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GB2051811A - Indoline derivatives, their production and pharmaceutical composition containing them - Google Patents

Indoline derivatives, their production and pharmaceutical composition containing them Download PDF

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Publication number
GB2051811A
GB2051811A GB8020753A GB8020753A GB2051811A GB 2051811 A GB2051811 A GB 2051811A GB 8020753 A GB8020753 A GB 8020753A GB 8020753 A GB8020753 A GB 8020753A GB 2051811 A GB2051811 A GB 2051811A
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hydrogen
salt form
alkoxy
och3
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GB2051811B (en
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

A 1-aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position is an anti-depressant agent.

Description

SPECIFICATION Indoline derivatives, their production and pharmaceutical compositions containing them This invention relates to indoline derivatives, their production and pharmaceutical compositions containing them.
The present invention provides a 1-aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position, hereinafter referred to as a compound of the invention. The 3 position bears only one phenyl substituent and additionally may have a hydrogen atom attached thereto or another substituent which is other than a phenyl group. The remaining positions of the nucleus may be unsubstituted or substituted.
The present invention provides particularly a compound of formula i
wherein R1 and R2 independently are hydrogen, halogen of atomic number from 9 to 35, (C1.4)alkyl, (C1.4)alkoxy, hydroxy, ortrifluoromethyl.
R1' and R2, independently are hydrogen, halogen of atomic number from 9 to 35, (C1.4)alkyl, (C1.4)alkoxy, or hydroxy, R2" is hydrogen or (C1.4)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2, are alkoxy, R3, R4, and R5 are hydrogen or (C1.4)alkyl and X is straight chain (C2.4) alkylene, which may bear a (C1.3) alkyl radical when R3 is hydrogen, in free base form or in pharmaceutically acceptable acid addition salt form.
In formula I, alkyl and alkoxy contain preferably 1 or 2, and especially 1, carbon atom. Halogen is preferably chlorine or fluorine, especially chlorine. Xis preferably an unsubstituted straight chain alkylene, preferably ethylene. R3, R4, and R5 are preferably hydrogen. R1 is preferably in the 5 or 6 position of the indoline nucleus. R1 and R1' are conveniently other than chlorine in the 5 position of the indoline nucleus. R2 is preferably in the meta or para position.
The present invention provides additionally a process for the production of a compound of the invention which comprises reducing a corresponding indole. In particular a compound of formula I may be produced by reducing a compound of formula II
wherein R1, F1, R2, F2, R2" R3, R4, R5 and X are as defined above.
The process may be effected in conventional mannerforthe reduction of an indoleto an indoline. For example the process may be effected with nascent hydrogen, e.g. with lithium, sodium, or potassium in liquid ammonia. Preferably for halogen-containing compounds, an alternative reduction using diborane or a complex borohydride, e.g. Na-BH4/BF3 or a borane/dimethylsulphide complex is effected.
The reduction in liquid ammonia may be effected in the presence of an inert organic solvent such as an ether, e.g. tetrahydrofuran. Suitable temperatures may be from about -70 C to about -30"C, preferably -40" to -30 C. The reduction with boron compounds is conveniently effected likewise in an organic solvent.
Suitable reaction temperatures may be from about 0 C to the reflux temperature of the reaction mixture. Any resultant boron complex may be conveniently decomposed with acid, e.g. 4N-5N HCI.
The compounds may be isolated from the reaction mixture and purified in conventional manner The compounds of the invention may exist in the form of optical isomers or racemates. When X bears an alkyl substituent or when R3 is alkyl, the compounds may exist in diastereoisomeric forms. The individual optical isomers and diastereoisomers may be obtained in conventional manner, e.g. by fractional crystallization of salt forms with appropriate acids.
