkyl include prop-2-enyl, but-2-enyl, but:-3-enyl, 1-methylenepropy 1 and l-inethyl-prop-2-enyl in their E and Z forms when stereoisomerism exists.

R5/R6 is preferably methyl or ethyl, most preferably methyl.

900517. e_Bspe. 037, eompoursdo. X , — <-f.

I Preferred compounds of the present invention may be selected from the following:

1- ( 2 , 3-Dihydro ) -indolyltrichlorornethyl carbamate , l-(2, 3-<aihydro-3-methyl)indolyl-0-(l- succinimidyl)carbamate, l-(2,3-dihydro-5-fluoro)indolyl-0-(1- succinimidyl)carbamate, l-(2,3-dihydro-5-methoxy Jindolyl trichloromethyl carbamate, 1-(2,3-dihydro-3-ethyl)indolylearbony1 chloride, 1- (2,3-dihydro-5-nitro)indolyl-trichloromethyl carbamate, 1-[1-(2,3-dihydro-6-nitro)indolylcarbony1]-imidazole/ or \X 900517,c »Bp*. 037,compounds.1,6 Compounds of the formula (V) may be prepared by reacting a compound of the formula (VI):

(VI) witn a compound of the formula (VII):

RCOQ1 wherein R is a leaving group \ hich may be the same as Q or different; and Q, hereinbefore defined.

R- l4 X and Y are as Compounds of the formula (V) are useful as intermediates in the preparation of compounds of the formula (I) as previously mentioned. As described in our co-pending patent application No.67121/87, compounds of the formula (I) may be prepared by reacting a compound of formula (V):

G (V) with a compound of formula (VI):

J-ZJ (VI) wherein 900517.c_sBpe.037.compound*.1,7 kydf l or- hydcoae-* G Is COQyj where Q is a leaving group ail-hgecsngsaa,; and, when G is COQ, J is NH2, or OH or a reactive derivative thereof or, when G is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-L-linkage with the compound of formula (V); Z1 is Z as defined or wherein R5/R5 is replaced by a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting any R3 and R4 group to another R3 and R4 group respectively, converting Z1, when other than Z, to Z; converting X and Y to other X and Y; and optionally forming a pharniaceutically acceptable salt of the resultant compound of formula (1).

Further details of reaction conditions are set forth in application No.67121/87 which is incorporated herein by reference - The c.ompoujad& of the pge-sntodasaBfeAea may bo in tho form pharniaceutically acceptable salts. Acid addition saS may be formed conventionally, for example, by reacion of the base compound of the formula (V) with a gdrmaceutically acceptable organic or inorganic acid.

This invention also providesapharmaceutical composition comprising a compounK' of the formula (V), or a pharmaceutically *dcceptable salt thereof, and a pharmaceuticaUyacceptable carrier. The preparation of pharmaceutidal compositions and nature of pharmaceutically acceBJfe=able carriers are. well known in the art, and are fkfrnrihp.d, for ftxnmple, in .appjjf r.HfrJ r)n-No-rfr?±2±&fe- The following Examples illustrate the preparation of compounds of the formula (V):

900517,c_»spe.037.compoundn.1.8 _ 9 _ Example 1 1-(2.3-Pihydro)-inaolyItrichloromethyl carbamate (Dl) O c - cxxi.

(D3 ) To 2,3-d2hydroindole (5g) in dry dichloromethane (140ml) and triethylamine (5.85ml) at 0° was added dropwise trichloromethyl chloroformate (5ml) in dry dichloromethane (20ml). The reaction mixture was stirred at room temperature for 2h, tnen washed with water (5ml) and 5N hydrochloric acid solution (5ml).

The organic phase was dried (Na2S04), the solvent evaporated in vacuo and the residue purified by filtration through a short alumina column, elating with dichloromethane to give the title compound (Dl) (S.Sg, 72%) as a buff solid m.p. 59-60°.

iB-NMR (CDCI3) 60MHz 6 7,85-7.55 (m, 1H) 7.3C-6.70 (m, 3H) 4.25-3.70 (m, 2H) 3.25-2.80 (m, 2H) Example 2 2,3-Dihydro-3-methylincl)Oig (D2) (S2 ) FoUowing the procedure outlined t>y G.W. Gnbble and J.H. Hoffman, Synthesis 859, 1977, 3-methyl indole (5g ) was converted to the title compound (D2) (4.17g( 82%).

ih NMR (CDCI3) 60MH2 6 7.30-6.30 (m, 4H) 3.80-2.80 (m, 4H) 1.30 (d, 3H) Example 3 2,3-Dihydro-5-fluoroindole (D3) (D3) Following the procedure outlined in Example 2, 5-fluoroindole (3g) was converted to the title compound (D3) (2.54g, 84%).

