CA2288274A1 - Regioisomeric benzothiopyranopyridines having antitumor activity - Google Patents
Regioisomeric benzothiopyranopyridines having antitumor activity Download PDFInfo
- Publication number
- CA2288274A1 CA2288274A1 CA002288274A CA2288274A CA2288274A1 CA 2288274 A1 CA2288274 A1 CA 2288274A1 CA 002288274 A CA002288274 A CA 002288274A CA 2288274 A CA2288274 A CA 2288274A CA 2288274 A1 CA2288274 A1 CA 2288274A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- group
- nr2r3
- ppm
- formula
- 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.)
- Abandoned
Links
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention is directed to benzothiopyrano [2,3-b]-, [3,2-b]- and [3,2-c]-pyridines substituted in the positions 6 and 9. The compounds of the invention have general formula (I) wherein: one of X, Y or Z is nitrogen (-N=), the others being carbon (-CH=); R' is selected from the group consisting of (C1-C4)alkyl, nitro or -NH-R1, wherein R1 is selected from the group consisting of -CO-CH2-NR2R3, (C1-C10)alkyl, (C2-C10)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2-C10)alkyl interrupted by one or two oxygen atoms or by one -NR5- group, and said (C2-C10)alkyl being optionally substituted by one or two hydroxy or -NR2R3 groups;
R is selected in the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2-C10)alkyl interrupted by one or two oxygen atoms or by one -NR5- group, and said (C2-C10)alkyl being optionally substituted by one or two hydroxy or -NR2R3 groups. These compounds have antitumor activity against human leukemias and solid tumors sensitive to treatment with mitoxantrone and antitumor antibiotics, such as doxorubicin.
R is selected in the group consisting of hydrogen, (C1-C10)alkyl, (C2-C10)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2-C10)alkyl interrupted by one or two oxygen atoms or by one -NR5- group, and said (C2-C10)alkyl being optionally substituted by one or two hydroxy or -NR2R3 groups. These compounds have antitumor activity against human leukemias and solid tumors sensitive to treatment with mitoxantrone and antitumor antibiotics, such as doxorubicin.
Description
BACKGROUND OF THE INVENTION
Field of the invention 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.
Background Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been reported which show antitumor activity in clinical trials. Of particular interest has been ametantrone, 1,4-bis[(2-(2-hydroxyethylamino)ethyl) amino]anthracene-9,10- dione, and mitoxantrone, 5,8-dihydroxy-1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione [Zee-Cheng et al., J. Med. Chem., 21, 291-4 (1978); Cheng et al., "Progress in Medicinal Chemistry", Ellis, G.P. and West, G.B., eds.;
Elsevier: Amsterdam, 1983, vol. 20, pp. 83 and references cited therein].
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)]. Although animal studies have demonstrated a diminished cardiotoxicity in comparison to doxorubicin, some clinical cardiotoxicity has been observed also with mitoxantrone, mostly in patients previously treated with doxorubicin [R. Stuart Harris et al., Lancet, 219 (1984) and references cited therein].
Ametantrone has been reported to be, in animals, about 10-fold less potent and cardiotoxic than mitoxantrone. Because a delayed toxicity is observed only with mitoxantrone after administration of the two drugs by the i.p.
route to non-tumor bearing rats at equieffective antitumor dosages, it is suggested that the presence of the 5,8-dihydroxy substitution in mitoxantrone might be implicated in the delayed deaths [Corbett et al., Cancer Chemother. Pharmacol., 6, 161 (1981 )].
fn addition, both mitoxantrone and ametantrone have remarkable myelodepressive toxicity and both compounds show cross-resistance to cell hystotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. Such a resistance, which is named multidrug resistance (MDR), involves a number of antitumor antibiotics, among which amsacrine and podophyllotoxinic derivatives, and it is one of the main reasons for therapeutical failures in the treatment of solid tumors with said antibiotics.
In an attempt to overcome the above mentioned drawbacks some chromofore modified anthracenediones have been prepared.
WO 92/15300 discloses aza-anthracenediones, in which a nitrogen atom replaces a carbon atom in the 9 position of the aromatic skeleton.
Analogously, EP 0574433 describes 2,3-diazaanthracendiones and WO 92/15566 discloses N-oxide derivatives of aza-anthracenediones.
On the other hand, several derivatives of lucanthone have been prepared [S. Archer et al., J. Med. Chem., 25, 220-227 and 328-331 (1982)]:
R
Field of the invention 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.
Background Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been reported which show antitumor activity in clinical trials. Of particular interest has been ametantrone, 1,4-bis[(2-(2-hydroxyethylamino)ethyl) amino]anthracene-9,10- dione, and mitoxantrone, 5,8-dihydroxy-1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione [Zee-Cheng et al., J. Med. Chem., 21, 291-4 (1978); Cheng et al., "Progress in Medicinal Chemistry", Ellis, G.P. and West, G.B., eds.;
Elsevier: Amsterdam, 1983, vol. 20, pp. 83 and references cited therein].
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)]. Although animal studies have demonstrated a diminished cardiotoxicity in comparison to doxorubicin, some clinical cardiotoxicity has been observed also with mitoxantrone, mostly in patients previously treated with doxorubicin [R. Stuart Harris et al., Lancet, 219 (1984) and references cited therein].
Ametantrone has been reported to be, in animals, about 10-fold less potent and cardiotoxic than mitoxantrone. Because a delayed toxicity is observed only with mitoxantrone after administration of the two drugs by the i.p.
route to non-tumor bearing rats at equieffective antitumor dosages, it is suggested that the presence of the 5,8-dihydroxy substitution in mitoxantrone might be implicated in the delayed deaths [Corbett et al., Cancer Chemother. Pharmacol., 6, 161 (1981 )].
fn addition, both mitoxantrone and ametantrone have remarkable myelodepressive toxicity and both compounds show cross-resistance to cell hystotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. Such a resistance, which is named multidrug resistance (MDR), involves a number of antitumor antibiotics, among which amsacrine and podophyllotoxinic derivatives, and it is one of the main reasons for therapeutical failures in the treatment of solid tumors with said antibiotics.
In an attempt to overcome the above mentioned drawbacks some chromofore modified anthracenediones have been prepared.
WO 92/15300 discloses aza-anthracenediones, in which a nitrogen atom replaces a carbon atom in the 9 position of the aromatic skeleton.
Analogously, EP 0574433 describes 2,3-diazaanthracendiones and WO 92/15566 discloses N-oxide derivatives of aza-anthracenediones.
On the other hand, several derivatives of lucanthone have been prepared [S. Archer et al., J. Med. Chem., 25, 220-227 and 328-331 (1982)]:
R
wherein R' is an aminoalkyl chain, R" is hydrogen or methyl and R has several meanings such as hydrogen, amino or hydroxy. Taking as example the 4-methyl series substituted in the positions 5 or 7, only the 7-hydroxy derivative showed a good activity in the "in vivo" antitumor test.
Aza-derivatives of lucanthone have 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 ~R
Me O NH O
N~ ~ /
I
\ / Y~ /
Me S ~ X S
Me (17 (2) wherein R is an aminoalkyl chain and, in (2), one of X or Y is hydrogen and the other is carbon.
In both the cases these compounds showed little if not any antitumor activity.
We have found that the insertion of a nitrogen atom (=N-) in the 5- (only in the 1,4-bis-aminoalkylamino series), 7- or 8-position of the ring imparts a marked antitumor activity to the molecules, while the presence of a nitrogen atom in the 6 position brings to compounds devoid of any significant activity. We consider that this result is particularly surprising, since such little structural modifications with respect to the above described prior art compounds are able to increase strongly the antitumor properties and this could not be predicted by the prior art teachings.
BRIEF SUMMARY OF THE INVENTION
In the following description of the invention the numbering of the positions on the ring will be consistent with the nomenclature adopted for the benzothiopyrano-pyridines. For example, the following 6- and 9-positions corresponds to the 1- and 4- positions indicated in the previous section.
Aza-derivatives of lucanthone have 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 ~R
Me O NH O
N~ ~ /
I
\ / Y~ /
Me S ~ X S
Me (17 (2) wherein R is an aminoalkyl chain and, in (2), one of X or Y is hydrogen and the other is carbon.
In both the cases these compounds showed little if not any antitumor activity.
We have found that the insertion of a nitrogen atom (=N-) in the 5- (only in the 1,4-bis-aminoalkylamino series), 7- or 8-position of the ring imparts a marked antitumor activity to the molecules, while the presence of a nitrogen atom in the 6 position brings to compounds devoid of any significant activity. We consider that this result is particularly surprising, since such little structural modifications with respect to the above described prior art compounds are able to increase strongly the antitumor properties and this could not be predicted by the prior art teachings.
BRIEF SUMMARY OF THE INVENTION
In the following description of the invention the numbering of the positions on the ring will be consistent with the nomenclature adopted for the benzothiopyrano-pyridines. For example, the following 6- and 9-positions corresponds to the 1- and 4- positions indicated in the previous section.
We have found that benzothiopyrano [2,3-b)-, [3,2-b]- and [3,2-c)-pyridines substituted in the positions 6 and 9 with alkyl or nitrogen carrying side arms possess high antitumor activity.
The compounds of the invention have the general formula (I):
~z Y
(I) X
wherein:
- one of X, Y or Z is nitrogen (-N=), the others being carbon (-CH=);
- R' is selected from the group consisting of (C,-C4)alkyl, nitro or -NH-R,, wherein R, is selected from the group consisting of -CO-CH2-NR2R3, (C,-C,o)alkyl, (C2-C,o)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2-C,o)alkyl interrupted by one or two oxygen atoms or by one -NRS- group, and said (C2-C,o)alkyl being optionally substituted by one or two hydroxy or -NRzR3 groups;
- R is selected in the group consisting of hydrogen, (C,-C,o)alkyl, (C2-C,o)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2 C,o)alkyl interrupted by one or two oxygen atoms or by one -NRS- group, and said (C2-C,o)alkyl being optionally substituted by one or two hydroxy or -NR2R3 groups;
- R2 and R3 may be the same or different and are selected from the group consisting of hydrogen, (C,-C,o)alkyl, (C2 C,o)alkyl substituted with one or two hydroxy groups, or RZ and R3 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 heteraatom such as sulfur, oxygen or nitrogen;
- R4 is selected from the group consisting of hydrogen, (C,-C6)alkyl, -S(OZ)R6, (Cz Cs)alkyl optionally substituted by -NR2R3;
- RS is selected in the group consisting of hydrogen, (C,-C,o)alkyl, (C2-C,o)hydroxyalkyl, (C2-C,o)alkyl substituted with -NR2R3;
- R6 is selected from the group consisting of (C,-C,o)alkyl, phenyl, phenylalkyl, with the proviso that when R' is (C1-C4)alkyl, X is carbon 5 (-CH=), as free bases and their salts with pharmaceutically acceptable acids.