Free base forms of the compounds of the invention may be converted into acid addition salt forms in conventional manner, and vice versa. Suitable acids for salt formation include the hydrochloric, maleic, fumaric, cyclohexylsulfamic, and naphthalen-1,5-disulphonic acids.
The starting materials of formula II may be produced in conventional manner, e.g. from the compound of formula III,
as follows:i) Compounds of formula II wherein -X-NR4R5 = -X'-CH2-NR4RS, wherein X' = a straight chain (C1.3) alkylene chain which may bear an (C, 3)alkyl group, may be obtained by introducing a group -X'-CONR4RS or -X'-CN into a compound of formula III (e.g. with Hal-X'-CONR4RS or Hal-X'-CN) and reducing the resultant amide or nitrile to the amine, if desired alkylating any free amino group present.
ii) Compounds of formula II wherein -X-NR4R5 -CH2-CHR-CH2-NR4R5 wherein F = H or (C, 3)alkyl may be obtained by reacting a compound of formula Ill with CH2 = CR-CN, and hydrogenating the resultant 1-cyonoethyl derivative, with Raney-Nickel in ethanol and in the presence of ammonia, to the corresponding amine which, if desired, may be alkylated.
iii) Compounds offormula II wherein -X-NF4F5 = -CH2-X'-NF4R5 may be obtained by treatment of a compound of formula Ill with a Grignard compound and treatment of the resultant product with an ester of an amino-acid of formula HOOC-X'- N R4R5 a nd final reduction of the resultant compound of formula IV,
e.g. with an appropriate amount of a borane/dimethylsulphide complex.
Insofar as the production of any starting material is not particularly described these are known or may be produced in analogous manner to known compounds orto processes described herein.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
In the tables the melting point refers to the hydrogen maleate salt form except when stated, e.g.
1) hydrogenfumarate 2) bis [base] fumarate 3) base 4) hydrochloride 5) Cyclohexylsulfamate 6) Naphthalin-1,5-disulfonate.
Other abbreviations:7) Decomposition Point starting at about temperature given.
+) Diastereoisomeric isomer EXAMPLE 1: 1-(2-aminoethyl)-3-phenylindoline A solution of 34.7 g 1-(2-aminoethyl)-3- phenylindole in 300 ml tetrahydrofuran is dropped into a solution of 17 g sodium in liquid ammonia. After a further 30 minutes the sodium excess is decomposed by the addition of solid ammonium chloride. The ammonia is evaporated off to give the title compound. M.pt.
(hydrogen maleate) 169-1705, (from ethanol).
The starting material is produced as follows: a) A solution of 100 g 3-phenylindole in 350 ml dimethylformamide is dropped into a suspension of 22.7 g sodium hydride (55% by weight in oil) in 350 ml dimethylformamide. After hydrogen formation has finished, 73 g solid chloroacetamide are added. The mixture is stirred for 17 hours at room temperature and poured onto ice-water causing 3-phenylindolyl-1 -acetamide to precipitate. (M.pt. 200-202" from CH2CI2).
b) A solution of 14.4 ml conc. H2SO4 in 200 ml tetrahydrofuran is added dropwise to a 54.6 g lithium aluminium hydride in 1 litre tetrahydrofuran at -30". The mixture is allowed to warm to 0", then treated dropwise with a suspension of 90.2 g 3-phenylindolyl-1- acetamide in 700 ml tetrahydrofuran and stirred thereafter for 2 hours at room temperature. The resultant 1 -(2-aminoethyl)-3-phenylindole melts at 268 to 270 (Hydrochloride salt form).
EXAMPLE 2: 1-(3-aminoprop yJ)-3-phenylindoline Prepared analogous to Example 1. M.pt. (cyclohexylsulfamate) 167-168".
The starting material, 1-(3-aminopropyl)-3-phenylindole (M.pt. of oxalate 194-195" from ethanol), is obtained by reacting 3-phenylindole with acrylnitrile in dioxane in the presence of benzyltrimethylammonium hydroxide and hydrogenating the resultant 1-(2-cyanoethyl)-3- phenylindole with Raney Nickel at normal pressure and at 50 .
