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IE41562B1 - Indolinone and fluorenone derivatives - Google Patents

Indolinone and fluorenone derivatives

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Publication number
IE41562B1
IE41562B1 IE1359/75A IE135975A IE41562B1 IE 41562 B1 IE41562 B1 IE 41562B1 IE 1359/75 A IE1359/75 A IE 1359/75A IE 135975 A IE135975 A IE 135975A IE 41562 B1 IE41562 B1 IE 41562B1
Authority
IE
Ireland
Prior art keywords
compound
group
het
fluorenone
formula
Prior art date
Application number
IE1359/75A
Other versions
IE41562L (en
Original Assignee
Sandoz Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CH838174A external-priority patent/CH602710A5/en
Priority claimed from CH838074A external-priority patent/CH599160A5/en
Application filed by Sandoz Ltd filed Critical Sandoz Ltd
Publication of IE41562L publication Critical patent/IE41562L/en
Publication of IE41562B1 publication Critical patent/IE41562B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C07D203/10—Radicals substituted by singly bound oxygen atoms
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

1500063 2-Indolinone and fluorenone derivatives SANDOZ Ltd 16 June 1975 [19 June 1974 (2)] 25530/75 Heading C2C Novel 2-indolinone and fluorenone derivatives of the general formula wherein Het is a radical formed by removing a hydrogen atom from the phenyl ring of 2-indolinone or fluorenone, and R is a group having one of the following Formulµ A, B, C and D in which n is 2 or 3, n1 is 1-4, X-X1 is ethylene or vinylene and in D the two C atoms adjacent to the N atom are identically unsubstituted or substituted by one or two C 1-4 alkyl groups and acid addition salts thereof are prepared by reacting Het-O-CH 2 -CH(OH)-CH 2 Y, in which Y is a leaving group, or an epoxy compound of the general Formula IIa with H-R, followed optionally by salification of the product. Pharmaceutical compositions having antiarrhythmic activity comprise, as active ingredient, a 2-indolinone or fluorenone derivative (I) or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or diluent.