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.
DETAILED DESCRIPTION OF THE INVENTION
in compounds (I) the term "phenyl" means phenyl rings which can optionally contain substituents such as (C,-C4)alkyl groups, CF3, halogen atoms, nitro, amino, acetylamino, formylamino, dimethyfamino, diethylamino, hydroxy, methoxy, and ethoxy groups.
Preferred examples of (C,-C,o)alkyl groups are methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
Preferred example of phenylalkyl is 4-methylphenyl. When in compounds of formula (I) R and R' are (C2 C,o)alkyl interrupted by one or two oxygen atoms or by one -NR5- group and optionally substituted by one or two hydroxy or -NR2R3 groups, at least two carbon atoms are preferentially interposed between said oxygen atoms andlor the -NRS- and -NR2R3 groups.
The compounds of the invention have the general formula (I):
~z Y
(I) X
wherein:
- one of X, Y or Z is nitrogen (-N=), the others being carbon (-CH=);
- R' is selected from the group consisting of (C,-C4)alkyl, nitro or -NH-R,, wherein R, is selected from the group consisting of -CO-CH2-NR2R3, (C,-C,o)alkyl, (C2-C,o)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2-C,o)alkyl interrupted by one or two oxygen atoms or by one -NRS- group, and said (C2-C,o)alkyl being optionally substituted by one or two hydroxy or -NRzR3 groups;
- R is selected in the group consisting of hydrogen, (C,-C,o)alkyl, (C2-C,o)alkyl having one or two substituents selected from the group consisting of -OR4 and -NR2R3, (C2 C,o)alkyl interrupted by one or two oxygen atoms or by one -NRS- group, and said (C2-C,o)alkyl being optionally substituted by one or two hydroxy or -NR2R3 groups;
- R2 and R3 may be the same or different and are selected from the group consisting of hydrogen, (C,-C,o)alkyl, (C2 C,o)alkyl substituted with one or two hydroxy groups, or RZ and R3 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 heteraatom such as sulfur, oxygen or nitrogen;
- R4 is selected from the group consisting of hydrogen, (C,-C6)alkyl, -S(OZ)R6, (Cz Cs)alkyl optionally substituted by -NR2R3;
- RS is selected in the group consisting of hydrogen, (C,-C,o)alkyl, (C2-C,o)hydroxyalkyl, (C2-C,o)alkyl substituted with -NR2R3;
- R6 is selected from the group consisting of (C,-C,o)alkyl, phenyl, phenylalkyl, with the proviso that when R' is (C1-C4)alkyl, X is carbon 5 (-CH=), as free bases and their salts with pharmaceutically acceptable acids.
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.
DETAILED DESCRIPTION OF THE INVENTION
in compounds (I) the term "phenyl" means phenyl rings which can optionally contain substituents such as (C,-C4)alkyl groups, CF3, halogen atoms, nitro, amino, acetylamino, formylamino, dimethyfamino, diethylamino, hydroxy, methoxy, and ethoxy groups.
Preferred examples of (C,-C,o)alkyl groups are methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
Preferred example of phenylalkyl is 4-methylphenyl. When in compounds of formula (I) R and R' are (C2 C,o)alkyl interrupted by one or two oxygen atoms or by one -NR5- group and optionally substituted by one or two hydroxy or -NR2R3 groups, at least two carbon atoms are preferentially interposed between said oxygen atoms andlor the -NRS- and -NR2R3 groups.
When in compounds of formula (I) the -NR2R3 substituent is a .5- or 6-member aromatic or non-aromatic heterocyclic ring which may contain another heteroatom such as sulfur, oxygen and nitrogen, preferred examples of said heterocyclic rings are 1-imidazolyl, 4-hydroxy-1-imidazolyl, 2-imino-1(3H)-imidazolyl, 1-pyrrolyl, 1-tetraydropyrrolyl, 1-pyrazolyl, 4-morpholinyl, 1-piperidinyi, 1-piperazinyl, 1-(4-methyl)piperazinyl, 1-(4-benzyl)piperazinyl.
The compounds of formula (I) can be prepared by a multistep process comprising the following steps:
(a) reacting an intermediate of formula (II):
,z Y/
(II) X
with an amine of formula R-NH2, wherein R, X, Y and Z have the above meanings, to give a compound of formula (I') with R' = vitro group:
H~ ~R
Z
Y cI' ) X
Such conversion can be performed in a solvent, preferably dimethylformamide, and at temperatures ranging from -10°C to 50°C, preferably room temperature;
(b) reducing the vitro group of the compound of formula (I') to an amino group, to give an intermediate of formula (IV):
H~'-/R
Y /Z
(IV) ~X S
The compounds of formula (I) can be prepared by a multistep process comprising the following steps:
(a) reacting an intermediate of formula (II):
,z Y/
(II) X
with an amine of formula R-NH2, wherein R, X, Y and Z have the above meanings, to give a compound of formula (I') with R' = vitro group:
H~ ~R
Z
Y cI' ) X
Such conversion can be performed in a solvent, preferably dimethylformamide, and at temperatures ranging from -10°C to 50°C, preferably room temperature;
(b) reducing the vitro group of the compound of formula (I') to an amino group, to give an intermediate of formula (IV):
H~'-/R
Y /Z
(IV) ~X S
Such a reduction can be performed with all the usual reducing agents employed for the reduction of an aromatic vitro group, preferentially with SnClz~2H20 in a mixture of hydrochloric acid and an alcohol, preferably methanol;
(c) alkylating the amino group of intermediate of formula (IV) with a reagent of formula R,-alg, wherein R, has the above meanings and alg is chlorine, bromine or iodine, to give the compounds of formula (I) wherein R' is a -NH-R, group.
Such an alkyiation 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.
The compounds of formula (I) in which R' is a (C,-C4)alkyl group can be obtained by reacting an intermediate of formula (II'):
cl z Y~ \
(II') X S
(~1-C4)alkyl with an amine of formula R-NH2, in which R is as above defined, according to the reaction conditions of the above step (a), but at temperatures up to 200°C.
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 (V) so obtained:
(c) alkylating the amino group of intermediate of formula (IV) with a reagent of formula R,-alg, wherein R, has the above meanings and alg is chlorine, bromine or iodine, to give the compounds of formula (I) wherein R' is a -NH-R, group.
Such an alkyiation 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.
The compounds of formula (I) in which R' is a (C,-C4)alkyl group can be obtained by reacting an intermediate of formula (II'):
cl z Y~ \
(II') X S
(~1-C4)alkyl with an amine of formula R-NH2, in which R is as above defined, according to the reaction conditions of the above step (a), but at temperatures up to 200°C.
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 (V) so obtained:
c1 co~H
/ I I ~ (~l N S
is then cyciized by reaction with thionyl chloride in the presence of an acidic catalyst, such as a lewis acid (AIC13), or with a polyphosphoric acid or, as a preferred reactant, with fuming sulfuric acid (18-24% S03), to give the intermediate of formula (II).
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 refiux the mixture of the two reactants in acetone as a solvent. The intermediate of formula (V') so obtained:
ci CO H
N~
(~' s is then cyciized in the presence of an acidic catalyst, preferentially fuming sulfuric acid (18-24% S03), to give the intermediate of formula (II).
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.
2-mercapto-4-chloronitrobenzene is obtained by reacting 2,4-dichloronitrobenzene with sodium sulfide and finally separating the desired regioisomer.
/ I I ~ (~l N S
is then cyciized by reaction with thionyl chloride in the presence of an acidic catalyst, such as a lewis acid (AIC13), or with a polyphosphoric acid or, as a preferred reactant, with fuming sulfuric acid (18-24% S03), to give the intermediate of formula (II).
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 refiux the mixture of the two reactants in acetone as a solvent. The intermediate of formula (V') so obtained:
ci CO H
N~
(~' s is then cyciized in the presence of an acidic catalyst, preferentially fuming sulfuric acid (18-24% S03), to give the intermediate of formula (II).
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.
2-mercapto-4-chloronitrobenzene is obtained by reacting 2,4-dichloronitrobenzene with sodium sulfide and finally separating the desired regioisomer.
The intermediate of formula (II) in 'which Z is nitrogen can be-obtained starting from the intermediate of formula (VI), which is described in U.S.
Pat. 3,086,972 (which is herein incorporated by reference):
o c1 N
/ \
cvi) s 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 (II') 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. The subsequent cyclization of the intermediate obtained, analogous to intermediate (V') but with the (C,-C,)alkyl group instead of the nitro group, with thionyl chloride in the presence of an acidic catalyst, preferentially AIC13, gives the desired compounds of formula (II').
2-mercapto-4-chlorotoluene can be prepared, for example, according to the methodology described in J. Org. Chem., 27, 4455-61 (1962), which is herein incorporated by reference.
The intermediates of formula (II') in which Z is nitrogen can be obtained by condensation of 4-chloro-1-[(C,-C4)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):
(VIII
S
CON(CH~)z 10 which is finally converted into the desired product via hydrolysis with aqueous sodium carbonate in methanol.
BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION
The evaluation of the biological activity of the compounds of the invention was performed "in vitro" following the protocols developed by the U.S.
National Cancer Institute, using the following cell lines: 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 (LoVo) 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 were tested according to the MTT assay (Mosman, T.
"Rapid Colorimetric Assay for Cellular Growth ad Survival: Application to Proliferation and Cytotoxicity Assay", J. Immunol. Methods, (1983), 65, 55-63; Green, L.M., "Rapid Colorimetric Assay for Cell Viability: Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines", J.
Immunol. Methods, (1984), 70, 257-2fi8) in comparison with the corresponding carbon derivatives (analogues or derivatives of lucanthone).
The pharmacological data of some representative compounds of the invention in comparison with the corresponding carbon derivatives are provided in table I.
Pat. 3,086,972 (which is herein incorporated by reference):
o c1 N
/ \
cvi) s 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 (II') 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. The subsequent cyclization of the intermediate obtained, analogous to intermediate (V') but with the (C,-C,)alkyl group instead of the nitro group, with thionyl chloride in the presence of an acidic catalyst, preferentially AIC13, gives the desired compounds of formula (II').
2-mercapto-4-chlorotoluene can be prepared, for example, according to the methodology described in J. Org. Chem., 27, 4455-61 (1962), which is herein incorporated by reference.
The intermediates of formula (II') in which Z is nitrogen can be obtained by condensation of 4-chloro-1-[(C,-C4)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):
(VIII
S
CON(CH~)z 10 which is finally converted into the desired product via hydrolysis with aqueous sodium carbonate in methanol.
BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION
The evaluation of the biological activity of the compounds of the invention was performed "in vitro" following the protocols developed by the U.S.
