WO1983002610A1 - Derivatives of 3,3-dialkyl-indolin and of 3,3-alkylene-indolin, method for producing them and pharmaceutical preparations containing them - Google Patents

Derivatives of 3,3-dialkyl-indolin and of 3,3-alkylene-indolin, method for producing them and pharmaceutical preparations containing them Download PDF

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Publication number
WO1983002610A1
WO1983002610A1 PCT/CH1983/000008 CH8300008W WO8302610A1 WO 1983002610 A1 WO1983002610 A1 WO 1983002610A1 CH 8300008 W CH8300008 W CH 8300008W WO 8302610 A1 WO8302610 A1 WO 8302610A1
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WO
WIPO (PCT)
Prior art keywords
indoline
formula
indolines
acid addition
free form
Prior art date
Application number
PCT/CH1983/000008
Other languages
German (de)
English (en)
French (fr)
Inventor
Ag Sandoz
Roland Achini
Original Assignee
Ag Sandoz
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
Application filed by Ag Sandoz filed Critical Ag Sandoz
Publication of WO1983002610A1 publication Critical patent/WO1983002610A1/en

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Classifications

    • 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
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems

Definitions

  • the present invention relates to new 3,3-dialkyl and 3,3-alkylene indoline derivatives with valuable pharmacological properties, processes for their preparation, pharmaceutical preparations which contain these derivatives, and the use of these derivatives as pharmaceuticals.
  • the present invention relates to 3,3-dialkyl and 3,3-alkylene indolines which are unsubstituted in positions 1 and 2 and in positions 4 or 6 by an optionally etherified hydroxy group or in positions 5 or 7 by an etherified one Hydroxy group are substituted, as well as the physiologically hydrolyzable and compatible esters of these compounds in free form or as acid addition salts.
  • R 4 represents hydrogen or alkyl having 1 to 3 carbon atoms, and their physiologically hydrolyzable and compatible esters, in free form or as acid addition salts.
  • R 1 and R 2 are particularly preferably independently of one another alkyl having 1 to 3 carbon atoms. Most preferably R 1 and R 2 are both methyl.
  • R 4 is hydrogen
  • R 3 is preferably in position 5 or 6.
  • a connecting group according to the invention comprises indolines of the formula I as defined above, in which R 3 is alkoxy with 6 to 6 carbon atoms in position 5, in free form or as acid addition salts.
  • a further connecting group according to the invention comprises indolines of the formula I, as defined above, in which R 3 is hydroxy or alkoxy having 1 to 6 C atoms in position 6, in free form or as acid addition salts.
  • the indolines according to the invention can be present as racemates or in optically active form.
  • the present invention encompasses both the individual isomeric forms and their mixtures.
  • the present invention comprises the physiologically hydrolyzable and compatible esters of the indolines according to the invention with a hydroxyl group in position 4 or 6, for example the indolines of the formula I in which R 3 is hydroxyl.
  • Physiologically hydrolyzable and compatible esters are understood to mean those esters which can be hydrolyzed under physiological conditions and which give rise to acids which are themselves physiologically compatible, ie which are non-toxic at the desired doses.
  • Such esters include esters with mono- or dicarboxylic acids, especially with carboxylic acids with 2 to 5 carbon atoms.
  • the invention further relates to a process for the preparation of the 3,3-dialkyl- or 3,3-alkyleneindolines defined above or their physiologically hydrolyzable and compatible esters in free form or as acid addition salts.
  • This process comprises the reduction of the corresponding 3,3-dialkyl- or 3,3-alkylene-2-oxo-indolines in free or N-protected form and in the last If the N-protecting group is removed and, if desired, the reaction of a 3,3-dialkyl- or 3,3-alkyleneindoline thus obtained into another 3,3-dialkyl- or 3,3-alkylene-indoline as defined above and / or the acylation of a 3,3-dialkyl- or 3,3-alkyleneindoline obtained containing a hydroxyl group in position 4 or 6 with a suitable acid to produce a physiologically hydrolyzable and compatible ester. thereof and the recovery of indoline or its ester in free form or as an acid addition salt.
  • the process also relates to a process for the preparation of the indolines of the formula I, as defined above, or their physiologically hydrolyzable and compatible esters, in free form or as acid addition salts, characterized in that 2-oxoindolines of the formula II
  • the above process can be carried out according to methods known per se.
  • reducing agents which are customary in the conversion of an amide to an amino group can be used.
  • Particularly suitable reducing agents are metal hydrides such as LiAlH 4 , B 2 H 6 or AlH 3 .
  • the reduction is preferably carried out in the presence of a solvent or diluent, such as tetrahydrofuran.
  • R 1 , R 2 and R 4 have the meanings given for the formula I, R 5 is hydroxyl or alkoxy with 1 to 6 carbon atoms and Z is a protective group.
  • a suitable protective group for use in the reduction stage for example as Z in formula II, is for example the benzyl group.
  • Suitable protecting groups for use in the transalkylation or acylation of the indolines originally obtained, for example of the formula I, are acyl groups (especially acetyl) for the transalkylation and the benzyl group for the transalkylation or acylation.
  • the protective group can be removed by methods known per se, for example by hydrolysis or hydrogenolysis.
  • the hydrolysis can be carried out in an acidic or alkaline medium, preferably in an aqueous-alcoholic solvent mixture such as H 2 O / CH 3 OH or H 2 O / C 2 H 5 -OH under reflux.
  • the hydrogenolysis for example of the benzyl group, is preferably carried out using Pd / C as a catalyst in an inert solvent or diluent, such as methanol, at 20-60 ° C. under normal or elevated pressure on H 2 .