iH-NMR (CDGI3} ,60MH2 6 7.05-6.10 (m, 3H) 4.10-2.60 (ms 5H) Example 4 2,3-Dihydro-5-chloroindole (D4) (D4) following the procedure outlined m Example 2, 5-chloroindole (0.b6g) was converted to tne title convound (D4J (0.84g, 97%).

ih-NMR (CDCI3) 60MHz 6 7.30-6.65 (m, 2H) 6.60-6.25 (m, 1H) 4.10-3.25 (m, 3H) 3.20-2.70 (m, 2H) Example 2, 3-Dihydro-5-methoxyindole (D5 ) MeO (D5) A solution of 5-methoxyindole (Ig) in glacial acetic at?id (20inl) was hydrogenated over platinum oxide (0.27g) at room temperature. After absorption of the theoretical amount of hydrogen (153ml), the catalyst was filtered off and the solvent evaporated in vacuo.

The residue was basified with saturated potassium carbonate solution and extracted with diethyl ether.

The organic phase was dried (Na2S04), the solvent evaporated in vacuo to give the title compound (D5) (0.439, 42* :.

iH-NMR (CDCI3) 6QMriz 6 6.85-6.35 (m, 3H) 3.65 (s, 3H) 3.60-2,70 (m, 5H) _ 12 Example 6 2,3-Dihydro-3-etnyiindole (D6) (D6) Following the procedure outlined in Example 2, 3-ethylindole (2.3g) (J.T. Fitzpatrick and R.D. Hiser, J. Org. Chem. , _22, 1703-4, 1957) was converted to the title compound (D6) (1.3g, 56%).

1-H-NMR (CDCI3) 60MHz 6 7.20-6.40 (m, 4H) 3.90-2.90 (m, 4H) 2.10-0.8 (m, 2H) 0.9 (t, 3H) F.xampl'. 7 1-(2,3-Dihydro-3-methyl)iadolyl-0-(i-succinimidyl)- carbamate (D7) O.

c - o - (D7) N,N-Disuccinimidyl carbonete (&.03g) and 2,3-dihydro-3- methylindole (D2) (4.17g) in dry toluene (150ml) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in dichloromethane, washed with 5N hydrochloric acid solution (10ml), saturated potassium bicarbonate (10ml) and brine (30ml). The organic phase was dried (Na2S04), evaporated in vacuo and the residue purified by filtration through a short silica column, eluting with dichloromethane to give the title compound (D7) (6.85g, 80%).

J-H-NMR (CDCI3) 60MHz 6 7.85-6.80 (m, 4H) 4.60-4.00 (m, 1H) 3.95-3.10 (m, 2H) 2.7-/ (s, 4H) 1.30 (bd, 3H) Example 8 1-(2,3-Pihydro-5-fluoro )indolyl-0-(1-succinimidyl)- carbamate (D8) - O - N (D8) Following the procedure outlined in Example 7, reaction of N#N-disuccinimidyl carbonate (4. '75g) with 2,3-dihydro-5-fluoroindole (D3) afforded the title compound (D8) (5g, 97*).

iH-NMR (CDCI3) 60MHz 6 7.90-7.60 (m, 1H) 7.30-6.60 (m, 3H) 4.40-4.00 (m, 2H) 3.40-2.90 (m, 2H) 2.85 (s, 4H) Example 9 1-(2,3-Dihydro-S-methoxy)indolyl trichloromethyl carbamate (D9) V C - 0CC1.

MeO (D9) Following the procedure outlined in Example 1, reaction of 2,3-dihydro-5-inethoxyindole (D5) (0.43g) with trichloromethylchloroformate (0.35ml) afforded the title compound (D9) (0.52g, 58%).

iH-NMR (CDCI3) 60MHz 6 7.88-7.58 (m, 1H) 6.85-6.48 (m, 2H) 4.35-3.80 (m, 2H) 3.70 (s, 3H) 3.35-2.80 (m, 2H) Example 1-(2,3-Dlhydro)indolylcarbonyl chloride (D10) (D10) To phosgene [110ml (12.5% w/w solution in toluene)] in dry dichloromethane (150ml) at O" was added dropwise a solution of triethylamine (17ml) and freshly distilled 2,3-dihydro- indole (14.5g) in dry dichloromethane (100ml). The reaction mixture was then stirred at O" for Ih, and then poured into pentane (2.51), washed with 5N sulphuric acid solution (100ml) and brine (100ml). The organic phase was dried (Na2S04), the solvent evaporated in vacuo and the residue (D10) (18.37g, 83%).

Example 11 l-(2,3-Dihydro-3-ethyl)indolylcarbonyl chloride (Dll) 0C1 fcll) Following the procedure outlined in Example 10, reaction of 2,3-dihydro-3-ethylindole (D6) (1.25g) with phosgene [7.7ml (12.5% w/w solution in toluene)] afforded the title compound (Dll) (1.6g, 90%).

