WO1992003419A1 - Isocarbostiryl compounds and antitumor use thereof - Google Patents

Isocarbostiryl compounds and antitumor use thereof Download PDF

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Publication number
WO1992003419A1
WO1992003419A1 PCT/CA1991/000302 CA9100302W WO9203419A1 WO 1992003419 A1 WO1992003419 A1 WO 1992003419A1 CA 9100302 W CA9100302 W CA 9100302W WO 9203419 A1 WO9203419 A1 WO 9203419A1
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compound
alkyl
triazol
substituted
alkoxy
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PCT/CA1991/000302
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French (fr)
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Mohsen Daneshtalab
Ronald G. Micetich
Yutaka Yamamoto
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Synphar Laboratories, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel alkyl 3- substituted-6,8-dihydroxy-l(2H)-oxoisoquinoline-4-carboxylates.
  • the invention further relates to the process for the preparation and to the cytotoxicity and anti-tumor use of such compounds.
  • R is C 1 _ 7 alkyl; unsubstituted phenyl or a phenyl substituted by different electron donating or electron attracting groups at different positions; an optionally substituted 5-or 6-membered ring azine, preferably pyridine or pyrimidine; or a C- ⁇ g alkylene, substituted terminally with optionally substituted phenyl, azinyl, or C- j ⁇ alkyl carboxylate; R 2 is hydrogen or a C 1-Q alkyl chain;
  • R 3 , R 4 , R 5 and R 6 independently are hydrogen, hydroxy, C x _ 6 alkoxy, or halogen.
  • the physiologically acceptable compounds of formula I possess pharmacological properties exhibiting cytotoxicity, in particular, against a wide variety of tumor cell lines.
  • the compounds of the- present invention may be utilized as active compounds in medicaments, being formulated with one or more pharmaceutically acceptable carriers.
  • R ⁇ is an alkylene moiety substituted terminally with optionally substituted phenyl, azinyl or alkyl carboxylate, it is preferably of the formula -R 8 -R 9 , wherein R 8 is C 1-6 alkylene and R g is phenyl, which is unsubstituted or is substituted by different electron donating or electron attracting groups at different positions, azinyl, or C- ⁇ ⁇ alkyl carboxylate.
  • R ⁇ or R 9 are substituted phenyl
  • the phenyl ring is preferably substituted by one or two substituents, which are preferably in the m- or p- positions, and are C- ⁇ C ⁇ alkyl, C- L *- ⁇ alkoxy, or halogen, preferably fluorine.
  • R or R 9 are azinyl or azole, they are a 5- or 6- membered ring azole or azine.
  • Suitable 5 membered azole rings include 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, pyrrol-2-yl, pyrrol-3-yl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, l,2,4-triazol-2-yl,
  • Suitable 6 membered azinyl rings include 2-pyridyl, 4- pyridyl (unsubstituted or substituted with one or two electron donating moieties such as C j -C ⁇ j alkoxy, halogen or ⁇ -0 4 alkyl; or electron withdrawing substituents such as C 2 -C 6 acyl, 0 -0 4 alkoxy carbonyl, and nitro) , 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl (unsubstituted or substituted by one or two electron donating moieties such as - ⁇ -C ⁇ alkoxy, halogen or 0 ⁇ 0 4 alkyl; or electron withdrawing substituents such as C 2 -C 6 acyl, ⁇ -0 4 alkoxy carbonyl, and nitro, at positions other than the point of attachment), l,2,4-triazine-3-yl, -5-yl, and -6-yl (unsubsti
  • the compounds of formula I are preferably prepared by treating an appropriately substituted pyridine derivative of formula II
  • R an ⁇ R 2 are defined above and R 7 is 0 -0 4 alkyl, with an alkali metal 0 -0 4 alkoxide in ethanol at a temperature of 5° to 95°C, preferably at room temperature, followed by acidification to a pH of less than 6.0, preferably 2.0 to 6.0, more preferably about 5.0.
  • Compounds of formula II may suitably be prepared by treating an appropriately substituted 4-oxo-l,3-oxazine derivative of formula III with a suitably substituted 1,3- acetonedicarboxylate of formula IV in the presence of a base, for example, potassium t-butoxide, in an aprotic solvent, for example, tetrahydrofurane, at a temperature of 5° to 95°C, preferably at room temperature.
  • a base for example, potassium t-butoxide
  • an aprotic solvent for example, tetrahydrofurane
  • the 4-oxo-l, 3-oxazine derivatives of formula II may suitably be prepared according to the conventional procedure of reacting an appropriately substituted amide with meldrum's acid followed by catalytic cyclization of the acetoacetamide intermediate preferably at room temperature.
  • SUBSTITUTE SHEET reactions of a compound of formula II with sodium ethoxide and the reaction of a compound of formula III with a compound of formula IV may involve varying reaction times (suitably 2 to 24 hours or more) but preferably if at room temperature or below will involve a time of at least 12 hours to ensure complete reaction.
  • the alkali metal 0 -0 4 alkoxide is a methoxide or an ethoxide.
  • the alkali metal preferably is potassium or sodium.
  • the compounds of the present invention can be used to treat leukemia, such as acute lymphoblastic leukemia, as well as solid tumors, such as breast carcinoma, gynecologic carcinoma, bronchagenic carcinoma, and gastric carcinoma in mammals, including man.
  • solid tumors that may be treated by compounds of the present invention are e.g., tumors of the lung, breast, ovary and colon.
  • the compounds may be administered to the patient, generally a human patient, by any convenient method, but i.v. injection is preferred, suitably at a dosage level of 50 to 80 mg/m 2 , preferably 60 to 75 mg/m .
  • Selected compounds of this invention were tested for cytotoxicity and other potential pharmacological activity in accordance with known techniques.
  • Example 9 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2(lH-pyridone) .
  • KB cells were cultivated in Eagles minimum essential medium supplemented with 10% calf serum and incubated at 37°C in a humidified 5% C0 2 atmosphere to prepare a cell stock.