  • the ether cleavage of the compounds of the formula I in which R 3 is alkoxy having 1 to 6 C atoms in position 4 or 6 can also be carried out by methods known per se, for example using boron trihalides, preferably BBr 3 , or using HBr.
  • the ether cleavage proceeds best when using compounds of the formula I in which R 3 is 4- or 6-methoxy.
  • acylation for example of the compounds of the formula I in which R 3 is hydroxy to obtain physiologically hydrolyzable and compatible esters, can also be carried out by methods known per se, for example by reaction with a suitable acid halide or anhydride, preferably in Presence of a suitable acid-binding agent or condensing agent with intermediate protection of the N atom, for example protection of the N atom from acylation and subsequent removal of the N-protecting group after acylation.
  • Transalkylation for example of the indolines of the formula I, in which R 3 is alkoxy having 1 to 6 carbon atoms, can be carried out, for example, by ether cleavage as described above and subsequent alkylation, for example by reaction with a suitable alkyl halide in the presence of an acid-binding agent.
  • the N atom is also protected as an intermediate, for example by protecting the N atom from ether cleavage and removing the N protecting group after the alkylation.
  • the transalkylation can, as mentioned, be carried out with indolines of the formula I, in which R 3 is alkoxy having 1 to 6 C atoms in the 4, 5, 6 or 7 position, via intermediates of the formula III, in which R 5 is hydroxyl both in the Positions 5 or 7 as well as positions 4 or 6 can be.
  • the indolines of formula I and their esters can be obtained as free bases or as acid addition salts and the free bases obtained can be converted into their acid addition salts and vice versa.
  • Suitable acid addition salts for pharmaceutical use are both the pharmaceutically acceptable acid addition salts with inorganic acids, such as HCl or HBr, and with organic acids, such as maleic acid.
  • optically active isomers of the indolines according to the invention for example the indolines of the formula I in which R 1 and R 2 have different meanings, can be obtained by methods known per se, for example by resolving racemates or starting from optically active starting compounds.
  • the starting products of the formula II, in which R 3 is alkoxy having 1 to 6 carbon atoms, can be prepared according to the reaction scheme below.
  • R 1 , R 2 and R 4 have the meanings given for the formula I;
  • R 1 is alkyl with 1 to 3 C atoms;
  • R 3 is alkoxy with 1 to 6 carbon atoms, preferably methoxy;
  • reaction steps a) to k) can be carried out according to methods known per se for oxindole synthesis or as described in the examples below and comprise the following basic processes: a) O-alkylation, b) reaction with diethyl oxalate in the presence of t.
  • the 3,3-dimethyl-5-methoxy-indolin2-one used as the starting material can be obtained as follows:
  • a mixture of 120.0 g of 5-methoxy-indolin-2-one and 1, 21 acetic anhydride is heated under reflux for 4 hours. After evaporating the mixture, the residue is shaken at 0 ° between aqueous NaHC0 3 solution and CH 2 Cl 2 . The organic phase provides after drying (MgS0 4 ) and evaporation l-acetyl-5-methoxy-indolin-2-one (mp. 139-140 °, from ether).
  • the starting product can be obtained as follows: a) l-acetyl-5-isopropoxy-indolin-2-one:
  • the starting product can also be produced from the combination of Example 1 in the following way: c) 3,3-Dimethyl-5-hydroxy-indolin-2-one:
  • the starting product can also be prepared from the compound of Example 2c) analogously to the process of Example 2d).
  • connection is established analogously to example 1.
  • the hydrochloride is obtained as an amorphous product.
  • the 5-methoxy-3,3,7-trimethyl-indolin-2-one used as the starting product is prepared as follows: a) 3- (5-methoxy-3-methyl - 2-nitrophenyl) -2-oxo-propionic acid :
  • the starting product is manufactured as follows:
  • the starting product is prepared as follows: a) l-acetyl-4-acetyloxy-indolin-2-one:
  • the 3,3-dialkyl- and 3,3-alkyleneindolines according to the invention especially the previously defined indolines of formula I, as well as their physiologically hydrolyzable and compatible esters and the pharmaceutically acceptable acid addition salts of these indolines and esters, have valuable pharmaceutical, particularly anaetic properties.
  • these are shown, for example: a) in the arthritis pain test (based on the test described by AW Pircio et al. In Eur. J. Pharmacol. 31, 207-215, 1975) on the rat at doses of 3 to 50 mg / kg body weight po and b) in the Randall-Seiitto test on the inflamed hind paw of the rat (Arch. Int. Pharmacodyn. 61, 409-19, 1957) at doses of 20 to 200 mg / kg body weight p.o.
  • the indolines, esters and salts according to the invention are therefore suitable for use as analgesics, for example in the treatment of pain.
  • a daily dose of 100 to 500 mg is suitable for this use.
  • This dose can optionally be administered in 2 to 4 portions or as a slow-release form.
  • the partial doses contain about 25 to 250 mg of the indolines or esters in free form or as pharmaceutically acceptable acid addition salts in addition to pharmaceutically acceptable diluents or carriers.
  • the invention also relates
  • the pharmaceutical preparations mentioned under 3) above can be prepared by galenic methods known per se. Suitable galenical forms of administration are e.g. Tablets and liquid preparations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/CH1983/000008 1982-01-21 1983-01-19 Derivatives of 3,3-dialkyl-indolin and of 3,3-alkylene-indolin, method for producing them and pharmaceutical preparations containing them WO1983002610A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH37382 1982-01-21
CH373/82-3 1982-01-21
CH374582 1982-06-17
CH3745/82-7820617 1982-06-17