EXAMPLE 3: 1-(2-aminoprop yI)-3-phenyllndoline (isomers A and B) Prepared analogous to Example 1 the title compounds are obtained as an isomer mixture which is fractionally crystallized from ethanol and ethanol/ether. M.pt. isomer A = 249-251" (hydrochloride); isomer B = 238 - 240 (hydrochloride).
The starting material is obtained as follows: A mixture of 10 ml methyl iodide in 50 ml diethyl ether is added dropwise to 3.6 g magnesium turnings in 50 ml diethyl ether. The mixture is heated until all magnesium goes into solution. A solution of 29 g 3-phenylindole in 100 ml tetrahydrofuran is added, followed, 15 minutes thereafter, by 11.7 g DL-alanine ethyl ester in 100 ml tetrahydrofuran. The mixture is refluxed for 18 hours and then treated with a mixture of ammonium chloride, water and ether. The organic phase is separated off. The required 1-(2aminopropionyl)- 3-phenylindole is extracted from the organic layer by shaking with an aqueous tartaric acid solution. M.pt. (bis[base] fumarate) 241-243 .
b) 15.8 ml borane;dimethylsulphide complex are added to a solution of 14 g 1-(2-aminopropionyl)3-phenylindole in 100 ml tetrahydrofuran. The mixture is refluxed for 30 minutes and concentrated under a vacuum to a residue. The residue is dissolved in 50 ml acetic acid, maintained at room temperature for 2 hours, poured onto ice-water, made alkaline with conc. NH40H and extracted with ether. The ether extracts are washed with water, dried over Na2SO4 and concentrated to give 1-(2-aminopropyl)- 3-phenylindole as an oil. M.pt. (hydrogen maleate) 186-189" (from ethanol).
In analogous manner compounds wherein R,' = F2, = R2" = R3 = R4 = R5 = H and X = -CH2-CH2- may be made as follows: TABLE 1 Ex R1 R2 M.pt No 4 5-F H 143-144 5 7-F H 180-183 6 7-Cl H 177-180 7 7-CH3 H 188-190 8 H o-Cl 172-176 9 H m-CI 175-178 1) 10 H p-Cl 168-170 11 4-Cl H 171-173 2) 12 6-Cl H 162-164 13 H m-CF3 172-177 14 H o-F 159-163 15 H m-F 154-157 16 H p-F 154-159 17 5-Cl H 154-156 18 5-OCH3 H 156-158 19 6-F H 130-134 20 4-F H 170-172 21 5-OH H 168-170 22 6-Cl m-CI 155-158 23 6-Cl p-F 24 6-F p-F 166-167 25 5-OH m-CI 182-185 26 5-OH p-F 193-197 Ex R1 R2 M.pt No 27 6-F m-cL 208-210 4 28 6-OH H 172-175 31 29 H m-OH 135-139 3@ 30 H p-OH 182-185 31 H p-CF3 164-167 32 6-CF3 H 176-179 33 4-CF3 H 195-198 4 34 5-Br H 168-170 35 6-OCH3 H 160-165 36 H p-OCH3 37 H m-OCH3 175-177 1) 38 5-OCH3 p-F 130-135 39 5-OCH3 m-Cl 38-142 TABLE 2 In analogous manner the following compounds wherein R1' and R2" = H may be made.
Ex R1 R2 R'2 R3 X R4 R5 M.pt.
No 40 H H H H CH2-CH2 H CH3 161-162 5) 41 H H H H CH2-CH2 CH3 CH3 150-151 5) 42 H H H H CH2-CH2-CH2 H CH3 163-164 5) 43 H H H H CH2-CH2-CH2 CH3 CH3 235-237 6) 44 H H H H CH2-CH2-CH2-CH2 H H 170-172 1) 45A+ H H H H CH(CH3)-CH2 H H 224-226 2) 45B+ H H H H CH(CH3)-CH2 H H 172-174 1) 46A+ H H H CH3 CH2-CH2 H H 194-197 4) 46B+ H H H CH3 CH2-CH2 H H 178-181 1) 47 H m-Cl p-Cl H CH2-CH2 H H 128-132 48 H p-F H H CH2-CH2 CH3 CH3 146-150 5) 49 6-Cl H H H CH2-CH2 CH3 CH3 242 4)7) 50 6-F H H H CH2-CH2 CH3 CH3 250 4)7) 51 H p-F H H CH2-CH2 CH3 H 158-162 5) The compounds of the invention exhibit pharmacological activity in animals, in particular anti-depressant activity, as indicated by an inhibition of ptosis and catalepsy induced by tetrabenazine in rats in i.p.
administration of 1 to 50 mg/kg of the compounds.
The compounds are therefore indicated for use as anti-depressant agents. For this indication an indicated daily dose is from 1 to 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 0.25 to 150 mg (e.g. 1.5 to 75 mg), or in sustained release form.
The compounds of the invention may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of the invention, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
The compound of Example 1 exhibits particularly interesting properties.
In one group of compounds of formula I R2 is hydrogen, halogen, alkoxy, hydroxy, ortrifluoromethyl, R1' is hydrogen, R2, is hydrogen or halogen, and R2" is hydrogen.
In another group of compounds of formula I B1, R2, and R2" are each hydrogen.
In a further group of compounds of formula I R1 and R1' are other than chlorine in the 5 position when R2, R2', R2" and R3, R4 and R5 are each hydrogen and X is ethylene.