  • SUBSTITUTE SH ⁇ ET ISA/EP Cells were counted using a neubauer hemocytomer and seeded in 96 well plates at 100 ⁇ l of 3 X 10 3 cells per ml and cultured for 1 day. Test compounds were diluted and 100 ⁇ l of the solution was added in triplicate wells to give five final concentrations of 10, 5, 1, 0.5 and 0.1 ⁇ ml "1 . Control wells were identical except that test compound was absent. These were cultured " for three days. Then the cells were fixed with addition of 20 ⁇ l of 25% glutaraldehyde for 15 minutes, washed with water and dried. Then the cells were stained with 100 ⁇ l of 0.05% crystal violet for 15 minutes, washed with water and dried.
  • Example l was reacted with potassium t-butoxide as in Example l to produce a compound of the formula.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Alkyl 3-substituted-6,8-dihydroxy-1(2H)-oxoisoquinoline-4-carboxylates, such as ethyl 6,8-dihydroxy-3-phenyl-1(2H)-oxoisoquinoline-4-carboxylate, exhibit cytotoxicity against a wide variety of tumor cell lines, and can thus be used to treat cancer such as leukemias and carcinomas.

Description

ISOCARBOSTIRYL COMPOUNDS AND ANTITUMOR USE THEREOF
BACKGROUND OF THE INVENTION:
The present invention relates to novel alkyl 3- substituted-6,8-dihydroxy-l(2H)-oxoisoquinoline-4-carboxylates. The invention further relates to the process for the preparation and to the cytotoxicity and anti-tumor use of such compounds.
3-carboxy-2,4-dialkyl-l(2H)-oxoisoquinolines have been reported to possess local anesthetic activity, and 4-formyl-2- substituted-l(2H)-oxoquinolines have also been reported to possess anti-allergic activity. Note, for instance, Farmaco. Ed. Sci., 39(3), 229045 [CA. 100(23), 185342n] , and Chem. Pharm. Bull., 31(4), 1277-82 [C . 99(17), 139728f] . SUMMARY OF THE INVENTION:
In accordance with the present invention, there are provided compounds having the formula:
Figure imgf000003_0001
wherein R is C1_7 alkyl; unsubstituted phenyl or a phenyl substituted by different electron donating or electron attracting groups at different positions; an optionally substituted 5-or 6-membered ring azine, preferably pyridine or pyrimidine; or a C-^g alkylene, substituted terminally with optionally substituted phenyl, azinyl, or C-j^ alkyl carboxylate; R2 is hydrogen or a C1-Q alkyl chain;
R3, R4, R5 and R6 independently are hydrogen, hydroxy, Cx_6 alkoxy, or halogen.
Advantageously, the physiologically acceptable compounds of formula I possess pharmacological properties exhibiting cytotoxicity, in particular, against a wide variety of tumor cell lines. Thus, the compounds of the- present invention may be utilized as active compounds in medicaments, being formulated with one or more pharmaceutically acceptable carriers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS: When Rλ is an alkylene moiety substituted terminally with optionally substituted phenyl, azinyl or alkyl carboxylate, it is preferably of the formula -R8-R9, wherein R8 is C1-6 alkylene and Rg is phenyl, which is unsubstituted or is substituted by different electron donating or electron attracting groups at different positions, azinyl, or C-^ ^ alkyl carboxylate.
When Rλ or R9 are substituted phenyl, the phenyl ring is preferably substituted by one or two substituents, which are preferably in the m- or p- positions, and are C-^C^ alkyl, C-L*-^ alkoxy, or halogen, preferably fluorine. When R or R9 are azinyl or azole, they are a 5- or 6- membered ring azole or azine.
Suitable 5 membered azole rings include 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, pyrrol-2-yl, pyrrol-3-yl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, l,2,4-triazol-2-yl, triazol-5-yl, and triazol-4- yl.
Suitable 6 membered azinyl rings include 2-pyridyl, 4- pyridyl (unsubstituted or substituted with one or two electron donating moieties such as Cj-C^j alkoxy, halogen or ^-04 alkyl; or electron withdrawing substituents such as C2-C6 acyl, 0 -04 alkoxy carbonyl, and nitro) , 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl (unsubstituted or substituted by one or two electron donating moieties such as -^-C^ alkoxy, halogen or 0^04 alkyl; or electron withdrawing substituents such as C2-C6 acyl, ^-04 alkoxy carbonyl, and nitro, at positions other than the point of attachment), l,2,4-triazine-3-yl, -5-yl, and -6-yl (unsubstituted or substituted by one or two electron donating moieties such as _ -C^ alkoxy, C - 4 alkyl or halogen or electron withdrawing substituents such as C2-C6 acyl, C1-C4
SUBSTITUTE SHEET alkoxy carbonyl, and nitro, at positions other than the point of attachment) .
The compounds of formula I are preferably prepared by treating an appropriately substituted pyridine derivative of formula II
Figure imgf000005_0001
wherein R an~ R 2 are defined above and R7 is 0 -04 alkyl, with an alkali metal 0 -04 alkoxide in ethanol at a temperature of 5° to 95°C, preferably at room temperature, followed by acidification to a pH of less than 6.0, preferably 2.0 to 6.0, more preferably about 5.0.
Compounds of formula II may suitably be prepared by treating an appropriately substituted 4-oxo-l,3-oxazine derivative of formula III with a suitably substituted 1,3- acetonedicarboxylate of formula IV in the presence of a base, for example, potassium t-butoxide, in an aprotic solvent, for example, tetrahydrofurane, at a temperature of 5° to 95°C, preferably at room temperature.
Figure imgf000005_0002
The 4-oxo-l, 3-oxazine derivatives of formula II may suitably be prepared according to the conventional procedure of reacting an appropriately substituted amide with meldrum's acid followed by catalytic cyclization of the acetoacetamide intermediate preferably at room temperature.
While the reactions described above will proceed very well at room temperature (which is preferred) , the reactions may be conducted at a temperature within the range of 5 - 95°C The
SUBSTITUTE SHEET reactions of a compound of formula II with sodium ethoxide and the reaction of a compound of formula III with a compound of formula IV may involve varying reaction times (suitably 2 to 24 hours or more) but preferably if at room temperature or below will involve a time of at least 12 hours to ensure complete reaction.
Preferably the alkali metal 0 -04 alkoxide is a methoxide or an ethoxide. The alkali metal preferably is potassium or sodium. The compounds of the present invention can be used to treat leukemia, such as acute lymphoblastic leukemia, as well as solid tumors, such as breast carcinoma, gynecologic carcinoma, bronchagenic carcinoma, and gastric carcinoma in mammals, including man. Among other solid tumors that may be treated by compounds of the present invention are e.g., tumors of the lung, breast, ovary and colon. The compounds may be administered to the patient, generally a human patient, by any convenient method, but i.v. injection is preferred, suitably at a dosage level of 50 to 80 mg/m2, preferably 60 to 75 mg/m . Selected compounds of this invention were tested for cytotoxicity and other potential pharmacological activity in accordance with known techniques.