Publications (1)

Publication Number Publication Date
WO1983002610A1 true WO1983002610A1 (en) 1983-08-04

Family

ID=25684383

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH1983/000008 WO1983002610A1 (en) 1982-01-21 1983-01-19 Derivatives of 3,3-dialkyl-indolin and of 3,3-alkylene-indolin, method for producing them and pharmaceutical preparations containing them

Country Status (26)

Country Link
US (1) US4622336A (en, 2012)
AT (1) AT381490B (en, 2012)
AU (1) AU565538B2 (en, 2012)
CA (1) CA1191857A (en, 2012)
CH (1) CH657848A5 (en, 2012)
CY (1) CY1431A (en, 2012)
DE (1) DE3300522A1 (en, 2012)
DK (1) DK161071C (en, 2012)
ES (1) ES519108A0 (en, 2012)
FI (1) FI79098C (en, 2012)
FR (1) FR2519982B1 (en, 2012)
GB (1) GB2113682B (en, 2012)
HK (1) HK56888A (en, 2012)
HU (1) HU189215B (en, 2012)
IE (1) IE54878B1 (en, 2012)
IL (1) IL67715A (en, 2012)
IT (1) IT1197546B (en, 2012)
KE (1) KE3813A (en, 2012)
MY (1) MY8600467A (en, 2012)
NL (1) NL8300159A (en, 2012)
NZ (1) NZ203056A (en, 2012)
PH (1) PH22848A (en, 2012)
PT (1) PT76110B (en, 2012)
SE (1) SE453293B (en, 2012)
SG (1) SG22688G (en, 2012)
WO (1) WO1983002610A1 (en, 2012)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690943A (en) * 1984-09-19 1987-09-01 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
US4803217A (en) * 1986-12-24 1989-02-07 Merck & Co., Inc. Hapalindolinone compounds as vassopressin antagonists
GB8723157D0 (en) * 1987-10-02 1987-11-04 Beecham Group Plc Compounds
GB9108965D0 (en) * 1991-04-26 1991-06-12 Sandoz Ltd Improvements in or relating to organic compounds
FR2708606B1 (fr) * 1993-07-30 1995-10-27 Sanofi Sa Dérivés du N-phénylalkylindol-2-one, leur préparation, les compositions pharmaceutiques en contenant.
WO2016179157A1 (en) 2015-05-05 2016-11-10 Carafe Drug Innovation, Llc Substituted 5-hydroxyoxindoles and their use as analgesics and fever reducers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2154520A1 (en, 2012) * 1971-09-16 1973-05-11 Kabi Ab
FR2245353A1 (en, 2012) * 1973-09-10 1975-04-25 Lepetit Spa