Description

The present invention relates to ne·.·.’ hetero cyclic compounds.
In accordance with the invention there are provide·! new compounds of formula I, OH Het-O-CH2-CB-CH2-R I whereir Het is a radical formed by removing one of th hydrogens from the phenyl ring of 2indolinone or fluorenone, and is the group A, B, C or D, Ιΰ 571 · / X 'Pw Aj Λ \ -M (CH„) X* C \/ 2 n X wherein n is the number 2 or 3, n* is the number 1, 2, 3 or 4, and ί-X’ is ethylene or vinylene - 3 415 6 3 wherein in group D both C atoms adjacent to the N atom are identically unsubstituted or substituted by one or two alkyl groups of 1 to 4 carbon atoms.
The propoxy side chain can be in the 4, 5, or 7 position of the indolinone radical, preferably in the 4 position. The side chain may be in the 1, 2, or 4 position of the fluorenone radical, conveniently in the 1, 2 or 4 position, especially in the 4 position.
When R is the group C, X-X' preferably signifies ethylene.
When R is the group D, n' preferably signifies 3 or 4 . The c atoms adjacent to the N atom are preferably alkylated, especially dialkylated. These alkyl substituents preferably contain 1 or 2, especially 1 carbon atom.
The radical R preferably signifies a tertiary amino group, the nitrogen atom thereof being linked with branched carbon atoms, e.g. a 2,2,5,5-tetramethyl20 pyrrolidinyl or 2,2,6,6-tetramethylpiperidino radical.
Further, in accordance with the invention a compound of formula I may be obtained by a process comprising reacting a compound of formula Ila, O \ Het-O-CH2-CH-CH2 Ila -4 or of formula lib, OH I Het-0-CH2-CH-CH2Y lib wherein Y is a leaving group? with a compound of formula III, H - R III wherein R is as defined above.
Acid addition salt forms may be obtained from the free base forms in known manner and vice versa a suitable acid is hydrochloric acid.
The reaction of a compound of formula Ila or lib with a compound of formula III may be effected i1 a manner analogous to the methods described for the production of known 3-amino-2-hydroxypropoxy compounds. Y in formula lib is preferably the acid radical of a reactive ester especially halogen, preferably chlorine or bromine, or a group R^SC^-O-, wherain R2 is phenyl, tolyl or lower alkyl. The reaction is preferably effected in an inert organic solvent, e.g. in a cyclic or open chain ether such as dioxane or diethylene glycol dimethyl ether. An excess of the compound oi formula III may optionally be used as solve it. The reaction may also be effected by fusion. The reaction temperature conveniently is between about room temperature and 200°C. The reaction time depends inter a7 la on the reaction temperature. 41563 -5The compounds of formula I may be obtained from the reaction mixture and purified in accordance with known methods.
The starting materials of formulae Ila and lib are known or may be produced in a manner analogous to known methods, using the corresponding hydroxyindole or hydroxyfluoren-9-one as starting material.
The compounds of formula III are known. Insofar as the production of the required starting materials is not described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.
In the following non-limitative Examples 15 all temperatures are indicated in degrees Centigrade. -6EXAMPLE 1; 4-[2-hydroxy-3-(2,2,5,5-tetramethyl1-pyrrolidlnyl)propoxy]-9-fluorenone g of 4-(2,3-epoxypropoxy)-9-fluorenone are heated to 150° in an autoclave for 15 hours together with 4 g of 2,2,5,5-tetramethylpyrrolidine in 30 cc of dioxane. After cooling, the reaction mixture is concentrated by evaporation. The residue is taken up in ether and extracted with 2 N hydrochloric acid. The aqueous solution is made alkaline and thoroughly extracted with methylene chloride. The methylene chloride phase is concentrated by evaporation and the; residue is crystallized from ethyl acetate/petroleum ether. The title compound has an M.P. of 137-139°.
EXAMPLE 2: 4- [3-(1-aziridinyl)-2-hydroxypropoxy]9-fluorenone g of 4-(2,3-epoxypropoxy)-9-fluorenone are allowed to stand at room temperature over night together with 15 cc of ethylene imine. The excess ethylene imine is removed by evaporation, the resic ue is taken up in ether and the solution is concentrate d by evaporation until crystallization commences.
The title compound has an M.P. of 113-116°. 415 6 3 -7EXAMPLE 3: 4-[2-hydroxy-3-(1,2-dihydro-2-imino1-pyrimidlny1) propoxy]-9-fluorenone g of 4-(2,3-epoxypropoxy)-9-fluorenone and 3.8 g of 2-amino-pyrimidine are heated to 100° for minutes. The melted material is taken up in ethyl acetate and is extracted with 2 N hydrochloric acid. The hydrochloride obtained as a resin is made alkaline and extracted with methylene chloride. The solvent is evaporated and the residue is crystallized from ethanol. M.P. 178-179°.
The following compounds of formula I are obtained in analogous manner, using the corresponding starting materials of formulae Ila or lib, wherein Y is chlorine,and III as starting materials: rH U w nJ rH o ffi nJ w y op α w 0 0 0 0 0 o 0 0 0 0 kO in O' co AO Ch O rH Ol Ol rp o n o- Vo ch in OJ in «—ί rH •H OJ rH rH H oi rH rH OJ cn in O cn toOl co O oj Ch Si· o «-J Ol t ch 1 , 1 1 G 0 1 G 1 1 -rH rH 0 d 0 rH rH I 0« | G •Ρ G 1 f ι—, XJ r—, o rH >1 >1 >1 rH •Ρ rH G >Ί XJ Λ Λ .b • Ρ • •P Χί -μ -μ -P P ΓΏ (1) m ε χ) fl, a) 0 fl) • Ch • P 0 £ ε & Γ0 rH -Ρ ΓΩ 1 β H rH rrt nJ 3 L_J >, CU —« Ol 0 P >4 M rH Ρ p rH o G Ρ 0 1 Ρ •μ G •P >1 -μ -μ >1 rH •Ρ >1 rH 0 •μ n> 0 fli fl) a φ a, a ϋ <ΰ χί a P 0 EH G di Eh •P ΕΗ Eh •P >. •Ρ χ) Π3 0 1 0 ί ϋ rp α> □ >1 I kO XJ P in •P ID C in •Ρ •Ρ 0 ε •P XJ rP ιη a. •P K I—{ * -rH ·» rH Λ Ρ •Ρ Λ -H >, kO μ P in 0 ko Ό in 0 0 Ρ Q 0 a n ιη «. o) o ·» P ** -H >» P Ν >, 1 N 1 ·Ρ * OJ & z OJ P oj p Ol M < Ρι kO OJ p OJ a. -rl 1 *. >5 " 0 >1 1 r4 - I rH - >. * OJ a co Ol 0. Ol Cu OJ cu σι >ι γΗ OJ σι >, «Ρ οι GJ Ή £ GJ O OJ -Ρ H •Ρ 0 ·Ρ 0 ω X 0 ο -μ χί ω *3« οι Μ* *3· *3« Μ* *3» rH (U 0 X’ 0 0 0 0 0 0 0 0 0 0 d d G G G G d d d G G 0 0 0 ο 0 Ο 0 0 0 0 O G G G G d G G d G G G 0 0 0 •Ρ Ή Ή 0 0 0 0 0 Ρ Ρ Ρ «Ρ rH rH Ρ Ρ P P P Ο η ο 0 0 0 0 0 0 O 0 G 0 g Ό τ) d G G G G rH G G d rH rH rH rH rH -μ Εμ Εμ Dm Η Η Η Dm Dm Em Em Em Π) I 1 1 I 1 1 1 £ σ\ σ\ σ\ οι 03 ΟΙ σ\ σι Ch Ch Ch « I 2 P m ο o G th-P · 3 0 X «Ρ w HCl = Hydrochloride Oi rH <=r H OS 1 1 fi fi 0 0 fi fi r—» »—» Η H • · 1 O >i hl >i 1 0 ο 0 cn •HI *H I Λ β eQ β (DO) to Φ N 1 N 1 < CM < CM Position of the side chain on the heterocycle 4J 0) W G) 0 β β 0 0 β β ω -η Η Η Ο 0 β *0 Η β Pu Η 1 1 σι <μ Ana- logous to Ex.Nr. <—1 r-i ω κ ιη ιο Η ίΗ 41563 -10The compounds exhibit pharmacological activity In particular they exhibit anti-arrhythmic activity as indicated in the chloroform arrhythmia test with mice (method of J.W. Lawson, J.Pharm.exper.Therap. 160, 22-31 [1968]).
The compounds are therefore indicated for use as anti-arrhythmic agents, e.g. for the treatment of heart rhythmi-disorders, such as heart fibrillation.
For this use an indicated daily dose is from about to about 400 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1 to about 200 mg, or in sustained release form.
The compounds of formula I may be ad15 ministered in pharmaceutically acceptable acid addition salt form. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution or a tablet. -1141562 Preferred compounds of formula I, axe those wherein Het has the side chain in the 4 position, R is group D, wherein both ring carbons adjacent to the nitrogen atoms are dialkylated by alkyl of 1 to 4 carbon atoms, and n* is 3 or 4.
The Example 1 compound shows especially interesting activity.
In one group of compounds R is C or D. In 10 a sub-group Het is derived from fluorenone. In another sub-group Het is derived from indolinone. ι -1241562 having now particularly described