More particularly, Ethyl 6,8-dihydroxy-3-phenyl-l(2H)- oxoisoqύinoline-4-carboxylate, Ethyl 6,8-dihydroxy-3-ethyl- l(2H)-oxoisoquinoline-4-carboxylate, Ethyl 6,8-dihydroxy-3- phenylmethyl-l(2H)-oxoisoquinoline-4-carboxylate, Ethyl 6,8- dihydroxy-3-(2-pyridyl)-l(2H)-oxoisoquinoline-4-carboxylate, and Ethyl 6,8-dihydroxy-3-(4-fluorophenyl) -l(2H) - oxoisoquinoline-4-carboxylate demonstrated remarkable cytotoxicity against KB tumor lines.
Example 1 Ethyl 6,8-dihydroxy-3-phenyl-l(2H)-oxoisoquinoline-4- carboxylate.
3-Acetyl-5-ethoxycarbonyl-4-ethoxy carbonyl methyl-6- phenyl-2(lH)-pyridone (3.713 g. 10 mmol) was added to a solution of metallic sodium (0.250 g; 11 g atom) in ethanol (15 ml) . The solution was stirred at room temperature over night. The mixture was poured into water (160 ml) and
SUBSTITUTE SHEET acidified with 10% hydrochloric acid, followed by concentration under reduced pressure. The residue was purified by recrystallization from ethylacetate to obtain colorless prisms of the title compounds, mp 280 - 282°C, yield 96%.
NMR (CDC13 + DMSO -d6, 300 MHZ): 0.94 (3H,6, J = 2 Hz); 6.70 (1H, d, J = 2 Hz); 7.53 (5H, s) ; 10.30-12.30 (2H, br, exchangeable- with D20) ; 13.20 (1H, s) (Exchangeable with D20) .
Analysis found: 0,66.68; H; 4.64; N, 4.38
Required C18H 5NOs
C, 66.46; H, 4.65; N, 4.31
IR (KBr) : 1690 cm-1
Schematic for Example 1
1. EϊO
Figure imgf000007_0001
Figure imgf000007_0002
Employing the procedure of Example 1 and starting with the appropriately • 6-substituted-3-acetyl-5-ethoxycarbσnyl-4- ethoxycarbonyl methyl-2(lH)-pyridone derivative, the following compounds were prepared.
Example 2
Ethyl 6,8-dihydroxy-3-ethyl-l(2H)-oxoisoquinoline-4- carboxylate, yield 94% mp 245 - 246 βC (AcOET) .
NMR (CDCI3 + DMSO - d6) 1.30 (3H, t, J = 7 Hz) ; 1.42 (3H, t, J = 7 HZ); 2.67 (2H, q, J = 7 Hz); 4.43 (2H, q, J = 7 Hz); 6.35 (1H, d, J = 2 Hz); 6.63 (1H, d, J = 2 Hz); 9.60 - 10.50 (1H, br, exchangeable with D20) ; 11.20 - 12.00 (1H, br, exchangeable with D20) ; 12.60 - 13.60 (1H, br, exchangeable with D20) . IR (KBr) : 1700 cm -1
Analysis found: C, 60. 53 ; H, 5.48 ; N, 4 . 98 Required: Cl4H15N05
C, 60. 65 ; H, 5. 45 ; N, 5 . 05 Example 3 Ethyl 6 , 8-dihydroxy-3-benzyl-l (2H) -oxoisoquinoline-4 - carboxylate
SUBSTITUTE SHEET A/EP Yield: 87%; mp: 238 - 239°C (MeOH)
NMR (CDC13 + DMSO - d6): 1.30 (3H, t, J *= 7 Hz); 4.03 (2H, s); 4.34 (2H, q, J = 7 Hz); 6.33 (IH, d, J - 2 Hz); 6.58 (IH, d, J = 2 Hz); 7.30 (5H, s); 10.17 (IH, br, exchangeable with D20) ; 13.03 (IH, br, exchangeable with D20) . IR (KBr).: 1690 cm-1
Analysis" found: C, 67.43; H, 5.20; N, 4.09 Required: C19H27N05
C, 67.25; H, 5.05; N, 4.13 Example 4
Ethyl 6 , 8 -dihydroxy-3 - (p-f luorophenyl ) - l ( 2H ) - oxoisoquinoline-4 -carboxylate
Yield: 90%; mp: 303 - 307°C (AcOEt)
NMR (CDCI3 + DMSO - d6) : 0.93 (3H, t, J = 7 Hz) ; 4.03 (2H, q, J = 7 Hz); 6.35 (IH, d, J = 2 Hz); 6.63 (IH, d, J = 2 Hz);
7.03 - 7.63 (4H, ) ; 10.10 - 12.10 (IH, br, exchangeable with
D20) ; 11.60 (IH, br, exchangeable with D20) ; 13.07 (IH, s, exchangeable with D20)
Hi-Ms m/e observed: 343.0861 Required C18H24N05F: 343.0856
Example 5 Ethyl 6,8-dihydroxy-3-(p-bromophenyl)-l(2H)- oxoisoquinoline-4-carboxylate
Yield: 77%; p: 314 - 317°C (AcOET) NMR (CDCI3, DMSO - d6) : 0.93 (3H, t, J = 7 Hz); 4.05 (2H, q, J = 7 Hz); 6.37 (IH, d, J = 2 Hz); 6.65 (IH, d, J = 2 Hz); 7.33 - 7.77 (4H, m) , 10.25 (IH, s, exchangeable with D20) ; 11.50 - 12.10 (IH, br, exchangeable with D20) . IR (KBr) : 1690 cm"1 Example 6
Ethyl 6,8-dihydroxy-3-(2-Furyl)-1(2H)-oxoisoquinoline-4- carboxylate
Yield: 76%; mp: 274 - 276°c (AcOET)
NMR (CDCI3 + DMSO - d6) : 1.27 (3H, t, J = 7 Hz); 4.37 (2H, q, J = 7 Hz); 6.38 (IH, d, J = 2 Hz); 6.50 (IH, d, J = 2 Hz);
6.57 - 6.67 (IH, m) ; 7.18 - 7.29 (IH, m) ; 7.62 - 7.70 (IH, ) ;
10.23 (IH, s, exchangeable with D20) ; 10.30 - 10.80 (IH, br, exchangeable with D20) ; 13.03 (IH, s, exchangeable with D20) .
