CA2226310A1 - New pyrido-thiopyranoindazoles with anti-tumor activity - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—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 three hetero rings
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Abstract
This invention is directed to compounds of formula (I) wherein one of X, Y, Z or T is nitrogen (=N-) and the others are =CH-; these compounds have been shown to have antitumor activity.
Description
CA 022263l0 l998-Ol-0~
NEW PYRIDO-THIOPYRANOINDAZOLES WITH ANTI-TUMOR ACTIVITY
BACKGROUND OF THE INVENTION
Field of the invention This invention is directed to 2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazoles,2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazoles, 2H-pyrido[3'4':5,6]thiopyrano[4,3,2-cd]indazoles and 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazoles substituted in the positions 2 and 5.
These compounds have been shown to have antitumor activity.
Backqround Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been re~o,led lS which show antitumor activity in clinical trials. Of particular interest has been ameta"l,ù"e, 1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione and mitoxar,l,o,1e, 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., UProgress in Medicinal ChemistryD, Ellis, G.P. and West, G.B., eds.; Elsevier: Amsterdam, 1983, vol. 20, pp. 83 andreferences cited therein]. Miloxa"L,o"e 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 Iy",pho",a [Legha, Druqs of Todav, 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 inpatients previously treated with doxorubicin [R. Stuart Harris et al., Lancet, 219, (1984) and references cited therein].
Ametanlru, ,e has been reported to be, in animals, about 1 0-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 miloxa,1Lrc,"e might be implicated in the delayed deaths [Corbett et al. Cancer Chemother. F: I ,a""acol. 6 161 (1981)].
In ~d~lition, both mitoka,ll,une and ar"ela"l,o~,e have a remarkable myelodepressive toxicity and both co",pounds show cross-resislar,ce to cell 5 histotypes developing resistance against doxorubicin mediated by overe,~,.ession of glycoprolein P. Such a resi~lance which is named multidrug resistance (MDR) involves a number of antitumor anliL ic,lics among which ar"s~. ine and podophyllotoxinic In addition both mitox~nl.ui ,e and a,,,eta,,l,ùne have a remarkable myelodepressive toxicity and both derivatives, 10 and it is one of the main reasons for therapeutic failures in the treatment of solid tumors with said antibiotics.
In an alle,n~t to overcome the above mentioned drawbacks some cl"ur.,opl)ore modified anll .racenediones have been prepared. For example E. P. Patent Application 103.381 discloses 2-aminoalkyl-5-aminoalkylamino sl ~hstitut~d lS anthra[1 9-cd]pyrazol-6(2H)-ones (a"ll ,rapyrazoles) which are claimed to have antitumor activity. The antitumor activity of said compounds in a number of preclinical models has been reported by H.D. Hollis Showalter et al. [J. Med.
Chem. 30 121 -131 (1987)]. However a"LI " ~pyrazoles are not devoid of toxic side effects with severe leukopenia (W.H.O. grade 3 and 4) and neutropenia 20 (W.H.O. grade 4) being dose limiting in phase I and phase ll clinical trials with the ar,ll)ra~yrazole Cl-941 [I.E. Smith et al. J. Clin. Oncol. 9 2141-2147 (1991)]. Moreover a marked nephrotoxicity is associated with Cl-941 treatment in the rat [D. Campling and M.E.C. Robbins NePhrotoxicitY Peter H. Dekker Bach editor pp. 345-352 (1991) New York; see Chemical Abstract 116: 294n 25 (1992)] and these authors suggest that renal injury may be a clinical problemwith a,lllua,oyrazole therapy. In addition recent reports rDruqs of the Future 17 725 (1992); Judson l.R. et al. Proc. Amer. Assoc. Cancer Res. 32 abstr. 1059 (1991)] indicate that the anthrapyrazole Cl-941 induces irreversible cardiotoxicity in humans although no symptoms of cardiac failure or acute 30 cardiac events have been reported.
Furthermore W094/06795 (31.03.94) describes aza-a, ltl ,rapyrazole derivatives which are endowed with antitumor activity.
_ CA 02226310 1998-01-0~
In the alle"~ to reduce the radical formation "in vivo" by elimi.I~ling the "quinonoid" structure, benzothiopyranoindazoles have been prepared [H.D.
Hollis Showalter et al., J. Med. Chem.. 31, 1527-1539 (1988)]. In these compounds a carbonyl group at C~ position has been replaced by a sulphur 5 atom. A compound of this series, Cl-958, has been chosen for development toward ciinical trials.
However, the search for newer active analogues is still highly desirable.
We have now discovered that the introduction of one nitrogen atom in the positions 7, 8, 9 or 10 of the above mentioned benzothiopyranoinrl~ol~
provides 2H-pyrido[3',2':~,6]thiopyrano[4,3,2-cd]indazoles, 2H-pyrido[4',3':5,6~thiopyrano~4,3,2-cd]indazoles, 2H-pyrido[3'4':5,6]thiopyrano[4,3,2-cd]indazoles and 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazoles substituted in the positions 2 and 5, which have showed a marked antitumor activity.
The compounds of the invention have the general formula (I):
Z~T~ (I) N--N
20 wherein:
one of X, Y, Z or T is nitrogen (=N-) and the others are a =CH- group;
D is selected from the group consisting of nitro or -NH-A, wherein A is on its turn selected in the group consisting of hydrogen, -CO-CH2-NR2R3, C,-C,O alkyl; C2-C,O alkyl having one or two substituents selected from the group consisting of 25 OR, and -NR2R3; C2-C~O alkyl interrupted by one or two oxygen atoms or by one-NR4- group, and said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
B is selected in the group consisting of C1-C~o alkyl; C2-C,0 alkyl having one or two substituents selected from the group consisting of OR, and -NR2R3; C2-C,0 CA 02226310 1998-01-0~
alkyi interrupted by one or two oxygen atoms or by one -NR4- group, and said C2-C,0 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
R~ is selected from the group consisting of hydrogen, C~-C6 alkyl, -S(02)Rs, C2-5 C6 alkyl optionally substituted by -NR2R3;
R2 and R3 may be the same or different and are selected from the group co, Isisling of hydrogen, C~-C10 alkyl, C2-C~O alkyl substituted with one or twohydroxy (OH) groups, or R2 and R3 taken together with the nitrogen atom to which they are linked form a 5- or 6-member a~u~alic or non-aro",dlic 10 1 ,etero~;yclic ring which optionally contains another heteroatom such as sulfur, oxygen or nitrogen;
R4 is selected from the group consisting of hydrogen, C,-C10 alkyl, C2-C~O
hydroxyalkyl, C2-C,O alkyl substituted with -NR2R3;
R5 is selected from the group consisting of C,-C,0 alkyl, phenyl, phenylalkyl, 15 as free bases and their salts with pharmaceutically acceptable acids.
The present invention also concerns the tautomeric forms, the single e"anlio",e,~i and diastereoisomers of the compounds of formula (I), as well as mixtures thereof.
The present invention also concerns the non-toxic salts of the compounds of 20 formula (I) with acids acceptable for pharmaceutical and veterinary use such as those obtained by addition of i,~orga"ic acids like hydrochloric, hy-J,obron,ic,sulfuric, phosphoric, pyrophosphoric acid andtor of organic acids such as acetic, propionic, citric, benzoic, lactic, maleic, fumaric, succinic, tartaric, glutamic, aspartic, gluconic, ascorbic acids and the like.
In compounds (I) the term "phenyl" means phenyl rings which can optionally contain substituents such as (C,-C4)alkyl groups, CF3, halo~en atoms, nitro, amino, acetylamino, formylamino, dimethylamino, diethylamino, hydroxy, m ell ,oxy and ethoxy groups.
30 r,er~r,ed examples of C,-C,0 alkyl groups are methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
Preferred examples of phenylalkyl is 4-methylphenyl. When in compounds of formula (I) A and B are a C2-C,0 alkyl interrupted by one or two oxygen atoms or CA 022263l0 l998-0l-05 by one -NR4- group and optionally s~ ~hstit~ted by one or two hydroxy or -NR2R3 groups, at ieast two carbon atoms are prererably interposed between said oxygen atoms and/or the -NR4- and -NR2R3 groups.
When in compounds of formula (I) the -NR2R3 substituent is a 5~ member 5 aro"lalic or not aror,lalic heterocyclic ring which may co"lai,~ another ~,elerualc,,,, such as sulfur, oxygen and nitrogen, preferred examples of said heterocyclic rings are 1-imidazolyl, 4-hydroxy-1-imida~olyl, 2-imino-1 (3H)-i",id~,olyl, 1-pyrrolyl, 1-tetrahydropyrrolyl, 1-pyrazolyl, 4-",or~ olinyl, 1-piperidinyl, 1-piperazinyl, 1-(4-methyl)piperazinyl, 1-(4-benzyl)piperazinyl.
lO The compounds of formula (I) are those depicted in table 1, wherein D and B
are as above defined.
Z~T ~l (I) N N
X Y Z T .I- ~ name of the ~ y~tem CH CH CH N N--N~ 2H-pyrido[2',3':5,6311u~ [4,3,2-cA]in~
N~
CH CH N CH N--N, 2H-pyrido[3~4~:s~6~ol4~3~2 cd]i~
N~
CH N CH CH N--N, 2H-pyrido[4',3':5,6]thiopyrano[4,3,2-s~3i ~
N CH CH CH N--N, 2H-pylido[3',2':5,6]11..u~ 1,3,2-CA,i Pl~rer,ed cGmpounds are those according to formula (I) wherein X, Y, Z and T
are as above defined, D is a -NH-A group and A and B are independently 5 selected from the group coi)sislin-a of:
~ residue of formula -(CH2)p-NH2 wherein p is the integer 2 or 3;
~ residue of formula -(CH2)p-NR2R3 wherein p is as above defined and both R2 and R3 are methyl or ethyl or 2-hydroxyethyl;
~ residue of formula -(CH2)p-NR2R3 wherein p is above defined and R2 is l0 hydrogen and R3 is methyl;
~ residue of formula -(CH2)p-NR2R3 wherein p is above defined and -NR2R3 is 4-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-imidazolyl;
~ residue of formula -(CH2)p-OH wherein p is as above defined;
~ residue of formula -(CH2)p-NH-(CH2)q-OH wherein p and q are independently 15 an integer selected from the group consisting of 2 or 3 Other preferred compounds are those in which D is selected in the group consisting of nitro, amino and -NHCO-CH2-NH2 and B is as just above defined.
Particularly preferred compounds of formula (I) are those in which A and B are as previously defined and X or Z are nitrogen.
20 Even more particularly preferred compounds are those in which X or Z are nitrogen, D is a -NH-A group and A and B are independently a residue of formula -(CH2)p-NR2R3, wherein p is as above defined and both R2 and R3 are methyl or ethyl or 2-hydroxyethyl.
The compounds of formula (I) can be prepared by the reaction of a compound of 25 formula (Ill):
CA 022263l0 l998-Ol-0~
y~X~
O U
c wherein X, Y, Z and T are as above defined and U is selected from the group consisting of F or Cl, with a hydrazine of formula (IV):
s H2N-N H-B' ( IV) wherein B' has the same meanings as B is defined in formula (1), or B' is a group that can be converted into B by removal of protective groups for the primary or o secondary amines and hydroxy groups optionally present in B', to give compound of formula (11):
Z- T~ (Il) N N
S in which X, Y, Z, T and B' are as above defined.
The removal of protecting groups optionally present gives the compounds of formula (I) in which D is a nitro group.
Alternatively, said intermediate (Il) is subjected to reduction of the nitro group to give the intermediate of formula (lla):
Z~T~l (lla) N N~
which is then converted into the compounds of formula (I) in which D is an amino group by removal of the protecting groups optionally present.
CA 02226310 1998-01-0~
Allerl ,aLively, the intermediate (lla) is converted into the compounds of formula (I) in which D is a -NH-A group and A has the meanings above defined, with the e,c~,c lion of hyd(c,yen and -CO-CH2-NR2R3, by co"-le, Isdlio n of the amino group with a reactant of formula (V):
t L-A' (V) in which A' has the same meanings as A is defined in formula (I) or A' is a group that can be converted into A by removal of protective groups for the primary or 10 secondary amines or hydroxy groups optionally present in A' and L is an atom selected in the group of chlorine, bromine and iodine or is a -O-Tosyl group, and sl ~hsequent removal of protective groups optionally present on the side chains A' and B'.
Aller. ,dli~ely, A' is a group of formula -CO-A", in which on its turn A" is selecte~l in the group consisting of C1-Cg alkyl; C,-Cg alkyl having one or two s~ 'hstitl ~ents selected from the group consisting of OR1 and -NR2R3; C1-Cg alkyl interrupted by one or two oxygen atoms or by one -NR4- group, and said C1-Cg alkyl is oplio. .ally substituted by one or two hydroxy (OH) or -NR2R3 groups, and in which the hydroxy or the amine group can optionally be protected with 20 conventional protective groups. In this case, L is a OH group, a halogen atom(chlorine, bromine or iodine) or a suitable leaving group well known to the skilled artisan. Such a reaction, followed by the removal of the protecting groups optionally present, gives the compounds of formula (I) in which A is a -CO-CH2-NR2R3group. They on their turn give the other compounds of formula (I) by 2s red~ ~ction of the amidic moiety to amine.
~, olecti~/e groups for the primary and/or secondary amines optionally present in A' and/or B' which can advantageously be used for the preparation of co",pounds of formula (I) are represented by (C1-C3)acyl derivatives (~,rerer~bly acetyl derivatives), (C1-C4)alkoxycarbonyl derivatives (preferably tert-30 butoxycarbonyl derivatives) and by (C7-C10)aralkyloxycarbonyl derivatives (prerer~bly benzyloxycarbonyl derivatives).
The rea~;Lioi. of compounds (111) with the hydrazines (IV) can be performed by reacting compounds (111) with a stoichiometric amount of hydrazines (IV) or an CA 022263l0 l998-Ol-0~
excess of hydrazines (IV). The reaction is usually performed in an inert solventsuch as methylene chloride, chloroform, 1,1,1-trichloroethane, dimethoxyelht~"e,tetrahydrofuran, di,nethylsulfoxide, dimeth~,lrur,,,ta,,,ide, pyridine, picoline and mixtures thereof, or if it is desired, using compound (IV) itself as the solvent, 5 optionally in the presence of an inorganic base such as an alkaline or alkaline-earth carbonate or hydrogen carbonate or an organic base such as a trialkylamine, at a temperature from -20~C to the reflux temperature of the solvent. P, ererably, the reaction is carried out in a solvent such as di",~:ll"~lformamide, pyridine, tetrahydrofuran, dimethylsulfoxide or N,N,N',N'-o tetramethylethylenediamine, using 1 to 10 equivalents of compound (IV) for 1equivalent of compound (Ill) and working at a temperature ranging from 5~C to 50~C.
If necess~ry, the removal of the protective group for the primary and/or secondary amino functions is carried out following the procedures well known to 15 those skilled in the art. Useful teachings can be found in Green, T.W., Wuts,P.G.M., "Protective Groups in Organic Synthesis", second Edition, John Wiley &
Sons, 1991.
For example, the removal of the N-(tert-butoxycarbonyl) protective group can be performed by treatment of the compound with an excess of anhydrous or 20 aqueous hydrochloric acid in a solvent such as a (C,-C4)alkanol, dichloromethane, chloroform or mixtures thereof, at a temperature of 0~C to the reflux temperature of the solvent and for a time ranging from several minutes toa few hours. Preferably the reaction is performed in ethanol or in chloroform using from 10 to 20 molar equivalents of anhydrous hydrochloric acid at a 25 temperature of from 20~C to 50~C, and is generally complete in four hours.
The reaction of reduction of the nitro group of compounds (Il) to give compounds (lla) is performed by catalytic hydrogenation, treating in hydrogen t-~LIIIospl ,ere a compound (Il), in a suitable solvent such as glacial acetic acid, an alkanol such as methanol or ethanol, an ether such as 1,4-dioxane, 30 tetrahydrofuran or a solvent such as methylene chloride or chloroform, in thepresence of catalytic amounts (from 0.1 to 0.3 equivalents) of a catalyst such as 10% palladium on carbon, Nickel Raney or 10% platinum on carbon and at a pressure of from atmospheric pressure to 100 psi.
CA 02226310 1998-01-0~
P,ererably, the reaction is carried out in glacial acetic acid, using 10% p~ m on carbon as a catalyst and at a pressure of about 70 psi.
Alle" ,dLi~ely, the reduction of the nitro group of compounds (Il) to give co""~ounds (lla) may be pe, rO",.ed following other methods known in the art, s such as the use of FeSO4 in basic conditions (allllllonia or sodium hydluxi.le) or the use of metals or salts thereof, optionally in acidic co, Idiliol ,s. Suitable examples of such reducing agents are SnCI2, SnCI2 in the presence of hydrochloric acid or Zn in the presence of hydrochloric acid.
The alkylation of intermedi~tes (lla) with intermedi~t~s of formula L-A' to givel0 the compounds of formula (I) is performed by reacting the illler",ediate (lla) with a molar excess of the reactant of formula (V) in an inert solvent such as be"~ene, toluene, chlorobenzene and the like, or an alcohol such as isopropanol or in a nitrile such as acetonitrile, and in the presence of an inorganic base such as an alkaline or alkaline-earth carbonate or 15 hydrogencarbonate or an organic base such as trialkylamine. Preferably, the reaction is carried out in an aro",aLic solvent such as toluene, in the presence of potassium carbonate and at a temperature ranging from room temperature to the reflux temperature of the solvent.
The acylation reaction of intermediates (lla) with compounds of formula L-CO-A"
20 iS usually pelru""ed, when L is a OH group, in the presence of a cGndensin agent such as dicyclohexylcarbodiimide and the like, at a temperature ranging from -1 0~C to room temperature and in an inert solvent such as an ether (tetrahydrofuran, diethyl ether and the like).
The redl ~ction of amidic moiety into amine can be preferentially performed in an 25 inert solvent such as toluene or benzene, at a temperature ranging from room temperature to the reflux temperature of the solvent and in the presence of a reducing agent such as Red-AI, LiAlH4 or other suitable hydrides.
The intermediates (Ill) can be prepared by cyclization of the compounds of formula (Vl):
CA 02226310 1998-01-0~
Z T3~2H ~l (Vl) in which X, Y, Z, T and U are as above defined.