Claims (5)

AND ASCERTAINED THE NATURE OF OUR SAID INVENTION AND IN WHAT MANNER THE SAME IS TO BE PERFORMED, WE DECLARE THAT WHAT WE CLAIM IS:
1. A process for the production of a compound of formula I, OH I Het-O-CH 2 -CH-CH 2 -R I wherein Het is a radical formed by removing one of 10 the hydrogens from the phenyl ring of 2indolinone or fluorenone, R is the group A, B, C or D, wherein n is the number 2 or 3, n' is the number 1, 2, 3 or 4, and X-X 1 is ethylene or vinylene, -1341562 wherein in group D both C atoms adjacent to the N atom are identically unsubstituted or substituted bv one or two alkyl groups of 1 to 4 carbon atoms, 5 comprising reacting a compound of formula Ila, Λ Het-O-CH 2 -CH-CII 2 Ila or of formula lib, Ϊ Het-O-CH 2 -CH-CII 2 Y lib wherein Y is a leaving group, with a compound of 10 formula III, H - R III wherein R is as defined above. 2. ,2,6,6-tetramethylpiperidino. 35. A compound of claim 33, wherein R is 2,2,5,5-Cetramethyl-l-pyrrolidinyl. 36. A compound of claim 33, wherein R is 9-,azabicyclo(3.3.1]non-9-yl. 37. A compound of claim 33, wherein R is g^afeabicyclo [3.3 . l]non-2-en-9-yl. 38. A compound of claim 4, which is 10 4-[2-hydroxy-3-(2,2,5,5-tetramethyl-l-pyrrolidinyl) propoxy]-9-fluorenone. 39. A compound of claim 4, which is 2,6- dimethylpiperidino. 5 27. A compound of claim 22, 9-azahicyclo Γ3.3.1]non-9-yl. 28. A compound of claim 22, 1,2- dihydro-2-imino-l-pyridyl. 29. A compound of claim 22, 10 9-azabicyclo Γ3.3.1]non-2-en-9-yl. 30. A compound of claim 21, side chain is in the 2 position and 1 Tetramethyl-l-pyrrolidinyl. 31. A compound of claim 21 15 side chain is in the 1 position and I tetramethyl-l-pyrrolidinyl. 32. A compound of claim 4, is derived from 2-indolinOn£l· 33. A compound of claim 32, 20 side chain is in the 4 position. wherein R wherein R is wherein R is wherein R is wherein R is wherein the t is 2,2,5,5, wherein the ! is 2,2,5,5wherein Het wherein the -17' 34. A compound of claim 33, wherein R is
2. A process for the production of a compound of formula I, as stated in claim 1, substantially 15 as hereinbefore described with reference to any one of the Examples.
3. A compound of formula I, whenever produced by a process according to claim 1 or 2. -144. A compound of formula I, as defined in claim 1. 5. A compound of claim 4, wherein Het has the side chain in the 4 position. 5 6. A compound of claim 4 or 5, wherein R is group D, wherein both ring carbons adjacent to the nitrogen atom are dialkylated by alkyl of 1 to
4. - [3-(1-aziridinyl)-2-hydroxypropoxy]-9-fluorenone. 40. A compound of claim 4, which is 15 4-[2-hydroxy-3-(l,2-dihydro-2-imino-l-pyrimidinyl) propoxy]-9-fluorenone. 41. A compound of claim' 4, wherein Het is derived from 2-indolinone and R is group C or D » 42. A compound according to any one of 20 claims 3 to 41 in free base form. -1841562 43. A compound according to any one of claims 3 to 41 in acid addition salt form. 44. A pharmaceutical composition comprising a compound according to any one of claims 3 to 41 4 or 5, wherein R 12. A compound of claim 11, wherein X-X’ 20 is ethylene. 13. A compound of claim 11, wherein X-X' is vinylene. -15· 14. A compound of claim 11, 12 or 13, wherein n is 2. 15. A compound of claims 11, 12 or 13, wherein n is 3. 5 16. A compound of claim 4 or 5, wherein R is group D. 17. A compound of claim 16, wherein n 1 is 1. 18. A compound of claim 16, wherein n' is 2. 19. A compound of claim 16, wherein n' is 3. 20. A compound of claim 16, wherein n' is 4. 21. A compound of claim 4, wherein Het is derived from fluorenone. 22. A compound of claim 21, wherein the side chain is in the 4 position. 23. A compound of claim 22, wherein R is 2,2,6,6-t etramethylpiperidino. 24. A compound of claim 22, wherein R is 8-Nortropanyl. -1641562 25. A compound of claim 22, is 1-pyrrolidinyl. 26. A compound of claim 22, 4 or 5, wherein R 4 or 5, wherein R 4, wherein Het is group C or D. 4, 5 or 6 , wherein 4 carbon atoms. 7. 10 n' is 3 or 4 8. derived from 9. is group A. 15 10. is group B. 11. is group C. A compound of claim in group D. A compound of claim fluorenone and R is A compound of claim A compound of claim A compound of claim
5. In free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
IE1359/75A 1974-06-19 1975-06-17 Indolinone and fluorenone derivatives IE41562B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH838174A CH602710A5 (en) 1974-06-19 1974-06-19 Substd. 9-fluorenone and 2-indolinone derivs
CH838074A CH599160A5 (en) 1974-06-19 1974-06-19 Substd. 9-fluorenone and 2-indolinone derivs