SUBSTITUTE SHEET ISA/EP IR (KBr) : 1685 cm"1
Hi - Ms m/e observed: 315.0741
Required C16H13N06: 315.0743
Example 7 Ethyl 6,8-dihydroxy-3-(2-pyridyl)-l(2H)-oxoisoquinoline-4- carboxylate *
Yield: 91%; mp: 245 - 246°C (AcOET)
NMR (CDC13 + DMSO - d6): 1.03 (3H, t, J = 7 Hz) ; 4.14 (2H, q, J = 7 HZ); 6.42 (IH, d, J = 2 Hz) ; 6.72 (2H, d, J = 2 Hz) ; 7.33 - 8.12 (3H, m) ; 8.66 - 8.77 (IH, m) ; 10.33 (IH, s, exchangeable with D20) ; 11.30 - 12.00 (IH, br, exchangeable with D20) ; 13.07 (IH, s, exchangeable with D20) . IR (KBr) : 1685 cm Hi - Ms m/e observed: 326.0974 Required C17H14N205: 326.0903
Example 8 Ethyl 6,8-dihydroxy-3-ethoxycarbonylmethyl-l (2H) - oxoisoquinoline-4-carboxylate
Yield: 75%; mp: 210 - 212°C (AcOET) NMR (CDCI3 + DMSO - d6) : 1.26 (3H, t, J = 7 Hz) ; 1.37 (3H, t, J = 7 Hz); 3.77 (2H, s) ; 4.22 (2H, q, J = 7 Hz); 4.35 (2H, q, J = 7 Hz); 6.32 (IH, d, J = 2 Hz) ; 6.85 (IH, d, J = 2 Hz); 9.50 - 11.00 (IH, br exchangeable with D20) ; 11.53 - 11.94 (IH, br, exchangeable with D20) ; 12.67 - 13.29 (IH, br, exchangeable with D20) .
IR (KBr): 1725, 1705 cm"1
Hi - Ms m/e observed: 335.1091
Required C16H17N07: 335.1005
Example 9 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2(lH-pyridone) .
A solution of potassium t-butoxide (1.1 g: 10 mmol) and diethyl 1,3-acetonedicarboxylate (2g, 10 mmol) in tetrahydrofuran (THF) (20 ml) was stirred at room temperature for 30 min. 2-Phenyl-6-methyl-l,3-oxazine-4-one (1.87 g, 10 mmol) was added to the solution, and the mixture was stirred at room temperature overnight followed by acidification with 10% HCl. The resulting solution was concentrated under reduced
SUBSTITUTE SHEET pressure, and purified by recrystallization from methanol to colorless prisms of the titled compound, mp 182 - 183°C
Yield 90%
NMR (CDC13) 0.83 (3H, t, J = 7 Hz); 1.24 (3H, t, J = Hz); 2.36 (3H, s); 3.80 (2H, s) ; 3.94 (2H, q, J = 7 Hz); 4.13 (2H, q, J = 7 Hz);-7.44 (5H, s); 12.50 - 13.50 (IH, br, exchangeable with D20) .
Figure imgf000010_0001
Schematic for Example 9
Figure imgf000010_0002
By procedures similar to those used in Example 9 and startingwithappropriate2-substituted-6-methyl-l,3-oxazine-4- one the following compounds were prepared.
Example 10 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6-ethyl- 2(IH)-pyridone
Yield 83% mp 136°C (Et20)
NMR (CDCI3) 1.27 (3H, t, J = 7 Hz); 1.37 (6H, t, J = 7 Hz); 2.60 (3H, s) ; 2.78 (2H, q, J = 7 Hz); 3.83 (2H, s) ; 4.18 (2H, q, J = 7 Hz); 4.35 (2H, q, J = 7 Hz); 13.30 - 14.20 (IH, br, exchangeable with D20) .
IR (KBr) 1725, 1695 cm' -1
SUBSTITUTE SHEET ISA/EP Example 11
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-benzyl- 2(IH)-pyridone
Yield: 86%; mp: 162 - 163°C (MeOH) NMR (CDC13): 1.27 (6H, t, J = 7 Hz); 2.56 (3H, s) ; 3.83 (2H, s); 4.17 (2H, s) ; 4.20 (2H, q, J - 7 Hz); 4.32 (2H, q, J - 7 Hz), 7.30 (5H, s) ; 12.50 - 13.60 (IH, b, exchangeable with D20).
IR (KBr): 1715, 1695 cm"1 Example 12
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(p- fluorophenyl)-2 (IH)-pyridone
Yield: 86%; mp: 187 - 189°C (MeOH)
NMR (CDCI3) : 0.93 (3H, t, J = 7 Hz); 1.27 (3H, t, J - 7 Hz); 2.40 (3H, s) ; 3.88 (2H, s) ; 4.03 (2H, q, J = 7 Hz); 4.20 (2H, q, J = 7 Hz); 7.03 - 7.67 (4H, m) . IR (KBr): 1740, 1715, 1695 cm"1 Hi - Ms m/e observed: 389.1265 Required C20H20FNO6: 389.1875 Example 13
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(p- bromophenyl-2(IH)-pyridone
Yield: 83%; mp: 175 - 176 °C (MeOH)
NMR (CDCI3) : 0.93 (3H, t, J = 7 Hz); 1.27 (3H, t, J = 7 Hz); 2.40 (3H, s) ; 3.88 (2H, s) ; 4.03 (2H, q, J 7 Hz) ; 4.20 (2H, q, J = 7 HZ); 7.27 - 7.73 (4H, m) ; 12.30 - 13.60 (IH, br, exchangeable with D2θ)
IR (KBr): 1735, 1715, 1690 cm"1
Example 14 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(2- furyl)-2(IH)-pyridone
Yield: 85%; mp: 138 - 140°C (EtOH)
NMR (CDCI3) : 1.27 (6H, t, J = 7 Hz); 2.60 (3H, s) ; 3.83 (2H, s) ; 4.20 (2H, q, J = 7 Hz) ; 4.33 (2H, q, J = 7 Hz) ; 6.53 - 6.63 (IH, m) ; 7.40 - 7.60 (2H, m) ; 12.00 - 13.80 (IH, br, exchangeable with D20) .