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT311332B (de) * 1971-12-06 1973-11-12 Pierrel Spa Verfahren zur Herstellung eines neuen Esters von 3,3-Bis(p-hydroxyphenyl)-2-indolinon und dessen Salzen
BE524637A (en, 2012) * 1972-05-17
AT346841B (de) * 1976-11-30 1978-11-27 Delmar Chem Verfahren zur herstellung von neuen 3- phenylindolinen und ihren salzen
FI59246C (fi) * 1974-06-24 1981-07-10 Otsuka Pharma Co Ltd Foerfarande foer framstaellning av benscykloamidderivat anvaendbara vid trombos- och emboliterapin
JPS597699B2 (ja) * 1977-02-04 1984-02-20 イハラケミカル工業株式会社 インドリン類の製造方法
DE2816380A1 (de) * 1977-04-21 1978-12-07 Hoechst Ag Spiro eckige klammer auf indolin- 3,4'-piperidine eckige klammer zu und verwandte verbindungen
DE2805620A1 (de) * 1978-02-10 1979-08-23 Basf Ag Verfahren zur herstellung von indoleninen
US4307235A (en) * 1978-08-23 1981-12-22 American Hoechst Corporation Spiro[indoline-3,4'-piperidine]s
JPS597700B2 (ja) * 1978-10-31 1984-02-20 イハラケミカル工業株式会社 インドリン類の製造方法
US4408050A (en) * 1980-02-15 1983-10-04 American Hoechst Corporation Spiro(indoline-3,4'-piperidine) and related compounds
US4345081A (en) * 1980-02-15 1982-08-17 American Hoechst Corporation Spiro[indoline-3,4'-piperidine]s
DE3143327A1 (de) * 1980-11-12 1982-06-09 Dr. Karl Thomae Gmbh, 7950 Biberach "neue indolinone, ihre herstellung und ihre verwendung als arzneimittel"
IT1143242B (it) * 1980-11-18 1986-10-22 Upjohn Co 1,2,8,ba-ciclopropa(c)-benzo(1,2-b-4,3-b)dipirrol-4(5h)-one antibatte ricamente attivo e relativo metodo di preparazione

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2154520A1 (en, 2012) * 1971-09-16 1973-05-11 Kabi Ab
FR2245353A1 (en, 2012) * 1973-09-10 1975-04-25 Lepetit Spa

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemische Berichte, March 1978, published by, D. Döpp and H. Weiler: "Persäure-oxidationen einiger 3,3-Dimethyl-3H-Indole", pages 3806-3817 *

Also Published As

Publication number Publication date
SE8300289D0 (sv) 1983-01-20
AU565538B2 (en) 1987-09-17
DE3300522A1 (de) 1983-07-28
ES8402819A1 (es) 1984-03-01
GB2113682A (en) 1983-08-10
PT76110A (en) 1983-02-01
ATA17483A (de) 1986-03-15
IL67715A0 (en) 1983-05-15
FI830137A0 (fi) 1983-01-14
DK161071B (da) 1991-05-27
MY8600467A (en) 1986-12-31
FI79098B (fi) 1989-07-31
HK56888A (en) 1988-08-05
IT8347588A0 (it) 1983-01-20
SE453293B (sv) 1988-01-25
FI830137L (fi) 1983-07-22
AT381490B (de) 1986-10-27
CH657848A5 (de) 1986-09-30
KE3813A (en) 1988-08-05
GB8301383D0 (en) 1983-02-23
GB2113682B (en) 1985-07-24
FR2519982A1 (fr) 1983-07-22
CY1431A (en) 1988-09-02
DK20983D0 (da) 1983-01-19
SE8300289L (sv) 1983-07-22
NL8300159A (nl) 1983-08-16
DK20983A (da) 1983-07-22
FI79098C (fi) 1989-11-10
ES519108A0 (es) 1984-03-01
US4622336A (en) 1986-11-11
FR2519982B1 (fr) 1985-06-14
NZ203056A (en) 1986-04-11
IE54878B1 (en) 1990-03-14
DK161071C (da) 1991-11-11
IT1197546B (it) 1988-12-06
AU1061183A (en) 1983-07-28
DE3300522C2 (en, 2012) 1992-01-09
SG22688G (en) 1988-07-08
PT76110B (en) 1985-12-09
IE830115L (en) 1983-07-21
CA1191857A (en) 1985-08-13
HU189215B (en) 1986-06-30
PH22848A (en) 1989-01-19
IL67715A (en) 1987-03-31

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