National Cancer Institute, using the following cell lines: 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 (LoVo) 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 were tested according to the MTT assay (Mosman, T.
"Rapid Colorimetric Assay for Cellular Growth ad Survival: Application to Proliferation and Cytotoxicity Assay", J. Immunol. Methods, (1983), 65, 55-63; Green, L.M., "Rapid Colorimetric Assay for Cell Viability: Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines", J.
Immunol. Methods, (1984), 70, 257-2fi8) in comparison with the corresponding carbon derivatives (analogues or derivatives of lucanthone).
The pharmacological data of some representative compounds of the invention in comparison with the corresponding carbon derivatives are provided in table I.
As can be seen, all the tested compounds of the invention exhibit an enhanced activity with respect to the carbon analogues. This result could not be predicted in the light of the teachings of the prior art aza derivatives of Croisy-Delcey and Blanz showed in the previous background discussion.
Moreover, the compounds of the invention showed an antitumor activity similar or even better than that of doxorubicin.
Therefore, the compounds of the present invention are expected to be operative against human feukemias 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.
The pharmaceutical 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.
Preparation 1 - 2-l2-nitro-5-chloro)thiophenoxynicotinic acid 2-mercaptonicotinic acid (10 g) was added to a sodium ethoxide solution which was prepared by treatment of ethanol (135 ml) with sodium metal (3.1 g). To the stirred suspension was then added 2,4-dichloronitro-benzene (12.4 g). The mixture was heated at reflux for 24 h and then concentrated to dryness. This residue was washed thoroughly with ether and added to water (200 ml). Acidification of the aqueous layer with concentrated hydrochloric acid to pH about 1 led to yellow solid which was collected by filtration and dried (19.2 g). This crude sample was recrystallized from ethyleneglycolmonpethyl ether (175 ml) to yield 12.1 g of the product, m.p. 248-249°C.
'H-NMR in d6-DMSO: 8.39 ppm (dd, 1 H); 8.27 ppm (dd, 1 H); 8.10 ppm (d, 1 H); 7.85 ppm (d, 1 H); 7.76 ppm (dd, 1 H); 7.30 ppm (dd, 1 H).
Elem. Anal. (calcd/found): C 46.39146.39; H 2.27/2.27; N 9.01/8.80.
Preparation 2 -6-chloro-9-nitro-5H-[1],benzothiopyrano[2.3-blpvridin-5-one Route 1 (18-24% fuming sulfuric acid) 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). This material was dissolved in hot dimethyl formamide (11 ml) which on cooling immediately led to a yellow crystalline fluffy solid which was collected by filtration, washed with ether to remove residual dimethyl formamide and dried to yield 0.54 g of the product (89% yield), m.p. 267-270°C.
'H-NMR in CDC13: 8.84 ppm (dd, J=1.77 Hz, J=4.60 Hz); 8.60 ppm (dd, J=1.77 Hz, J=8.05 Hz); 8.51 ppm (d, J=8.80 Hz); 7.68 ppm {d, J=8.80 Hz); 7.51 ppm (dd, J=4.6 Hz, J=8.00 Hz).
Elem. Anal. (calcdlfound): C 49.24149.23; H 1.72/1.63; N 9.58/9.51 ).
Route 2 (SOCIz/AICl3) A mixture of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (5 g), toluene (27 ml) and thionyl chloride (6 ml) was heated at reflux for 1.5 hours. Upon cooling, the acid chloride separated as yellow needles. The resultant mixture was concentrated to dryness by distillation and a yellow crystalline solid remained. Nitrobenzene (25 ml) was added and the suspension was cooled in an ice bath for 0.5 hour. Aluminum chloride (2 g) was slowly added while keeping the temperature below 35°C. The mixture darkened and it was stirred at room temperature for 20 hours. The dark black suspension was poured into ice water (130 m!) and the mixture was stirred for 1 hour. The aqueous layer was removed by decantation, methanol (100 ml) was added to the nitrobenzene and the resultant solid was collected by filtration. Addition of methanol (200 ml) to the filtrate led to additional product, total weight 3.1 g (66% yield), m.p. 265-270°C. For purification the crude material was recrystallized from ethyleneglycolmono-ethyl ether to yield the product as yellow fluffy solid.
Route 3 (PPSE) A mixture of PPSE (2 g) and phosphorus pentoxide (0.25 g) was heated in an oil bath to 210°C.
2-(2-nitro-5-chloro)thiophenoxynicotinic acid (0.1 g) was added to the hot mixture and the mixture was held at this temperature for 20 minutes. The hot mixture was quenched into cold hydrochloric acid (6 N, 6 ml) and the resultant mixture was allowed to stand overnight. After neutralization with sodium hydroxide the solid was collected by fltration and dried (0.085 g).
The crude material was heated in ethyl acetate and collected by filtration while hot to remove some brownish insoluble material. Removal of the solvent led to 0.045 g of the product (48% yield).
Preparation 3 - 2-mercanto-4-chloronitrobenzene Sodium sulfide nonahydrate (19 g) was placed in methanol (75 ml) and the mixture was stirred until all the sulfide dissolved. The mixture was placed in an ice bath and a solution of 2,4-dichloronitrobenzene (15 g) in methanol (50 ml) was added from a dropping funnel over a period of 1.25 hours (an additional amount of 20 ml of methanol was added to the funnel). The resultant suspension was allowed to warm to room temperature and allowed to stir for 23 hours. At this point a deep red coloration along with some yellow insoluble material resulted. 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 soiid (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. This crude product (3.4 g) was redissolved in hot hexane (70 ml) to which ethyl acetate (1-2 ml) was added. On cooling yellow crystals of the pure product were obtained, 1.8 g, m.p. 87-88°C.
'H-NMR in CDCI3: 8.18 ppm (d, J=8.9 Hz, 1 H); 7.44 ppm (d, J=2.1 Hz, 1 H); 7.23 ppm (dd, J=8.9 Hz, J=2.2 Hz, 1 H); 4.08 ppm (s, 1 H}.
Preparation 4 - 4-(2-nitro-5-chlor~thiophenoxynicotinic acid A solution of 2-mercapto-4-chloronitrobenzene (1.09 g) in acetone (12 ml) was added to 4-chloronicotinic acid (0.85 g). The yellow coloration of the thiol quickly disappeared and the mixture was refluxed for 1 hour. Upon cooling to room temperature, the product was collected by filtration and washed with acetone to yield 1.72 g of the product as hydrochloride salt, as pale yellow solid, m.p. 228-229°C.
' H-NMR in a6-DMSO: 9.05 ppm (s, 1 H); 8.50 ppm (d, 1 H); 8.23 ppm (d, 1 H); 7.98 ppm (d, 1 H); 7.92 ppm (dd, 1 H); 6.98 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 41.52/41.33; H 2.32/2.34; N 8.07/7.78.
Preparation 5 -6-chloro-9-nitro-10H ~j1 ]-benzothiopyranof3.2-clavridin-5-one 0.60 g of 4-(2-nitro-5-chloro)thiophenoxynicotinic acid were added to fuming sulfuric acid (3.3 ml, 18-24% sulfur trioxide) and the mixture was placed in a bath which was preheated to 40°C. The dark reddish-amber solution was heated to 50°C during 50 minutes and kept at this temperature for 1 hour. The cooled mixture was poured over ice water (25 ml) and the mixture neutralized with solid sodium bicarbonate. The resultant bright yellow solid was collected by filtration and dried (0.44 g).
5 The solid was boiled in chloroform (40 ml), treated with activated charcoal and collected by filtration through celite bed to remove the charcoal.
Concentration of the filtrate led to 0.41 g of the product, m.p. 220-222°C.
' H-NMR in CDC13: 9.43 ppm (s, 1 H); 8.74 ppm (d, 1 H); 8.50 ppm (d, 1 H);
7.70 ppm (d, 1 H); 7.51 ppm (d, 1 H).
10 Elem. Anal. (calcd/found): C 49.24/49.41; H 1.72/1.75; N 9.58/9.53.
Preparation 6 - meth5rl 3-h~rdroxy~aicolinate The 3-hydroxypicolinic acid (2 g) was refiuxed in methanol (100 ml) containing concentrated sulfuric acid (4 ml) for 15 hours. The mixture 15 was concentrated to about 40 ml, diluted with water (to 250 ml), adjusted to pH 6 with sodium carbonate and then extracted with chloroform (3x100 ml). The extracts were washed with water (2X100 ml), dried over magnesium sulfate and the filtrate concentrated to dryness. The white crystalline solid was collected to yield 1.7 g of the product, m.p. 73-74°C.
'H-NMR in CDCI3: 10.57 ppm (s, 1 H); 8.23 ppm (dd, 1 H); 7.39-7.32 ppm (m, 2H); 4.01 ppm (s, 3H).
P_ret~aration 7 - carbamic acid dimetl~rlthio-O-3 ~p~,~yl ester A solution of methyl 3-hydroxypicolinate (3.5 g), dimethylthiocarbamoyl chloride (2.84 g), diazabicyclooctane (8.7 g) in dry dimethylformamide (7 ml) was stirred at room temperature for 4 hours. The mixture was poured over crushed ice (100 ml), the solid was recovered by filtration and dried to give 4.25 g of the product, m.p. 76-77°C.
'H-NMR in CDC13: 8.60 ppm (m, 1 H); 7.53 ppm (m, 2H); 3.94 ppm (s, 3H);
3.47 ppm (s, 3H); 3.42 ppm (s, 3H).
Elem. Anal. (calcd/found): C 49.99/49.92; H 5.03/4.86; N 11.66/11.55.
Moreover, the compounds of the invention showed an antitumor activity similar or even better than that of doxorubicin.
Therefore, the compounds of the present invention are expected to be operative against human feukemias 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.
The pharmaceutical 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.
Preparation 1 - 2-l2-nitro-5-chloro)thiophenoxynicotinic acid 2-mercaptonicotinic acid (10 g) was added to a sodium ethoxide solution which was prepared by treatment of ethanol (135 ml) with sodium metal (3.1 g). To the stirred suspension was then added 2,4-dichloronitro-benzene (12.4 g). The mixture was heated at reflux for 24 h and then concentrated to dryness. This residue was washed thoroughly with ether and added to water (200 ml). Acidification of the aqueous layer with concentrated hydrochloric acid to pH about 1 led to yellow solid which was collected by filtration and dried (19.2 g). This crude sample was recrystallized from ethyleneglycolmonpethyl ether (175 ml) to yield 12.1 g of the product, m.p. 248-249°C.
'H-NMR in d6-DMSO: 8.39 ppm (dd, 1 H); 8.27 ppm (dd, 1 H); 8.10 ppm (d, 1 H); 7.85 ppm (d, 1 H); 7.76 ppm (dd, 1 H); 7.30 ppm (dd, 1 H).
