EP0981528A1 - Benzothiopyranopyridines regioisomeres a activite antitumorale - Google Patents

Benzothiopyranopyridines regioisomeres a activite antitumorale

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Publication number
EP0981528A1
EP0981528A1 EP98918764A EP98918764A EP0981528A1 EP 0981528 A1 EP0981528 A1 EP 0981528A1 EP 98918764 A EP98918764 A EP 98918764A EP 98918764 A EP98918764 A EP 98918764A EP 0981528 A1 EP0981528 A1 EP 0981528A1
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EP
European Patent Office
Prior art keywords
alkyl
group
ppm
formula
hydroxy
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98918764A
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German (de)
English (en)
Inventor
A. Paul Krapcho
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Vermont
Original Assignee
University of Vermont
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 University of Vermont filed Critical University of Vermont
Publication of EP0981528A1 publication Critical patent/EP0981528A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention is directed to benzothiopyrano [2,3-b]-, [3,2-b]- and [3,2-c]-pyridines substituted in the positions 6 and 9. These compounds have been shown to have antitumor activity.
  • Mitoxantrone is a broad spectrum oncolytic agent , whose activity is similar to that of the anthracycline antibiotic doxorubicin. Clinical trials have demonstrated that mitoxantrone has particularly promising activity in the treatment of advanced breast cancer, acute leukemia and lymphoma [Legha, Drugs of Today, 20, 629 (1984)].
  • MDR multidrug resistance
  • WO 92/15566 discloses N-oxide derivatives of aza-anthracenediones.
  • several derivatives of lucanthone have been prepared [S. Archer et al., J. Med. Chem., 25, 220-227 and 328-331 (1982)]:
  • R' is an aminoalkyi chain
  • R" is hydrogen or methyl and R has several meanings such as hydrogen, amino or hydroxy.
  • R' is an aminoalkyi chain
  • R" is hydrogen or methyl and R has several meanings such as hydrogen, amino or hydroxy.
  • lucanthone has also been described [(1) M. Croisy-Delcey et al., J. Med. Chem., 26, 1329-1333 (1982); (2) E.J. Blanz et al., J. Med. Chem., 6, 185-191 (1963)]:
  • R is an aminoalkyi chain and, in (2), one of X or Y is hydrogen and the other is carbon.
  • R' is selected from the group consisting of (C 1 -C 4 )alkyl, nitro or -NH-R ⁇ wherein R 1 is selected from the group consisting of -CO-CH 2 -NR 2 R 3 , (C C 10 )alkyl, (C 2 -C 10 )alkyl having one or two substituents selected from the group consisting of -OR 4 and -NR 2 R 3 , (C 2 -C 10 )alkyl interrupted by one or two oxygen atoms or by one -NR 5 - group, and said (C 2 -C 10 )alkyl being optionally substituted by one or two hydroxy or -NR 2 R 3 groups;
  • - R is selected in the group consisting of hydrogen, (C ⁇ C ⁇ alkyl, (C 2 -C 10 )alkyl having one or two substituents selected from the group consisting of -OR 4 and -NR 2 R 3 , (C 2 -C 10 )alkyl interrupted by one or two oxygen atoms or by one -NR 5 - group, and said (C 2 -C 10 )alkyl being optionally substituted by one or two hydroxy or -NR 2 R 3 groups;
  • R 2 and R 3 may be the same or different and are selected from the group consisting of hydrogen, (C C 10 )alkyl, (C 2 -C 10 )alkyl substituted with one or two hydroxy groups, or R 2 and R 3 taken together with the nitrogen to which they are linked form a 5- or 6-member aromatic or non-aromatic heterocyclic ring which optionally contains another heteroatom such as sulfur, oxygen or nitrogen;
  • - R 4 is selected from the group consisting of hydrogen, (C C 6 )alkyl, -S(0 2 )R 6 , (C 2 -C 6 )alkyl optionally substituted by -NR 2 R 3 ;
  • - R 5 is selected in the group consisting of hydrogen, (C C 10 )alkyl, (C 2 -C 10 )hydroxyalkyl, (C 2 -C 10 )alkyl substituted with -NR 2 R 3 ;
  • the present invention also concerns the tautomeric forms, the single enantiomers and diastereoisomers of the compounds of formula (I), as well as mixtures thereof.
  • Another object of the present invention is to provide a process for obtaining compounds of formula (I).
  • a further object of the present invention is to provide a method of treating mammals affected by tumors by administering effective amounts of one or more compounds of formula (I), as well as pharmaceutical compositions containing one or more compounds of formula (I) in admixture with suitable excipients.