Claims (77)

1. A process for the production of 1-aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position, which comprises reducing a corresponding indole.
2. A process for the production of a compound of formula I
wherein R1 and R2 independently are hydrogen, halogen of atomic number from 9 to 35, (C1.4)alkyl, (C1.4)alkoxy, hydroxy, ortrifluoromethyl, R1' and R2' independently are hydrogen, halogen of atomic number from 9 to 35, (C1.4)alkyl, (C1 4)alkoxy, or hydroxy, R2" is hydrogen or (C1 4)alkoxy, with the proviso that, when R2" is alkoxy, then R2 and R2' are alkoxy, R3, R4, and R5 are hydrogen or (C1.4)alkyl and Xis straight chain (C2 4)alkylene, which may bear a (C1.3)alkyl radical when R3 is hydrogen, which comprises reducing a compound of formula 11
wherein R1, R1', R2, R2,, R2", R3, R4, R5 and X are as defined above.
3. A process for the production of a 1 -aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position substantially as hereinbefore described with reference to any one of the examples.
4. A process for the production of a compound of formula las defined in claim 2 substantially as hereinbefore described with reference to any one of the examples.
5. A 1-aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position whenever produced by the process of claim 1 or 3.
6. A compound of formula I whenever produced by the process of claim 2 or 4.
7. A 1-aminoalkyl-indoline substituted in the 3 position by a single phenyl group and either unsubstituted or having a mono-valent substituent in the 2 position.
8. A compound of formula las defined in claim 2.
9. A compound of claim 8 which is 1 -(2-aminoethyl)-3-phenylindoline.
10. A compound of claim 8 which is 1-(3-aminopropyl)-3-phenylindoline.
11. A compound of claim 8 wherein R1', R2,, R2'', R3, R4 and R5 are each hydrogen, and Xis ethylene.
12. A compound of claim 11 wherein R1 and R2 are respectively 5-F and H.
13. A compound of claim 11 wherein R1 and R2 are respectively 7-F and H.
14. A compound of claim 11 wherein R1 and R2 are respectively 7-Cl and H.
15. A compound of claim 11 wherein R1 and R2 are respectively 7-CH3 and H.
16. A compound of claim 11 wherein R1 and R2 are respectively H and o-CI.
17. A compound of claim 11 wherein R1 and R2 are respectively H and m-CI.
18. A compound of claim 11 wherein R1 and R2 are respectively H and p-CI.
19. A compound of claim 11 wherein R1 and R2 are respectively 4-Cl and H.
20. A compound of claim 11 wheren R1 and R2 are respectively 6-Cl and H.
21. A compound of claim 11 wherein R1 and R2 are respectively H and m-CF3.
22. A compound of claim 11 wherein R1 and R2 are respectively H and o-F.
23. A compound of claim 11 wherein R1 and R2 are respectively H and m-F.
24. A compound of claim 11 wherein R1 and R2 are respectively H and p-F.
25. A compound of claim 11 wherein R1 and R2 are respectively 5-Cl and H.
26. A compound of claim 11 wherein R1 and R2 are respectively 5-OCH3 and H.
27. A compound of claim 11 wherein R1 and R2 are respectively 6-F and H.
28. A compound of claim 11 wherein R1 and R2 are respectively 4-F and H.
29. A compound of claim 11 wherein R1 and R2 are respectively 5-OH and H.
30. A compound of claim 11 wherein R1 and R2 are respectively 6-Cl and m-Cl.
31. A compound of claim 11 wherein R1 and R2 are respectively 6-Cl and p-F.
32. A compound of claim 11 wherein R1 and R2 are respectively 6-F and p-F.
33. A compound of claim 11 wherein R1 and R2 are respectively 5-OH and m-CI.
34. A compound of claim 11 wherein R1 and R2 are respectively 5-OH and p-F.
35. A compound of claim 11 wherein R1 and R2 are respectively 6-F and m-CI.
36. A compound of claim 11 wherein R1 and R2 are respectively 6-OH and H.
37. A compound of claim 11 wherein R1 and R2 are respectively H and m-OH.
38. A compound of claim 11 wherein R1 and R2 are respectively H and p-OH.