Elem. Anal. (calcd/found): C 46.39146.39; H 2.27/2.27; N 9.01/8.80.
Preparation 2 -6-chloro-9-nitro-5H-[1],benzothiopyrano[2.3-blpvridin-5-one Route 1 (18-24% fuming sulfuric acid) 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). This material was dissolved in hot dimethyl formamide (11 ml) which on cooling immediately led to a yellow crystalline fluffy solid which was collected by filtration, washed with ether to remove residual dimethyl formamide and dried to yield 0.54 g of the product (89% yield), m.p. 267-270°C.
'H-NMR in CDC13: 8.84 ppm (dd, J=1.77 Hz, J=4.60 Hz); 8.60 ppm (dd, J=1.77 Hz, J=8.05 Hz); 8.51 ppm (d, J=8.80 Hz); 7.68 ppm {d, J=8.80 Hz); 7.51 ppm (dd, J=4.6 Hz, J=8.00 Hz).
Elem. Anal. (calcdlfound): C 49.24149.23; H 1.72/1.63; N 9.58/9.51 ).
Route 2 (SOCIz/AICl3) A mixture of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (5 g), toluene (27 ml) and thionyl chloride (6 ml) was heated at reflux for 1.5 hours. Upon cooling, the acid chloride separated as yellow needles. The resultant mixture was concentrated to dryness by distillation and a yellow crystalline solid remained. Nitrobenzene (25 ml) was added and the suspension was cooled in an ice bath for 0.5 hour. Aluminum chloride (2 g) was slowly added while keeping the temperature below 35°C. The mixture darkened and it was stirred at room temperature for 20 hours. The dark black suspension was poured into ice water (130 m!) and the mixture was stirred for 1 hour. The aqueous layer was removed by decantation, methanol (100 ml) was added to the nitrobenzene and the resultant solid was collected by filtration. Addition of methanol (200 ml) to the filtrate led to additional product, total weight 3.1 g (66% yield), m.p. 265-270°C. For purification the crude material was recrystallized from ethyleneglycolmono-ethyl ether to yield the product as yellow fluffy solid.
Route 3 (PPSE) A mixture of PPSE (2 g) and phosphorus pentoxide (0.25 g) was heated in an oil bath to 210°C.
2-(2-nitro-5-chloro)thiophenoxynicotinic acid (0.1 g) was added to the hot mixture and the mixture was held at this temperature for 20 minutes. The hot mixture was quenched into cold hydrochloric acid (6 N, 6 ml) and the resultant mixture was allowed to stand overnight. After neutralization with sodium hydroxide the solid was collected by fltration and dried (0.085 g).
The crude material was heated in ethyl acetate and collected by filtration while hot to remove some brownish insoluble material. Removal of the solvent led to 0.045 g of the product (48% yield).
Preparation 3 - 2-mercanto-4-chloronitrobenzene Sodium sulfide nonahydrate (19 g) was placed in methanol (75 ml) and the mixture was stirred until all the sulfide dissolved. The mixture was placed in an ice bath and a solution of 2,4-dichloronitrobenzene (15 g) in methanol (50 ml) was added from a dropping funnel over a period of 1.25 hours (an additional amount of 20 ml of methanol was added to the funnel). The resultant suspension was allowed to warm to room temperature and allowed to stir for 23 hours. At this point a deep red coloration along with some yellow insoluble material resulted. 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 soiid (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. This crude product (3.4 g) was redissolved in hot hexane (70 ml) to which ethyl acetate (1-2 ml) was added. On cooling yellow crystals of the pure product were obtained, 1.8 g, m.p. 87-88°C.
'H-NMR in CDCI3: 8.18 ppm (d, J=8.9 Hz, 1 H); 7.44 ppm (d, J=2.1 Hz, 1 H); 7.23 ppm (dd, J=8.9 Hz, J=2.2 Hz, 1 H); 4.08 ppm (s, 1 H}.
Preparation 4 - 4-(2-nitro-5-chlor~thiophenoxynicotinic acid A solution of 2-mercapto-4-chloronitrobenzene (1.09 g) in acetone (12 ml) was added to 4-chloronicotinic acid (0.85 g). The yellow coloration of the thiol quickly disappeared and the mixture was refluxed for 1 hour. Upon cooling to room temperature, the product was collected by filtration and washed with acetone to yield 1.72 g of the product as hydrochloride salt, as pale yellow solid, m.p. 228-229°C.
' H-NMR in a6-DMSO: 9.05 ppm (s, 1 H); 8.50 ppm (d, 1 H); 8.23 ppm (d, 1 H); 7.98 ppm (d, 1 H); 7.92 ppm (dd, 1 H); 6.98 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 41.52/41.33; H 2.32/2.34; N 8.07/7.78.
Preparation 5 -6-chloro-9-nitro-10H ~j1 ]-benzothiopyranof3.2-clavridin-5-one 0.60 g of 4-(2-nitro-5-chloro)thiophenoxynicotinic acid were added to fuming sulfuric acid (3.3 ml, 18-24% sulfur trioxide) and the mixture was placed in a bath which was preheated to 40°C. The dark reddish-amber solution was heated to 50°C during 50 minutes and kept at this temperature for 1 hour. The cooled mixture was poured over ice water (25 ml) and the mixture neutralized with solid sodium bicarbonate. The resultant bright yellow solid was collected by filtration and dried (0.44 g).
5 The solid was boiled in chloroform (40 ml), treated with activated charcoal and collected by filtration through celite bed to remove the charcoal.
Concentration of the filtrate led to 0.41 g of the product, m.p. 220-222°C.
' H-NMR in CDC13: 9.43 ppm (s, 1 H); 8.74 ppm (d, 1 H); 8.50 ppm (d, 1 H);
7.70 ppm (d, 1 H); 7.51 ppm (d, 1 H).
10 Elem. Anal. (calcd/found): C 49.24/49.41; H 1.72/1.75; N 9.58/9.53.
Preparation 6 - meth5rl 3-h~rdroxy~aicolinate The 3-hydroxypicolinic acid (2 g) was refiuxed in methanol (100 ml) containing concentrated sulfuric acid (4 ml) for 15 hours. The mixture 15 was concentrated to about 40 ml, diluted with water (to 250 ml), adjusted to pH 6 with sodium carbonate and then extracted with chloroform (3x100 ml). The extracts were washed with water (2X100 ml), dried over magnesium sulfate and the filtrate concentrated to dryness. The white crystalline solid was collected to yield 1.7 g of the product, m.p. 73-74°C.
'H-NMR in CDCI3: 10.57 ppm (s, 1 H); 8.23 ppm (dd, 1 H); 7.39-7.32 ppm (m, 2H); 4.01 ppm (s, 3H).
P_ret~aration 7 - carbamic acid dimetl~rlthio-O-3 ~p~,~yl ester A solution of methyl 3-hydroxypicolinate (3.5 g), dimethylthiocarbamoyl chloride (2.84 g), diazabicyclooctane (8.7 g) in dry dimethylformamide (7 ml) was stirred at room temperature for 4 hours. The mixture was poured over crushed ice (100 ml), the solid was recovered by filtration and dried to give 4.25 g of the product, m.p. 76-77°C.
'H-NMR in CDC13: 8.60 ppm (m, 1 H); 7.53 ppm (m, 2H); 3.94 ppm (s, 3H);
3.47 ppm (s, 3H); 3.42 ppm (s, 3H).
Elem. Anal. (calcd/found): C 49.99/49.92; H 5.03/4.86; N 11.66/11.55.
Preparation 8 - carbamic acid dimethylthio-S-3-pyridyl ester A mixture of carbamic acid dimethylthio-O-3-pyridyl ester (2.5 g) and diphenylether (21 ml) was heated in an oil bath held at 200-210°C.
After 1.75 hours, the mixture was removed from the bath, cooled and purified by flash chromatography over silica gel using chloroform : methanol 99 : 1 as the eluent. The product fractions were pooled and concentrated to a thick oil under a slow stream of nitrogen gas. The resultant solid (2.4 g) was recrystallized from a mixture of petroleum ether (35-60°C) and benzene to yield 2.1 g of the product, m.p. 80-81 °C.
' H-NMR in CDCI3: 8.60 ppm (dd, 1 H); 7.96 ppm (dd, 1 H); 7.39 ppm (dd, 1 H); 3.93 ppm (s, 3H); 3.0 ppm (broad d, 6H).
Elem. Anal. (calcd/found): C 49.99/50.23; H 5.03/5.03; N 11.66/22.56.
Preparation 9 - 3-merca~topyridine-2-carboxylic acid A mixture of carbamic acid dimethylthio-S-3-pyridyl ester, sodium carbonate (1.6 g), water (6.2 ml) and methanol (40 ml) was refluxed under a nitrogen atmosphere for 20 hours. The excess sodium carbonate was removed by filtration. The mixture was concentrated to an aqueous residue which was acidified to pH 2. This easily oxidizable solid (a mixture of the mercapto pyridine and the corresponding disulfide) was collected by filtration rapidly, washed with water and dried. Upon crystallization from water, the product separated as orange prisms which were collected by filtration, 0.25 g, m.p. 183-184°C.
'H-NMR in a6-DMSO: 8.30 ppm (dd, 1 H); 8.19 ppm (dd, 1 H); 7.53 ppm (dd, 1 H).
Elem. Anal. (calcd/found): C 46.44/46.11; H 3.29/3.12; N 9.03/8.79.
Preparation 10 -[(2-methyl-5-chlorophenyl thiojpyridine-3-carboxylic acid ~drochloride salt A solution of 4-chloro-2-marcaptotoiuene (0.76 g) in dry acetone (5 ml) was added to 4-chloronicotinic acid (0.5 g). The white suspension was then refluxed for three hours. Upon cooling, the precipitate was collected by filtration, washed with cold anhydrous acetone and air dried to give 0.95 g of the product, m.p. 168-170°C.
'H-NMR in a6-DMSO: 9.04 ppm (s, 1 H); 8.43 ppm (d, 1 H); 7.69 ppm (s, 1 H); 7.61 ppm (d, 1 H); 7.56 ppm (d, 1 H); 6.64 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 55.19/55.26; H 3.6113.89; N 65.91/66.07.
Preparation 11 -6-chloro-9-methyl-10H-j1~-benzothiopyranoj3 2-c]pyridin 5 one A mixture of [(2-methyl-5-chlorophenyl)thio]pyridine-3-carboxylic acid hydrochloride salt (0.25 g; preparation 10) and thionyl chloride (1 ml) was refluxed for 1.5 hour. The excess of thionyl chloride was removed by vacuum aspiration. The residue was then dissolved in nitrobenzene, followed with aluminium chloride (0.6 g). This dark red solution was heated in an oil bath at 100°C for three hours and poured on ice. The precipitate was collected by filtration, dried as possible and washed with ligroin. The residue was suspended in ammonium hydroxide 7% (25 ml), steam was passed through. The cooled suspension was collected by filtration, washed thoroughly with water and air dried. This solid was crystallized in dimethylformamide to give 0.21 g of the product as white needles, m.p.