IR (KBr): 1735, 1720, 1700 cm"1
Hi - Ms m/e observed: 361.1078
SUBSTITUTE SHEET ISA/EP Required C28H19N07: 361.1761
Example 15 3-Acety1-5-ethoxycarbony1-4-ethoxycarbonylmethy1-6-(2- pyridyl)-2(IH)-pyridone Yield: 87%; mp: 175 - 176°C (MeOH)
NMR (CDC13): 1.02 (3H, t, J = 7 Hz) ; 1.27 (3H, t, J = 7 Hz); 2.53 (3H, S) ; 3.95 (2H, s) ; 4.i6 (2H, q, J = 7 Hz); 4.22 (2H, q, J = 7 Hz); 7.37 - 8.03 (3H, ) ; 8.70 - 8.83 (IH, m) ; 12.00 - 13.90 (IH, br, exchangeable with D20) . IR (KBr): 1735, 1715, 1685 cm"1
Example 16 3-Acetyl-4,6-diethoxycarbonylmethyl-5-ethoxycarbonyl-2- (1H)-pyridone
Yield: 72%; mp: 120 - 122°C (MeOH) NMR (CDCI3) : 1.27 (6H, t, J = 7 Hz) ; 1.35 (3H, t, J = 7 HZ); 2.58 (3H, s); 3.93 (4H, s) ; 4.15 (2H, q, J = 7 Hz) ; 4.18 (2H, q, J = 7 Hz); 4.27 (2H, q, J - 7 Hz); 13.00 - 14.50 (IH, br, exchangeable with D20) .
Hi - Ms m/e observed: 381.1370 Required C18H23N08: 381.1424
In Vitro KB Cell Cvtotoxic Assay The method employed in the assay was a modification of the crystal violet assay (Gillies et al. Anal. Biochem. , 159 , 109 (1986) . Materials:
- KB cells (ATCC CCL 17)
- Minimum Essential Medium, Eagles (Modified with Earles salt) supplemented with 10% calf serum, 100 IUml-1 penicillin G, 100 ugml"1 streptomycin. - Compounds dissolved in DMSO to 20 mgl"1 and further diluted in the 10% CS-MEM
- Crystal violet
- 25% glutaraldehyde
- deionized water Procedure:
KB cells were cultivated in Eagles minimum essential medium supplemented with 10% calf serum and incubated at 37°C in a humidified 5% C02 atmosphere to prepare a cell stock.
SUBSTITUTE SHΕET ISA/EP Cells were counted using a neubauer hemocytomer and seeded in 96 well plates at 100 μl of 3 X 103 cells per ml and cultured for 1 day. Test compounds were diluted and 100 μl of the solution was added in triplicate wells to give five final concentrations of 10, 5, 1, 0.5 and 0.1 μml"1. Control wells were identical except that test compound was absent. These were cultured" for three days. Then the cells were fixed with addition of 20 μl of 25% glutaraldehyde for 15 minutes, washed with water and dried. Then the cells were stained with 100 μl of 0.05% crystal violet for 15 minutes, washed with water and dried. The wells were eluted with 100 μl of 0.05 M NaH2P04/ethanol (l:lv/v) and read at OD540 on a multiscan spectrophotometer. ED50 values were calculated using the formula -
% inhibition greater than 50% - 50%
% inhibition greater than 50% - % inhibition less than 50% to give the interpolative value between two dilutions.
The selected compounds of this invention were tested against KB tumor cell lines. The results are shown in the following Table.
TD50 OF ISOCARBOSTERYL DERIVATIVES
Figure imgf000013_0001
Compound # 1 2 4
7
Figure imgf000013_0002
Adriamycin 0.04
SUBSTITUTE SHEET Example 17 An intermediate of the formula
Figure imgf000014_0001
was reacted with potassium t-butoxide as in Example 1 to produce a compound of the formula
Figure imgf000014_0002
Example 18 An intermediate of the formula
Figure imgf000014_0003
was reacted with potassium t-butoxide as in Example l to produce a compound of the formula.
Figure imgf000014_0004
SUBSTITUTE SHEET Example 19 3-Acetyl-5-ethyoxycarbonyl-4-ethoxycarbonylmethyl-6-(3- pyridyl)-2(IH)-pyridone.
A solution of potassium t-butoxide (0.178 g, 1.59 mmol) and diethyl-l,3-acetonedicarboxylate (0.322 g, 1.59 mmol) in tetrahydrofuran (THF) (5ml) was stirred at room temperature for 30 min. 2-(3-pyridyl)-6-methyl-l,3-oxazin-4-one (0.300 g, 1.59 mmol) was added to the solution, and the mixture was stirred at room temperature overnight followed by acidification with 10% HCl. The resulting solution was concentrated under reduced pressure and purified by elution through a silica gel column using methanol-chloroform (1:10) as eluent to give colorless powder of the titled compound, mp 209 - 211°c Yield: 47% NMR (CDC13, 200 MHz): 0.89 (3H, t, J = 7Hz) ; 1.25 (3H, t, J = 7Hz) ; 2.39 (3H, s) ; 3.83 (2H, s) ; 3.97 (2H, q, J = 7Hz) ; 4.14 (2H, q, J = 7Hz) 7.31 - 7.37 (IH, m) ; 7.75 - 7.79 (IH, m) ; 8.53 - 8.64 (2H, m) ; 12.40 - 13.50 (IH, br, exchangeable with D20) . IR (KBr): 1735, 1715, 1685 cm"1
Analysis found: C, 61.36; H, 5.31; N, 7.47 Required: C19H20N2O6: C, 61.27; H, 5.42; N, 7.52
Figure imgf000015_0001
Example 20 3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(2- fluorophenyl)-2(IH)-pyridone
By procedure similar to that used in Example 19 and starting with the appropriate 2-substituted-6-methyl-l,3- oxazine-4-one, the title compound was prepared.