Said reaction can be performed using different methods known in the art, such 5 as for example:
i) transforming the carboxylic acid moiety into an acyl chloride by reaction with thionyl chloride, for example, and subsequently performing a Friedel-Craft reaction in the presence of a Lewis acid such as alluminum trichloride, in a suitable solvent such nitrobenzene and at a temperature ranging from -1 0~C to o 50~C;
ii) cyclizing the compounds (Vl) in the presence of fuming sulfuric acid (10-30% sulfur trioxide), at a temperature ranging from room temperature to 1 50~C;
iii) cyclizing the compounds (Vl) in the presence of polyphosphoric acid silyl ester (PPSE) and of phosphorus pentoxide, at a temperature ranging from 50~C
to 210~C.
The compounds of formula (Vl) can be obtained starting from the compounds of formula (Vlll):
z~T CO2H
Y~X~Q (Vlll) in which X, Y, Z and T are as above defined and Q is a chlorine atom or a diazo group -N2'CI-, by reaction with a compound of formula (Vll):
CA 022263l0 l998-Ol-0~
H'S~J (Vll) in which U is as above defined.
When X or Z are nitrogen, then Q is prererentially chlorine; when Y or T are 5 nitrogen, Q is preferentially a -N2+CI- group.
When Q is chlorine, the reaction is preferentially performed in a suitable solvent such as a ketone (acetone, methyl ethyl ketone and the like) and at a temperature ranging from room temperature to the boiling point of the solvent.
When Q is a -N2+CI- group, the compounds (Vlll) are prepared ain situ", following lO the methods known in the art, by reaction of the amine derivatives (IX):
z~T~C02H
~X NH2 with sodium nitrite in the presence of hydrochloric acid at a temperature ran~in~
15 from -10~C to 10~C. The compounds (Vlll) so prepared are then reacted withoutisolation with the compounds (Vll) at a temperature ranging from 0~C to 70~C, oblai"in~ the compounds of formula (Vl).
Alternatively, compounds (Vlll) in which Q is a -N2+CI- can be reacted without isolation with equimolar amounts of O-ethylxanthic acid, potassium salt. The 20 resulting interme~ es give compounds (Vl) by treatment with sodium elhoxide in ethanol and subsequently with 2,4-dichloronitrobenzene.
The con,pounds of formula (Vlll) when Q is a chlorine atom or the con,pounds of formula (IX) are commercial product or can be prepared starting from commercial product following methods known in the art, such as for example 25 those described in:
- Ross, W.C.J., J.C.S., C, 1816-21 (1966): synthesis of 4-chloro nicotinic acid;- Winn, M. et al., J. Med. Chem., 36, 2676-88 (1993);
CA 02226310 1998-01-0~
- Fibel, C.R. et al., J.A.C.S., 70, 3908 (1948): synthesis of 3-amino isonicotinic acid.
BIOLOGICAL EVALUATION OF THE COMPOUNDS OF THE INVENTION
The evaluation of the biological activity for the compounds of this invention was s performed ~in vitro" and uin vivo" following the protocols developed by the U.S.
National Cancer Institute.
The evaluation of the uin vitro" cytotoxic activity of the co"lpounds of the invention was performed using the following cell lines: a murine sarcon~a (S-180) and its subline expressing multidrug resistance (S-180/A-10), a leukemia (L1210), a human colon adenocarcinoma cell line (LoVo) isolated from a metaslalic nodule and its subline expressing multidrug resistance. This latter subline is resistant to a number of antitumor agents, among which are doxorubicin, VP-16 and vi"c, i~line. This subline (named LoVo/DX) shows red~ ~ced accumulation of doxorubicin and overexpression of a protein (Grandi, M., Geroni, C., Giuliani, F.C., British J. Cancer, (1986), 54, 515). The compounds were tested according to the MTT assay (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay", J. Immunol. Methods, (1983), 65, 55~3; Green, L.M., "Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation ofC~loloxic and Growth Inhibitory Lymphokines", J. Immunol. Methods, (1984), 70, 257-268) in cor"p~rison with mitoxd, lll u, ,e and doxorubicin.
The ~I ,a" "acological data for some representative compounds of the present invention are reported in Tables ll and lll. A co",parison with the prior art compound Cl941 and with doxorubicin and mitoxantrone is also provided in Table ll. The columns headed L1210, S180 LoVo and LoVo/Dx contain the IC50 values against said tumor cell lines, as above described.
In general, represer!lali~/e compounds of this invention exhibited a high cytotoxicity in all the cell lines tested. When mitoxantrone was tested in the LoVo/DX cell line, a resistance index Rl (defined as the ratio of the ICso for the resistance cell line to the IC50for the sensitive cell line) as high as 22.5 wasfound, showing that this subiine does have an acquired resistance to mitoxantrone. On the other hand, representative compounds of this invention, when tested in the same resistant subline, show no cross resistance with CA 022263l0 l998-Ol-0~
~iLuxd~ u~ ~e. The uin vitro" evaluation of representative compounds of this invention suggests that they are able to retain a high activity also in the resistant cell line, while the prior art compound C1-941 loses completely its activity.
Studies of the biological activity "in vivon of represe~ Li~e compounds of the invention were performed using the P388 murine leukemia model. P388 murine Ieukemia cells were intravenously (iv) i"j~cted in CD2F1 mice. Tredl",enl was initiated ap~l oxi")dlely 24 hours after tumor transpla,)L~liot) and dos~ges of the drug were administered iv (P388 iv/iv) according to preestablished prul(,cols, usually at 3-day intervals. The studies were done over a 60-day period and the o date of death for each animal was recorded. The % T/C was deler" ,ined usingthe mean survival time (MST) for each group accordil lg to the formula % T/C = [~MST treated) / (MST control)] x 100 Representative compounds of this invention were able to increase the survival time of treated animals, leading to high % T/C values at well tolerated d os~ges.
Since represenlative compounds of this invention show good results aga;. Isl this significant"in vivo" model of murine P388 leukemia, which is considered to be predictive of antitumor activity in humans, the compounds disclosed herein are expected to be operative against human leukemias and solid tumors sensitive to treatment with antitumor antibiotics.
The compounds of the invention may therefore be used as active ingredients of therapeutic co",posilions to induce regression and/or palliation of cancers in mammals when administered in amounts ranging from about 1 mg to about 0.4 9 per kilogram of body weight. A prefe, l~d 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 9 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 composition may be in the form of tablets, capsules, gel capsules, suppositories, Iyophilized powders and solutions for intravenous adminislralion.
CA 022263l0 l998-Ol-0~
The invention is illustrated by the following non-limiting examples and va, ialictr,s which are readily a~ r~nl to those skilled in the art.
EXPERIMENTAL PART
Preparation 1 - 2-(2-nitro-5-chloro)thioPhenoxvnicotinic acid (compound (Vl): X
5 = N) A solution of 2-nitro-5-chlorobenzenethiol (0.26 9) in acetone (2 ml) was added to 2-chloronicotinic acid (0.11 9). The suspension was refluxed for 5 hrs and the resultant mixture was cooled to room te"" eralure. The bright yellow preCirit~tewas collected by filtration, washed with acetone to yield a yellow solid (0.12 9), lO m.p. 248-249~C.
H NMR in d6-DMSO 8.39 ppm (dd, J = 1.7 Hz, 4.7 Hz,1 H); 8.27 ppm (dd, J =
1.7 Hz, 7.9 Hz,1H); 8.10 ppm (d, J = 8.7 Hz,1H); 7,85 ppm (d, J = 2.3 Hz,1H);
7.76 ppm (dd, J = 2.3 Hz, 8.7 Hz, 1 H); 7.30 ppm (dd, J = 4.7 Hz, 7.7 Hz,1 H).
Anal. Calcd. for C,2H7CIN2O4S: C 46.39, H 2.27, N 9.01. Found: C 46.39, H
NEW PYRIDO-THIOPYRANOINDAZOLES WITH ANTI-TUMOR ACTIVITY
BACKGROUND OF THE INVENTION
Field of the invention This invention is directed to 2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazoles,2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazoles, 2H-pyrido[3'4':5,6]thiopyrano[4,3,2-cd]indazoles and 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazoles substituted in the positions 2 and 5.
These compounds have been shown to have antitumor activity.
Backqround Certain 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones have been re~o,led lS which show antitumor activity in clinical trials. Of particular interest has been ameta"l,ù"e, 1,4-bis[(2-(2-hydroxyethylamino)ethyl)amino]anthracene-9,10-dione and mitoxar,l,o,1e, 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., UProgress in Medicinal ChemistryD, Ellis, G.P. and West, G.B., eds.; Elsevier: Amsterdam, 1983, vol. 20, pp. 83 andreferences cited therein]. Miloxa"L,o"e 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 Iy",pho",a [Legha, Druqs of Todav, 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 inpatients previously treated with doxorubicin [R. Stuart Harris et al., Lancet, 219, (1984) and references cited therein].
Ametanlru, ,e has been reported to be, in animals, about 1 0-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 miloxa,1Lrc,"e might be implicated in the delayed deaths [Corbett et al. Cancer Chemother. F: I ,a""acol. 6 161 (1981)].
In ~d~lition, both mitoka,ll,une and ar"ela"l,o~,e have a remarkable myelodepressive toxicity and both co",pounds show cross-resislar,ce to cell 5 histotypes developing resistance against doxorubicin mediated by overe,~,.ession of glycoprolein P. Such a resi~lance which is named multidrug resistance (MDR) involves a number of antitumor anliL ic,lics among which ar"s~. ine and podophyllotoxinic In addition both mitox~nl.ui ,e and a,,,eta,,l,ùne have a remarkable myelodepressive toxicity and both derivatives, 10 and it is one of the main reasons for therapeutic failures in the treatment of solid tumors with said antibiotics.
In an alle,n~t to overcome the above mentioned drawbacks some cl"ur.,opl)ore modified anll .racenediones have been prepared. For example E. P. Patent Application 103.381 discloses 2-aminoalkyl-5-aminoalkylamino sl ~hstitut~d lS anthra[1 9-cd]pyrazol-6(2H)-ones (a"ll ,rapyrazoles) which are claimed to have antitumor activity. The antitumor activity of said compounds in a number of preclinical models has been reported by H.D. Hollis Showalter et al. [J. Med.
Chem. 30 121 -131 (1987)]. However a"LI " ~pyrazoles are not devoid of toxic side effects with severe leukopenia (W.H.O. grade 3 and 4) and neutropenia 20 (W.H.O. grade 4) being dose limiting in phase I and phase ll clinical trials with the ar,ll)ra~yrazole Cl-941 [I.E. Smith et al. J. Clin. Oncol. 9 2141-2147 (1991)]. Moreover a marked nephrotoxicity is associated with Cl-941 treatment in the rat [D. Campling and M.E.C. Robbins NePhrotoxicitY Peter H. Dekker Bach editor pp. 345-352 (1991) New York; see Chemical Abstract 116: 294n 25 (1992)] and these authors suggest that renal injury may be a clinical problemwith a,lllua,oyrazole therapy. In addition recent reports rDruqs of the Future 17 725 (1992); Judson l.R. et al. Proc. Amer. Assoc. Cancer Res. 32 abstr. 1059 (1991)] indicate that the anthrapyrazole Cl-941 induces irreversible cardiotoxicity in humans although no symptoms of cardiac failure or acute 30 cardiac events have been reported.
Furthermore W094/06795 (31.03.94) describes aza-a, ltl ,rapyrazole derivatives which are endowed with antitumor activity.
_ CA 02226310 1998-01-0~
In the alle"~ to reduce the radical formation "in vivo" by elimi.I~ling the "quinonoid" structure, benzothiopyranoindazoles have been prepared [H.D.
Hollis Showalter et al., J. Med. Chem.. 31, 1527-1539 (1988)]. In these compounds a carbonyl group at C~ position has been replaced by a sulphur 5 atom. A compound of this series, Cl-958, has been chosen for development toward ciinical trials.
However, the search for newer active analogues is still highly desirable.
We have now discovered that the introduction of one nitrogen atom in the positions 7, 8, 9 or 10 of the above mentioned benzothiopyranoinrl~ol~
provides 2H-pyrido[3',2':~,6]thiopyrano[4,3,2-cd]indazoles, 2H-pyrido[4',3':5,6~thiopyrano~4,3,2-cd]indazoles, 2H-pyrido[3'4':5,6]thiopyrano[4,3,2-cd]indazoles and 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazoles substituted in the positions 2 and 5, which have showed a marked antitumor activity.
The compounds of the invention have the general formula (I):
Z~T~ (I) N--N
20 wherein:
one of X, Y, Z or T is nitrogen (=N-) and the others are a =CH- group;
D is selected from the group consisting of nitro or -NH-A, wherein A is on its turn selected in the group consisting of hydrogen, -CO-CH2-NR2R3, C,-C,O alkyl; C2-C,O alkyl having one or two substituents selected from the group consisting of 25 OR, and -NR2R3; C2-C~O alkyl interrupted by one or two oxygen atoms or by one-NR4- group, and said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
B is selected in the group consisting of C1-C~o alkyl; C2-C,0 alkyl having one or two substituents selected from the group consisting of OR, and -NR2R3; C2-C,0 CA 02226310 1998-01-0~
alkyi interrupted by one or two oxygen atoms or by one -NR4- group, and said C2-C,0 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
R~ is selected from the group consisting of hydrogen, C~-C6 alkyl, -S(02)Rs, C2-5 C6 alkyl optionally substituted by -NR2R3;
R2 and R3 may be the same or different and are selected from the group co, Isisling of hydrogen, C~-C10 alkyl, C2-C~O alkyl substituted with one or twohydroxy (OH) groups, or R2 and R3 taken together with the nitrogen atom to which they are linked form a 5- or 6-member a~u~alic or non-aro",dlic 10 1 ,etero~;yclic ring which optionally contains another heteroatom such as sulfur, oxygen or nitrogen;
R4 is selected from the group consisting of hydrogen, C,-C10 alkyl, C2-C~O
hydroxyalkyl, C2-C,O alkyl substituted with -NR2R3;
R5 is selected from the group consisting of C,-C,0 alkyl, phenyl, phenylalkyl, 15 as free bases and their salts with pharmaceutically acceptable acids.
The present invention also concerns the tautomeric forms, the single e"anlio",e,~i and diastereoisomers of the compounds of formula (I), as well as mixtures thereof.
The present invention also concerns the non-toxic salts of the compounds of 20 formula (I) with acids acceptable for pharmaceutical and veterinary use such as those obtained by addition of i,~orga"ic acids like hydrochloric, hy-J,obron,ic,sulfuric, phosphoric, pyrophosphoric acid andtor of organic acids such as acetic, propionic, citric, benzoic, lactic, maleic, fumaric, succinic, tartaric, glutamic, aspartic, gluconic, ascorbic acids and the like.
In compounds (I) the term "phenyl" means phenyl rings which can optionally contain substituents such as (C,-C4)alkyl groups, CF3, halo~en atoms, nitro, amino, acetylamino, formylamino, dimethylamino, diethylamino, hydroxy, m ell ,oxy and ethoxy groups.
30 r,er~r,ed examples of C,-C,0 alkyl groups are methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
Preferred examples of phenylalkyl is 4-methylphenyl. When in compounds of formula (I) A and B are a C2-C,0 alkyl interrupted by one or two oxygen atoms or CA 022263l0 l998-0l-05 by one -NR4- group and optionally s~ ~hstit~ted by one or two hydroxy or -NR2R3 groups, at ieast two carbon atoms are prererably interposed between said oxygen atoms and/or the -NR4- and -NR2R3 groups.
When in compounds of formula (I) the -NR2R3 substituent is a 5~ member 5 aro"lalic or not aror,lalic heterocyclic ring which may co"lai,~ another ~,elerualc,,,, such as sulfur, oxygen and nitrogen, preferred examples of said heterocyclic rings are 1-imidazolyl, 4-hydroxy-1-imida~olyl, 2-imino-1 (3H)-i",id~,olyl, 1-pyrrolyl, 1-tetrahydropyrrolyl, 1-pyrazolyl, 4-",or~ olinyl, 1-piperidinyl, 1-piperazinyl, 1-(4-methyl)piperazinyl, 1-(4-benzyl)piperazinyl.
lO The compounds of formula (I) are those depicted in table 1, wherein D and B
are as above defined.
Z~T ~l (I) N N
X Y Z T .I- ~ name of the ~ y~tem CH CH CH N N--N~ 2H-pyrido[2',3':5,6311u~ [4,3,2-cA]in~
N~
CH CH N CH N--N, 2H-pyrido[3~4~:s~6~ol4~3~2 cd]i~
N~
CH N CH CH N--N, 2H-pyrido[4',3':5,6]thiopyrano[4,3,2-s~3i ~
N CH CH CH N--N, 2H-pylido[3',2':5,6]11..u~ 1,3,2-CA,i Pl~rer,ed cGmpounds are those according to formula (I) wherein X, Y, Z and T
are as above defined, D is a -NH-A group and A and B are independently 5 selected from the group coi)sislin-a of:
~ residue of formula -(CH2)p-NH2 wherein p is the integer 2 or 3;
~ residue of formula -(CH2)p-NR2R3 wherein p is as above defined and both R2 and R3 are methyl or ethyl or 2-hydroxyethyl;
~ residue of formula -(CH2)p-NR2R3 wherein p is above defined and R2 is l0 hydrogen and R3 is methyl;
~ residue of formula -(CH2)p-NR2R3 wherein p is above defined and -NR2R3 is 4-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-imidazolyl;
~ residue of formula -(CH2)p-OH wherein p is as above defined;
~ residue of formula -(CH2)p-NH-(CH2)q-OH wherein p and q are independently 15 an integer selected from the group consisting of 2 or 3 Other preferred compounds are those in which D is selected in the group consisting of nitro, amino and -NHCO-CH2-NH2 and B is as just above defined.
Particularly preferred compounds of formula (I) are those in which A and B are as previously defined and X or Z are nitrogen.
20 Even more particularly preferred compounds are those in which X or Z are nitrogen, D is a -NH-A group and A and B are independently a residue of formula -(CH2)p-NR2R3, wherein p is as above defined and both R2 and R3 are methyl or ethyl or 2-hydroxyethyl.
The compounds of formula (I) can be prepared by the reaction of a compound of 25 formula (Ill):
CA 022263l0 l998-Ol-0~
y~X~
O U
c wherein X, Y, Z and T are as above defined and U is selected from the group consisting of F or Cl, with a hydrazine of formula (IV):
s H2N-N H-B' ( IV) wherein B' has the same meanings as B is defined in formula (1), or B' is a group that can be converted into B by removal of protective groups for the primary or o secondary amines and hydroxy groups optionally present in B', to give compound of formula (11):
Z- T~ (Il) N N
S in which X, Y, Z, T and B' are as above defined.