Publications (2)

Publication Number Publication Date
IE41562L IE41562L (en) 1975-12-19
IE41562B1 true IE41562B1 (en) 1980-01-30

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EP0005828B1 (en) * 1978-06-06 1981-03-11 Hoechst Aktiengesellschaft New substituted phenylpiperazine derivatives, pharmaceutical compositions containing them and process for their preparation
EP1144384B1 (en) 1999-01-22 2007-10-31 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by vla-4
TW200307671A (en) 2002-05-24 2003-12-16 Elan Pharm Inc Heteroaryl compounds which inhibit leukocyte adhesion mediated by α 4 integrins
TWI281470B (en) 2002-05-24 2007-05-21 Elan Pharm Inc Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
US7727996B2 (en) 2005-09-29 2010-06-01 Elan Pharmaceuticals, Inc. Carbamate compounds which inhibit leukocyte adhesion mediated by VLA-4
AU2006297220B8 (en) 2005-09-29 2013-01-31 Elan Pharmaceuticals, Inc. Pyrimidinyl amide compounds which inhibit leukocyte adhesion mediated by VLA-4
MX2008010988A (en) 2006-02-27 2008-10-20 Elan Pharm Inc Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by vla-4.
US8367836B2 (en) 2009-04-27 2013-02-05 Elan Pharmaceuticals, Inc. Pyridinone antagonists of alpha-4 integrins

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GB1500063A (en) 1978-02-08
AU8216875A (en) 1976-12-23
DD118086A5 (en) 1976-02-12
IL47503A0 (en) 1975-08-31
NL7507131A (en) 1975-12-23
SE7506757L (en) 1975-12-22
CA1036163A (en) 1978-08-08
FI751727A (en) 1975-12-20
IE41562L (en) 1975-12-19
JPS51125060A (en) 1976-11-01
ES438637A1 (en) 1977-06-01
NO752078L (en) 1975-12-22
DE2525656A1 (en) 1976-01-15
DK259475A (en) 1975-12-20
FR2275200A1 (en) 1976-01-16
FR2275200B1 (en) 1979-06-08
HU169926B (en) 1977-02-28
ATA466375A (en) 1979-08-15

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