  • phenyl means phenyl rings which can optionally contain substituents such as (C C 4 )alkyl groups, CF 3 , halogen atoms, nitro, amino, acetylamino, formylamino, dimethylamino, diethylamino, hydroxy, methoxy, and ethoxy groups.
  • substituents such as (C C 4 )alkyl groups, CF 3 , halogen atoms, nitro, amino, acetylamino, formylamino, dimethylamino, diethylamino, hydroxy, methoxy, and ethoxy groups.
  • Preferred examples of (C r C 10 )alkyl groups are methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
  • R and R' are (C 2 -C 10 )alkyl interrupted by one or two oxygen atoms or by one -NR 5 - group and optionally substituted by one or two hydroxy or -NR 2 R 3 groups, at least two carbon atoms are preferentially interposed between said oxygen atoms and/or the -NR 5 - and -NR 2 R 3 groups.
  • the -NR 2 R 3 substituent is a 5- or
  • 6-member aromatic or non-aromatic heterocyclic ring which may contain another heteroatom such as sulfur, oxygen and nitrogen
  • heterocyclic rings are 1-imidazolyl
  • the compounds of formula (I) can be prepared by a multistep process comprising the following steps:
  • Such conversion can be performed in a solvent, preferably dimethylformamide, and at temperatures ranging from -10°C to 50°C, preferably room temperature;
  • Such a reduction can be performed with all the usual reducing agents employed for the reduction of an aromatic nitro group, preferentially with
  • Such an alkylation for example can be performed in a solvent, preferably toluene, in the presence of a base, preferably an alkaline or alkaline-earth carbonate, and at temperatures ranging from room temperature to 130°C, preferably above 100°C.
  • a solvent preferably toluene
  • a base preferably an alkaline or alkaline-earth carbonate
  • the intermediate of formula (II) in which X is nitrogen can be obtained reacting 2-mercapto nicotinic acid and 2,4-dichloronitrobenzene - which are both sold by FLUKA AG - in the presence of at least one equivalent of a strong base, preferentially an alkoxide of an alkaline metal, in a solvent and at temperature ranging from room temperature up to the boiling point of the solvent.
  • a preferred reactive mean is sodium ethoxide in ethanol at reflux.
  • the intermediate of formula (II) in which Y is nitrogen can be obtained by reacting 4-chloronicotinic acid and 2-mercapto-4-chloronitrobenzene in a solvent at temperatures from room temperature up to the boiling point of the solvent.
  • a preferred reaction condition is to reflux the mixture of the two reactants in acetone as a solvent.
  • 4-chloronicotinic acid is prepared via the direct metallation of 4-chloropyridine hydrochloride, by treating it with 2 equivalents of lithium diisopropylamide, followed by bubbling carbon dioxide into the reaction mixture.
  • Intermediate (VI) is nitrated with fuming nitric acid in the presence of concentrated sulfuric acid, to give a mixture of products of nitration in ortho and para position with respect of the chlorine atom. By separation of the two regioisomers the desired product is obtained.
  • the intermediates of formula (IT) in which Y is nitrogen can be obtained by reacting 4-chloronicotininc acid and 2-mercapto-4-chlorotoluene in a solvent, preferentially at temperatures between 50 and 130°C.
  • 2-mercapto-4-chlorotoluene can be prepared, for example, according to the methodology described in J. Org. Chem., 2Z, 4455-61 (1962), which is herein incorporated by reference.
  • the intermediates of formula (IT) in which Z is nitrogen can be obtained by condensation of 4-chloro-1-[(C 1 -C 4 )alkyl]benzenes with
  • 3-mercaptopyridine-2-carboxylic acid in the presence of concentrated sulfuric acid and by separation of the desired regioisomer.
  • 3-mercaptopyridine-2-carboxylic acid can be obtained, starting from 3-hydroxy -2-picolinic acid (FLUKA AG), by esterification of the carboxylic moiety with methanol at reflux in the presence of concentrated sulfuric acid as a catalyst, followed by the treatment of this ester with dimethyl- thiocarbamoyl chloride in the presence of diazabicyclooctane as a basic catalyst, to give, after rearrangement by heating in diphenylether at 210°C, the thiocarbamate of formula (VII):
  • a murine sarcoma S-180 and its subline expressing multidrug resistance (S-180/A-10)
  • a leukemia L 1210