SUBSTITUTE SHEET Yield: 59%, mp 195 - 197°C
NMR (CDC13 200 MHz): 0.87 (3H, t, J = 7Hz) ; 1.25 (3H, t, J = 7Hz); 2.35 (3H, s) ; 3.91 (2H, s) ; 3.97 (2H, q, J = 7Hz) ; 4.15 (2H, q, J = 7HZ); 7.20 - 7.64 (4H, m) ; 12.2 - 13.7 (IH, br, exchangeable with D20)
IR (KBr): 1740, 1715, 1695 cm"1
Analysis found: C, 61.63; H, 5.31; N, 3.74.
Required: C2oH2oFN06: C, 61.68; H7 5.19; N, 3.60
Figure imgf000016_0001
Example 21 Ethyl-6,8-dihydroxy-3-(3-pyridyl)-1(2H)-oxoisoquinoline-4- carboxylate.
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6-(3- pyridyl)-2(IH)-pyridone (0.280 g, 0.754 mmol) was added to a solution of metallic sodium (0.019 g, 0.829 mmol) in ethanol (5 ml) . The solution was stirred at room temperature overnight. The mixture was poured into water (40 ml) and acidified with 10% hydrochloric acid, followed by concentration under reduced pressure. The residue was purified by elution through a silica gel column using methanol-chloroform (1:9) as eluent to give the titled compound as a fine colorless powder, m.p. 278 - 280°C
Yield: 61%
NMR (CDCI3 + DMSO - d5, 200 MHz): 0.93 (3H, t, J = 7Hz) ; 4.03 (2H, t, J = 7HZ) ; 6.43 (IH, d, J = 2Hz) ; 6.76 (IH, d, J = 2 Hz); 7.39 - 7.46 (IH, m) ; 7.79 - 7.85 (IH, m) ; 8.68 - 8.71 (2H, m) ; 9.90 - 10.00 (IH, br, exchangeable with D20) ; 11.40 - 11.60 (IH, br, exchangeable with D20) ; 12.89 - 12.95 (IH, br, exchangeable with D20) . IR: 1685 cm"1 Analysis found: C, 62.49; H, 4.19; N, 8.72.
Required: C17H14N205: C, 62.57; H, 4.33; N. 8.59
SUBSTITUTE SHEET
Figure imgf000017_0001
Example 22
Ethyl-6 ,8-dihydroxy-3-(2-fluorophenyl)-l(2H)- oxoisoquinoline-4-carboxylate.
By procedure used in Example 21 and starting with the appropriate 6-substituted-3-acetyl-5-ethoxycarbonyl-4- ethoxycarbonylmethyl-2(lH)-pyridone derivative, the title compound was prepared.
Yield: 64%, m.p. 279 - 281°C
NMR (CDC13 + DMSO - d6, 200 MHz): 0.89 (3H, t, J = 7Hz) ; 4.01 (2H, q, J -= 7HZ); 6.47 (IH, d, J = 2 Hz) ; 6.90 (IH, d, J = 2Hz); 7.13 - 7.3 (2H, m) ; 7.36 - 7.53 (2H, m) ; 9.50 - 9.90 (IH, br, exchangeable with D20) ; 10.10 - 11.10 (IH, br, exchangeable with D20) ; 12.60 - 12.70 (IH, br, exchangeable with D20) .
IR (KBr) : 1690 cm"1
Analysis found: C, 63 .10 ; N, 4. 19 ; N, 4.01
Required: C18H14N05F: C, 62.97 ; H, 4.12 ; N, 4.08
Figure imgf000017_0002
SUBSTITUTE SHEET ISA/EP

Claims

CLAIMS :
1. A compound of the formula
Figure imgf000018_0001
wherein.R2 is C^C, alkyl; phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of 0 -04 alkyl, ι- 4 alkoxy and halogen; an optionally substituted 5- or 6-membered ring azine selected
Figure imgf000018_0002
l,2,3-triazol-4-yl, triazol-5-yl, triazol-l-yl, 1,2,4-triazol- triazol-2-yl, triazol-5-yl, triazol-4-yl, 2-pyridyl, 4-pyridyl, unsubstituted or substituted with at least one electron donating moiety or electron withdrawing substituent, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, unsubstituted or substituted by at least one electron donating moiety or electron withdrawing substituent at a position other than the point of attachment; l,2,4-triazine-3-yl, 1,2,4-triazine -5-yl, l,2,4-triazine-6-yl, unsubstituted or substituted by at least one electron donating moiety electron withdrawing substituent at a position other than the point of attachment and -R8-R9; R2.is hydrogen or C2-C8 alkyl; R3 and R5 are independently hydrogen or an electron donating group which is C2-C6 alkyl, C2-C4 alkoxy or
-NRaRb?
R4 and R6 are independently hydroxy, halogen, or C -C4 alkoxy;- C-i -Cg alkylene;
SUBSTITUTE SHEET
Figure imgf000018_0003
JSA/EP R9 is phenyl which is unsubstituted or is substituted by at least one substituent selected from the group consisting of
C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted
5- or 6-membered ring azole or azine, and C2-C4 alkyl carboxylate; and
Ra and Rjj are independently hydrogen or C2-C4 alkyl.
2. The compound of claim 1, wherein the electron donating moiety is selected from the group consisting of C2-C4 alkoxy, C^-C^ alkyl or halogen.
3. The compound of claim 1, wherein the electron withdrawing substituent is selected from the group consisting of C2-C6 acyl, C2-C alkoxy carbonyl, and nitro.
4. The compound of claim 1, wherein Rλ is hydrogen, methyl, ethyl, isopropyl, t-butyl, n-pentyl, n-hexyl or n- heptyl.
5. The compound of claim 4, wherein R2 is ethyl, R3 and R5 are both hydrogen atoms, and R4 and R6 are both hydroxyl groups.