The removal of protecting groups optionally present gives the compounds of formula (I) in which D is a nitro group.
Alternatively, said intermediate (Il) is subjected to reduction of the nitro group to give the intermediate of formula (lla):
Z~T~l (lla) N N~
which is then converted into the compounds of formula (I) in which D is an amino group by removal of the protecting groups optionally present.
CA 02226310 1998-01-0~
Allerl ,aLively, the intermediate (lla) is converted into the compounds of formula (I) in which D is a -NH-A group and A has the meanings above defined, with the e,c~,c lion of hyd(c,yen and -CO-CH2-NR2R3, by co"-le, Isdlio n of the amino group with a reactant of formula (V):
t L-A' (V) in which A' has the same meanings as A is defined in formula (I) or A' is a group that can be converted into A by removal of protective groups for the primary or 10 secondary amines or hydroxy groups optionally present in A' and L is an atom selected in the group of chlorine, bromine and iodine or is a -O-Tosyl group, and sl ~hsequent removal of protective groups optionally present on the side chains A' and B'.
Aller. ,dli~ely, A' is a group of formula -CO-A", in which on its turn A" is selecte~l in the group consisting of C1-Cg alkyl; C,-Cg alkyl having one or two s~ 'hstitl ~ents selected from the group consisting of OR1 and -NR2R3; C1-Cg alkyl interrupted by one or two oxygen atoms or by one -NR4- group, and said C1-Cg alkyl is oplio. .ally substituted by one or two hydroxy (OH) or -NR2R3 groups, and in which the hydroxy or the amine group can optionally be protected with 20 conventional protective groups. In this case, L is a OH group, a halogen atom(chlorine, bromine or iodine) or a suitable leaving group well known to the skilled artisan. Such a reaction, followed by the removal of the protecting groups optionally present, gives the compounds of formula (I) in which A is a -CO-CH2-NR2R3group. They on their turn give the other compounds of formula (I) by 2s red~ ~ction of the amidic moiety to amine.
~, olecti~/e groups for the primary and/or secondary amines optionally present in A' and/or B' which can advantageously be used for the preparation of co",pounds of formula (I) are represented by (C1-C3)acyl derivatives (~,rerer~bly acetyl derivatives), (C1-C4)alkoxycarbonyl derivatives (preferably tert-30 butoxycarbonyl derivatives) and by (C7-C10)aralkyloxycarbonyl derivatives (prerer~bly benzyloxycarbonyl derivatives).
The rea~;Lioi. of compounds (111) with the hydrazines (IV) can be performed by reacting compounds (111) with a stoichiometric amount of hydrazines (IV) or an CA 022263l0 l998-Ol-0~
excess of hydrazines (IV). The reaction is usually performed in an inert solventsuch as methylene chloride, chloroform, 1,1,1-trichloroethane, dimethoxyelht~"e,tetrahydrofuran, di,nethylsulfoxide, dimeth~,lrur,,,ta,,,ide, pyridine, picoline and mixtures thereof, or if it is desired, using compound (IV) itself as the solvent, 5 optionally in the presence of an inorganic base such as an alkaline or alkaline-earth carbonate or hydrogen carbonate or an organic base such as a trialkylamine, at a temperature from -20~C to the reflux temperature of the solvent. P, ererably, the reaction is carried out in a solvent such as di",~:ll"~lformamide, pyridine, tetrahydrofuran, dimethylsulfoxide or N,N,N',N'-o tetramethylethylenediamine, using 1 to 10 equivalents of compound (IV) for 1equivalent of compound (Ill) and working at a temperature ranging from 5~C to 50~C.
If necess~ry, the removal of the protective group for the primary and/or secondary amino functions is carried out following the procedures well known to 15 those skilled in the art. Useful teachings can be found in Green, T.W., Wuts,P.G.M., "Protective Groups in Organic Synthesis", second Edition, John Wiley &
Sons, 1991.
For example, the removal of the N-(tert-butoxycarbonyl) protective group can be performed by treatment of the compound with an excess of anhydrous or 20 aqueous hydrochloric acid in a solvent such as a (C,-C4)alkanol, dichloromethane, chloroform or mixtures thereof, at a temperature of 0~C to the reflux temperature of the solvent and for a time ranging from several minutes toa few hours. Preferably the reaction is performed in ethanol or in chloroform using from 10 to 20 molar equivalents of anhydrous hydrochloric acid at a 25 temperature of from 20~C to 50~C, and is generally complete in four hours.
The reaction of reduction of the nitro group of compounds (Il) to give compounds (lla) is performed by catalytic hydrogenation, treating in hydrogen t-~LIIIospl ,ere a compound (Il), in a suitable solvent such as glacial acetic acid, an alkanol such as methanol or ethanol, an ether such as 1,4-dioxane, 30 tetrahydrofuran or a solvent such as methylene chloride or chloroform, in thepresence of catalytic amounts (from 0.1 to 0.3 equivalents) of a catalyst such as 10% palladium on carbon, Nickel Raney or 10% platinum on carbon and at a pressure of from atmospheric pressure to 100 psi.
CA 02226310 1998-01-0~
P,ererably, the reaction is carried out in glacial acetic acid, using 10% p~ m on carbon as a catalyst and at a pressure of about 70 psi.
Alle" ,dLi~ely, the reduction of the nitro group of compounds (Il) to give co""~ounds (lla) may be pe, rO",.ed following other methods known in the art, s such as the use of FeSO4 in basic conditions (allllllonia or sodium hydluxi.le) or the use of metals or salts thereof, optionally in acidic co, Idiliol ,s. Suitable examples of such reducing agents are SnCI2, SnCI2 in the presence of hydrochloric acid or Zn in the presence of hydrochloric acid.
The alkylation of intermedi~tes (lla) with intermedi~t~s of formula L-A' to givel0 the compounds of formula (I) is performed by reacting the illler",ediate (lla) with a molar excess of the reactant of formula (V) in an inert solvent such as be"~ene, toluene, chlorobenzene and the like, or an alcohol such as isopropanol or in a nitrile such as acetonitrile, and in the presence of an inorganic base such as an alkaline or alkaline-earth carbonate or 15 hydrogencarbonate or an organic base such as trialkylamine. Preferably, the reaction is carried out in an aro",aLic solvent such as toluene, in the presence of potassium carbonate and at a temperature ranging from room temperature to the reflux temperature of the solvent.
The acylation reaction of intermediates (lla) with compounds of formula L-CO-A"
20 iS usually pelru""ed, when L is a OH group, in the presence of a cGndensin agent such as dicyclohexylcarbodiimide and the like, at a temperature ranging from -1 0~C to room temperature and in an inert solvent such as an ether (tetrahydrofuran, diethyl ether and the like).
The redl ~ction of amidic moiety into amine can be preferentially performed in an 25 inert solvent such as toluene or benzene, at a temperature ranging from room temperature to the reflux temperature of the solvent and in the presence of a reducing agent such as Red-AI, LiAlH4 or other suitable hydrides.
The intermediates (Ill) can be prepared by cyclization of the compounds of formula (Vl):
CA 02226310 1998-01-0~
Z T3~2H ~l (Vl) in which X, Y, Z, T and U are as above defined.
Said reaction can be performed using different methods known in the art, such 5 as for example:
i) transforming the carboxylic acid moiety into an acyl chloride by reaction with thionyl chloride, for example, and subsequently performing a Friedel-Craft reaction in the presence of a Lewis acid such as alluminum trichloride, in a suitable solvent such nitrobenzene and at a temperature ranging from -1 0~C to o 50~C;
ii) cyclizing the compounds (Vl) in the presence of fuming sulfuric acid (10-30% sulfur trioxide), at a temperature ranging from room temperature to 1 50~C;
iii) cyclizing the compounds (Vl) in the presence of polyphosphoric acid silyl ester (PPSE) and of phosphorus pentoxide, at a temperature ranging from 50~C
to 210~C.
The compounds of formula (Vl) can be obtained starting from the compounds of formula (Vlll):
z~T CO2H
Y~X~Q (Vlll) in which X, Y, Z and T are as above defined and Q is a chlorine atom or a diazo group -N2'CI-, by reaction with a compound of formula (Vll):
CA 022263l0 l998-Ol-0~
H'S~J (Vll) in which U is as above defined.
When X or Z are nitrogen, then Q is prererentially chlorine; when Y or T are 5 nitrogen, Q is preferentially a -N2+CI- group.
When Q is chlorine, the reaction is preferentially performed in a suitable solvent such as a ketone (acetone, methyl ethyl ketone and the like) and at a temperature ranging from room temperature to the boiling point of the solvent.
When Q is a -N2+CI- group, the compounds (Vlll) are prepared ain situ", following lO the methods known in the art, by reaction of the amine derivatives (IX):
z~T~C02H
~X NH2 with sodium nitrite in the presence of hydrochloric acid at a temperature ran~in~
15 from -10~C to 10~C. The compounds (Vlll) so prepared are then reacted withoutisolation with the compounds (Vll) at a temperature ranging from 0~C to 70~C, oblai"in~ the compounds of formula (Vl).
Alternatively, compounds (Vlll) in which Q is a -N2+CI- can be reacted without isolation with equimolar amounts of O-ethylxanthic acid, potassium salt. The 20 resulting interme~ es give compounds (Vl) by treatment with sodium elhoxide in ethanol and subsequently with 2,4-dichloronitrobenzene.
The con,pounds of formula (Vlll) when Q is a chlorine atom or the con,pounds of formula (IX) are commercial product or can be prepared starting from commercial product following methods known in the art, such as for example 25 those described in:
- Ross, W.C.J., J.C.S., C, 1816-21 (1966): synthesis of 4-chloro nicotinic acid;- Winn, M. et al., J. Med. Chem., 36, 2676-88 (1993);
CA 02226310 1998-01-0~
- Fibel, C.R. et al., J.A.C.S., 70, 3908 (1948): synthesis of 3-amino isonicotinic acid.
BIOLOGICAL EVALUATION OF THE COMPOUNDS OF THE INVENTION
The evaluation of the biological activity for the compounds of this invention was s performed ~in vitro" and uin vivo" following the protocols developed by the U.S.
National Cancer Institute.
The evaluation of the uin vitro" cytotoxic activity of the co"lpounds of the invention was performed using the following cell lines: a murine sarcon~a (S-180) and its subline expressing multidrug resistance (S-180/A-10), a leukemia (L1210), a human colon adenocarcinoma cell line (LoVo) isolated from a metaslalic nodule and its subline expressing multidrug resistance. This latter subline is resistant to a number of antitumor agents, among which are doxorubicin, VP-16 and vi"c, i~line. This subline (named LoVo/DX) shows red~ ~ced accumulation of doxorubicin and overexpression of a protein (Grandi, M., Geroni, C., Giuliani, F.C., British J. Cancer, (1986), 54, 515). The compounds were tested according to the MTT assay (Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay", J. Immunol. Methods, (1983), 65, 55~3; Green, L.M., "Rapid Colorimetric Assay for Cell Viability; Application to the Quantitation ofC~loloxic and Growth Inhibitory Lymphokines", J. Immunol. Methods, (1984), 70, 257-268) in cor"p~rison with mitoxd, lll u, ,e and doxorubicin.
The ~I ,a" "acological data for some representative compounds of the present invention are reported in Tables ll and lll. A co",parison with the prior art compound Cl941 and with doxorubicin and mitoxantrone is also provided in Table ll. The columns headed L1210, S180 LoVo and LoVo/Dx contain the IC50 values against said tumor cell lines, as above described.
In general, represer!lali~/e compounds of this invention exhibited a high cytotoxicity in all the cell lines tested. When mitoxantrone was tested in the LoVo/DX cell line, a resistance index Rl (defined as the ratio of the ICso for the resistance cell line to the IC50for the sensitive cell line) as high as 22.5 wasfound, showing that this subiine does have an acquired resistance to mitoxantrone. On the other hand, representative compounds of this invention, when tested in the same resistant subline, show no cross resistance with CA 022263l0 l998-Ol-0~
~iLuxd~ u~ ~e. The uin vitro" evaluation of representative compounds of this invention suggests that they are able to retain a high activity also in the resistant cell line, while the prior art compound C1-941 loses completely its activity.
Studies of the biological activity "in vivon of represe~ Li~e compounds of the invention were performed using the P388 murine leukemia model. P388 murine Ieukemia cells were intravenously (iv) i"j~cted in CD2F1 mice. Tredl",enl was initiated ap~l oxi")dlely 24 hours after tumor transpla,)L~liot) and dos~ges of the drug were administered iv (P388 iv/iv) according to preestablished prul(,cols, usually at 3-day intervals. The studies were done over a 60-day period and the o date of death for each animal was recorded. The % T/C was deler" ,ined usingthe mean survival time (MST) for each group accordil lg to the formula % T/C = [~MST treated) / (MST control)] x 100 Representative compounds of this invention were able to increase the survival time of treated animals, leading to high % T/C values at well tolerated d os~ges.
Since represenlative compounds of this invention show good results aga;. Isl this significant"in vivo" model of murine P388 leukemia, which is considered to be predictive of antitumor activity in humans, the compounds disclosed herein are expected to be operative against human leukemias and solid tumors sensitive to treatment with antitumor antibiotics.
The compounds of the invention may therefore be used as active ingredients of therapeutic co",posilions to induce regression and/or palliation of cancers in mammals when administered in amounts ranging from about 1 mg to about 0.4 9 per kilogram of body weight. A prefe, l~d 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 9 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 composition may be in the form of tablets, capsules, gel capsules, suppositories, Iyophilized powders and solutions for intravenous adminislralion.
CA 022263l0 l998-Ol-0~
The invention is illustrated by the following non-limiting examples and va, ialictr,s which are readily a~ r~nl to those skilled in the art.
EXPERIMENTAL PART
Preparation 1 - 2-(2-nitro-5-chloro)thioPhenoxvnicotinic acid (compound (Vl): X
5 = N) A solution of 2-nitro-5-chlorobenzenethiol (0.26 9) in acetone (2 ml) was added to 2-chloronicotinic acid (0.11 9). The suspension was refluxed for 5 hrs and the resultant mixture was cooled to room te"" eralure. The bright yellow preCirit~tewas collected by filtration, washed with acetone to yield a yellow solid (0.12 9), lO m.p. 248-249~C.
H NMR in d6-DMSO 8.39 ppm (dd, J = 1.7 Hz, 4.7 Hz,1 H); 8.27 ppm (dd, J =
1.7 Hz, 7.9 Hz,1H); 8.10 ppm (d, J = 8.7 Hz,1H); 7,85 ppm (d, J = 2.3 Hz,1H);
7.76 ppm (dd, J = 2.3 Hz, 8.7 Hz, 1 H); 7.30 ppm (dd, J = 4.7 Hz, 7.7 Hz,1 H).
Anal. Calcd. for C,2H7CIN2O4S: C 46.39, H 2.27, N 9.01. Found: C 46.39, H
2.27, N 8.80.
rt el~arctlion 2 - 6-chloro-9-nitro-5H-~1 lbenzothioPYrano~2.3:blPYridin-5-one (compound (Ill)~ X = N) Route 1 (with fuminq sulfuric acid) 0.645 9 of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid were added to 2 ml of 20 fuming sulfuric acid (18-24% sulfur trioxide) and the mixture was placed in an oil bath preheated to 75~C. The solution was heated at 125-130~C for 1.25 hrs. 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 with water and dried, to give 0.60 9 of a solid. This material was 25 dissolved in dimethyl formamide (DMF,11 ml) which on cooling immediately led to a yellow crystalline fluffy solid. This solid was collected by filtration andwashed with diethyl ether to remove residual DMF, yielding 0.54 9 of product, m.p. 267-270~C.
1H NMR in CDC13 8.84 ppm (dd, J = 1.77 Hz, J = 4.60 Hz,1 H); 8.60 ppm (dd, J
- 30 = 1.77 Hz, J = 8.05 Hz,1 H); 8.51 ppm (d, J = 8.80 Hz, 1 H); 7.68 ppm (d, J =
8.80 Hz,1H); 7.51 ppm (dd, J = 4.6 Hz, J = 8.00 Hz,1H).
Route 2 (with thionvl chloride/ alluminum trichloride) CA 022263l0 l998-Ol-0~
A mixture of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (5 9), toluene (27 ml) and thionyl chloride (6 ml) was heated at reflux for 1.5 hrs. Upon cooling, the acid chloride se~,araled as yellow needles. The resultant mixture was co,-ce, lll ~led 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 hrs. Alluminum chloride (2 9) was slowly added while keeping the tel "pel alure below 35~C. The mixture darkened and it was stirred at room temperature for 20 hrs. The dark black suspension was poured into ice water (130 ml) and the mixture was stirred for 1 hr. The aqueous layer was removed by deca"lalion, methanol (100 ml) was added to the nitrobenzene and the resultant solid was collected by filtration. Addition of methanol (200 ml) to the fiitrate led to additional product, total weight 3.1 9. For purification, the crude material was recrystallized from ethylene glycol monoethyl ether to yield a yellow fluffy solid, m.p. 265-270~C, identical in its 1H-NMR spectrum to the product obtained following route 1.
Route 3 (with PolvphosPhoric acid silvl ester PPSE) A mixture of PPSE (2 9) and phosphorus pentoxide (0.25 9) was heated in an oil bath to 210~C. 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (0.10 9) 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 filtration and dried to give 0.085 9 of a solid. The crude material was heated in ethyl ~cet~te and filtered while hot to remove some brownish insoluble material. Removal of the solvent led to product (0.045 9) identical to that prepared following routes 1 and 2.
PreParation 3 - 3-(2-nitro-5-chlorothioPhenoxv)isonicotinic acid (comPound (Vl).Y= N) A solution of 3-amino-4-carboxypyridine (1.4 9), sodium nitrite (0.81 9) and ~9ueo~ ~s sodium hydroxide 2.9 M (13.3 ml) was added to a solution of a~ueous hydrochloric acid 4.3 M (9.8 ml) while the temperature was maintained at 0-5~C.