  • a human colon adenocarcinoma cell line LiVo isolated from a metastatic nodule and its subline expressing multidrug resistance to a number of antitumor agents such as doxorubicin, VP-16 and vincristine.
  • the compounds of the present invention are expected to be operative against human leukemias and solid tumors sensitive to treatment with mitoxantrone and antitumor antibiotics (to which doxorubicin belongs).
  • the compounds of the invention may be used as active ingredients of therapeutic compositions to induce regression and/or palliation of cancers in mammals when administered in amounts ranging from about 1 mg to about 0.4 g per kilogram of body weight.
  • a preferred dosage regimen would be from about 1 mg to about 50 mg per kilogram of body weight per day.
  • Unit dosage may be employed so that from about 70 mg to about 3.5 g of the active compound for a subject of about 70 kg of body weight are administered in a 24-hour period.
  • the dosage may be adjusted to be compatible to other treatment regimens, such as radiation therapy.
  • compositions may be in the form of tablets, capsules, gel capsules, suppositories, lyophilized powders and solutions for intravenous administration and can contain suitable eccipients which can vary according with the type of the desired composition. Said compositions are prepared following procedures well known to the skilled in the art. The invention is illustrated by the following examples.
  • 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (0.645 g) was added to fuming sulfuric acid (18-24% sulfur trioxide) (2 ml) and the mixture was placed in an oil bath preheated to 75°C. The solution was heated at 125-130°C for 1.25 hours. The mixture was removed from the oil bath, cooled to room temperature and poured over ice water (150 ml). The yellow precipitate was collected by filtration, washed well with water and dried (0.6 g).
  • the mixture was quenched over ice water (300 ml) and insoluble material was removed by filtration. Some insoluble material remained in the flask.
  • the filtrate was recollected by filtration through a celite bed and the filtrate acidified with concentrated hydrochloric acid to pH 1.5.
  • the yellow precipitate was allowed to stand for a few hours and collected by filtration and air dried to yield a yellow crude solid (5.4 g).
  • the crude product was heated in hexane (175 ml) and then decanted from a small amount of an orange oil. On cooling and standing for 24 hours, a yellow solid was collected by filtration (3.4 g) which was still contaminated with about 10% of the other regioisomer.
  • Example 3 -e-f ⁇ Jdimethylaminotethyllaminol-g- Jdimethylamino ⁇ ethyl]amino]-5H-[1]benzothiopyrano[2.3-b]pyridin-5-one
  • 6-[[2-(dimethylamino)ethyl]amino]-9-amino-5H- [1]benzothiopyrano[2,3-b]pyridin-5-one 0.5 g; example 2
  • 2-(dimethylamino)ethylbromide hydrobromide (1.86 g)
  • potassium carbonate (2.21 g) in toluene 15 ml was refluxed for 72 hours.
  • the mixture was cooled and the residue was collected by filtration and washed thoroughly with toluene.
  • the filtrate was concentrated to dryness.
  • the residue was triturated with hexane, collected by filtration and air dried, to give 0.6 g of the crude product.
  • the product was purified by column chromatography over silica gel eluting with methanol : dichloromethane (15 : 85) until all the unreacted starting material was eluted.
  • the desired product was eluted with methanol : dichloromethane : ammonium hydroxide (50 : 50 : 1).
  • the product fractions were pooled together and concentrated to a purple solid, 0.4 g, m.p. 170-172°C.
  • the product was purified by column chromatography over silica gel (40 x 1.5 cm) eluting with methanol : dichloromethane (5 : 95) until all the unreacted starting material was eluted.
  • the desired product was held strongly on the column and needed to be eluted with methanol : dichloromethane : ammonium hydroxide (50 : 50 : 1).
  • the product fractions were pooled together and concentrated to a purple solid, 0.025 g, m.p. 170-172°C.
  • Example 9 -6-[f2-(dimethylamino)ethyl]amino]-9-[[2-(dimethylamino) ethyl]amino]-5H-[1]benzothiopyrano[3.2-c]pyridin-5-one
  • a mixture of 6-[[2-(dimethylamino)ethyl]amino]-9-amino-10H- [1]benzothiopyrano[3,2-c]pyridin-5-one (0.25 g; example 8), 2-(dimethylamino)ethylbromide (0.93 g) and potassium carbonate (1.1 g) in toluene (8 ml) was refluxed for 5 days.