6. The compound of claim 1, wherein R2 is phenyl which is unsubstituted or substituted by halogen or C -C3 alkoxy.
7. The compound of claim 1, wherein Rx is pyridyl or furyl.
8. The compound of claim 1, wherein R2 is benzyl or ethoxy carbonylmethyl.
9. The compound of claim 1, wherein said compound is selected from the group consisting of:
Ethyl 6,8-dihydroxy-3-phenyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6,8-dihydroxy-3-ethyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6,8-dihydroxy-3-benzyl-l(2H)-oxoisoquinoline-4- carboxylate;
Ethyl 6 , 8 -d ihydroxy- 3 - ( p- f luoropheny l ) - 1 ( 2 H ) - oxoisoquinoline-4-carboxylate ; Ethy l 6 , 8 - d i hydr o xy - 3 - ( p - br omoph e ny 1 ) - 1 ( 2 H ) - oxoisoquinoline-4-carboxylate;
Ethyl 6,8-dihydroxy-3-(2-furyl)-l(2H)-oxoisoquinoline-4- carboxylate;
SUBSTITUTE SHEET ISA/EP Ethyl 6,8-dihydroxy-3-(2-pyridyl)-1(2H)-oxoisoquinoline-4- carboxylate; and
Ethyl 6,8-dihydroxy-3-ethoxycarbonylmethyl-l-(2H)- oxoisoquinoline-4-carboxylate.
10. The compound of claim 1, wherein R2 is C2-C4 alkyl.
11. The compound of claim 1, wherein R9 is 2-pyridyl.
12. A" pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 10, and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition for the treatment of tumors comprising an anti-tumor effective amount of the compound of claim 11, and a pharmaceutically acceptable carrier.
15. A method of treating leukemia or a solid tumor in a patient in need of such treatment, said method comprising administering to said patient an anti-tumor effective amount of a compound of claim 1.
16. The method of claim 13, wherein the solid tumor is breast carcinoma, gynecologic carcinoma, bronchogenic carcinoma or gastric carcinoma.
17. A compound of the formula
Figure imgf000020_0001
wherein R1 is C^G**, alkyl; phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-
SUBSTITUTE SHEET furyl, pyrrol-2-yl, pyrrol-3-yl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-1-yl, 1,2,4-triazol- triazol-2-yl,-triazol-4-yl, triazol-5-yl, 2-pyridyl, 4-pyridyl unsubstituted or substituted with at least one electron donating moiety or electron withdrawing substituent, 1,2,4- triazine-3-yl, l,2,4-triazine-5-yl, l,2,4-triazine-6-yl, unsubstituted or substituted by at least one electron donating moiety or electron withdrawing substituent at a position other than the point of attachment, or -R8-R9; R2 is hydrogen or C-^Cg alkyl; R3 and R5 are independently hydrogen or an electron donating group which is C2-C6 alkyl, C2-C4 alkoxy or
- RaRb
R and R6 are independently hydroxy, halogen, or C2-C4 alkoxy; R7 is C2-C8 alkyl;
R8 is C2-C6 alkylene;
R9 is phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C -C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine, and C -C4 alkyl carboxylate; and
Ra and Rb are independently hydrogen or C2-C4 alkyl.
18. The compound of claim 17, wherein R is hydrogen, methyl, ethyl, isopropyl, t-butyl, n-pentyl, n-hexyl or n- heptyl.
19. The compound of claim 18, wherein R2 is ethyl.
20. The compound of claim 17, wherein is phenyϊ which is unsubstituted or substituted by halogen or 0 -03 alkoxy.
21. The compound of claim 13, wherein x is pyridyl or furyl.
22. The compound of claim 13, wherein Rλ is benzyl or ethoxy carbonylmethyl.
SUBSTITUTE SHEET
23. The compound of claim 13 , wherein said compound is selected from the group consisting of
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6- phenyl-2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonyl methyl-6-ethyl- 2 (IH) -pyridone;
3 -Acety 1-5 -ethoxycarbony 1-4 -ethyoxycarbonylmethy 1-6- benzyl-2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethyoxycarbonylmethyl-6- (p- f luorophenyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (p- bromo-phenyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (2- furyl) -2 (IH) -pyridone;
3-Acetyl-5-ethoxycarbonyl-4-ethoxycarbonylmethyl-6- (2- pyridyl) -2 ( IH) -pyridone ; and
3-Acetyl-4 , 6-diethoxycarbonylmethyl-5-ethoxycarbonyl-2- ( IH) -pyridone .
24. A method of making a compound of the formula:
Figure imgf000022_0001
wherein Rx is C2-C7 alkyl; phenyl which is unsubstituted or is substituted by at least one substituent selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine selected from the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3- furyl, pyrrol-2-yl, pyrrol-3-yl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, l,2,3-triazol-4-yl, triazol-5-yl, triazol-l-yl, 1,2,4-triazol-
SUBSTITUTE SHEET triazol-2-yl, triazol-5-yl, triazol-4-yl, l,2,4-triazine-3-yl, l,2,4-triazine-5-yl, l,2,4-triazine-6-yl, unsubstituted or substituted by at least one electron donating moiety or electron withdrawing substituent at a position other than the point of attachment, 2-pyridyl, 4-pyridyl, unsubstituted or substituted with at least one electron donating moiety or electron withdrawing substituent, and -R8-R9;
R2 is hydrogen or C -C8 alkyl;
R3 and R5 are independently hydrogen or an electron donating group which is C2-C6 alkyl, C2-C4 alkoxy or -NRaRb;
R4 and R6 are independently hydroxy, halogen, or -1- -4 alkoxy;
R8 is C2-C6 alkylene; and
R9 is phenyl which is unsubstituted or is substituted by at least one substituent which is selected from the group consisting of C2-C4 alkyl, C2-C4 alkoxy and halogen, an optionally substituted 5- or 6-membered ring azine and C2-C4 alkyl carboxylate;
Ra and Rb are independently hydrogen or C -C4 alkyl; said method comprising (i) reacting a compound of the formula
Figure imgf000023_0001
wherein Rχ and R2 are defined above and R7 is C2-C8 alkyl with an alkali metal C2-C4 alkoxide at a temperature of about 5 to 95°C and (ii) acidifying at a temperature of 5° to 95°C the resulting reaction product to a pH of less than 6.0.