219-220°C.
' H-NMR in CDC13: 9.30 ppm (s, 1 H); 8.72 ppm (d, 1 H); 7.87 ppm (d, 1 H);
7.65 ppm (d, 1 H); 7.58 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 59.77/59.25; H 3.09/2.97; N 5.37/5.57.
Exam leis 1 -6-[j2-(dimethylamin ~eth~llamino]-9-nitro-5H-[1 ]benzothio~yrano j2 3-b~avridin-5-one A suspension of 6-chloro-9-vitro-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (2 g; preparation 2) in dimethylformamide (13 ml) under a nitrogen blanket was cooled in an ice bath and N,N-dimethylethylene diamine (2.02 g) was added dropwise. The slurry was stirred at room temperature for 23 hours and the mixture was quenched over crushed ice (75 ml). The mixture was basified with sodium bicarbonate to pH 10.5. The bright yellow solid was collected by filtration, washed with cold water and dried to yield 2.3 g of the product, m.p. 234-236°C.
' H-NMR in CDC13: 11.68 ppm (broad s, 1 H); 8.79 ppm (dd, 1 H); 8.73 ppm (dd, 1 H); 8.50 ppm (d, 1 H); 7.43 ppm (dd, 1 H); 6.68 ppm (d, 1 H); 3.47 ppm (q, 2H); 2.71 ppm (t, 2H); 2.37 ppm (s, 6H).
Elem. Anal. (calcd/found): C 55.80155.74; H 4.68/4.50; N 16.27/16.20.
Example 2 -6-ff2-(dimethylamino)ethyl]amino]-9-amino-5H-j1lbenzothioyrano[2.3-blpyridin-5-one A solution of stannous chloride dihydrate (6.6 g) in concentrated hydrochloric acid (12 ml) was added dropwise to a stirred solution of 6-[[2-(dimethylamino)ethyl]amino]-9-vitro-5H-[1 ]benzothiopyrano[2,3-b]pyridin-5-one (2.34 g; example 1 ) in a mixture of ethanol : hydrochloric acid (12 ml : 12 ml). The orange suspension was heated at reflux for 23 hours and cooled to room temperature. The red precipitate was collected by filtration, placed in water (5 ml) and the mixture was strongly basified by addition of sodium hydroxide solution to bring the pH to 12. The suspension was stirred in an ice bath for 1 hour. The dark purple solid was collected by filtration, washed with water and air dried. The solid was boiled in acetonitrile (150 ml), collected by filtration from insoluble material and allowed to crystallize at room temperature. Sparkling red purple needles were collected and air dried to give 1.75 g of the product, m.p. 220-222°C.
'H-NMR in CDC13: 9.86 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.35 ppm (dd, 1 H); 7.05 ppm (d, 1 H); 6.58 ppm (d, 1 H); 3.39 ppm (broad s, 2H); 3.34 ppm (q, 2H); 2.67 ppm (t, 2H); 2.34 ppm (s, 6H).
Elem. Anal. (calcd/found): C 61.20161.20; H 5.77/5.53; N 17.82/17.66.
After 1.75 hours, the mixture was removed from the bath, cooled and purified by flash chromatography over silica gel using chloroform : methanol 99 : 1 as the eluent. The product fractions were pooled and concentrated to a thick oil under a slow stream of nitrogen gas. The resultant solid (2.4 g) was recrystallized from a mixture of petroleum ether (35-60°C) and benzene to yield 2.1 g of the product, m.p. 80-81 °C.
' H-NMR in CDCI3: 8.60 ppm (dd, 1 H); 7.96 ppm (dd, 1 H); 7.39 ppm (dd, 1 H); 3.93 ppm (s, 3H); 3.0 ppm (broad d, 6H).
Elem. Anal. (calcd/found): C 49.99/50.23; H 5.03/5.03; N 11.66/22.56.
Preparation 9 - 3-merca~topyridine-2-carboxylic acid A mixture of carbamic acid dimethylthio-S-3-pyridyl ester, sodium carbonate (1.6 g), water (6.2 ml) and methanol (40 ml) was refluxed under a nitrogen atmosphere for 20 hours. The excess sodium carbonate was removed by filtration. The mixture was concentrated to an aqueous residue which was acidified to pH 2. This easily oxidizable solid (a mixture of the mercapto pyridine and the corresponding disulfide) was collected by filtration rapidly, washed with water and dried. Upon crystallization from water, the product separated as orange prisms which were collected by filtration, 0.25 g, m.p. 183-184°C.
'H-NMR in a6-DMSO: 8.30 ppm (dd, 1 H); 8.19 ppm (dd, 1 H); 7.53 ppm (dd, 1 H).
Elem. Anal. (calcd/found): C 46.44/46.11; H 3.29/3.12; N 9.03/8.79.
Preparation 10 -[(2-methyl-5-chlorophenyl thiojpyridine-3-carboxylic acid ~drochloride salt A solution of 4-chloro-2-marcaptotoiuene (0.76 g) in dry acetone (5 ml) was added to 4-chloronicotinic acid (0.5 g). The white suspension was then refluxed for three hours. Upon cooling, the precipitate was collected by filtration, washed with cold anhydrous acetone and air dried to give 0.95 g of the product, m.p. 168-170°C.
'H-NMR in a6-DMSO: 9.04 ppm (s, 1 H); 8.43 ppm (d, 1 H); 7.69 ppm (s, 1 H); 7.61 ppm (d, 1 H); 7.56 ppm (d, 1 H); 6.64 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 55.19/55.26; H 3.6113.89; N 65.91/66.07.
Preparation 11 -6-chloro-9-methyl-10H-j1~-benzothiopyranoj3 2-c]pyridin 5 one A mixture of [(2-methyl-5-chlorophenyl)thio]pyridine-3-carboxylic acid hydrochloride salt (0.25 g; preparation 10) and thionyl chloride (1 ml) was refluxed for 1.5 hour. The excess of thionyl chloride was removed by vacuum aspiration. The residue was then dissolved in nitrobenzene, followed with aluminium chloride (0.6 g). This dark red solution was heated in an oil bath at 100°C for three hours and poured on ice. The precipitate was collected by filtration, dried as possible and washed with ligroin. The residue was suspended in ammonium hydroxide 7% (25 ml), steam was passed through. The cooled suspension was collected by filtration, washed thoroughly with water and air dried. This solid was crystallized in dimethylformamide to give 0.21 g of the product as white needles, m.p.
219-220°C.
' H-NMR in CDC13: 9.30 ppm (s, 1 H); 8.72 ppm (d, 1 H); 7.87 ppm (d, 1 H);
7.65 ppm (d, 1 H); 7.58 ppm (d, 1 H).
Elem. Anal. (calcd/found): C 59.77/59.25; H 3.09/2.97; N 5.37/5.57.
Exam leis 1 -6-[j2-(dimethylamin ~eth~llamino]-9-nitro-5H-[1 ]benzothio~yrano j2 3-b~avridin-5-one A suspension of 6-chloro-9-vitro-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (2 g; preparation 2) in dimethylformamide (13 ml) under a nitrogen blanket was cooled in an ice bath and N,N-dimethylethylene diamine (2.02 g) was added dropwise. The slurry was stirred at room temperature for 23 hours and the mixture was quenched over crushed ice (75 ml). The mixture was basified with sodium bicarbonate to pH 10.5. The bright yellow solid was collected by filtration, washed with cold water and dried to yield 2.3 g of the product, m.p. 234-236°C.
' H-NMR in CDC13: 11.68 ppm (broad s, 1 H); 8.79 ppm (dd, 1 H); 8.73 ppm (dd, 1 H); 8.50 ppm (d, 1 H); 7.43 ppm (dd, 1 H); 6.68 ppm (d, 1 H); 3.47 ppm (q, 2H); 2.71 ppm (t, 2H); 2.37 ppm (s, 6H).
Elem. Anal. (calcd/found): C 55.80155.74; H 4.68/4.50; N 16.27/16.20.
Example 2 -6-ff2-(dimethylamino)ethyl]amino]-9-amino-5H-j1lbenzothioyrano[2.3-blpyridin-5-one A solution of stannous chloride dihydrate (6.6 g) in concentrated hydrochloric acid (12 ml) was added dropwise to a stirred solution of 6-[[2-(dimethylamino)ethyl]amino]-9-vitro-5H-[1 ]benzothiopyrano[2,3-b]pyridin-5-one (2.34 g; example 1 ) in a mixture of ethanol : hydrochloric acid (12 ml : 12 ml). The orange suspension was heated at reflux for 23 hours and cooled to room temperature. The red precipitate was collected by filtration, placed in water (5 ml) and the mixture was strongly basified by addition of sodium hydroxide solution to bring the pH to 12. The suspension was stirred in an ice bath for 1 hour. The dark purple solid was collected by filtration, washed with water and air dried. The solid was boiled in acetonitrile (150 ml), collected by filtration from insoluble material and allowed to crystallize at room temperature. Sparkling red purple needles were collected and air dried to give 1.75 g of the product, m.p. 220-222°C.
'H-NMR in CDC13: 9.86 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.35 ppm (dd, 1 H); 7.05 ppm (d, 1 H); 6.58 ppm (d, 1 H); 3.39 ppm (broad s, 2H); 3.34 ppm (q, 2H); 2.67 ppm (t, 2H); 2.34 ppm (s, 6H).
Elem. Anal. (calcd/found): C 61.20161.20; H 5.77/5.53; N 17.82/17.66.
Examale 3 -6-[[2-ldimethylamin Methyl]aminol-9-ff2-ldimethvlamino ethvllamino]-5H-[1]!benzothiop~rrano[2 3-b]hyridin-5-one A mixture of 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) and 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.
'H-NMR in CDC13: 9.78 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.10 ppm (d, 1 H); 6.62 ppm (d, 1 H); 3.35 ppm (q, 2H); 3.17 ppm (t, 2H); 2.67 ppm (t, 2H); 2.60 ppm (t, 2H); 2.34 ppm (s, 6H); 2.29 ppm (s, 6H).
Elem. Anal. (calcdlfound): C 62.31/61.33; H 7.06/6.94; N 18.17/17.56.
Examale 4 -6-[2-(t-butyl-N-(aminoethyl)carbamate~]-9-vitro-5H-[1]benzo thiol~yrano[2.3-bjpvridin-5-one A mixture of 6-chloro-9-vitro-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (0.91 g; preparation 2) suspended in dimethylformamide (7 ml) was cooled in an ice bath for 0.5 hour. The cooled mixture was treated with t-butyl-N-(aminoethyl)carbamate (1.5 g). The slurry mixture was stirred at room temperature for 24 hours and the mixture was quenched over crushed ice followed by addition of sodium bicarbonate to bring the pH to 11. The bright orange solid was collected by filtration, washed with cold water and ether and dried to yield 1.14 g of the product, m.p. 201-202°C.