39. A compound of claim 11 wherein R1 and R2 are respectively H and p-CF3.
40. A compound of claim 11 wherein R1 and R2 are respectively 6-CF3 and H.
41. A compound of claim 11 wherein R1 and R2 are respectively 4-CF3 and H.
42. A compound of claim 11 wherein R1 and R2 are respectively 5-Br and H.
43. A compound of claim 11 wherein R1 and R2 are respectively 6-OCH3 and H.
44. A compound of claim 11 wherein R1 and R2 are respectively H and p-OCH3.
45. A compound of claim 11 wherein R1 and R2 are respectively H and m-OCH3.
46. A compound of claim 11 wherein R1 and R2 are respectively 5-OCH3 and p-F.
47. A compound of claim 11 wherein R1 and R2 are respectively 5-OCH3 and m-CI.
48. A compound of claim 8 wherein R1' and R2'' are each hydrogen.
49. A compound of claim 48 wherein R1, R2, R2', R3, X, R4 and P5 are respectively H, H, H, H, CH2-CH2, H, CH3.
50. A compound of claim 48 wherein P1, R2, R2', R3, X, R4 and P5 are respectively H, H, H, H, CH2-CH2, CH3, CH3.
51. A compound of claim 48 wherein P1, R2, R2'. R3, X, R4 and R6 are respectively H, H, H, H, CH2-CH2-CH2, H, CH3.
52. A compound of claim 48 wherein R1, R2, R2', R3, X, R4 AND R6 are respectively H, H, H, H,
52. A compound of claim 48 wherein R1, R2, R2', R3, X, R4 and P5 are respectively H, H, H, H, CH2-CH2-CH2, CH3, CH3.
53. A compound of claim 48 wherein P1, R2, R2', R3, X, R4 and R5 are respectively H, H, H, H, CH2-CH2-CH2-CH2, H, H.
54. A compound of claim 48 wherein R1, R2, R2', R3, X, R4 and R5 are respectively H, m-CI, p-CI, H, CH2-CH2, H, H.
55. A compound of claim 48 wherein R1, R2, R2', R3, X, R4 and R5 are respectively H, p-F, H, H, CH2-CH2, CH3, CH3.
56. A compound of claim 48 wherein R1, P2, R2', R3, X, R4 and R5 are respectively 6-CI, H, H, H, CH2-CH2, CH3, CH3.
57. A compound of claim 48 wherein P1, P2, R2', R3, X, R4 and R5 are respectively 6-F, H, H, H, CH2-CH2, CH3, CH3.
58. A compound of claim 48 wherein P1, R2, R2', R3, X, R4 and R5 are respectively H, p-F, H, H, CH2-CH2, CH3,H.
59. A compound of claim 8 which is 1-(2-aminopropyl)-3-phenylindoline.
60. A compound of claim 59 which, in hydrochloride salt form, melts at 249 to 251 C.
61. A compound of claim 59 which, in hydrochloride salt form melts at 238 to 240 C.
62. A compound of claim 8 which is 1 -(3- amino-2-propyl)- 3-phenylindoline.
63. A compound of claim 62 which, in bis[base] fumarate salt form, melts at 224 to 226 C.
64. A compound of claim 62 which, in hydrogen fumarate salt form, melts at 172 to 174 C.
65. Acompound of claim 8 which is 1-(2-aminoethyl)-2-methyl-3-phenylindoline.
66. A compound of claim 65 which, in hydrochloride salt form, melts at 194to 197"C.
67. A compound of claim 65 which, in hydrogen fumarate salt form, melts at 178 to 181"C.
68. A compound of claim 8 wherein R2 is hydrogen, halogen, alkoxy, hydroxy, ortrifluoromethyl, R1' is hydrogen, R2' is hydrogen or halogen, and R2" is hydrogen.
69. A compound of claim 8 wherein R1', R2' and R2" are each hydrogen.
70. A compound of claim 8 wherein R1 and R1' are other than chlorine in the 5 position when R2, R2,, R2", R3, R4 and Rg are each hydrogen and X is ethylene.
71. A compound of claim 8 wherein R1 and R1' are other than chlorine in the 5 position of the indoline nucleus.
72. A compound of claim 8 wherein R3 is hydrogen.
73. A compound of any one of claims 4 to 72 in free base form.
74. A compound of any one of claims 4 to 72 in acid addition salt form.
75. A compound of any one of claims 4 to 74 for therapeutic use.
76. A compound of any one of claims 4 to 74 for use as an anti-depressant.
77. A pharmaceutical composition comprising a compound of any one of claims 4 to 72 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
GB8020753A 1979-06-29 1980-06-25 Indoline derivatives their production and pharmaceutical composition containing them Expired GB2051811B (en)