25. The method of claim 24, wherein the pH is about 5.0.
26. The method of claim 24, wherein the acidification is by addition of a mineral acid.
27. The compound of claim 1 wherein R2 is a C2-C8 alkyl chain.
SUBSTITUTE SHEET
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5696159A (en) * 1994-08-03 1997-12-09 Cell Pathways, Inc. Lactone compounds for treating patients with precancerous lesions
US5776962A (en) * 1994-08-03 1998-07-07 Cell Pathways, Inc. Lactone compounds for treating patient with precancerous lesions
US5852035A (en) * 1997-12-12 1998-12-22 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to substituted N- arylmethyl and heterocyclmethyl-1H-pyrazolo (3,4-B) quinolin-4-amines
US5874440A (en) * 1995-06-07 1999-02-23 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyrimidinone derivatives
US5942520A (en) * 1998-01-27 1999-08-24 Cell Pathways, Inc. Method for inhibiting neoplastic cells by exposure to substituted N-cycloalkylmethyl-1-H-pyrazolo (3,4-B) quinolone-4 amines
US5990117A (en) * 1998-04-15 1999-11-23 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to quinazoline derivatives
US6020379A (en) * 1999-02-19 2000-02-01 Cell Pathways, Inc. Position 7 substituted indenyl-3-acetic acid derivatives and amides thereof for the treatment of neoplasia
US6034099A (en) * 1998-11-24 2000-03-07 Cell Pathways, Inc. Method for inhibiting neoplastic lesions by administering 4-(arylmethylene)- 2, 3- dihydro-pyrazol-3-ones
US6046199A (en) * 1998-01-14 2000-04-04 Cell Pathways, Inc. Method of inhibiting neoplastic cells with tetracyclic pyrido[3,4-B]indole derivatives
US6046216A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyridinone derivatives
US6046206A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
US6060477A (en) * 1995-06-07 2000-05-09 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl cycloamino pyrimidinone derivatives
US6077842A (en) * 1998-11-24 2000-06-20 Cell Pathways, Inc. Method of inhibiting neoplastic cells with pyrazolopyridylpyridazinone derivatives
US6124303A (en) * 1998-09-11 2000-09-26 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 9-substituted 2-(2-N-aloxyphenyl) purin-6-ones
US6130053A (en) * 1999-08-03 2000-10-10 Cell Pathways, Inc. Method for selecting compounds for inhibition of neoplastic lesions
US6133271A (en) * 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US6156528A (en) * 1997-05-30 2000-12-05 Cell Pathways, Inc Methods for using a phosphodiesterase in pharmaceutical screening to identify compounds for treatment of neoplasia
US6177471B1 (en) 1999-01-29 2001-01-23 Cell Pathways, Inc. Method for treating patients with acne by administering a CGMP-specific PDE inhibitor
US6180629B1 (en) 1998-08-14 2001-01-30 Cell Pathways, Inc. [4,5]-Fused-1,3-disubstituted-1,2-diazine-6-one derivatives with nitrogen containing substitutents in position one for the treatment of neoplasia
US6187779B1 (en) 1998-11-20 2001-02-13 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives
US6200771B1 (en) 1998-10-15 2001-03-13 Cell Pathways, Inc. Method of using a novel phosphodiesterase in pharmaceutical screeing to identify compounds for treatment of neoplasia
US6200980B1 (en) 1995-06-07 2001-03-13 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl purinone derivatives
US6232312B1 (en) 1995-06-07 2001-05-15 Cell Pathways, Inc. Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides
US6262059B1 (en) 1995-06-07 2001-07-17 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with quinazoline derivatives
US6268372B1 (en) 1998-09-11 2001-07-31 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones
US6369092B1 (en) 1998-11-23 2002-04-09 Cell Pathways, Inc. Method for treating neoplasia by exposure to substituted benzimidazole derivatives
US6486155B1 (en) 1998-11-24 2002-11-26 Cell Pathways Inc Method of inhibiting neoplastic cells with isoquinoline derivatives
US6500610B1 (en) 1997-05-30 2002-12-31 Cell Pathways, Inc Methods for identifying compounds for inhibiting of neoplastic lesions, and pharmaceutical compositions containing such compounds
US6555547B1 (en) 2000-02-28 2003-04-29 Cell Pathways, Inc. Method for treating a patient with neoplasia by treatment with a vinca alkaloid derivative
US6569638B1 (en) 2000-03-03 2003-05-27 Cell Pathways, Inc Method for screening compounds for the treatment of neoplasia
US7115647B2 (en) 1998-01-14 2006-10-03 Osi Pharmaceuticals, Inc. Method of inhibiting neoplastic cells with indole derivatives
WO2011107709A1 (en) * 2010-03-01 2011-09-09 Universite Joseph Fourier Use of isoquinolones for preparing drugs, novel isoquinolones and method for synthesising same
WO2015015420A1 (en) * 2013-07-30 2015-02-05 Narodowy Instytut Zdrowia Publicznego Państwowy Zakład Higieny Novel derivatives of a 3,4-dihydroisoquinoline-3-carboxylic acid having anti-cancer properties, a method for their synthesis, pharmaceutical compositions comprising said derivatives, and their use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3491101A (en) * 1967-05-19 1970-01-20 American Cyanamid Co 5,8-dioxygenated isoquinoline-4-carboxylates
GB1480737A (en) * 1973-10-11 1977-07-20 Beecham Group Ltd Isocoumarins thiaisocoumarins and isocarbostyrils and pharmaceutical compositions containing them
US4393210A (en) * 1980-08-28 1983-07-12 Seiyaku Co., Ltd. 1(2H)-Isoquinolone compounds and acid addition salts thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3491101A (en) * 1967-05-19 1970-01-20 American Cyanamid Co 5,8-dioxygenated isoquinoline-4-carboxylates
GB1480737A (en) * 1973-10-11 1977-07-20 Beecham Group Ltd Isocoumarins thiaisocoumarins and isocarbostyrils and pharmaceutical compositions containing them
US4393210A (en) * 1980-08-28 1983-07-12 Seiyaku Co., Ltd. 1(2H)-Isoquinolone compounds and acid addition salts thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical and Pharmaceutical Bulletin, volume 31, no. 4, April 1983 (Tokyo, JP) M. Kimura et al.: "1(2H)-isoquinolones as potential antiallergic agents", pages 1277-1282, see the whole article (cited in the application) *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US5696159A (en) * 1994-08-03 1997-12-09 Cell Pathways, Inc. Lactone compounds for treating patients with precancerous lesions
US6262059B1 (en) 1995-06-07 2001-07-17 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with quinazoline derivatives
US5874440A (en) * 1995-06-07 1999-02-23 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl pyrimidinone derivatives
US6200980B1 (en) 1995-06-07 2001-03-13 Cell Pathways, Inc. Method of treating a patient having precancerous lesions with phenyl purinone derivatives
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US6046206A (en) * 1995-06-07 2000-04-04 Cell Pathways, Inc. Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
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