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

Abstract

La présente invention concerne des benzothiopyrano [2,3-b]-, [3,2-b]- et [3,2-c]-pyridines substituées en positions 6 et 9. Les composés de l'inventions sont représentés par la formule générale (I). En l'occurrence, X, Y ou Z est azote (-N=), les autres étant carbone (-CH=). R' appartient au groupe des (C1-C4)alkyle, nitro ou -NH-R1, R1 appartenant au groupe des -CO-CH2-NR2R3, (C1-C10)alkyle, (C2-C10)alkyle où un ou deux substituants appartiennent au groupe des -OR4 et -NR2R3, (C1-C10)alkyle interrompu par un ou deux atomes d'oxygène ou par un groupe -NR5-, et où ledit (C2-C10)alkyle est éventuellement substitué par un ou deux groupes hydroxy ou -NR2R3. R appartient au groupe des hydrogène, (C1-C10)alkyle et (C2-C10)alkyle où un ou deux substituant appartiennent au groupe des -OR4, -NR2R3 et (C2-C10)alkyle interrompu par un ou deux atomes d'oxygène ou par un groupe -NR5-, et où ledit (C2-C10)alkyle est éventuellement substitué par un ou deux groupes hydroxy ou -NR2R3. Ces composés font preuve d'une activité antitumorale contre la leucémie humaine et les tumeurs solides sensible au traitement par la mitoxantrone et des antibiotiques antitumoraux tels que la doxorubicine.
EP98918764A 1997-04-28 1998-04-28 Benzothiopyranopyridines regioisomeres a activite antitumorale Withdrawn EP0981528A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4497097P 1997-04-28 1997-04-28
US44970P 1997-04-28
PCT/US1998/008398 WO1998049172A1 (fr) 1997-04-28 1998-04-28 Benzothiopyranopyridines regioisomeres a activite antitumorale

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EP (1) EP0981528A1 (fr)
AU (1) AU7162898A (fr)
CA (1) CA2288274A1 (fr)
WO (1) WO1998049172A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6747039B2 (en) 2002-03-12 2004-06-08 Albany Molecular Research, Inc. Aza-benzothiopyranoindazoles with antitumor activity
US20030212061A1 (en) * 2002-03-12 2003-11-13 Haydar Simon N. Aza-thioxanthenones with antitumor activity
WO2007032818A2 (fr) * 2005-09-12 2007-03-22 Zoltan Laboratories Llc Composés et compositions permettant de contrôler une croissance cellulaire anormale
GB201214169D0 (en) * 2012-08-08 2012-09-19 Biostatus Ltd New compounds and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55122785A (en) * 1979-03-15 1980-09-20 Yoshitomi Pharmaceut Ind Ltd Preparation of benzopyranopyridine derivative
WO1997002267A1 (fr) * 1995-07-06 1997-01-23 University Of Vermont Nouveaux pyrido-thiopyranoindazoles a activite antitumorale

Non-Patent Citations (1)

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Title
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CA2288274A1 (fr) 1998-11-05
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