'H-NMR in CDC13: 11.74 ppm (broad s, 1 H); 8.81 ppm (m, 1 H); 8.68 ppm (m, 1 H); 8.52 ppm (d, 1 H); 7.45 ppm (m, 1 H); 6.82 ppm (d, 1 H); 4.91 ppm (broad s, 1 H); 3.55 ppm (m, 4H); 1.48 ppm (s, 9H).
Elem. Anal. (calcd/found): C 54.80/54.62; H 4.84/5.03; N 13.45/13.39.
Example 5 -6-j2-(t-butt-N-(aminoethyl)carbamate)1-9-amino-5H-(1lbenzothiopvrano~2 3-b]pyridin-5-one A mixture of 6-[2-(t-butyl-N-(aminoethyl)carbamate)]-9-vitro-5H-(1]
benzothiopyrano [2,3-b]pyridin-5-one (0.2 g; example 4) and 10% Pd/C
10 (0.035 g) in anhydrous methanol (3 ml) was placed in a Parr bomb and hydrogenated for 24 hours at about 100 psi. The mixture was collected by filtration through a celite bed and washed thoroughly with chloroform. The filtrate was concentrated to yield 0.12 g of the product, m.p. 181-183°C.
'H-NMR in CDC13: 9.87 ppm (broad s, 1 H); 8.69 ppm (m, 2H); 7.36 ppm 15 (m, 1 H); 7.04 ppm (d, 1 H); 6.64 ppm (d, 1 H); 4.87 ppm (broad s, 1 H);
3.34 ppm (broad s, 6H); 1.46 ppm (s, 9H).
Elem. Anal. (calcd/found): C 59.05159.45; H 5.74/5.68; N 14.50/14.62.
Example 6 6.j(2 aminoeth~lamino~-9-[[2-~(dimethyrlaminolethvllaminol-5H-20 [1lbenzothiop~rrano~2 3-b]p~rridin-5-one A mixture of 6-[2-(t-butyl-N-(aminoethyl)carbamate)]-9-amino-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (0.1 g; example 5), 2-(dimethylamino)athylbromide (0.181 g) and potassium carbonate (0.215 g) in toluene (7 ml) was refluxed for 48 hours. The mixture was cooled and the residue was collected by filtration and washed thoroughly with toluene. The filtrate was concentrated to dryness. 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.
' H-NMR in CDCl3: 9.89 ppm (broad s, 1 H); 8.72 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.12 ppm (d, 1 H); 6.66 ppm (d, 1 H); 3.66 ppm {q, 2H); 3.18 ppm {t, 2H); 3.07 ppm (t, 2H); 2.62 ppm (t, 2H); 2.31 ppm (s, 6H).
Elem. Anal. (calcd/found): C 60.48/60.19; H 6.45/6.75; N 19.59/19.75.
Example 7 -6-[[2-(dimethylamino)ethyl~amino~j-9-vitro-10H-j1]benzothiopyrano[3.2-c]lyridin-5-one A suspension of 6-chloro-9-vitro-10H-[1J-benzothiopyrano [3,2-c)pyridin-5-one (1.1 g; preparation 5) in dimethylformamide (7 ml) under a nitrogen blanket was cooled in an ice bath and N,N-dimethylethylene diamine (1.1 g) was added dropwise. The slurry was stirred at room temperature for 23 hours and the mixture was quenched over crushed ice (35 ml). The mixture was basified with sodium bicarbonate to pH 10.5. The bright yellow solid was collected by filtration, washed with cold water and dried to yield 1.3 g of the product, m.p.
220-223°C.
'H-NMR in CDC13: 11.67 ppm (broad s, 1 H); 9.61 ppm (s, 1 H); 8.67 ppm (d, 1 H); 8.50 ppm (d, 1 H); 7.50 ppm (d, 1 H); 6.71 ppm (d, 1 H); 3.47 ppm (q, 2H); 2.72 ppm (t, 2H); 2.37 ppm (s, 6H).
Elem. Anal. (calcd/found): C 55.80/55.50; H 4.68/4.60; N 16.27/15.97.
Exam 1e~8 -6-j[2-(dimethylamino~_e~l~,yl]amino]-9-amino-10H-j1lbenzothio_pvrano(_3 2-c]pyridin-5-one A solution of stannous chloride dihydrate (3.1 g) in concentrated hydrochloric acid (6 ml) was added dropwise to a stirred solution of 6-[[2-(dimethylamino)ethyl]aminoj-9-vitro-1 OH-[1 ]-benzothiopyrano[3,2-cJ
pyridin-5-one (1.1 g; example 7) in a mixture of ethanol : hydrochloric acid (6 m1 : 6 ml). The orange suspension was heated at reflux for 20 hours and cooled to room temperature. The bright orange precipitate was collected by filtration, placed in water (5 ml) and the mixture was strongly basified by addition of sodium hydroxide solution to bring the pH to 12.
The suspension was stirred in an ice bath for 1 hour. The dark purple solid was collected by filtration, washed with water and air dried. The solid was boiled in acetonitrile (150 ml), collected by filtration from insoluble material and allowed to crystallize at room temperature. Sparkling red-purple needles were collected and air dried to give 0.66 g of the product, m.p.
178-180°C.
'H-NMR in CDC13: 9.84 ppm (broad s, 1 H); 9.54 ppm {s, 1 H); 8.53 ppm (d, 1 H); 7.33 ppm (d, 1 H); 7.03 ppm (d, 1 H); 6.55 ppm (d, 1 H); 3.39 ppm (broad s, 2H); 3.31 ppm (q, 2H); 2.66 ppm (t, 2H); 2.34 ppm (s, 6H).
Elem. Anal. (calcd/found): C 61.20/61.34; H 5.7715.64; N 17.82/18.05.
Examale 9 6 ff2 {dimethylamino~eth~l]amino]-9-[[2-(dimethylamino eth I amin_o]-5H~j11benzothiopyrano[3 2-clayridin-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. 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 and 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 burgundy solid, 0.030 g, m.p. 132-134°C.
'H-NMR in CDC13: 9.78 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.10 ppm (d, 1 H); 6.62 ppm (d, 1 H); 3.35 ppm (q, 2H); 3.17 ppm (t, 2H); 2.67 ppm (t, 2H}; 2.60 ppm (t, 2H); 2.34 ppm (s, 6H); 2.29 ppm (s, 6H).
Elem. Anal. (calcd/found): C 62.31/62.45; H 7.06/7.25; N 18.17118.45.
Example 10 -6-[[2-~(dimethyrlamino}ethyljamino]!-9-methyl-10H-[1]benzothipyrano[3,2-c],pyridin-5-one A mixture of 6-chloro-9-methyl-10H-[1]benzothipyrano[3,2-c]pyridin-5-one (0.3 g; preparation 11) and N,N-dimethylethylenediamine (1.5 g) was heated at 165°C for 4 hours. Upon cooling the red solution a yellow suspension was formed which was diluted with crushed ice (25 ml) containing potassium hydroxide 50% (2 ml). The yellow precipitate was collected by filtration, washed thoroughly with cold water and air dried.
This solid was crystallized from methanol to give 0.36 g of the product as nice yellow needles, m.p. 158-159°C.
'H-NMR in CDC13: 10.12 ppm (s, 1 H); 9.56 ppm (s, 1 H); 9.54 ppm (d, 1 H);
7.35 ppm (d, 1 H); 7.27 ppm (d, 1 H); 6.58 ppm (d, 1 H); 2.35 ppm (q, 2H);
2.67 ppm (t, 2H); 2.34 ppm (s, 6H); 2.31 ppm (s, 3H).
Elem. Anal. (calcd/found): C 65.15/65.34; H 6.12/6.30; N 13.42/13.16.
Exam Ip a 11 According to the methodologies described in preparations 2, 5 or 11 and in examples 1-6 or 7-10, starting from the suitable starting materials, th'e following compounds are obtained:
-6-[[(2-dimethylamino)ethyl]amino]-9-[[2-(dimethylamino)acetylJaminoJ-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one;
-6-[[(2-dimethylamino)ethyl)amino]-9-butylamino-5H-[1 ]benzothiopyrano[2, 3-b]pyridin-5-one;
-6-[(2-aminoethyl]amino]-9-[[2-(2-hydroxyethylamino}ethyl]amino]-5H-[1 ]benzothiopyrano[2,3-b]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethylJamino]-9-[[2-(dimethylamino)ethyl]
amino]-5H-[1 ]benzothiopyrano[2,3-bjpyridin-5-one;
'H-NMR in CDC13: 9.78 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.10 ppm (d, 1 H); 6.62 ppm (d, 1 H); 3.35 ppm (q, 2H); 3.17 ppm (t, 2H); 2.67 ppm (t, 2H); 2.60 ppm (t, 2H); 2.34 ppm (s, 6H); 2.29 ppm (s, 6H).
Elem. Anal. (calcdlfound): C 62.31/61.33; H 7.06/6.94; N 18.17/17.56.
Examale 4 -6-[2-(t-butyl-N-(aminoethyl)carbamate~]-9-vitro-5H-[1]benzo thiol~yrano[2.3-bjpvridin-5-one A mixture of 6-chloro-9-vitro-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (0.91 g; preparation 2) suspended in dimethylformamide (7 ml) was cooled in an ice bath for 0.5 hour. The cooled mixture was treated with t-butyl-N-(aminoethyl)carbamate (1.5 g). The slurry mixture was stirred at room temperature for 24 hours and the mixture was quenched over crushed ice followed by addition of sodium bicarbonate to bring the pH to 11. The bright orange solid was collected by filtration, washed with cold water and ether and dried to yield 1.14 g of the product, m.p. 201-202°C.
'H-NMR in CDC13: 11.74 ppm (broad s, 1 H); 8.81 ppm (m, 1 H); 8.68 ppm (m, 1 H); 8.52 ppm (d, 1 H); 7.45 ppm (m, 1 H); 6.82 ppm (d, 1 H); 4.91 ppm (broad s, 1 H); 3.55 ppm (m, 4H); 1.48 ppm (s, 9H).
Elem. Anal. (calcd/found): C 54.80/54.62; H 4.84/5.03; N 13.45/13.39.