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DK (1) DK280380A (en)
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FI (1) FI802002A7 (en)
FR (2) FR2460296A1 (en)
GB (1) GB2051811B (en)
IL (1) IL60420A (en)
IT (1) IT8049093A0 (en)
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EP1147107A4 (en) * 1999-01-20 2002-05-22 Merck & Co Inc ANGIOGENESIS INHIBITORS

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TW270114B (en) * 1993-10-22 1996-02-11 Hoffmann La Roche

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DK96884C (en) * 1959-09-14 1963-09-16 Dumex Ltd As Process for the preparation of indole derivatives or their salts.
US4080330A (en) * 1975-06-23 1978-03-21 Delmar Chemicals Limited Phenylindolines and process for their production

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* Cited by examiner, † Cited by third party
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EP1147107A4 (en) * 1999-01-20 2002-05-22 Merck & Co Inc ANGIOGENESIS INHIBITORS

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AU5973980A (en) 1981-01-08
IL60420A (en) 1983-10-31
PT71465B (en) 1981-07-03
ES8105284A1 (en) 1981-06-01
ZA803888B (en) 1982-02-24
FR2460296B1 (en) 1983-08-05
DK280380A (en) 1980-12-30
IT8049093A0 (en) 1980-06-27
FI802002A7 (en) 1981-01-01
CA1134370A (en) 1982-10-26
PT71465A (en) 1980-07-01
ES492884A0 (en) 1981-06-01
IL60420A0 (en) 1980-09-16
FR2514352A1 (en) 1983-04-15
BE884013A (en) 1980-12-29
JPS568363A (en) 1981-01-28
NL8003674A (en) 1980-12-31
FR2460296A1 (en) 1981-01-23
GB2051811B (en) 1983-11-23

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