The mixture was stirred for 10 minutes and then added dropwise over the course of 2 hrs to a stirred mixture of 5-chloro-2-nitrothiophenol (2.34 9) and CA 022263l0 l998-Ol-0~
sodium hydroxide (2.63 9) in water (21 ml) ,nainlained at about 53~C (a brisk nitrogen evolution occurred). The mixture was stirred for 15 minutes, cooled to room temperature and filtered. The fltrate was made strongly acidic (pH = 2) with hydrochloric acid 12 M and the precipitated solid was collected by rillldlio"
and dried to yield a brownish-orange solid (3 9). The solid was washed with dichloromethane:acetonitrile (30 ml) and dried to leave crude product (1.2 9).
Cryst~ tion from ethyl cellosolve led to the pure product, m.p. 280-281 ~C.
'H NMR in d6-DMSO 8.77 ppm (d, J = 4.8 Hz,1 H); 8.67 ppm (s, 1 H), 8.23 ppm (d, J = 8.8 Hz,1 H); 7.77 ppm (d, J = 4.8 Hz,1 H); 7.56 ppm (dd, J = 8.8 Hz, J =o 2.2 Hz,1H); 6.99 ppm (d, J = 2.1 Hz, 1H).
PreParation 4 - 6-chloro-9-nitro-5H-r11benzothioPvranor2.3-clPvridin-5-one (co" "~ound (Ill) Y = N) A mixture of the compound of the preparation 3 (0.45 9) and thionyl chloride (2.5 ml) was heated at reflux for 1.5 hrs. The mixture changed to a dark reddish coloralion. The mixture was conce"l, ~Led to dryness by distillation to yield a dark red amber solid. Nitrobenzene (3.5 ml) was added and the suspension was cooled in an ice bath for 0.5 hrs. Alluminum chloride (1.02 9) was added slowly and the dark mixture was allowed to warm to room temperature and then stirred at 80-90~C for 15 hrs. The dark suspension was poured over crushed ice (25 ml) and the mixture was stirred for 1 hr. The aqueous layer was decanted and methanol (25 ml) was added to the nitrobenzene layer. The resultant solid was collected by filtration to yield crude product (300 mg) as a dark grey solid. The solid was boiled with chloroform (75 ml) and filtered to remove some insoluble material. Conce, ll,alion of the filtrate led to the pure product (75 mg).
1H NMR in CDCI3 9.02 ppm (s,1H); 8.79 ppm (d, J = 5.2 Hz,1H); 8.54 ppm (d, J = 8.8 Hz,1H); 8.09 ppm (d, J - 5.2 Hz,1H); 7.70 ppm (d, ~ = 8.8 Hz,1H).
PreParation 5 - 4-t2-nitro-5-chloro)thioPhenoxv nicotinic acid fcomPound (Vl), Z= N) A solution of 2-nitro-5-chlorothiophenol (1.09 9) in acetone (12 ml) was added to 4-chloru"icc,li,lic acid (0.85 g). The yellow coloration of the thiol quickly disappeared and the mixture was refluxed for 1 hr. Upon cooling to room temperature, the product was filtered and washed with acetone to yield the titlecompound as pale yellow solid (1.72 9), m.p. 228-229~C.
CA 022263l0 l998-Ol-0~
H NMR in d6-DMSO 9.05 ppm (s,1H); 8.50 ppm (d, J = 5.9 Hz,1H); 8.23 ppm (d, ~I = 8.7 Hz,1H); 7.98 ppm (d, J = 2 Hz, 1H); 7.92 ppm (dd, J = 8.7 Hz, J = 2.2 Hz, 1H);6.98ppm(d,J=5.9Hz,1H).
Pl e~dralion 6 - 6-nitro9-chloro-10H-r11benzothioPvranor2.3-clPYridin-1 o-one 5 (co",~ound (Ill). Z = N) Thiophenoxynicotinic acid (0.50 9, preparation 5) was added to fuming sulfuric acid (18-24% sulfur trioxide, 3 ml) and the mixture was placed in an oil bath which was preheated to 40~C. The dark reddish amber solution was heated to 60 ~C during 10 minutes and kept at this temperature for 20 minutes. The cooled l0 mixture was poured over ice-water (25 ml) and neutralized with solid sodium bicarbonate. The resultant bright yellow solid was collected by filtration and dried, obtaining 0.38 9 of crude product. The solid was boiled in chlororcr", (40 ml) and filtered to remove some starting material. Concentration of the filtrateled to the pure product (0.33 g), m.p. 220-222~C.
'H NMR in CDC13 9.43 ppm (s,1 H); 8.74 ppm (d, J = 5.5 Hz,1 H); 8.50 ppm (d, J = 8.8 Hz,1H); 7.70 ppm (d, J = 8.8 Hz,1H); 7.51 ppm (d, J = 5.5 Hz,1H).
F'r~aralion 7 - N'-r2-(2-dimethYlamino)ethY11-5-t2'-(N-tertbutoxvcarbonYl)amino acetvlamino)-2H-pYridor3~.2~:5.6lthiopyranor4~3~2-cdlindazole 20 Dicyclohexylcarbodiimide (210 mg) was slowly added to a ll,ag,)elically stirred solution of N,N-dimethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]inda~ole-2-ethanamine (300 mg) of example 2 and N-BOC-glycine (168 mg) in dry tetrahydrofuran (8 ml) at 0~C. The mixture was stirred at 0-5 ~C for 20 hr and the cyclohexylurea which precipitated was removed by filtration. The filtrate 25 was refrigerated overnight and additional urea was removed by filtration. Thefiltrate was concentrated to dryness by rotary evaporation and the brownish red solid was collected (434 mg). This material was recrystallized from acetonitrile/chloroform 4:1 to give the product as a yellow solid (240 mg).
Purification was best accomplished by column chromatography over silica gel 30 using gradient elution by ethyl acetate: methanol as eluent, commencing with 5:1 and gradually changing to 1:1. Removal of the eluents led to the purified product (120 mg, m p.173-175 ~C).
CA 02226310 1998-01-0~
WO 97!02267 PCTIUS96/10966 'H-NMR in CDCI3 8.34 ppm (dd, J = 1.7 Hz, 4.7 Hz,1H); 8.23 ppm (dd, J = 1.7 Hz, 7.8 Hz,1H); 7.60 ppm (broad s, 1H); 7.49 ppm (d, J = 8.7 Hz,1H); 7.15 ppm (m, J = 4.7, 7.8 Hz,1 H); 6.97 ppm (d, J = 8.8 Hz,1 H); 5.21 ppm (broad d,1 H);
4.39ppm(t,J=6.9Hz,2H);4.00ppm(d,J=6.0Hz,2H);2.82ppm(t,J=8.9 Hz, 2H); 2.33 ppm (s, 6H); 1.49 ppm (s, 9H).
P,e~aralion 8 - N'-r2-(2-dimethYlamino)ethvll-5-(2'-(N-tertbutox~ca,bon~rl)amino acetvlamino)-2H-Pvridor3l~4~:5~6lthiopvrano~4~3~2-cdlindazole ACCGId;l~g to the procedure described in preparation 7, the title compound was prepdred.
'H-NMR in CDCI3 9.17 ppm (s,1H); 8.31 ppm (d, J = 5.4 Hz,1H); 7.70 ppm (broad s,1H); 7.40 ppm (d, J = 8.8 Hz,1 H); 7.73 ppm (d, J = 5.4 Hz,1H); 7.00 ppm (d, J = 8.8 Hz,1 H); 5.21 ppm (broad s, 1 H); 4.40 ppm (t, J = 6.9 Hz, 2H);
rt el~arctlion 2 - 6-chloro-9-nitro-5H-~1 lbenzothioPYrano~2.3:blPYridin-5-one (compound (Ill)~ X = N) Route 1 (with fuminq sulfuric acid) 0.645 9 of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid were added to 2 ml of 20 fuming sulfuric acid (18-24% sulfur trioxide) and the mixture was placed in an oil bath preheated to 75~C. The solution was heated at 125-130~C for 1.25 hrs. 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 with water and dried, to give 0.60 9 of a solid. This material was 25 dissolved in dimethyl formamide (DMF,11 ml) which on cooling immediately led to a yellow crystalline fluffy solid. This solid was collected by filtration andwashed with diethyl ether to remove residual DMF, yielding 0.54 9 of product, m.p. 267-270~C.
1H NMR in CDC13 8.84 ppm (dd, J = 1.77 Hz, J = 4.60 Hz,1 H); 8.60 ppm (dd, J
- 30 = 1.77 Hz, J = 8.05 Hz,1 H); 8.51 ppm (d, J = 8.80 Hz, 1 H); 7.68 ppm (d, J =
8.80 Hz,1H); 7.51 ppm (dd, J = 4.6 Hz, J = 8.00 Hz,1H).
Route 2 (with thionvl chloride/ alluminum trichloride) CA 022263l0 l998-Ol-0~
A mixture of 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (5 9), toluene (27 ml) and thionyl chloride (6 ml) was heated at reflux for 1.5 hrs. Upon cooling, the acid chloride se~,araled as yellow needles. The resultant mixture was co,-ce, lll ~led 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 hrs. Alluminum chloride (2 9) was slowly added while keeping the tel "pel alure below 35~C. The mixture darkened and it was stirred at room temperature for 20 hrs. The dark black suspension was poured into ice water (130 ml) and the mixture was stirred for 1 hr. The aqueous layer was removed by deca"lalion, methanol (100 ml) was added to the nitrobenzene and the resultant solid was collected by filtration. Addition of methanol (200 ml) to the fiitrate led to additional product, total weight 3.1 9. For purification, the crude material was recrystallized from ethylene glycol monoethyl ether to yield a yellow fluffy solid, m.p. 265-270~C, identical in its 1H-NMR spectrum to the product obtained following route 1.
Route 3 (with PolvphosPhoric acid silvl ester PPSE) A mixture of PPSE (2 9) and phosphorus pentoxide (0.25 9) was heated in an oil bath to 210~C. 2-(2-nitro-5-chloro)thiophenoxynicotinic acid (0.10 9) 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 filtration and dried to give 0.085 9 of a solid. The crude material was heated in ethyl ~cet~te and filtered while hot to remove some brownish insoluble material. Removal of the solvent led to product (0.045 9) identical to that prepared following routes 1 and 2.
PreParation 3 - 3-(2-nitro-5-chlorothioPhenoxv)isonicotinic acid (comPound (Vl).Y= N) A solution of 3-amino-4-carboxypyridine (1.4 9), sodium nitrite (0.81 9) and ~9ueo~ ~s sodium hydroxide 2.9 M (13.3 ml) was added to a solution of a~ueous hydrochloric acid 4.3 M (9.8 ml) while the temperature was maintained at 0-5~C.
The mixture was stirred for 10 minutes and then added dropwise over the course of 2 hrs to a stirred mixture of 5-chloro-2-nitrothiophenol (2.34 9) and CA 022263l0 l998-Ol-0~
sodium hydroxide (2.63 9) in water (21 ml) ,nainlained at about 53~C (a brisk nitrogen evolution occurred). The mixture was stirred for 15 minutes, cooled to room temperature and filtered. The fltrate was made strongly acidic (pH = 2) with hydrochloric acid 12 M and the precipitated solid was collected by rillldlio"
and dried to yield a brownish-orange solid (3 9). The solid was washed with dichloromethane:acetonitrile (30 ml) and dried to leave crude product (1.2 9).
Cryst~ tion from ethyl cellosolve led to the pure product, m.p. 280-281 ~C.
'H NMR in d6-DMSO 8.77 ppm (d, J = 4.8 Hz,1 H); 8.67 ppm (s, 1 H), 8.23 ppm (d, J = 8.8 Hz,1 H); 7.77 ppm (d, J = 4.8 Hz,1 H); 7.56 ppm (dd, J = 8.8 Hz, J =o 2.2 Hz,1H); 6.99 ppm (d, J = 2.1 Hz, 1H).
PreParation 4 - 6-chloro-9-nitro-5H-r11benzothioPvranor2.3-clPvridin-5-one (co" "~ound (Ill) Y = N) A mixture of the compound of the preparation 3 (0.45 9) and thionyl chloride (2.5 ml) was heated at reflux for 1.5 hrs. The mixture changed to a dark reddish coloralion. The mixture was conce"l, ~Led to dryness by distillation to yield a dark red amber solid. Nitrobenzene (3.5 ml) was added and the suspension was cooled in an ice bath for 0.5 hrs. Alluminum chloride (1.02 9) was added slowly and the dark mixture was allowed to warm to room temperature and then stirred at 80-90~C for 15 hrs. The dark suspension was poured over crushed ice (25 ml) and the mixture was stirred for 1 hr. The aqueous layer was decanted and methanol (25 ml) was added to the nitrobenzene layer. The resultant solid was collected by filtration to yield crude product (300 mg) as a dark grey solid. The solid was boiled with chloroform (75 ml) and filtered to remove some insoluble material. Conce, ll,alion of the filtrate led to the pure product (75 mg).
1H NMR in CDCI3 9.02 ppm (s,1H); 8.79 ppm (d, J = 5.2 Hz,1H); 8.54 ppm (d, J = 8.8 Hz,1H); 8.09 ppm (d, J - 5.2 Hz,1H); 7.70 ppm (d, ~ = 8.8 Hz,1H).
PreParation 5 - 4-t2-nitro-5-chloro)thioPhenoxv nicotinic acid fcomPound (Vl), Z= N) A solution of 2-nitro-5-chlorothiophenol (1.09 9) in acetone (12 ml) was added to 4-chloru"icc,li,lic acid (0.85 g). The yellow coloration of the thiol quickly disappeared and the mixture was refluxed for 1 hr. Upon cooling to room temperature, the product was filtered and washed with acetone to yield the titlecompound as pale yellow solid (1.72 9), m.p. 228-229~C.
CA 022263l0 l998-Ol-0~
H NMR in d6-DMSO 9.05 ppm (s,1H); 8.50 ppm (d, J = 5.9 Hz,1H); 8.23 ppm (d, ~I = 8.7 Hz,1H); 7.98 ppm (d, J = 2 Hz, 1H); 7.92 ppm (dd, J = 8.7 Hz, J = 2.2 Hz, 1H);6.98ppm(d,J=5.9Hz,1H).
Pl e~dralion 6 - 6-nitro9-chloro-10H-r11benzothioPvranor2.3-clPYridin-1 o-one 5 (co",~ound (Ill). Z = N) Thiophenoxynicotinic acid (0.50 9, preparation 5) was added to fuming sulfuric acid (18-24% sulfur trioxide, 3 ml) and the mixture was placed in an oil bath which was preheated to 40~C. The dark reddish amber solution was heated to 60 ~C during 10 minutes and kept at this temperature for 20 minutes. The cooled l0 mixture was poured over ice-water (25 ml) and neutralized with solid sodium bicarbonate. The resultant bright yellow solid was collected by filtration and dried, obtaining 0.38 9 of crude product. The solid was boiled in chlororcr", (40 ml) and filtered to remove some starting material. Concentration of the filtrateled to the pure product (0.33 g), m.p. 220-222~C.
'H NMR in CDC13 9.43 ppm (s,1 H); 8.74 ppm (d, J = 5.5 Hz,1 H); 8.50 ppm (d, J = 8.8 Hz,1H); 7.70 ppm (d, J = 8.8 Hz,1H); 7.51 ppm (d, J = 5.5 Hz,1H).
F'r~aralion 7 - N'-r2-(2-dimethYlamino)ethY11-5-t2'-(N-tertbutoxvcarbonYl)amino acetvlamino)-2H-pYridor3~.2~:5.6lthiopyranor4~3~2-cdlindazole 20 Dicyclohexylcarbodiimide (210 mg) was slowly added to a ll,ag,)elically stirred solution of N,N-dimethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]inda~ole-2-ethanamine (300 mg) of example 2 and N-BOC-glycine (168 mg) in dry tetrahydrofuran (8 ml) at 0~C. The mixture was stirred at 0-5 ~C for 20 hr and the cyclohexylurea which precipitated was removed by filtration. The filtrate 25 was refrigerated overnight and additional urea was removed by filtration. Thefiltrate was concentrated to dryness by rotary evaporation and the brownish red solid was collected (434 mg). This material was recrystallized from acetonitrile/chloroform 4:1 to give the product as a yellow solid (240 mg).
Purification was best accomplished by column chromatography over silica gel 30 using gradient elution by ethyl acetate: methanol as eluent, commencing with 5:1 and gradually changing to 1:1. Removal of the eluents led to the purified product (120 mg, m p.173-175 ~C).
CA 02226310 1998-01-0~
WO 97!02267 PCTIUS96/10966 'H-NMR in CDCI3 8.34 ppm (dd, J = 1.7 Hz, 4.7 Hz,1H); 8.23 ppm (dd, J = 1.7 Hz, 7.8 Hz,1H); 7.60 ppm (broad s, 1H); 7.49 ppm (d, J = 8.7 Hz,1H); 7.15 ppm (m, J = 4.7, 7.8 Hz,1 H); 6.97 ppm (d, J = 8.8 Hz,1 H); 5.21 ppm (broad d,1 H);
4.39ppm(t,J=6.9Hz,2H);4.00ppm(d,J=6.0Hz,2H);2.82ppm(t,J=8.9 Hz, 2H); 2.33 ppm (s, 6H); 1.49 ppm (s, 9H).
P,e~aralion 8 - N'-r2-(2-dimethYlamino)ethvll-5-(2'-(N-tertbutox~ca,bon~rl)amino acetvlamino)-2H-Pvridor3l~4~:5~6lthiopvrano~4~3~2-cdlindazole ACCGId;l~g to the procedure described in preparation 7, the title compound was prepdred.
'H-NMR in CDCI3 9.17 ppm (s,1H); 8.31 ppm (d, J = 5.4 Hz,1H); 7.70 ppm (broad s,1H); 7.40 ppm (d, J = 8.8 Hz,1 H); 7.73 ppm (d, J = 5.4 Hz,1H); 7.00 ppm (d, J = 8.8 Hz,1 H); 5.21 ppm (broad s, 1 H); 4.40 ppm (t, J = 6.9 Hz, 2H);
3.99 ppm (d, J = 6.0 Hz, 2H); 2.84 ppm (t, J = 6.9 Hz, 2H); 2.33 ppm (s, 6H);
1.48 ppm (s, 9H).