Example 5 -6-j2-(t-butt-N-(aminoethyl)carbamate)1-9-amino-5H-(1lbenzothiopvrano~2 3-b]pyridin-5-one A mixture of 6-[2-(t-butyl-N-(aminoethyl)carbamate)]-9-vitro-5H-(1]
benzothiopyrano [2,3-b]pyridin-5-one (0.2 g; example 4) and 10% Pd/C
10 (0.035 g) in anhydrous methanol (3 ml) was placed in a Parr bomb and hydrogenated for 24 hours at about 100 psi. The mixture was collected by filtration through a celite bed and washed thoroughly with chloroform. The filtrate was concentrated to yield 0.12 g of the product, m.p. 181-183°C.
'H-NMR in CDC13: 9.87 ppm (broad s, 1 H); 8.69 ppm (m, 2H); 7.36 ppm 15 (m, 1 H); 7.04 ppm (d, 1 H); 6.64 ppm (d, 1 H); 4.87 ppm (broad s, 1 H);
3.34 ppm (broad s, 6H); 1.46 ppm (s, 9H).
Elem. Anal. (calcd/found): C 59.05159.45; H 5.74/5.68; N 14.50/14.62.
Example 6 6.j(2 aminoeth~lamino~-9-[[2-~(dimethyrlaminolethvllaminol-5H-20 [1lbenzothiop~rrano~2 3-b]p~rridin-5-one A mixture of 6-[2-(t-butyl-N-(aminoethyl)carbamate)]-9-amino-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one (0.1 g; example 5), 2-(dimethylamino)athylbromide (0.181 g) and potassium carbonate (0.215 g) in toluene (7 ml) was refluxed for 48 hours. The mixture was cooled and the residue was collected by filtration and washed thoroughly with toluene. The filtrate was concentrated to dryness. 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.
' H-NMR in CDCl3: 9.89 ppm (broad s, 1 H); 8.72 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.12 ppm (d, 1 H); 6.66 ppm (d, 1 H); 3.66 ppm {q, 2H); 3.18 ppm {t, 2H); 3.07 ppm (t, 2H); 2.62 ppm (t, 2H); 2.31 ppm (s, 6H).
Elem. Anal. (calcd/found): C 60.48/60.19; H 6.45/6.75; N 19.59/19.75.
Example 7 -6-[[2-(dimethylamino)ethyl~amino~j-9-vitro-10H-j1]benzothiopyrano[3.2-c]lyridin-5-one A suspension of 6-chloro-9-vitro-10H-[1J-benzothiopyrano [3,2-c)pyridin-5-one (1.1 g; preparation 5) in dimethylformamide (7 ml) under a nitrogen blanket was cooled in an ice bath and N,N-dimethylethylene diamine (1.1 g) was added dropwise. The slurry was stirred at room temperature for 23 hours and the mixture was quenched over crushed ice (35 ml). The mixture was basified with sodium bicarbonate to pH 10.5. The bright yellow solid was collected by filtration, washed with cold water and dried to yield 1.3 g of the product, m.p.
220-223°C.
'H-NMR in CDC13: 11.67 ppm (broad s, 1 H); 9.61 ppm (s, 1 H); 8.67 ppm (d, 1 H); 8.50 ppm (d, 1 H); 7.50 ppm (d, 1 H); 6.71 ppm (d, 1 H); 3.47 ppm (q, 2H); 2.72 ppm (t, 2H); 2.37 ppm (s, 6H).
Elem. Anal. (calcd/found): C 55.80/55.50; H 4.68/4.60; N 16.27/15.97.
Exam 1e~8 -6-j[2-(dimethylamino~_e~l~,yl]amino]-9-amino-10H-j1lbenzothio_pvrano(_3 2-c]pyridin-5-one A solution of stannous chloride dihydrate (3.1 g) in concentrated hydrochloric acid (6 ml) was added dropwise to a stirred solution of 6-[[2-(dimethylamino)ethyl]aminoj-9-vitro-1 OH-[1 ]-benzothiopyrano[3,2-cJ
pyridin-5-one (1.1 g; example 7) in a mixture of ethanol : hydrochloric acid (6 m1 : 6 ml). The orange suspension was heated at reflux for 20 hours and cooled to room temperature. The bright orange precipitate was collected by filtration, placed in water (5 ml) and the mixture was strongly basified by addition of sodium hydroxide solution to bring the pH to 12.
The suspension was stirred in an ice bath for 1 hour. The dark purple solid was collected by filtration, washed with water and air dried. The solid was boiled in acetonitrile (150 ml), collected by filtration from insoluble material and allowed to crystallize at room temperature. Sparkling red-purple needles were collected and air dried to give 0.66 g of the product, m.p.
178-180°C.
'H-NMR in CDC13: 9.84 ppm (broad s, 1 H); 9.54 ppm {s, 1 H); 8.53 ppm (d, 1 H); 7.33 ppm (d, 1 H); 7.03 ppm (d, 1 H); 6.55 ppm (d, 1 H); 3.39 ppm (broad s, 2H); 3.31 ppm (q, 2H); 2.66 ppm (t, 2H); 2.34 ppm (s, 6H).
Elem. Anal. (calcd/found): C 61.20/61.34; H 5.7715.64; N 17.82/18.05.
Examale 9 6 ff2 {dimethylamino~eth~l]amino]-9-[[2-(dimethylamino eth I amin_o]-5H~j11benzothiopyrano[3 2-clayridin-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. 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 and 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 burgundy solid, 0.030 g, m.p. 132-134°C.
'H-NMR in CDC13: 9.78 ppm (broad s, 1 H); 8.73 ppm (dd, 1 H); 8.68 ppm (dd, 1 H); 7.34 ppm (dd, 1 H); 7.10 ppm (d, 1 H); 6.62 ppm (d, 1 H); 3.35 ppm (q, 2H); 3.17 ppm (t, 2H); 2.67 ppm (t, 2H}; 2.60 ppm (t, 2H); 2.34 ppm (s, 6H); 2.29 ppm (s, 6H).
Elem. Anal. (calcd/found): C 62.31/62.45; H 7.06/7.25; N 18.17118.45.
Example 10 -6-[[2-~(dimethyrlamino}ethyljamino]!-9-methyl-10H-[1]benzothipyrano[3,2-c],pyridin-5-one A mixture of 6-chloro-9-methyl-10H-[1]benzothipyrano[3,2-c]pyridin-5-one (0.3 g; preparation 11) and N,N-dimethylethylenediamine (1.5 g) was heated at 165°C for 4 hours. Upon cooling the red solution a yellow suspension was formed which was diluted with crushed ice (25 ml) containing potassium hydroxide 50% (2 ml). The yellow precipitate was collected by filtration, washed thoroughly with cold water and air dried.
This solid was crystallized from methanol to give 0.36 g of the product as nice yellow needles, m.p. 158-159°C.
'H-NMR in CDC13: 10.12 ppm (s, 1 H); 9.56 ppm (s, 1 H); 9.54 ppm (d, 1 H);
7.35 ppm (d, 1 H); 7.27 ppm (d, 1 H); 6.58 ppm (d, 1 H); 2.35 ppm (q, 2H);
2.67 ppm (t, 2H); 2.34 ppm (s, 6H); 2.31 ppm (s, 3H).
Elem. Anal. (calcd/found): C 65.15/65.34; H 6.12/6.30; N 13.42/13.16.
Exam Ip a 11 According to the methodologies described in preparations 2, 5 or 11 and in examples 1-6 or 7-10, starting from the suitable starting materials, th'e following compounds are obtained:
-6-[[(2-dimethylamino)ethyl]amino]-9-[[2-(dimethylamino)acetylJaminoJ-5H-[1]benzothiopyrano[2,3-b]pyridin-5-one;
-6-[[(2-dimethylamino)ethyl)amino]-9-butylamino-5H-[1 ]benzothiopyrano[2, 3-b]pyridin-5-one;
-6-[(2-aminoethyl]amino]-9-[[2-(2-hydroxyethylamino}ethyl]amino]-5H-[1 ]benzothiopyrano[2,3-b]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethylJamino]-9-[[2-(dimethylamino)ethyl]
amino]-5H-[1 ]benzothiopyrano[2,3-bjpyridin-5-one;
-6-propylamino-9-[2-(aminoethyl)amino]-5H-[1 ]benzothiopyrano[2,3b]
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-[[2-(dimethylamino)acetyl]amino]-1 OH-[1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[((2-dimethylamino)ethyl]amino]-9-butylamino-1 OH-[1 ]benzothiopyrano [3,2-c]pyridin-5-one;
-6-[(2-aminoethy!]amino]-9-[[2-{2-hydroxyethylamino)ethyl]amino]-1 OH-[1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethyl]amino]-9-([2-(dimethylamino)ethylJ
amino]-10H-[1]benzothiopyrano[3,2-c]pyridin-5-one;
-6-propyiamino-9-(2-(aminoethyl)amino]-1 OH-[1 ]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-butyl-1 OH-[1 ]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-ethyl-10H-[1]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-((2-aminoethyl]amino]-9-methyl-1 OH-(1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethyl]amino]-9-methyl-1 OH-[1 ]benzo-thiopyrano[3,2-c]pyridin-5-one;
-6-propylamino-9-methyl-1 OH-(1 ]benzothiopyrano[3,2-c]pyridin-5-one.
Ta i I - "In Vitro" activity against L 1210 and S 180 cell fines expressed as iC~~ (u4/mll (concentration of the drug that causes a 50% inhibitory act-ivitv of the cell growth) 5 Compound Example L 1210 S-180 doxorubicin - 0.035 -N ( cH~ ) z o NHS
I I ~ - 0.085 0.3 ~~N(CH3)~
~ ~ 0.04 0.08 I ( N s ~~N(CH3)z N ~ I I ~ 0.005 0.032 i s O ~N(CH~)z N VH
0.4 1.85 s NH
~N(cH,)z Table 1 - Continued Compound Example L 1210 S-180 N ( CHI ) z O NH~
/ \
a.o2 0.06 \ ~
N S
~N(Cx,)z ~ 'N ( CHI ) 2 O NH~
N ~ \ 0.095 0.45 I I
\ i s ~N(CH~)2 N(CH~)2 O NH~
/ \ -- 0.25 0.6 I
cH, N/CH~I~
O NH~
N i \ 0.0082 0.032 I I
\ i s cH,
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-[[2-(dimethylamino)acetyl]amino]-1 OH-[1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[((2-dimethylamino)ethyl]amino]-9-butylamino-1 OH-[1 ]benzothiopyrano [3,2-c]pyridin-5-one;
-6-[(2-aminoethy!]amino]-9-[[2-{2-hydroxyethylamino)ethyl]amino]-1 OH-[1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethyl]amino]-9-([2-(dimethylamino)ethylJ
amino]-10H-[1]benzothiopyrano[3,2-c]pyridin-5-one;
-6-propyiamino-9-(2-(aminoethyl)amino]-1 OH-[1 ]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-butyl-1 OH-[1 ]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-[[(2-dimethylamino)ethyl]amino]-9-ethyl-10H-[1]benzothiopyrano[3,2-c]
pyridin-5-one;
-6-((2-aminoethyl]amino]-9-methyl-1 OH-(1 ]benzothiopyrano[3,2-c]pyridin-5-one;
-6-[[2-(2-hydroxyethylamino)ethyl]amino]-9-methyl-1 OH-[1 ]benzo-thiopyrano[3,2-c]pyridin-5-one;
-6-propylamino-9-methyl-1 OH-(1 ]benzothiopyrano[3,2-c]pyridin-5-one.