O 900517e sspe.037,eempoundfr.1.15 1 Example 12 3 l-( 2, 3-Dihydro-5-nitro)indolyl-trichloromethyl 4 carbamate (D12) 11 (012) 12 Following the procedure outlined in Example 1, reaction of 13 2,3-dihydro-5-nitroindole (4.72g) with trichloromethyl- 14 chloroformate (3.44ml) afforded the title compound (D12) (5.5g, 59%) 16 -H-NMR (CDCI3) 60MHz 17 6 8.80-7.10 (m, 3H) 18 4.70-3.90 (m., 2H) 19 3.50-2.95 (m, 2H) 21 Example 13 23 !-[!-(2,3-Dihydro-6nitro)indolylcarbonyl3 imidazole (D13) 31 2,3-Dihydro-6-nitroindole (3g) and 1,1'-carbonyldi- 32 imidazole (2.96g) in dry toluene (75ml) was heated under 33 reflux for 5h* The reaction mixture was cooled and the 34 solvent evaporated in vacuo. The residue was dissolved in dichloromethane (100ml) and washed with 5N hydrochloric acid 36 solution (10ml) and water (20ml). The organic phase was 37 dried (Na2S04) and the solvent evaporated in vacuo to give 38 the title compound (D13) (4.7g/ 100%)* 900317, G__88p*. 037, Goopound».}, 16 fa! 3 J 1 Example 14 3 l-(2,3-Dihydro-3,3-dimethyl)lndolylcarbonyl chloride (D14) 9 3 f2>14i Following the procedure outlined in Example 10, reaction of 11 2,3-dihydro-3,3-dimethylindole (2.7g) with phosgene [16.5ml 12 (12.5% w/w solution in toluene)] afforded the title compound 13 (D14) (3.5g, 91%).

Example 15 - Synthesis of a compound of the Formula (I) 17 endo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2,3- 18 dihydroindole-l-cajrboxamide (El) 22 C— NH s1 27 To l-(2,3-dihydro)-indolyltrichloromethyl carbamate (Dl) 28 (3.64g) in dry toluene (100ml) was added endo-3-amino-9- 29 methyl-9-azabicyclo[3.3.l]nonane (2g) in dry toluene (20ml).

The reaction mixture was heated under reflux for 24h, then 31 the solvent evaporated in vacuo. The residue was extracted 32 with dichloromethane (200ml) and washed with saturated 33 potassium carbonate solution (2 x 20ml). The organic phase 34 was dried (Na2S04) concentrated and the residue purified by column chromatography on alumina, ©luting with CHCI3 to 36 give, after crystallisation from ethyl acetate the title 37 compound (El) (2g, 52%) m.p. 176-8°.

38 1K-NMR (CDCI3) 270MHz 90051t.e «Sp«.037,ceopouiwU. 1,17 2 6 7.85 (d, 1H) 3 7.25-7.05 (m, 2H) 4 6.95-6.85 (m, 1H) 4.45-4.25 (m, 2H) 6 4.00-3.80 (t, 2H) 7 3.25-3.05 (m, 4H) 8 2.65-2.40 (m, 2H) 9 2.50 (s, 3H) 2.15-1.85 (m, 3H) 11 1.65-1.00 (m, 5H) 90051"?,c sspe.037,compound*. 1.18 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of the formula (V):

G wherein G is COQi, where Q is a leaving group selected from halogen, C2_4 alkoxy, phenoxy, activated hydrocarbyloxy, succinimidyloxy and imidazolyloxy; X and Y are independently selected from hydrogen or Ci_4 alkyl, or together are a bond; R and R2 are independently selected from hydrogen, C-s alkyl, c2-6 alkenyl-C_4 alkyl, or together are 2-4 polymethylene; and R3 and R4 are independently selected from hydrogen; halogen; CF3; C.g alkyl; C_ alkoxy; C.g alkylthid; C.y aeyl; C.y acylamino; C.g alkylsulphonylamino; N-(Ci_6 alkylsulphonyl)- N-Ci_4 alkylamino; C.g alkylsulphinyl; hydroxy; nitro; and amino, aminocarbonyl, aroinosulphonyl, aminosulphonylamino or N-(aininosulphonyl )-C1_4 alkylamino optionally Nsubstituted by one or two group selected from C.g alkyl, C3_g cycloalkyl, c3-8 cycloalkyl Ci_& alkyl, phenyl or phenyl Ci_4 alkyl groups or optionally N-disubstituted by C4_5 polymethylene, excluding the compound l-(2,3-dihydro)-indolylcarbonyl chloride.

2. A compound according to claim 1 wherein Q is selected from halogen, £2.-4 alkoxy, activated hydrocarbyloxy, succinimidyloxy, and imidazolyloxy.

930112,p:\oper\dab,55147.spe,19