ExamPIe 1 - N,N-dimethVl-5-nitro-2H-Pyridor3~2~:5~6lthiopyranor4~3~2 cdlindazole-2-ethanamine (X = N) A suspension of 6-chloro-9-nitro-5H-[1]benzothiopyrano[2,3:b]pyridine-5-one (2.5 9) in DMF (25 ml) under a nitrogen blanket was cooled in an ice bath and N-(2-d;"~ell "~laminoethyl) hydrazine (1 9) was added dropwise. The coloration changed from yellow to bright orange. The suspension was stirred for 15 hrs at room temperature and the mixture was quenched over ice-water. The pH was adjusted to 10.5-11 by addition of a saturated solution of potassium carbonate.
The resultant mixture was extracted with chloroform (2x100 ml) and the chlororurm layer was washed with cold water (150 ml) and then with brine (2x150 ml). The chloroform was dried over magnesium sulfate, the drying agent removed by filtration and the filtrate concentrated to yield the product as a golden brown solid (2.5 9). This material crystallized readily from acetonitrile, m.p.173-174~C.
- 30 1H NMR in CDCI3 8.55 ppm (dd, J = 1.4 Hz, J = 4.6 Hz,1 H); 8.41 ppm (dd, J =
1.4 Hz, J = 7.9 Hz,1 H); 8.23 ppm (d, J = 9.2 Hz,1 H); 7.33 ppm (dd, J = 4.6 Hz,J = 7.8 Hz,1 H); 7.05 ppm (d, J = 9.2 Hz,1 H); 4.48 ppm (t, J = 6.6 Hz, 2H); 2.88 ppm ( t, J = 6.6 Hz, 2H); 2.30 ppm (s, 6H).
ExamPIe 2 - N,N-dimethyl-5-amino-2H-pyridor3',2':5,61thiopvranor4.3.2-cdlindazole-2-ethanamine (X = N) A mixture of the nitro analogue of example 1 (2.12 9) and 10% palladium/C
(0.35 9) in glacial acetic acid (38 ml) was placed in a Parr bomb and 5 hyd, oS~e, Idled for 18 hrs at about 100 psi. The mixture was filtered through celite and co,)cel-l,aled to yield a dark amber oil which was dissolved in chlorc,ru,.., (200 ml). This solution was washed with 5% aqueous a",monium hydlwdcle (200 ml), water (200 ml) and brine (2x200 ml). The chlolorur", layerwas dried over sodium sulfate, the drying agent removed by filtration and the filtrate co"ce"lraled to yield the product as a bright reddish-yellow solid (1.7 9). Thiswas crystallized from acetonitrile to yield pure product (1.1 9), m.p. 184-186~C.
'H NMR in CDCI3 8.28 ppm (dd, J = 1.6 Hz, J = 4.7 Hz, 1H); 8.16 ppm (dd, J =
1,6Hz,J=7.8Hz, 1H);7.10ppm(dd,J=4.7Hz,~l=7.8Hz, 1H);6.86ppm(d, J = 8.6 Hz, 1H); 6.78 ppm (d, J = 8.6 Hz, 1H); 4.35 ppm (t, J = 7.1 Hz, 2H); 3.39 ppm (s, 2H); 2.81 ppm (t, 7.1 Hz, 2H); 2.24 ppm (s, 6H).
Analogously, starting from the appropriate intermediate (example 3) the following compound was prepared (Y = N):
N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, 'H NMR in CDCI3 8.46 ppm (s, 1H); 8.34 ppm (d, J = 5.2 Hz, 1H); 7.76 ppm (d, J = 5.2 Hz, 1H); 6.88 ppm (d, J = 6.5 Hz, 1H); 6.80 ppm (d, J = 8.7 Hz, 1H); 4.37 ppm (t, 2H); 3.38 ppm (br s, 2H); 2.83 ppm (t, 2H); 2.31 ppm (s, 6H).
ExamPle 3 - N.N-dimethvl-5-nitro-2H-Pvridor4'.3':5.61thioPvranor4.3,2-cdlindazole-2-ethanamine (Y = N) A suspension of the compound of preparation 4 (0.10 9) in DMF (0.8 ml) under a nitrogen blanket was cooled in an ice bath and N-(2-dimethylaminoethyl)hydrazine (0.043 9) was added dropwise. The colour changed to bright orange and the suspension was allowed to stir at room temperature for 12 hrs. The mixture was quenched over ice water and basified with ~ueo~ ~s sodium bicarbonate. The resultant solid was collected by filtration and dried to yield the pure product (0.035 9), m.p. 205-206~C.
CA 022263l0 l998-Ol-0~
'H NMR in CDCI3 8.83 ppm (s, 1H); 8.59 ppm (d, J = 5.2 Hz, 1H); 8.30 ppm (d, J = 9.3 Hz, 1H); 8.10 ppm (d, J = 5.1 Hz, 1H); 7.11 ppm (d, J = 9.2 Hz, 1H); 4.52 ppm (t, J = 6.5 Hz, 2H); 2.90 ppm (t, J = 6.5 Hz, 2H), 2.31 ppm (s, 6H).
ExamPle 4 - N,N-d;.,leU,~/1-5-nitro-2H-Pvridor3'.4':5.61thioPYrano~4~3.2 s cdlindazole-2-ethanamine (Z = N) N-(2~i~"elh~/laminoethyl)hydrazine (25 mg) was added to a suspension of the co""~ound of ,ur~paralion 6 (60 mg) in DMF (0.5 ml). The resultant orange suspension was allowed to stir for 15 hrs at room temperature. The mixture was added to cold water (5 ml) and treated with aqueous sodium bicarbonate. The o orange solid was collected by filtration, washed thoroughly with water and dried to yield 57 mg of the product. The sample was recrystallized from aceto"il. ile.m.p. 214-215~C.
'H NMR in CDCI3 9.40 ppm (s, 1H); 8.52 ppm (d, J = 5.5 Hz, 1H); 8.27 ppm (d, J=9.3Hz, 1H);7.46ppm(d,J=5.6Hz, 1H);7.12ppm(d,J=9.3Hz, 1H);4.51 ppm (t, J = 6.5 Hz, 2H); 2.91 ppm (t, J = 6.5 Hz, 2H); 2.27 ppm (s, 6H).
Example 5 - N.N-dimethvl-5-amino-2H-Pvridor3'.4':5.61thioPvranor4.3.2-cdlinda,ole-2-ethanamine (Z = N) A mixture of the compound of example 4 (0.25 g) and 10% palladium/C (0.042 g) in glacial acetic acid (4.5 ml) was placed in a Parr bomb and hydroye"dled 20 for 18 hrs at about 70 psi pressure. The mixture was concentrated to dryness,diluted with 5% a~ueous ammonium hydroxide:chloroform (1:1 ) and then filtered over celite. The chloroform layer was separated from the filtrate and washed with water and brine. The chlororor", was removed by rotary evaporation to yieldthe product (0.15 9).
25 1H NMR in CDCI3 9.10 ppm (s, 1H); 8.25 ppm (d, J = 5.4 Hz, 1H); 7.12 ppm (d, J = 5.4 Hz, 1 H); 6.88 ppm (d, J = 8.7 Hz, 1 H); 6.78 ppm (d, J = 8.7 Hz, 1 H); 4.35 ppm (t, J = 7.0 Hz, 2H); 3.34 ppm (br s, 2H); 2.82 ppm (t, J = 7.0 Hz, 2H); 2.30ppm (s, 6H).
ExamPle 6 - N'-r2-r2-(dimethvlamino)ethYI1-2H-PYridor3~2~:5~6lthiopyranor4~3~2 - 30 cdlindd,ol-5-yll-N,N-dimethvl-1,2-ethanediamine (X = N) A mixture of the amino analogue of preparation 4 (0.50 g), 2-(climell"~lamino)ethyl bromide hyd,oL,ro"~ide (0.98 g) and potassium carbonate (1.37 g) in toluene (15 ml) was refluxed for 15 hrs. The mixture was cooled and CA 022263l0 l998-Ol-0~
the residue which was collected by filtration was triturated with hot acetor,il, ile.
The insoluble material was removed by filtration through a celite bed. The filtrate was concenl,a~ed to 15 ml and allowed to stand overnight. The productwas collected by filtration as a golden brown material (0.36 9). This crude ,nalerial 5 was dissolved in hot acetonitrile (10 ml), cooled to room teri"~er~Lure and placed in the refrigeralor overnight. The product as golden brown needles was collected byfiltration (0.26 9), m.p. 110-111~C.
~HNMRinCDCI3 8.27ppm(dd,J=1.6Hz,J=4.7Hz, 1H);8.16ppm(dd,J=
1.6 Hz, J = 7.7 Hz, 1 H); 7.09 ppm (dd, J = 4.7 Hz, J = 7.7 Hz, 1 H); 6.92 ppm (d, J = 8.7 Hz, 1H); 6.87 ppm (d, J = 7.1 Hz, 1H); 4.37 ppm (t, J = 7.0 Hz, 2H); 3.25 ppm(t,J=5.9Hz,2H);2.83ppm(t,J=7.0Hz,2H);2.60ppm(t,J=5.9Hz, 2H); 2.32 ppm (s, 6H); 2.34 ppm (s, 6H).
ExamPle 7 - N'-r2-r2-(dimethvlamino)ethYI1-2H-Pvridor3',2':5.61thioPvrarlor4.3.2cdlindazol-5-vll-1.2-ethanediamine (X = N) A commercial Red-AI solution (3.4 M in toluene, 0.6 ml) was added dropwise over a period o~ 3 minutes to a stirred suspension of the compound of the ~,,eparalion 12 (100 mg) in toluene (1 ml) held at 70 ~C. The resultant bright red solution was heated for an additional 5 hrs at 70-75 ~C, cooled to room temperature and treated cautiously with a saturated aqueous al~mo~ ~ium chloride solution. The yellow suspension was diluted with dichloromethane (3 ml) and the mixture was filtered through a celite bed. The organic layer was dried over magnesium sulfate and conce, ILI a~ed to yield the crude product (100mg). This material was purified by column chromatography over silica gel elutingsequentially with 2, 4, 8, 10 and 20 % methanol in dichloromethane. The center eluents were concentrated to yield the product as a yellow solid (50 mg, m.p.
77-80 ~C).
H-NMR in CDCI3 8.29 ppm (dd, J = 1.7, 4.7 Hz,1H); 8.17 ppm (dd, J = 1.7, 7.8 Hz, 1 H); 7.11 ppm (m, J = 4.7, 7.8 Hz, 1 H); 6.91 ppm (m, J = 8.8, 8.8 Hz, 2H);4.86 ppm (broad s, 1 H); 4.36 ppm (t, J = 7.0 Hz, 2H); 3.36 ppm (broad s, 4H);
2.82 ppm (t, J = 6.9 Hz, 2H); 2.32 ppm (s, 6H); 1.48 ppm (s, 9H).
Dry hydrogen chloride was briefly p~ssed through a solution of the title con"~ound (50 mg) in chloroform (0.5 ml). Upon removal of the chloroform, the hydrochloride salt of the product was obtained as an orange solid (43 mg).
CA 02226310 1998-01-0~
H-NMR in D20 8.23 ppm (dd, J = 1.4, 4.8 Hz, ~ H); 8.09 ppm (dd, J = 1.4, 7.8 Hz, 1H); 7.26 ppm (m, J = 4.9, 7.8 Hz, 1H); 7.13 ppm (d, J = 8.8 Hz, 1H); 7.08 ppm (d, J = 8.8 Hz, 1 H); 4.71 ppm (t, J = 5.9 Hz, 2H); 3.79 ppm (t, J = 5.9 Hz,2H); 3.59 ppm (t, J = 6.2 Hz, 2H); 3.34 ppm (t, J = 6.2 Hz, 2H); 3.05 ppm (s, 6H).
ExamPle 8 - N'-r2-r2-(dil"etl)~/lamino)ethvl-2H-Pvridor3'.4':5,61thiopvranor4,3,2-cdlindazol-5-vll-1,2-ethanediamine (Z = N) Accûr~ling to the procedure of example 7, starting from the intermediate of preparation 8, the title compound as hydrochloride salt is prepared.
1H-NMR in D2O 9.01 ppm (s, 1H); 8.39 ppm (d, J = 6.5 Hz, 1H); 7.90 ppm (d, J
= 6.5 Hz, 1 H); 7.39 ppm (d, J = 8.9 Hz, 1 H); 7.27 ppm (d, J = 8.9 Hz, 1 H); 4.86 ppm(t,J=5.9Hz,2H);3.88ppm(t,J=5.8Hz,2H);3.62ppm(t,J=6.2Hz, 2H); 3.36 ppm (t, J = 6.2 Hz, 2H); 3.09 ppm (s, 6H).
ExamPle 9 - coml,ounds (I) Following the methods described in example 6 or in example 7, starting from the a~propriate amine analogues obtained according to example 5 and from the a,c,prupriate aminoalkyl halide (method of example 6) or alternatively from aminoacids or derivative thereof (method of example 7), the following cG,~"~ounds of formula (I) are prepared:
(1) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-di",ell"~1-1,2-ethanediamine;
(2) N'-[2-~2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]in-ld~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(3) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
1.48 ppm (s, 9H).
ExamPIe 1 - N,N-dimethVl-5-nitro-2H-Pyridor3~2~:5~6lthiopyranor4~3~2 cdlindazole-2-ethanamine (X = N) A suspension of 6-chloro-9-nitro-5H-[1]benzothiopyrano[2,3:b]pyridine-5-one (2.5 9) in DMF (25 ml) under a nitrogen blanket was cooled in an ice bath and N-(2-d;"~ell "~laminoethyl) hydrazine (1 9) was added dropwise. The coloration changed from yellow to bright orange. The suspension was stirred for 15 hrs at room temperature and the mixture was quenched over ice-water. The pH was adjusted to 10.5-11 by addition of a saturated solution of potassium carbonate.
The resultant mixture was extracted with chloroform (2x100 ml) and the chlororurm layer was washed with cold water (150 ml) and then with brine (2x150 ml). The chloroform was dried over magnesium sulfate, the drying agent removed by filtration and the filtrate concentrated to yield the product as a golden brown solid (2.5 9). This material crystallized readily from acetonitrile, m.p.173-174~C.
- 30 1H NMR in CDCI3 8.55 ppm (dd, J = 1.4 Hz, J = 4.6 Hz,1 H); 8.41 ppm (dd, J =
1.4 Hz, J = 7.9 Hz,1 H); 8.23 ppm (d, J = 9.2 Hz,1 H); 7.33 ppm (dd, J = 4.6 Hz,J = 7.8 Hz,1 H); 7.05 ppm (d, J = 9.2 Hz,1 H); 4.48 ppm (t, J = 6.6 Hz, 2H); 2.88 ppm ( t, J = 6.6 Hz, 2H); 2.30 ppm (s, 6H).
ExamPIe 2 - N,N-dimethyl-5-amino-2H-pyridor3',2':5,61thiopvranor4.3.2-cdlindazole-2-ethanamine (X = N) A mixture of the nitro analogue of example 1 (2.12 9) and 10% palladium/C
(0.35 9) in glacial acetic acid (38 ml) was placed in a Parr bomb and 5 hyd, oS~e, Idled for 18 hrs at about 100 psi. The mixture was filtered through celite and co,)cel-l,aled to yield a dark amber oil which was dissolved in chlorc,ru,.., (200 ml). This solution was washed with 5% aqueous a",monium hydlwdcle (200 ml), water (200 ml) and brine (2x200 ml). The chlolorur", layerwas dried over sodium sulfate, the drying agent removed by filtration and the filtrate co"ce"lraled to yield the product as a bright reddish-yellow solid (1.7 9). Thiswas crystallized from acetonitrile to yield pure product (1.1 9), m.p. 184-186~C.
'H NMR in CDCI3 8.28 ppm (dd, J = 1.6 Hz, J = 4.7 Hz, 1H); 8.16 ppm (dd, J =
1,6Hz,J=7.8Hz, 1H);7.10ppm(dd,J=4.7Hz,~l=7.8Hz, 1H);6.86ppm(d, J = 8.6 Hz, 1H); 6.78 ppm (d, J = 8.6 Hz, 1H); 4.35 ppm (t, J = 7.1 Hz, 2H); 3.39 ppm (s, 2H); 2.81 ppm (t, 7.1 Hz, 2H); 2.24 ppm (s, 6H).
Analogously, starting from the appropriate intermediate (example 3) the following compound was prepared (Y = N):
N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, 'H NMR in CDCI3 8.46 ppm (s, 1H); 8.34 ppm (d, J = 5.2 Hz, 1H); 7.76 ppm (d, J = 5.2 Hz, 1H); 6.88 ppm (d, J = 6.5 Hz, 1H); 6.80 ppm (d, J = 8.7 Hz, 1H); 4.37 ppm (t, 2H); 3.38 ppm (br s, 2H); 2.83 ppm (t, 2H); 2.31 ppm (s, 6H).
ExamPle 3 - N.N-dimethvl-5-nitro-2H-Pvridor4'.3':5.61thioPvranor4.3,2-cdlindazole-2-ethanamine (Y = N) A suspension of the compound of preparation 4 (0.10 9) in DMF (0.8 ml) under a nitrogen blanket was cooled in an ice bath and N-(2-dimethylaminoethyl)hydrazine (0.043 9) was added dropwise. The colour changed to bright orange and the suspension was allowed to stir at room temperature for 12 hrs. The mixture was quenched over ice water and basified with ~ueo~ ~s sodium bicarbonate. The resultant solid was collected by filtration and dried to yield the pure product (0.035 9), m.p. 205-206~C.
CA 022263l0 l998-Ol-0~
'H NMR in CDCI3 8.83 ppm (s, 1H); 8.59 ppm (d, J = 5.2 Hz, 1H); 8.30 ppm (d, J = 9.3 Hz, 1H); 8.10 ppm (d, J = 5.1 Hz, 1H); 7.11 ppm (d, J = 9.2 Hz, 1H); 4.52 ppm (t, J = 6.5 Hz, 2H); 2.90 ppm (t, J = 6.5 Hz, 2H), 2.31 ppm (s, 6H).
ExamPle 4 - N,N-d;.,leU,~/1-5-nitro-2H-Pvridor3'.4':5.61thioPYrano~4~3.2 s cdlindazole-2-ethanamine (Z = N) N-(2~i~"elh~/laminoethyl)hydrazine (25 mg) was added to a suspension of the co""~ound of ,ur~paralion 6 (60 mg) in DMF (0.5 ml). The resultant orange suspension was allowed to stir for 15 hrs at room temperature. The mixture was added to cold water (5 ml) and treated with aqueous sodium bicarbonate. The o orange solid was collected by filtration, washed thoroughly with water and dried to yield 57 mg of the product. The sample was recrystallized from aceto"il. ile.m.p. 214-215~C.
'H NMR in CDCI3 9.40 ppm (s, 1H); 8.52 ppm (d, J = 5.5 Hz, 1H); 8.27 ppm (d, J=9.3Hz, 1H);7.46ppm(d,J=5.6Hz, 1H);7.12ppm(d,J=9.3Hz, 1H);4.51 ppm (t, J = 6.5 Hz, 2H); 2.91 ppm (t, J = 6.5 Hz, 2H); 2.27 ppm (s, 6H).
Example 5 - N.N-dimethvl-5-amino-2H-Pvridor3'.4':5.61thioPvranor4.3.2-cdlinda,ole-2-ethanamine (Z = N) A mixture of the compound of example 4 (0.25 g) and 10% palladium/C (0.042 g) in glacial acetic acid (4.5 ml) was placed in a Parr bomb and hydroye"dled 20 for 18 hrs at about 70 psi pressure. The mixture was concentrated to dryness,diluted with 5% a~ueous ammonium hydroxide:chloroform (1:1 ) and then filtered over celite. The chloroform layer was separated from the filtrate and washed with water and brine. The chlororor", was removed by rotary evaporation to yieldthe product (0.15 9).
25 1H NMR in CDCI3 9.10 ppm (s, 1H); 8.25 ppm (d, J = 5.4 Hz, 1H); 7.12 ppm (d, J = 5.4 Hz, 1 H); 6.88 ppm (d, J = 8.7 Hz, 1 H); 6.78 ppm (d, J = 8.7 Hz, 1 H); 4.35 ppm (t, J = 7.0 Hz, 2H); 3.34 ppm (br s, 2H); 2.82 ppm (t, J = 7.0 Hz, 2H); 2.30ppm (s, 6H).
ExamPle 6 - N'-r2-r2-(dimethvlamino)ethYI1-2H-PYridor3~2~:5~6lthiopyranor4~3~2 - 30 cdlindd,ol-5-yll-N,N-dimethvl-1,2-ethanediamine (X = N) A mixture of the amino analogue of preparation 4 (0.50 g), 2-(climell"~lamino)ethyl bromide hyd,oL,ro"~ide (0.98 g) and potassium carbonate (1.37 g) in toluene (15 ml) was refluxed for 15 hrs. The mixture was cooled and CA 022263l0 l998-Ol-0~
the residue which was collected by filtration was triturated with hot acetor,il, ile.
The insoluble material was removed by filtration through a celite bed. The filtrate was concenl,a~ed to 15 ml and allowed to stand overnight. The productwas collected by filtration as a golden brown material (0.36 9). This crude ,nalerial 5 was dissolved in hot acetonitrile (10 ml), cooled to room teri"~er~Lure and placed in the refrigeralor overnight. The product as golden brown needles was collected byfiltration (0.26 9), m.p. 110-111~C.
~HNMRinCDCI3 8.27ppm(dd,J=1.6Hz,J=4.7Hz, 1H);8.16ppm(dd,J=
1.6 Hz, J = 7.7 Hz, 1 H); 7.09 ppm (dd, J = 4.7 Hz, J = 7.7 Hz, 1 H); 6.92 ppm (d, J = 8.7 Hz, 1H); 6.87 ppm (d, J = 7.1 Hz, 1H); 4.37 ppm (t, J = 7.0 Hz, 2H); 3.25 ppm(t,J=5.9Hz,2H);2.83ppm(t,J=7.0Hz,2H);2.60ppm(t,J=5.9Hz, 2H); 2.32 ppm (s, 6H); 2.34 ppm (s, 6H).
ExamPle 7 - N'-r2-r2-(dimethvlamino)ethYI1-2H-Pvridor3',2':5.61thioPvrarlor4.3.2cdlindazol-5-vll-1.2-ethanediamine (X = N) A commercial Red-AI solution (3.4 M in toluene, 0.6 ml) was added dropwise over a period o~ 3 minutes to a stirred suspension of the compound of the ~,,eparalion 12 (100 mg) in toluene (1 ml) held at 70 ~C. The resultant bright red solution was heated for an additional 5 hrs at 70-75 ~C, cooled to room temperature and treated cautiously with a saturated aqueous al~mo~ ~ium chloride solution. The yellow suspension was diluted with dichloromethane (3 ml) and the mixture was filtered through a celite bed. The organic layer was dried over magnesium sulfate and conce, ILI a~ed to yield the crude product (100mg). This material was purified by column chromatography over silica gel elutingsequentially with 2, 4, 8, 10 and 20 % methanol in dichloromethane. The center eluents were concentrated to yield the product as a yellow solid (50 mg, m.p.
77-80 ~C).
H-NMR in CDCI3 8.29 ppm (dd, J = 1.7, 4.7 Hz,1H); 8.17 ppm (dd, J = 1.7, 7.8 Hz, 1 H); 7.11 ppm (m, J = 4.7, 7.8 Hz, 1 H); 6.91 ppm (m, J = 8.8, 8.8 Hz, 2H);4.86 ppm (broad s, 1 H); 4.36 ppm (t, J = 7.0 Hz, 2H); 3.36 ppm (broad s, 4H);
2.82 ppm (t, J = 6.9 Hz, 2H); 2.32 ppm (s, 6H); 1.48 ppm (s, 9H).
Dry hydrogen chloride was briefly p~ssed through a solution of the title con"~ound (50 mg) in chloroform (0.5 ml). Upon removal of the chloroform, the hydrochloride salt of the product was obtained as an orange solid (43 mg).
CA 02226310 1998-01-0~
H-NMR in D20 8.23 ppm (dd, J = 1.4, 4.8 Hz, ~ H); 8.09 ppm (dd, J = 1.4, 7.8 Hz, 1H); 7.26 ppm (m, J = 4.9, 7.8 Hz, 1H); 7.13 ppm (d, J = 8.8 Hz, 1H); 7.08 ppm (d, J = 8.8 Hz, 1 H); 4.71 ppm (t, J = 5.9 Hz, 2H); 3.79 ppm (t, J = 5.9 Hz,2H); 3.59 ppm (t, J = 6.2 Hz, 2H); 3.34 ppm (t, J = 6.2 Hz, 2H); 3.05 ppm (s, 6H).
ExamPle 8 - N'-r2-r2-(dil"etl)~/lamino)ethvl-2H-Pvridor3'.4':5,61thiopvranor4,3,2-cdlindazol-5-vll-1,2-ethanediamine (Z = N) Accûr~ling to the procedure of example 7, starting from the intermediate of preparation 8, the title compound as hydrochloride salt is prepared.
1H-NMR in D2O 9.01 ppm (s, 1H); 8.39 ppm (d, J = 6.5 Hz, 1H); 7.90 ppm (d, J
= 6.5 Hz, 1 H); 7.39 ppm (d, J = 8.9 Hz, 1 H); 7.27 ppm (d, J = 8.9 Hz, 1 H); 4.86 ppm(t,J=5.9Hz,2H);3.88ppm(t,J=5.8Hz,2H);3.62ppm(t,J=6.2Hz, 2H); 3.36 ppm (t, J = 6.2 Hz, 2H); 3.09 ppm (s, 6H).
ExamPle 9 - coml,ounds (I) Following the methods described in example 6 or in example 7, starting from the a~propriate amine analogues obtained according to example 5 and from the a,c,prupriate aminoalkyl halide (method of example 6) or alternatively from aminoacids or derivative thereof (method of example 7), the following cG,~"~ounds of formula (I) are prepared:
(1) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-di",ell"~1-1,2-ethanediamine;
(2) N'-[2-~2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]in-ld~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(3) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(4) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(5) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]incJa~ol-5-yl]-1,2-ethanediamine, 'H N.M.R. (200 MHz) in D20 8.69 ppm (s, 1 H); 8.49 ppm (d, J=5.7 Hz, 1 H);
8.22 ppm (d, J=5.7 Hz, 1 H); 7.39 ppm (d, J=8.7 Hz, 1 H); 7.27 ppm (d, J=8.5 Hz,1H); 4.90 ppm (t, J=5.8 Hz, 2H); 3.91 ppm (t, J=5.8 Hz, 2H); 3.63 ppm (t, J=5.8 Hz, 2H); 3.35 ppm (t, J=5.8 Hz, 2H); 3.0 ppm (s, 6H);
CA 022263l0 l998-Ol-0~
WO 97/02267 PCTtUS96/10966 (6) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-1,2-ethanediamine;
8.22 ppm (d, J=5.7 Hz, 1 H); 7.39 ppm (d, J=8.7 Hz, 1 H); 7.27 ppm (d, J=8.5 Hz,1H); 4.90 ppm (t, J=5.8 Hz, 2H); 3.91 ppm (t, J=5.8 Hz, 2H); 3.63 ppm (t, J=5.8 Hz, 2H); 3.35 ppm (t, J=5.8 Hz, 2H); 3.0 ppm (s, 6H);
CA 022263l0 l998-Ol-0~
WO 97/02267 PCTtUS96/10966 (6) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-1,2-ethanediamine;
(7) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]i.~d~oi-5-yl]-1,2-ethanediamine;
(8) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-e~h~r,edi~" ,i"e;
(9) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]inJd~ol-5-yl]-1,2-ethanediamine;
(10) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]-N-methyl-1,2-ethanediamine, m.p. 114-115~C, 'H N.M.R. in CDCI3 8.27 ppm (dd, J=4.7 Hz, J=7.8 Hz, 1H);
8.14 ppm (dd, J=1.8 Hz, J=7.8 Hz, 1H); 7.08 ppm (dd, J=4.7 Hz, J=7.8 Hz,1H);
6.89 ppm (d, J=8.7 Hz, 1H); 6.88 ppm (d, J=8.7 Hz, 1H); 4.34 ppm (t, J=7.1 Hz, 2H); 3.30 ppm (t, J=5.7 Hz, 2H); 2.86 ppm (t, J=5.7 Hz, 2H); 2.80 ppm (t, J=7.1 Hz, 2H); 2.47 ppm (s, 3H);2.30 ppm (s, 6H);
8.14 ppm (dd, J=1.8 Hz, J=7.8 Hz, 1H); 7.08 ppm (dd, J=4.7 Hz, J=7.8 Hz,1H);
6.89 ppm (d, J=8.7 Hz, 1H); 6.88 ppm (d, J=8.7 Hz, 1H); 4.34 ppm (t, J=7.1 Hz, 2H); 3.30 ppm (t, J=5.7 Hz, 2H); 2.86 ppm (t, J=5.7 Hz, 2H); 2.80 ppm (t, J=7.1 Hz, 2H); 2.47 ppm (s, 3H);2.30 ppm (s, 6H);
(11) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]i, ~d~,ol-5-yl]-N-methyl-1,2-ethanediamine;
m.p. 120-124~C, 'H N.M.R in CDCI3 9.07 ppm (s, 1H); 8.23 ppm (d, J=5.4 Hz, 1H); 7.11 ppm (d, J=5.4 Hz,1H); 6.93 ppm (d, J=8.8 Hz, 1H); 6.86 ppm (d, J=8.8 Hz, 1 H); 5.42 ppm (br s,1 H); 4.36 ppm (t, J=7.1 Hz, 2H); 3.36 ppm (t, J=5.6 Hz, 2H); 2.96 ppm (t, J=7.1 Hz, 2H); 2.93 ppm (t, J=5.5 Hz, 2H); 2.62 ppm (q, J=7.1 Hz, 4H); 2.59 ppm (s, 3H); 1.02 ppm (t, J=7.1, Hz 6 H);
m.p. 120-124~C, 'H N.M.R in CDCI3 9.07 ppm (s, 1H); 8.23 ppm (d, J=5.4 Hz, 1H); 7.11 ppm (d, J=5.4 Hz,1H); 6.93 ppm (d, J=8.8 Hz, 1H); 6.86 ppm (d, J=8.8 Hz, 1 H); 5.42 ppm (br s,1 H); 4.36 ppm (t, J=7.1 Hz, 2H); 3.36 ppm (t, J=5.6 Hz, 2H); 2.96 ppm (t, J=7.1 Hz, 2H); 2.93 ppm (t, J=5.5 Hz, 2H); 2.62 ppm (q, J=7.1 Hz, 4H); 2.59 ppm (s, 3H); 1.02 ppm (t, J=7.1, Hz 6 H);
(12) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(13) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(14) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(15) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(16) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
CA 022263l0 l998-Ol-0~
( 17) N'-[2-[2-(methyiamino)ethyl]-2H-pyrido[3',2': 5,6]thiopyrano[4,3,2-cd~i, nJd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(18) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1 ,2-ethanediamine;
s (19) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(20) N-[2-[2-(di"~eLl,ylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(21) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-o 5-yl]-2-aminoethanol;
(22) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]i"dd~ol-5-yl]-2-aminoethanol;
(23) N-[2-[2-aminoethyl]-2H-pyrido~3',2':5,6]thiopyrano[4,3,2-cd]il Idd~ol-5-yl]- 2-aminoethanol;
(24) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(25) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]il Idd~ol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(26) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]i,,dd~vl-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(27) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(28) N'-[2-[2-aminoethyl]- 2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd~indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(29) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(30) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(31) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(32) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
CA 022263l0 l998-Ol-0~
(33) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(34) N'-[2-12-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(35) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]illda ol-5-yl]-N-methyl-1,2-ethanediamine;
(36) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]in-J~ol-5-yl]-N-methyl-1,2-ethanediamine;
(37) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd3indd~ol-lO 5-yl]-N-methyl-1,2-ethanediamine;
(38) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd3illda~ol-5-yl]-N-methyl-1,2-ethanediamine;
(39) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
15 (40) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]i"da ol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(41) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]in-Jd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(42) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(43) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1,2-ethanediamine;
(44) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(45) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(46) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(47) N-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(48) N-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
CA 022263l0 l998-Ol-0~
(49) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6lthiopyrano[4,3,2-cd];, ldd~ol-5-yl]- 2-aminoethanol;
(50) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1,2-ethanediamine, 'H N.M.R. (200 MHz) in CDCI3 9.09 ppm (s, 1H); 8.25 ppm (d, J=5.3 Hz, 1H);
7.15 ppm (d, J=5.4 Hz, 1H); 6.99 ppm (d, J=8.8 Hz, 1H); 6.90 ppm (d, J=8.8 Hz, 1 H); 4.45 ppm (t, J=6.9 Hz, 2H); 3.34 ppm (t, J=5.9 Hz" 2H); 3.00 ppm (t, J=6.9Hz, 2H); 2.87 ppm (t, J=5.9 Hz, 2H); 2.45 ppm (s, 6H); 3.29 ppm (s, 6H);
(51) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]incl~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine, 'H N.M.R. (200 MHz) in CDCI3 8.29 ppm (dd, J=1.8 Hz, J=3.8 Hz, 1H); 8.16 ppm (dd, J=1.8 Hz, J=7.8 Hz, 1H); 7.10 ppm (dd, J=4.7 Hz, J=7.3 Hz, 1H); 6.97 ppm (d, J=8.8 Hz,1 H); 6.89 ppm (d, J=8.8 Hz, 1 H); 4.41 ppm (t, J=7.1 Hz, 2H);
3.33 ppm (t, J=6.1 Hz, 2H); 3.04 ppm (t, J=7.1 Hz, 2H); 2.71 ppm (m, 6H); 2.33 ppm (s, 6H); 1.05 ppm (t, 6H).;
(52) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in~ld~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(53) N'-[2-[2-aminoethyl]- 2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yll-N,N-dimethyl-1,2-ethanediamine;
(54) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(55) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-1,2-ethanediamine;
(56) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-1,2-ethanediamine;
(57) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(58) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]il l.la~ol-5-yl]-1,2-ethanediamine;
(59) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(60) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
CA 02226310 1998-01-0~
(61) N'-~2-[2-(methylamino)ethyl~-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]-N-methyl-1,2-ethanediamine;
(62) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda,u1-5-yl]-N-methyl-1,2-ethanediamine;
(63) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in.l~ol-5-yl]-N-methyl-1,2-ethanediamine;
(64) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]i"d~ol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(65) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2~d];, Idd ol-o 5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(66) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]i"d~,ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(67) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1,2-ethanediamine;
15 (68) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(69) N-[2-[2-(di,t~ ylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-2-aminoethanol;
(70) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(71) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in.ld~ol-5-yl]-2-aminoethanol;
(72) N-[2-~2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(73) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(74) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(75) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ir,d~,ol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(76) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4~3~2-cd]inda 5-yl]-N, N-dimethyl-1,2-ethanediamine;
CA 02226310 1998-01-0~
WO 97/02267 PCTIUS96tlO966 (77) N'-~2-[2-aminoethyl]- 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-N,N-dimethyl-1 ,2-ethanediamine;
(78) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd~il nJd~ol-5-yl]-N,N-dimethyl-1 ,2-ethanediamine;
s (79) N'-[2-[2-(dimethylamino)ethyl~-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]-1 ,2-ethanediamine;
(80) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i"d--,ol-5-yl]-1 ,2-ethanediamine;
(81) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-o 5-yl~-1,2-ethanediamine;
(82) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(83) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
15 (84) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1 ,2-ethanediamine;
(85) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i"da ol-5-yl]-N-methyl-1 ,2-ethanediamine;
(86) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(87) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1 ,2-ethanediamine;
(88) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i- ,da,ol-5-yl]-N-methyl-1 ,2-ethanediamine;
(89) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1 ,2-ethanediamine;
(90) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(91) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd];"da~ol-5-yl]-N- hydroxyethyl -1 ,2-ethanediamine;
(92) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1 ,2-ethanediamine;
CA 022263l0 l998-Ol-0~
(93) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdpndazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(94) N-[2-[2-(di",ell.yld",i,~o)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]il ,d~,ol-5-yl]-2-aminoethanol;
(95) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yll-2-aminoethanol;
(96) N-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i~dd,ol-5-yl]-2-aminoethanol;
(97) N-[2-[2-ar"i"oell,yl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdli~ d~ol-5-yl]-2-l0 aminoethanol;
(98) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]- 2-aminoethanol.
Example 10 - compounds (I), D = -NHCO-CH~-NR~R~
Starting from a chloroform solution of the suitable compounds prepared 15 accordi, ~~~ to preparations 7 or 8, by removal of the N-BOC protecting group with dry gaseous hydrogen chloride, the following compounds as hydrochloride salts are obtained:
(1) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole, 20 1H N.M.R. (200 MHz) in D20 3.0 ppm (s, 6H); 3.81 ppm (t, 2H); 4.13 ppm (t, 2H); 4.80 ppm (s, 2H); 7.30 ppm (m, 3H); 8.30 ppm (m, 2H);
(2) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(3) N'-[2-(2-dil "el~ ~ylamino)ethyl3-5-(2'-amino-acetylamino)-2H-25 pyrido[4',3':5,6]thiopyrano [4,3,2-cd]inda~ole;
(4) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(5) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
30 (6)_N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano ~4,3,2-cd]indazole;
(7) N'~ 2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
-CA 02226310 1998-01-0~
(8) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]illda~ole;
(9) N'-[2-(2-methyla",i"o)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
s ( 10) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyridol3',4':5,6]thiopyrano [4,3,2-cd]indazote;
(11 ) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(12) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(13) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(14) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(15) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4~3~2-cd]indazole;
(16) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
CA 022263l0 l998-Ol-0~
( 17) N'-[2-[2-(methyiamino)ethyl]-2H-pyrido[3',2': 5,6]thiopyrano[4,3,2-cd~i, nJd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(18) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1 ,2-ethanediamine;
s (19) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(20) N-[2-[2-(di"~eLl,ylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(21) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-o 5-yl]-2-aminoethanol;
(22) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]i"dd~ol-5-yl]-2-aminoethanol;
(23) N-[2-[2-aminoethyl]-2H-pyrido~3',2':5,6]thiopyrano[4,3,2-cd]il Idd~ol-5-yl]- 2-aminoethanol;
(24) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(25) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]il Idd~ol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(26) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]i,,dd~vl-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(27) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(28) N'-[2-[2-aminoethyl]- 2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd~indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(29) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1 ,2-ethanediamine;
(30) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(31) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(32) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
CA 022263l0 l998-Ol-0~
(33) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(34) N'-[2-12-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(35) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]illda ol-5-yl]-N-methyl-1,2-ethanediamine;
(36) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]in-J~ol-5-yl]-N-methyl-1,2-ethanediamine;
(37) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd3indd~ol-lO 5-yl]-N-methyl-1,2-ethanediamine;
(38) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd3illda~ol-5-yl]-N-methyl-1,2-ethanediamine;
(39) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
15 (40) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]i"da ol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(41) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]in-Jd~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(42) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(43) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1,2-ethanediamine;
(44) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(45) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(46) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(47) N-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(48) N-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
CA 022263l0 l998-Ol-0~
(49) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6lthiopyrano[4,3,2-cd];, ldd~ol-5-yl]- 2-aminoethanol;
(50) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1,2-ethanediamine, 'H N.M.R. (200 MHz) in CDCI3 9.09 ppm (s, 1H); 8.25 ppm (d, J=5.3 Hz, 1H);
7.15 ppm (d, J=5.4 Hz, 1H); 6.99 ppm (d, J=8.8 Hz, 1H); 6.90 ppm (d, J=8.8 Hz, 1 H); 4.45 ppm (t, J=6.9 Hz, 2H); 3.34 ppm (t, J=5.9 Hz" 2H); 3.00 ppm (t, J=6.9Hz, 2H); 2.87 ppm (t, J=5.9 Hz, 2H); 2.45 ppm (s, 6H); 3.29 ppm (s, 6H);
(51) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]incl~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine, 'H N.M.R. (200 MHz) in CDCI3 8.29 ppm (dd, J=1.8 Hz, J=3.8 Hz, 1H); 8.16 ppm (dd, J=1.8 Hz, J=7.8 Hz, 1H); 7.10 ppm (dd, J=4.7 Hz, J=7.3 Hz, 1H); 6.97 ppm (d, J=8.8 Hz,1 H); 6.89 ppm (d, J=8.8 Hz, 1 H); 4.41 ppm (t, J=7.1 Hz, 2H);
3.33 ppm (t, J=6.1 Hz, 2H); 3.04 ppm (t, J=7.1 Hz, 2H); 2.71 ppm (m, 6H); 2.33 ppm (s, 6H); 1.05 ppm (t, 6H).;
(52) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in~ld~ol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(53) N'-[2-[2-aminoethyl]- 2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yll-N,N-dimethyl-1,2-ethanediamine;
(54) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(55) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-1,2-ethanediamine;
(56) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-1,2-ethanediamine;
(57) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(58) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]il l.la~ol-5-yl]-1,2-ethanediamine;
(59) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(60) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
CA 02226310 1998-01-0~
(61) N'-~2-[2-(methylamino)ethyl~-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]-N-methyl-1,2-ethanediamine;
(62) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda,u1-5-yl]-N-methyl-1,2-ethanediamine;
(63) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in.l~ol-5-yl]-N-methyl-1,2-ethanediamine;
(64) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]i"d~ol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(65) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2~d];, Idd ol-o 5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(66) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]i"d~,ol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(67) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1,2-ethanediamine;
15 (68) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(69) N-[2-[2-(di,t~ ylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ol-5-yl]-2-aminoethanol;
(70) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(71) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in.ld~ol-5-yl]-2-aminoethanol;
(72) N-[2-~2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(73) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(74) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N, N-dimethyl-1,2-ethanediamine;
(75) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ir,d~,ol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(76) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4~3~2-cd]inda 5-yl]-N, N-dimethyl-1,2-ethanediamine;
CA 02226310 1998-01-0~
WO 97/02267 PCTIUS96tlO966 (77) N'-~2-[2-aminoethyl]- 2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indd~ol-5-yl]-N,N-dimethyl-1 ,2-ethanediamine;
(78) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd~il nJd~ol-5-yl]-N,N-dimethyl-1 ,2-ethanediamine;
s (79) N'-[2-[2-(dimethylamino)ethyl~-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]-1 ,2-ethanediamine;
(80) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i"d--,ol-5-yl]-1 ,2-ethanediamine;
(81) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-o 5-yl~-1,2-ethanediamine;
(82) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
(83) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1 ,2-ethanediamine;
15 (84) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1 ,2-ethanediamine;
(85) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i"da ol-5-yl]-N-methyl-1 ,2-ethanediamine;
(86) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(87) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1 ,2-ethanediamine;
(88) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i- ,da,ol-5-yl]-N-methyl-1 ,2-ethanediamine;
(89) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1 ,2-ethanediamine;
(90) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(91) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd];"da~ol-5-yl]-N- hydroxyethyl -1 ,2-ethanediamine;
(92) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl -1 ,2-ethanediamine;
CA 022263l0 l998-Ol-0~
(93) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdpndazol-5-yl]-N- hydroxyethyl -1,2-ethanediamine;
(94) N-[2-[2-(di",ell.yld",i,~o)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]il ,d~,ol-5-yl]-2-aminoethanol;
(95) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yll-2-aminoethanol;
(96) N-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]i~dd,ol-5-yl]-2-aminoethanol;
(97) N-[2-[2-ar"i"oell,yl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdli~ d~ol-5-yl]-2-l0 aminoethanol;
(98) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cdlindazol-5-yl]- 2-aminoethanol.
Example 10 - compounds (I), D = -NHCO-CH~-NR~R~
Starting from a chloroform solution of the suitable compounds prepared 15 accordi, ~~~ to preparations 7 or 8, by removal of the N-BOC protecting group with dry gaseous hydrogen chloride, the following compounds as hydrochloride salts are obtained:
(1) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole, 20 1H N.M.R. (200 MHz) in D20 3.0 ppm (s, 6H); 3.81 ppm (t, 2H); 4.13 ppm (t, 2H); 4.80 ppm (s, 2H); 7.30 ppm (m, 3H); 8.30 ppm (m, 2H);
(2) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(3) N'-[2-(2-dil "el~ ~ylamino)ethyl3-5-(2'-amino-acetylamino)-2H-25 pyrido[4',3':5,6]thiopyrano [4,3,2-cd]inda~ole;
(4) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(5) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
30 (6)_N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano ~4,3,2-cd]indazole;
(7) N'~ 2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
-CA 02226310 1998-01-0~
(8) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]illda~ole;
(9) N'-[2-(2-methyla",i"o)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
s ( 10) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyridol3',4':5,6]thiopyrano [4,3,2-cd]indazote;
(11 ) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(12) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(13) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(14) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(15) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4~3~2-cd]indazole;
(16) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(17) N'-[2-(2-hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6] thiopyrano [4,3,2-cd]indazole;
(18) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6 thiopyrano [4,3,2-cd]indazole;
(19) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6] thiopyrano [4,3,2-cd]indazole;
(20) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6] thiopyrano [4,3,2-cd]indazole.
ExamPle 11 - comPounds (I)~ D = nitro Accordi,lg to the procedures described in examples 1, 3 or 4, starting from the suitable intermediates, the following nitro derivatives are obtained:
(1 ) N,N-diethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, 'H N.M.R. (200 MHz) in CDCI3 9.38 ppm (s, 1H); 8.50 ppm (d, J=5.4 Hz, 1H);
8.23 ppm (d, J=9.3 Hz, 1H); 7.45 ppm (d, J=5.4 Hz, 1H); 7.11 ppm (d, J=9.3 Hz, CA 022263l0 l998-Ol-0~
WO 97t02267 PCT/US96/10966 1h); 4.45 ppm (t, J=6.4 Hz, 2H); 2.98 ppm (t, J=6.4 Hz, 2H); 2.54 ppm (q, J=7.1 Hz, 4H); 0.92 ppm (t, J=7.1 Hz, 6H);
(2) N,N-diethyl-5-nitro-2H-pyrido~3',2':5,6]thiopyrano[4,3,2-cd]i"dd~ole-2-ell ,ana")ine, m.p.132-133~C, s 'H N.M.R. (200 MHz) in CDCI3 8.56 ppm (dd, J=1.7 Hz, J=4.6 Hz,1 H); 8.43 ppm (dd, J=1.7 Hz, J=7.8 Hz,1 H); 8.25 ppm (d, J=9.3 Hz, 1 H); 7.33 ppm (dd, J=4.6 Hz, J=7.8 Hz,1 H); 7.08 ppm (d, J=9.3 Hz,1 H); 4.44 ppm (t, J=6.4 Hz, 2H); 2.98 ppm (t, J=6.4 Hz, "h9; 2.54 ppm (q, J=7.1 Hz, 4H); 0.94 ppm (t, J=7.1 Hz, 6H);
o (3) N,N-dimethyl-5-nitro-2H-pyrido[4',3':5,6~thiopyrano[4,3,2-cd]indazole-2- ethanamine;
(4) N,N-diethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,a"a" ,ine;
(5) N,N-cli."ell"/1-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-etl ,ana" ,ine;
(6) N,N-diethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-etl ,an~" ,i"e;
(7) N-methyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[473,2-cd]indazole-2-ell ,ana" ,ine;
(10) N-methyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ell,ana"-i--e;
(13) 5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethana"~ine;
(14) 5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-na~ine;
(16) N-hydroxyethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-eli,ana",i. ,e;
-CA 022263l0 l998-Ol-0~
(17) N-hydroxyethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~olQ 2-ell Idl Idllline;
(18) N-hydroxyethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind-~ol~ 2-eli ,a"a",ine.
ExamPle 12 - co",l~ounds (I). D = amino Accordil lg to the procedure described in examples 2 or 5, sldl li"~ from the nitro derivatives of example 11, the following amino derivatives are oblai,~ed:
(1) N,N-diethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ole-2-ell ,anan,ine, o 1H N.M.R. (200 MHz) in CDCI3 9.09 ppm (s, 1H); 8.24 ppm (d, J=5.5 Hz, 1H);
7.13 ppm (d, J=5.5 Hz, 1H); 6.88 ppm (d, J=8.6 Hz, 1H); 6.77 ppm (d, J=8.6 Hz, 1 H); 4.31 ppm (t, J=7.9 Hz, 2H); 3.33 ppm (br s, 2H); 2.92 ppm (t, J=7.0 Hz, 2H);
2.58 ppm (q, J=7.1 Hz, 4H); 1.01 ppm (t, J=7.1 Hz, 6H);
(2) N,N-diethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,ar,a" ,ine;
(3) N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]il ,~ ole-2-ethanamine;
(4) N,N-diethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~ ie 2-ell ,ana" ,ine;
(5) N,N-dimethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd];nda~ole-2-ethanamine;
(6) N,N-diethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,a"a",i"e;
(8) N-methyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,anar"ine;
(11 ) 5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-elhal,a",ine;
CA 02226310 1998-01-0~
(13) 5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~ le-2-ell,~"a"line;
(14) 5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind~le 2-ell,an&"line;
(15) N-hydroxyethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in~'~ Ne 2-ethana" ,ioe;
(16) N-hydroxyethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd];n~ olQ 2-ethanamine;
(17) N-hydroxyethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,ana",ine;
(18) N-hydroxyethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind~olQ 2-ethanamine.
TA~BLE ~ ¦ lC50(~gJn~) Sllucl~u~ Example L1210 S 180 LoVo LoVo~Dx N--N~
~ xHaxH2~ 7 0.0125 0.058 0.027 16.8 --NH, N~--N~NU-, ~ 6 0.008 0.028 2.4 2.6 N--N~
~ xHaxH2~ ex. lo-cpd 1 0 03 0.22 n.d. n.d.
HN~NH, N--N~NIU-, N~ 8HaxH20 ex.9-cpd 300.0140.058 n.d. ~.d.
HN NH, N~--N~
N~ xHaxH20 ex.10-cpd 2 n.dn.d. 0.04 0.21 HN~NH, --N~
N~ xHa.xH2o 80.0016 0.0029 0.008 0.26 HN NH, N~--N ~
~ 5 0.0030 0.0066 0.016 0.027 NH, N--N~N~, N~ ex.12-cpd 10.00150.0031 0.036 0.094 NH, CA 022263l0 lss8-0l-05 TABLE II - conti~ue IC50 (~lg/ml) Sl~llc;l~.leExaml)leL1210 S180LoVoLoVo/Dx Cl-941 -- n.d. n.dØ05344.5 d~,~o~l ~
-- n.d. n.dØ58 53.B
-- n.d. n.dØ0240.67 n.d. = not ~
IC50 is the r of the drug which caus~ a 50% ' ~ tion of the tumor cells growth CYTOTOXICITY ON LOVO AND LOVO/DX WAS DETERMINED BY Mrr ASSAY
I;OLLOWING 1 HOUR OF DRUG EXPOSURE
CA 022263l0 l998-0l-05 TABLE III ¦ IC50 (~lg/ml) Structure Example L1210 S180 LoVo LoVo/Dx N--N~Ntl, ~ ex. ll-cpd 1 0.00061 0.0031 n.d. n.d.
NO, ~ NM-, 0.00062 0.0032 n.d. n.d.
NO, Nl--N~NM~, N~ 3 0.050.14n.d. n.d.
NO, N--N ~h~t, ~¢l ex. 11-cpd2 0.2 0.22 n.d. n.d.
NO, N--N~NM~, ~ 1 0.08 0.17 n.d. n.d.
NO~
n.d. = not d~.; ~ ~ ' IC50 is lhe r ' ' of the drug which causes a 50% i~ r of the tumor cells g~owth CYTOTOXICITY ON LOVO AND LOVO/DX WAS DETERMINED BY MTT
ASSAY FOLLOWING I HOUR OF DRUG EXl'OSURE
ExamPle 11 - comPounds (I)~ D = nitro Accordi,lg to the procedures described in examples 1, 3 or 4, starting from the suitable intermediates, the following nitro derivatives are obtained:
(1 ) N,N-diethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, 'H N.M.R. (200 MHz) in CDCI3 9.38 ppm (s, 1H); 8.50 ppm (d, J=5.4 Hz, 1H);
8.23 ppm (d, J=9.3 Hz, 1H); 7.45 ppm (d, J=5.4 Hz, 1H); 7.11 ppm (d, J=9.3 Hz, CA 022263l0 l998-Ol-0~
WO 97t02267 PCT/US96/10966 1h); 4.45 ppm (t, J=6.4 Hz, 2H); 2.98 ppm (t, J=6.4 Hz, 2H); 2.54 ppm (q, J=7.1 Hz, 4H); 0.92 ppm (t, J=7.1 Hz, 6H);
(2) N,N-diethyl-5-nitro-2H-pyrido~3',2':5,6]thiopyrano[4,3,2-cd]i"dd~ole-2-ell ,ana")ine, m.p.132-133~C, s 'H N.M.R. (200 MHz) in CDCI3 8.56 ppm (dd, J=1.7 Hz, J=4.6 Hz,1 H); 8.43 ppm (dd, J=1.7 Hz, J=7.8 Hz,1 H); 8.25 ppm (d, J=9.3 Hz, 1 H); 7.33 ppm (dd, J=4.6 Hz, J=7.8 Hz,1 H); 7.08 ppm (d, J=9.3 Hz,1 H); 4.44 ppm (t, J=6.4 Hz, 2H); 2.98 ppm (t, J=6.4 Hz, "h9; 2.54 ppm (q, J=7.1 Hz, 4H); 0.94 ppm (t, J=7.1 Hz, 6H);
o (3) N,N-dimethyl-5-nitro-2H-pyrido[4',3':5,6~thiopyrano[4,3,2-cd]indazole-2- ethanamine;
(4) N,N-diethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,a"a" ,ine;
(5) N,N-cli."ell"/1-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-etl ,ana" ,ine;
(6) N,N-diethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-etl ,an~" ,i"e;
(7) N-methyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[473,2-cd]indazole-2-ell ,ana" ,ine;
(10) N-methyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ell,ana"-i--e;
(13) 5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethana"~ine;
(14) 5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-na~ine;
(16) N-hydroxyethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-eli,ana",i. ,e;
-CA 022263l0 l998-Ol-0~
(17) N-hydroxyethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~olQ 2-ell Idl Idllline;
(18) N-hydroxyethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind-~ol~ 2-eli ,a"a",ine.
ExamPle 12 - co",l~ounds (I). D = amino Accordil lg to the procedure described in examples 2 or 5, sldl li"~ from the nitro derivatives of example 11, the following amino derivatives are oblai,~ed:
(1) N,N-diethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]inda~ole-2-ell ,anan,ine, o 1H N.M.R. (200 MHz) in CDCI3 9.09 ppm (s, 1H); 8.24 ppm (d, J=5.5 Hz, 1H);
7.13 ppm (d, J=5.5 Hz, 1H); 6.88 ppm (d, J=8.6 Hz, 1H); 6.77 ppm (d, J=8.6 Hz, 1 H); 4.31 ppm (t, J=7.9 Hz, 2H); 3.33 ppm (br s, 2H); 2.92 ppm (t, J=7.0 Hz, 2H);
2.58 ppm (q, J=7.1 Hz, 4H); 1.01 ppm (t, J=7.1 Hz, 6H);
(2) N,N-diethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,ar,a" ,ine;
(3) N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]il ,~ ole-2-ethanamine;
(4) N,N-diethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~ ie 2-ell ,ana" ,ine;
(5) N,N-dimethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd];nda~ole-2-ethanamine;
(6) N,N-diethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,a"a",i"e;
(8) N-methyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,anar"ine;
(11 ) 5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-elhal,a",ine;
CA 02226310 1998-01-0~
(13) 5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]ind~ le-2-ell,~"a"line;
(14) 5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind~le 2-ell,an&"line;
(15) N-hydroxyethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]in~'~ Ne 2-ethana" ,ioe;
(16) N-hydroxyethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd];n~ olQ 2-ethanamine;
(17) N-hydroxyethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ell ,ana",ine;
(18) N-hydroxyethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]ind~olQ 2-ethanamine.
TA~BLE ~ ¦ lC50(~gJn~) Sllucl~u~ Example L1210 S 180 LoVo LoVo~Dx N--N~
~ xHaxH2~ 7 0.0125 0.058 0.027 16.8 --NH, N~--N~NU-, ~ 6 0.008 0.028 2.4 2.6 N--N~
~ xHaxH2~ ex. lo-cpd 1 0 03 0.22 n.d. n.d.
HN~NH, N--N~NIU-, N~ 8HaxH20 ex.9-cpd 300.0140.058 n.d. ~.d.
HN NH, N~--N~
N~ xHaxH20 ex.10-cpd 2 n.dn.d. 0.04 0.21 HN~NH, --N~
N~ xHa.xH2o 80.0016 0.0029 0.008 0.26 HN NH, N~--N ~
~ 5 0.0030 0.0066 0.016 0.027 NH, N--N~N~, N~ ex.12-cpd 10.00150.0031 0.036 0.094 NH, CA 022263l0 lss8-0l-05 TABLE II - conti~ue IC50 (~lg/ml) Sl~llc;l~.leExaml)leL1210 S180LoVoLoVo/Dx Cl-941 -- n.d. n.dØ05344.5 d~,~o~l ~
-- n.d. n.dØ58 53.B
-- n.d. n.dØ0240.67 n.d. = not ~
IC50 is the r of the drug which caus~ a 50% ' ~ tion of the tumor cells growth CYTOTOXICITY ON LOVO AND LOVO/DX WAS DETERMINED BY Mrr ASSAY
I;OLLOWING 1 HOUR OF DRUG EXPOSURE
CA 022263l0 l998-0l-05 TABLE III ¦ IC50 (~lg/ml) Structure Example L1210 S180 LoVo LoVo/Dx N--N~Ntl, ~ ex. ll-cpd 1 0.00061 0.0031 n.d. n.d.
NO, ~ NM-, 0.00062 0.0032 n.d. n.d.
NO, Nl--N~NM~, N~ 3 0.050.14n.d. n.d.
NO, N--N ~h~t, ~¢l ex. 11-cpd2 0.2 0.22 n.d. n.d.
NO, N--N~NM~, ~ 1 0.08 0.17 n.d. n.d.
NO~
n.d. = not d~.; ~ ~ ' IC50 is lhe r ' ' of the drug which causes a 50% i~ r of the tumor cells g~owth CYTOTOXICITY ON LOVO AND LOVO/DX WAS DETERMINED BY MTT
ASSAY FOLLOWING I HOUR OF DRUG EXl'OSURE
Claims
1. A compound of formula (I):
wherein:
one of X, Y, Z or T is nitrogen (=N-) and the others are =CH-;
D is selected from the group consisting of nitro or -NH-A, wherein A is selectedin the group consisting of hydrogen, -CO-CH2-NR2R3, C1-C10 alkyl; C2-C10 alkyl having one or two substituents selected from the group consisting of OR1 and -NR2R3; C2-C10 alkyl interrupted by one or two oxygen atoms or by one -NR4- group, and said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
B is selected from the group consisting of C1-C10 alkyl; C2-C10 alkyl having oneor two substituents selected from the group consisting of OR1 and -NR2R3; and C2-C10 alkyl interrupted by one or two oxygen atoms or by one -NR4- group, wherein said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R5, andC2-C6 alkyl optionally substituted by -NR2R3;
R2 and R3 may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl substituted with one or two hydroxy (OH) groups; or R2 and R3 taken together with the nitrogen atom to which they are linked form a 5- or 6-member aromatic or non-aromatic heterocyclic ring which optionally contains another heteroatom such as sulfur, oxygen or nitrogen;
R4 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, and C2-C10 alkyl substituted with -NR2R3;
R5 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenylalkyl;
as free bases and their salts with pharmaceutically acceptable acids.
2. The compound of claim 1 wherein C1-C10 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
3. The compound of claim 1 wherein phenylalkyl is 4-methylphenyl.
4. The compound of claim 1 wherein the -NR2R3 substituent is 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.
5. The compound of claim 1 selected from the group consisting of (1) N,N-dimethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(2) N'-[2-12-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(3) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(4) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(5) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(6) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine, (7) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(8) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(9) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(10) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(11) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(12) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(13) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(14) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(15) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(16) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(17) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(18) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(19) N-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(20) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(21) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(22) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(23) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(24) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(25) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(26) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(27) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(28) N'-[2-12-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(29) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(30) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(31) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(32) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(33) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(34) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(35) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(36) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(37) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5yl]-N-hydroxyethyl-1,2-ethanediamine;
(38) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(39) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(40) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(41) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(42) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(43) N-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(44) N-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(45) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(46) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine, (47) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine, (48) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd];indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(49) N'-[2-12-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(50) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(51) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(52) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(53) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(54) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(55) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(56) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(57) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(58) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(59) N'-12-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(60) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(61) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(62) N'-[2-[2-(methyiamino)ethyl]-2H-pyrido[3',4':5,6]thiopyranol4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(63) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(64) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyranol4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(65) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(66) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(67) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(68) N-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(69) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(70) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(71) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(72) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(73) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(74) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(75) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(76) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(77) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(78) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(79) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(80) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(81) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(82) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(83) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(84) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(85) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(86) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(87) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(88) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(89) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(90) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(91) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(92) N-12-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(93) N-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(94) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol.
7. The compound of claim 1 selected from the group consisting of:
(1) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole, (2) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(3) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(4) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(5) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(6) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(7) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(8) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(9) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(10) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(11) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(12) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(13) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(14) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,63thiopyrano [4,3,2-cd]indazole;
(15) N'-[2-aminoethyl3-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(16) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(17) N'-[2-(2-hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6] thiopyrano [4,3,2-cd]indazole;
(18) N'-[2-(2- hydroxyethylamino)ethyl3-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6 thiopyrano [4,3,2-cd]indazole;
(19) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6] thiopyrano [4,3,2-cd]indazole;
(20) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,63 thiopyrano [4,3,2-cd]indazole.
8. The compound of claim 1 selected from the group consisting of:
(1) N,N-diethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, (2) N,N-diethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(3) N,N-dimethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(4) N,N-diethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(5) N,N-dimethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(6) N,N-diethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(13) 5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(14) 5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(16) N-hydroxyethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;(17) N-hydroxyethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(18) N-hydroxyethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine.
9. The compound of claim 1 selected from the group consisting of:
(1) N,N-diethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamide, (2) N,N-diethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(3) N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(4) N,N-diethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(5) N,N-dimethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(6) N,N-diethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(13) 5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(14) 5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(16) N-hydroxyethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(17) N-hydroxyethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(18) N-hydroxyethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine.
10. A method of making a compound of formula (I) comprising:
a) reacting a compound of formula (III):
wherein X, Y, Z and T are as defined in claim 1 and U is selected from the groupconsisting of F or Cl, with a hydrazine of formula (IV):
H2N-NH-B' (IV) wherein B' has the same meanings as B is defined in formula (I), or B' is a group that can be converted into B by removal of protective groups for the primary or secondary amines and hydroxy groups optionally present in B', to give a compound of formula (II):
in which X, Y, Z, T and B' are as above defined.
11. The method of claim 10 further comprising removing protecting groups optionally present to give the compounds of formula (I) in which D is a nitro group.
12. The method of claim 10 further comprising a) reducing the nitro group of intermediate (II) to give the intermediate of formula (IIa):
b) converting the compounds of formula (I) in which D is an amino group by removal of the protecting groups optionally present.
13. A pharmaceuticals composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
14. A method of treating tumors in a patient in need of such treatment comprising administering an anti-tumor effective amount of the compound of claim 1 to the patient.
15. Use of the compound of claim 1 as an anti-tumor compound.
wherein:
one of X, Y, Z or T is nitrogen (=N-) and the others are =CH-;
D is selected from the group consisting of nitro or -NH-A, wherein A is selectedin the group consisting of hydrogen, -CO-CH2-NR2R3, C1-C10 alkyl; C2-C10 alkyl having one or two substituents selected from the group consisting of OR1 and -NR2R3; C2-C10 alkyl interrupted by one or two oxygen atoms or by one -NR4- group, and said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
B is selected from the group consisting of C1-C10 alkyl; C2-C10 alkyl having oneor two substituents selected from the group consisting of OR1 and -NR2R3; and C2-C10 alkyl interrupted by one or two oxygen atoms or by one -NR4- group, wherein said C2-C10 alkyl is optionally substituted by one or two hydroxy (OH) or -NR2R3 groups;
R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, -S(O2)R5, andC2-C6 alkyl optionally substituted by -NR2R3;
R2 and R3 may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, and C2-C10 alkyl substituted with one or two hydroxy (OH) groups; or R2 and R3 taken together with the nitrogen atom to which they are linked form a 5- or 6-member aromatic or non-aromatic heterocyclic ring which optionally contains another heteroatom such as sulfur, oxygen or nitrogen;
R4 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, and C2-C10 alkyl substituted with -NR2R3;
R5 is selected from the group consisting of C1-C10 alkyl, phenyl, and phenylalkyl;
as free bases and their salts with pharmaceutically acceptable acids.
2. The compound of claim 1 wherein C1-C10 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
3. The compound of claim 1 wherein phenylalkyl is 4-methylphenyl.
4. The compound of claim 1 wherein the -NR2R3 substituent is 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.
5. The compound of claim 1 selected from the group consisting of (1) N,N-dimethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(2) N'-[2-12-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(3) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(4) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(5) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(6) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine, (7) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(8) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(9) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(10) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(11) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(12) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(13) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(14) N'-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(15) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(16) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(17) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(18) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(19) N-[2-[2-aminoethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(20) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]- 2-aminoethanol;
(21) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(22) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(23) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(24) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(25) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(26) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(27) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(28) N'-[2-12-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(29) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(30) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(31) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(32) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(33) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(34) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(35) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(36) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(37) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5yl]-N-hydroxyethyl-1,2-ethanediamine;
(38) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(39) N'-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(40) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(41) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(42) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(43) N-[2-[2-(methylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(44) N-[2-[2-aminoethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(45) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(46) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine, (47) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine, (48) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd];indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(49) N'-[2-12-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(50) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(51) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(52) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(53) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(54) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(55) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(56) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(57) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(58) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(59) N'-12-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(60) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(61) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N- hydroxyethyl-1,2-ethanediamine;
(62) N'-[2-[2-(methyiamino)ethyl]-2H-pyrido[3',4':5,6]thiopyranol4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(63) N'-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(64) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyranol4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(65) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(66) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(67) N-[2-[2-(methylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(68) N-[2-[2-aminoethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(69) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(70) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(71) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(72) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(73) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(74) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N,N-dimethyl-1,2-ethanediamine;
(75) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(76) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(77) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(78) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(79) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine;
(80) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(81) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(82) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(83) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(84) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-methyl-1,2-ethanediamine;
(85) N'-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(86) N'-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(87) N'-[2-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(88) N'-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(89) N'-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-N-hydroxyethyl-1,2-ethanediamine;
(90) N-[2-[2-(dimethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(91) N-[2-[2-(diethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(92) N-12-[2-(methylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(93) N-[2-[2-aminoethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol;
(94) N-[2-[2-(2-hydroxyethylamino)ethyl]-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazol-5-yl]-2-aminoethanol.
7. The compound of claim 1 selected from the group consisting of:
(1) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole, (2) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(3) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(4) N'-[2-(2-dimethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(5) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(6) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(7) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(8) N'-[2-(2-diethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(9) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(10) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6]thiopyrano [4,3,2-cd]indazole;
(11) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(12) N'-[2-(2-methylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(13) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6]thiopyrano [4,3,2-cd]indazole;
(14) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,63thiopyrano [4,3,2-cd]indazole;
(15) N'-[2-aminoethyl3-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6]thiopyrano [4,3,2-cd]indazole;
(16) N'-[2-aminoethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,6]thiopyrano [4,3,2-cd]indazole;
(17) N'-[2-(2-hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[3',2':5,6] thiopyrano [4,3,2-cd]indazole;
(18) N'-[2-(2- hydroxyethylamino)ethyl3-5-(2'-amino-acetylamino)-2H-pyrido[3',4':5,6 thiopyrano [4,3,2-cd]indazole;
(19) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[4',3':5,6] thiopyrano [4,3,2-cd]indazole;
(20) N'-[2-(2- hydroxyethylamino)ethyl]-5-(2'-amino-acetylamino)-2H-pyrido[2',3':5,63 thiopyrano [4,3,2-cd]indazole.
8. The compound of claim 1 selected from the group consisting of:
(1) N,N-diethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine, (2) N,N-diethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(3) N,N-dimethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(4) N,N-diethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(5) N,N-dimethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(6) N,N-diethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(13) 5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(14) 5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-nitro-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(16) N-hydroxyethyl-5-nitro-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;(17) N-hydroxyethyl-5-nitro-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(18) N-hydroxyethyl-5-nitro-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine.
9. The compound of claim 1 selected from the group consisting of:
(1) N,N-diethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamide, (2) N,N-diethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(3) N,N-dimethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(4) N,N-diethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(5) N,N-dimethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(6) N,N-diethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(7) N-methyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(8) N-methyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(9) N-methyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(10) N-methyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(11) 5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(12) 5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(13) 5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(14) 5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(15) N-hydroxyethyl-5-amino-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(16) N-hydroxyethyl-5-amino-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(17) N-hydroxyethyl-5-amino-2H-pyrido[4',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine;
(18) N-hydroxyethyl-5-amino-2H-pyrido[2',3':5,6]thiopyrano[4,3,2-cd]indazole-2-ethanamine.
10. A method of making a compound of formula (I) comprising:
a) reacting a compound of formula (III):
wherein X, Y, Z and T are as defined in claim 1 and U is selected from the groupconsisting of F or Cl, with a hydrazine of formula (IV):
H2N-NH-B' (IV) wherein B' has the same meanings as B is defined in formula (I), or B' is a group that can be converted into B by removal of protective groups for the primary or secondary amines and hydroxy groups optionally present in B', to give a compound of formula (II):
in which X, Y, Z, T and B' are as above defined.
11. The method of claim 10 further comprising removing protecting groups optionally present to give the compounds of formula (I) in which D is a nitro group.
12. The method of claim 10 further comprising a) reducing the nitro group of intermediate (II) to give the intermediate of formula (IIa):
b) converting the compounds of formula (I) in which D is an amino group by removal of the protecting groups optionally present.
13. A pharmaceuticals composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
14. A method of treating tumors in a patient in need of such treatment comprising administering an anti-tumor effective amount of the compound of claim 1 to the patient.
15. Use of the compound of claim 1 as an anti-tumor compound.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88795P | 1995-07-06 | 1995-07-06 | |
| US1861296P | 1996-06-03 | 1996-06-03 | |
| US60/018,612 | 1996-06-03 | ||
| US60/000,887 | 1996-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2226310A1 true CA2226310A1 (en) | 1997-01-23 |
Family
ID=26668268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002226310A Abandoned CA2226310A1 (en) | 1995-07-06 | 1996-07-03 | New pyrido-thiopyranoindazoles with anti-tumor activity |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0837861A1 (en) |
| JP (1) | JPH11513020A (en) |
| KR (1) | KR19990028765A (en) |
| AU (1) | AU713107B2 (en) |
| CA (1) | CA2226310A1 (en) |
| WO (1) | WO1997002267A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2288274A1 (en) * | 1997-04-28 | 1998-11-05 | University Of Vermont | Regioisomeric benzothiopyranopyridines having antitumor activity |
| US6747039B2 (en) | 2002-03-12 | 2004-06-08 | Albany Molecular Research, Inc. | Aza-benzothiopyranoindazoles with antitumor activity |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE56749B1 (en) * | 1983-01-06 | 1991-12-04 | Warner Lambert Co | Benzothiopyrano(4,3,2-cd)indazoles,their pharmaceutical compositions and methods for their production |
| EP0662076B1 (en) * | 1992-09-08 | 2001-04-11 | The University Of Vermont | 2-aminoalkyl-5-aminoalkylamino substituted isoquinoindazole-6-(2h)-ones with antitumour activity |
-
1996
- 1996-07-03 WO PCT/US1996/010966 patent/WO1997002267A1/en not_active Application Discontinuation
- 1996-07-03 JP JP9504638A patent/JPH11513020A/en not_active Ceased
- 1996-07-03 KR KR1019980700064A patent/KR19990028765A/en not_active Application Discontinuation
- 1996-07-03 CA CA002226310A patent/CA2226310A1/en not_active Abandoned
- 1996-07-03 EP EP96923481A patent/EP0837861A1/en not_active Withdrawn
- 1996-07-03 AU AU63981/96A patent/AU713107B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU6398196A (en) | 1997-02-05 |
| KR19990028765A (en) | 1999-04-15 |
| WO1997002267A1 (en) | 1997-01-23 |
| AU713107B2 (en) | 1999-11-25 |
| JPH11513020A (en) | 1999-11-09 |
| EP0837861A1 (en) | 1998-04-29 |
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| Date | Code | Title | Description |
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| FZDE | Dead |