Ta i I - "In Vitro" activity against L 1210 and S 180 cell fines expressed as iC~~ (u4/mll (concentration of the drug that causes a 50% inhibitory act-ivitv of the cell growth) 5 Compound Example L 1210 S-180 doxorubicin - 0.035 -N ( cH~ ) z o NHS
I I ~ - 0.085 0.3 ~~N(CH3)~
~ ~ 0.04 0.08 I ( N s ~~N(CH3)z N ~ I I ~ 0.005 0.032 i s O ~N(CH~)z N VH
0.4 1.85 s NH
~N(cH,)z Table 1 - Continued Compound Example L 1210 S-180 N ( CHI ) z O NH~
/ \
a.o2 0.06 \ ~
N S
~N(Cx,)z ~ 'N ( CHI ) 2 O NH~
N ~ \ 0.095 0.45 I I
\ i s ~N(CH~)2 N(CH~)2 O NH~
/ \ -- 0.25 0.6 I
cH, N/CH~I~
O NH~
N i \ 0.0082 0.032 I I
\ i s cH,
Claims (7)
1. A compound of formula (I):
wherein one of X, Y and Z is nitrogen and the others are CH;
R1 is selected from the group consisting of C1-C4 alkyl, nitro and -NH-R1, wherein R1 is selected from the group consisting of (a)-CO-CH2-NR2R3, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5-group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5 group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R5 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, with the proviso that when R' is C1-C4 alkyl, X is CH, or a pharmaceutically acceptable salt thereof.
wherein one of X, Y and Z is nitrogen and the others are CH;
R1 is selected from the group consisting of C1-C4 alkyl, nitro and -NH-R1, wherein R1 is selected from the group consisting of (a)-CO-CH2-NR2R3, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5-group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5 group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R5 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, with the proviso that when R' is C1-C4 alkyl, X is CH, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring selected from the group consisting of 1-imidazolyl, 4-hydroxy-1-imidazolyl, 2-imino-1 (3H)-imidazolyl, 1-pyrrolyl, 1-tetrahydropyrrolyl, 1-pyrazolyl, 4-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-(4-methyl)piperazinyl and 1-(4-benzyl)piperazinyl.
3. A process for preparing a compound of formula (I), wherein one of X, Y and Z is nitrogen and the others are CH;
R' is selected from the group consisting of nitro and -NH-R1, wherein R1 is selected from the group consisting of (a) -CO-CH2-NR2R3, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5 group wherein-said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5- group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R6 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, the process comprising:
(a) reacting a compound of formula (II):
wherein X, Y and Z are as described above, with an amine of formula R-NH2, wherein R is as described above, to produce the compound of formula (I), wherein R' is nitro.
R' is selected from the group consisting of nitro and -NH-R1, wherein R1 is selected from the group consisting of (a) -CO-CH2-NR2R3, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5 group wherein-said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR5- group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R6 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, the process comprising:
(a) reacting a compound of formula (II):
wherein X, Y and Z are as described above, with an amine of formula R-NH2, wherein R is as described above, to produce the compound of formula (I), wherein R' is nitro.
4. The process of claim 3, further comprising:
(b) reducing the nitro group with a reducing agent, to produce a compound of formula (IV), wherein R, X, Y and Z are as described above; and (c) alkylating the amino group of the compound of formula (IV) with a reagent of formula R1-alg, wherein R1 is as described above and alg is selected from the group consisting of chlorine, bromine and iodine, to produce the compound of formula I, wherein R' is NH-R1.
(b) reducing the nitro group with a reducing agent, to produce a compound of formula (IV), wherein R, X, Y and Z are as described above; and (c) alkylating the amino group of the compound of formula (IV) with a reagent of formula R1-alg, wherein R1 is as described above and alg is selected from the group consisting of chlorine, bromine and iodine, to produce the compound of formula I, wherein R' is NH-R1.
5. A process for preparing a compound of formula (I), wherein one of X, Y and Z is nitrogen and the others are CH;
R' is C1-C4 alkyl;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR~- group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R6 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, the process comprising reacting a compound of formula (II'):
wherein X, Y and Z are as described above, with an amine of formula R-NH2, wherein R is as described above, to produce the compound of formula (I).
R' is C1-C4 alkyl;
R is selected from the group consisting of (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkyl having 1-2 substituents independently selected from the group consisting of -OR4 and -NR2R3, and (d) C2-C10 alkyl which is interrupted by 1-2 oxygen atoms or by a -NR~- group wherein said C2-C10 alkyl is unsubstituted or has 1-2 substituents independently selected from the group consisting of hydroxy and -NR2R3;
R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl having 1-2 hydroxy substituents, or R2 and R3, together with the nitrogen atom to which they are bound, form a 5- or 6-membered aromatic or non-aromatic heterocyclic ring which optionally contains a further heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or has a substituent selected from the group consisting of C1-C4 alkyl, hydroxy, amino, imino and benzyl;
R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R6, and C2-C6 alkyl which is substituted by -NR2R3;
R5 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl which is substituted by -NR2R3; and R6 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenyl(C1-C4)alkyl, the process comprising reacting a compound of formula (II'):
wherein X, Y and Z are as described above, with an amine of formula R-NH2, wherein R is as described above, to produce the compound of formula (I).
6. A process for treating leukemia or a solid tumor in a human patient in need thereof, the process comprising administering to the patient a leukemia or a solid tumor treating effective amount of the compound of claim 1.
7. A pharmaceutical composition, comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4497097P | 1997-04-28 | 1997-04-28 | |
| US60/044,970 | 1997-04-28 | ||
| PCT/US1998/008398 WO1998049172A1 (en) | 1997-04-28 | 1998-04-28 | Regioisomeric benzothiopyranopyridines having antitumor activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2288274A1 true CA2288274A1 (en) | 1998-11-05 |
Family
ID=21935312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002288274A Abandoned CA2288274A1 (en) | 1997-04-28 | 1998-04-28 | Regioisomeric benzothiopyranopyridines having antitumor activity |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0981528A1 (en) |
| AU (1) | AU7162898A (en) |
| CA (1) | CA2288274A1 (en) |
| WO (1) | WO1998049172A1 (en) |
Families Citing this family (4)
| 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 |
| US7589083B2 (en) * | 2005-09-12 | 2009-09-15 | Cancure Laboratories, Llc | Compounds and compositions to control abnormal cell growth |
| GB201214169D0 (en) * | 2012-08-08 | 2012-09-19 | Biostatus Ltd | New compounds and uses thereof |
Family Cites Families (2)
| 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 (en) * | 1995-07-06 | 1997-01-23 | University Of Vermont | New pyrido-thiopyranoindazoles with antitumor activity |
-
1998
- 1998-04-28 EP EP98918764A patent/EP0981528A1/en not_active Withdrawn
- 1998-04-28 AU AU71628/98A patent/AU7162898A/en not_active Abandoned
- 1998-04-28 CA CA002288274A patent/CA2288274A1/en not_active Abandoned
- 1998-04-28 WO PCT/US1998/008398 patent/WO1998049172A1/en active Search and Examination
Also Published As
| Publication number | Publication date |
|---|---|
| AU7162898A (en) | 1998-11-24 |
| EP0981528A1 (en) | 2000-03-01 |
| WO1998049172A1 (en) | 1998-11-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4690930A (en) | Pyrazolo[4,3-c]quinoline-3-one and imidazo[4,3-c]cinnolin-3-one derivatives and their use as psychotropic agents | |
| CA2517358A1 (en) | Isoquinoline derivatives and methods of use thereof | |
| US20020042412A1 (en) | Fused azepinone cyclin dependent kinase inhibitors | |
| PL185354B1 (en) | Novel analoques of campotectin, methods of obtaining them and applying them as medicines as well as pharmaceutic compounds containing them | |
| Heber et al. | Synthesis of 5H‐[1] benzopyrano [4, 3‐b] pyridin‐5‐ones containing an azacannabinoidal structure | |
| EP0555347A1 (en) | SUBSTITUTED INDOLIZINO 1,2-b]QUINOLINONES | |
| IE66260B1 (en) | Imidazoacridines and their antineoplastic use | |
| Ferlin et al. | Synthesis and Antiproliferative Activity of Some Ellipticine‐Like 11H‐Pyrido [a] carbazole Derivatives | |
| Jaszfold-Howorko et al. | Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5, 6-dimethyl)-6H-pyrido [4, 3-b] carbazole-1-N-[(dialkylamino) alkyl] carboxamides, a new promising series of antitumor olivacine derivatives | |
| EP1626050A1 (en) | Sulfur-containing naphthoylimide derivatives | |
| US4239887A (en) | Pyridothienotriazines | |
| CA2288274A1 (en) | Regioisomeric benzothiopyranopyridines having antitumor activity | |
| EP0662076B1 (en) | 2-aminoalkyl-5-aminoalkylamino substituted isoquinoindazole-6-(2h)-ones with antitumour activity | |
| Hutchinson et al. | Synthetic strategies to a telomere-targeted pentacyclic heteroaromatic salt | |
| PL131762B1 (en) | Process for preparing novel derivatives of benzodiazepine | |
| SK16022003A3 (en) | Tricyclic dihydro-quionoline derivatives, method for preparing same and pharmaceutical compositions containing same | |
| US5519029A (en) | 2-aminoalkyl-5-aminoalkylamino substituted-isoquinoindazole-6(2H)-ones | |
| AU713107B2 (en) | New pyrido-thiopyranoindazoles with antitumor activity | |
| CA2183735C (en) | Hetero-annulated indazoles | |
| US5935969A (en) | Pyrido-thiopyrandoinazoles with antitumor activity | |
| US5604246A (en) | 2-aminoalkyl-5-aminoalkylamino substituted-isoquinoindazole-6(2H)-ones | |
| US20030212061A1 (en) | Aza-thioxanthenones with antitumor activity | |
| Varvaresou et al. | New pyrazole‐annulated azathioxanthenes as potential intercalators: Synthesis and structure elucidation | |
| IE920704A1 (en) | Nitrogen oxides of aza- and diaza-anthracenedione¹derivatives as antitumor agents | |
| CA2143853C (en) | 2-aminoalkyl-5-aminoalkylamino substituted isoquinoindazole-6-(2h)-ones with antitumour activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |