WO2006098620A1 - Use of derivatives comprising a coumarin group for the preparation of an antiviral agent, derivatives comprising a coumarin group, a method for the preparation thereof, and pharmaceutical compositions containing them - Google Patents

Use of derivatives comprising a coumarin group for the preparation of an antiviral agent, derivatives comprising a coumarin group, a method for the preparation thereof, and pharmaceutical compositions containing them Download PDF

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WO2006098620A1
WO2006098620A1 PCT/NL2006/000142 NL2006000142W WO2006098620A1 WO 2006098620 A1 WO2006098620 A1 WO 2006098620A1 NL 2006000142 W NL2006000142 W NL 2006000142W WO 2006098620 A1 WO2006098620 A1 WO 2006098620A1
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branched
linear
alkyl
alkoxy
group
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PCT/NL2006/000142
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French (fr)
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Geert Jan Sterk
Bernardus Rademaker
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Rademaker Holding B.V.
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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • derivatives comprising a coumarin group for the preparation of an antiviral agent, derivatives comprising a coumarin group, a method for the preparation thereof, and pharmaceutical compositions containing them
  • the present invention relates to the use of 1,4- dihydropyridine-5-carboxylic acid derivatives comprising a coumarin group and pyridine-5-carboxylic acid derivatives comprising a coumarin group for the preparation of an anti-viral agent.
  • 1, 4-dihydropyridine-5-carboxylic acid ester derivatives comprising a coumarin group as anti-viral agents is known from the International patent application WO 01/14370 (Rephartox B. V.).
  • the virus diseases may be those virus diseases caused by: 1 Adenovirus type 2 2 Coxsackie virus B4
  • KOS Herpes simplex virus 1
  • F Herpes simplex virus 1
  • Mclntyre TK-B2006
  • TK-VMW1837 Herpes simplex virus 1
  • TK-Cheng C158/77 Herpes simplex virus 1
  • the object of the present invention is to provide a new use.
  • the present invention relates to the use of compounds comprising a coumarin group of the general formula (I) or (II)
  • R is hydrogen, CN, NO 2 or a -COOR' -group, wherein R' represents a linear or branched (Ci_ 6 ) alkyl group;
  • Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci- ⁇ ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_ e ) alkanol, carbox- amide;
  • R2 represents OH, linear or branched (Ci_ 6 ) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
  • R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
  • R4 represents H or a coumarinyl group of the formula III
  • X represents a single bond, - (CH 2 ) n -O-, or - (CH 2 ) ra -Y-
  • n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C 3 - ⁇ ) cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C 2 ) alkyl groups ;
  • R5 represents hydrogen, linear or branched (C 1 - ⁇ ) alkyl, linear or branched (Ci_ 6 ) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base for the preparation of a drug for the prevention of and/or treatment of Severe Acute Respiratory Syndrome (SARS) .
  • SARS Severe Acute Respiratory Syndrome
  • Rl- or R5-groups may be present. If there are more than 1 Rl (or R5) groups, these may optionally be different. R5 may be present on any carbon atom of the backbone of the coumarin ring system.
  • an optionally present alkyl group, alkanol group or alkoxy group preferably has 1 or 2 carbon atoms.
  • Alkanol is an alkylgroup substituted with an hydroxyl group.
  • cycloalkyl is understood to mean a cycloalkyl group having 3 to 8 carbon atoms.
  • Halogen is understood to mean a halogen atom chosen from the group consisting of fluoro, chloro, bromo or iode, preferably fluoro or chloro.
  • SARS is caused by a virus named SARS-CoV (SARS associated corona virus) .
  • SARS-CoV SARS associated corona virus
  • the largest group of anti-viral compounds known in the art include nucleoside-analogues .
  • the disadvantage is that virus strains are increasingly becoming resistant to these analogues. For this reason there is a strong need for new compounds having an anti-viral activity.
  • the compounds of the formulas (I) and (II) which are not nucleoside-analogues, show excellent anti-viral activity against SARS.
  • the importance of an effective medicine against SARS cannot be emphasized enough.
  • Literature also discloses other coumarine derivatives having anti-viral activity.
  • the International patent application WO92/18123 discloses coumarine derivatives, and as most related compounds alkoxy coumarine derivatives. These compounds are indicated to be suitable for inhibiting the replication of retrovirusses .
  • Preferred compounds are those wherein R4 is an optionally substituted coumarin-4-yl-group.
  • R2 and R3, R3' are chosen from an optionally substituted coumarin-4-yl-group and an optionally substituted coumarin-7-yl-group.
  • the present invention also relates to a pyridine-5-carboxylic acid ester derivative comprising a coumarine group, of the formula I
  • R represents hydrogen, CN, NO 2 or a -COOR' -group, wherein R' is a linear or branched (Ci- 6 ) alkyl group;
  • Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci_ 6 ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, an optionally esterified linear or branched (Ci_ 6 ) alkanol, carboxamide;
  • R2 represents OH, linear or branched (Ci- ⁇ ) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
  • R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
  • R4 represents H or a coumarinyl group of the formula III
  • X represents a single bond, - (CH 2 ) n -O-, or - (CH 2 ) ra -Y-
  • Y represents phenylene, (C 3 _ 8 ) cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C 2 ) alkyl groups ;
  • R5 represents hydrogen, linear or branched (Ci- ⁇ ) alkyl, linear or branched (Ci_ 6 ) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base. If there is more than 1 Rl group
  • the present invention also relates to a method for the preparation of a compound of the formula (I) (i;
  • R represents hydrogen, CN, NO 2 or a -COOR' -group, wherein R' is a linear or branched (Ci_ 6 ) alkyl group;
  • Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci- ⁇ ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, an optionally esterified linear or branched (Cx-g) alkanol, carboxamide;
  • R2 represents OH, linear or branched (Ci- ⁇ ) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
  • R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
  • R4 represents H or a coumarinyl group of the formula III
  • X represents a single bond, -(CHa) n -O-, or - (CH 2 ) m ⁇ Y ⁇ (CH 2 J k -O, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C 3 _ 8 ) cycloalkylene, or represents a carbon atom substituted with 1 or 2 (C 1 -C 2 ) alkyl groups;
  • R5 represents hydrogen, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci- 6 ) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, by subjecting a compound of the formula (II),
  • Suitable oxidizing agents are, for example, 3-chloroperbenzoic acid, hydrogen peroxide, silver oxide, hydroxy (tosyloxy) iodobenzene .
  • the present invention relates to new coumarine derivatives of the formula (II'), a subset of the compounds of the formula II ( II '
  • R represents hydrogen, CN, NO 2 or a -COOR' -group, wherein R' is a linear or branched (C ⁇ - 6 ) alkyl group;
  • Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci_ 6 ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_ 6 ) alkanol, carbox- amide;
  • R2 represents OH, linear or branched (Ci_ 6 ) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
  • R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
  • R4 represents H or a coumarinyl group of the formula III
  • X represents a single bond, - (CH 2 ) n -0 ⁇ , or - (CH 2 ) m -Y- (CH 2 ) k -0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C 3 _ 8 ) cycloalkylene, or a carbon atom._ s ⁇ b.At.itj ⁇ .te.d..._with 1 or 2 (Ci-C 2 ) alkyl groups;
  • Rl R ⁇ or R4;
  • R2 (Ci-C 6 ) alkoxy or R4;
  • R3 H or R4;
  • R4 a coumarine group of the formula III;
  • R5 H, (Ci-C 6 ) alkyl, (Ci-C 5 ) alkoxy, halogen, nitro, hydroxyl, or amino;
  • R6 H, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a (Ci-C 6 ) alkanol, carboxamide, optionally substituted with 1-2 (Ci-C 6 ) alkyl groups ;
  • the disclaimer aims to exclude all compounds as disclosed in WO 01/14370 and in Dutch patent application NL1012886 on which it is based.
  • the new compounds as claimed herein can be prepared using the method as disclosed in WO 01/14370 and NL1012886.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient.
  • the present invention will now be elucidated on the basis of the following embodiments and in vivo experiments. Starting materials can either be obtained commercially or can be easily prepared by those skilled in the art analogous to known compounds. Known starting materials are disclosed in PCT WO 94/12488. The invention will now be elucidated on the basis of the following examples.
  • Method D which includes the steps of a) subjecting 2, 6-dimethyldihydropyridine derivative of the formula
  • R represents hydrogen, CN, NO 2 or a -COOR' -group, wherein R' is a linear or branched (Ci_ 6 ) alkyl group;
  • Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (C ⁇ -6) alkyl, linear or branched (Ci_ 6 ) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified a linear or branched (C ⁇ - ⁇ ) alkanol, carboxamide;
  • R2 represents OH, linear or branched (Ci- ⁇ ) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
  • R3, R3' represent hydrogen
  • R4 represents H or a coumarinyl group of the formula III
  • X represents a single bond, - (CH 2 ) n -0-, or - (CH 2 ) m -Y- (CH 2 ) k ⁇ 0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and
  • Y represents phenylene, (C 3 _ 8 ) cycloalkylene, or a carbon atom substituted with 1 or 2 (C 1 -C 2 ) alkyl groups ;
  • R5 represents hydrogen, linear or branched (Ci_ 6 ) alkyl, linear or branched (Ci- ⁇ ) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cy- cloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro;
  • R, Rl, R2, R3, R3' and R4 are as defined before, with the provisio that at least 1 of R3 and R3' is an optionally substituted coumarinyl group.
  • Suitable bromination reagents for carrying out step a) are, for example, bromine, fosfortribromide, N-bromosuccinimide, pyridinium- bromideperbromide .
  • a purification step may be carried out, for example, chromatography over silica or crystallisation, wherein the purified product can be used in the subsequent step.
  • the method for the preparation of the 2-bromoethyl- dihydropyridine derivative, intermediate obtained after step a) takes place analogous to that disclosed by D. Alker et al in: Tetrahedron Letter, 3JL' P- 1479-1482, 1990.
  • Solid pyridiniumbromideperbromide (15 mmol) was added portion- wise to a stirred ice-cold solution of a dihydropyridine (10 mmol) in CH 2 Cl 2 . After completing the addition, the mixture was stirred for another 15 minutes, washed with ice-cold 2 M HCl, dried over MgSO 4 and concentrated by evaporation without heating.
  • Method D is visualized in the diagram of the sole figure, wherein 1: pyridiniumbromideperbromide in CH 2 Cl 2 , 0°C 2: hydroxycoumarine, K 2 CO 3 , DMF, 60°C
  • IC50 Concentration of the substance to be tested at which the virus production is inhibited by 50 %.
  • CC50 Concentration of the substance to be tested required to reduce cell growth by 50%.

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Abstract

The present invention relates to the use of 1, 4-dihydropyridine-5- carboxylic acid derivatives comprising a coumarine group and pyridine-5-carboxylic acid derivatives 1, 4-dihydropyridine-5-carboxylic acid derivatives comprising a coumarine group of the general formula (I) or (II) for the preparation of a drug against SARS. The invention also relates to new coumarine compounds of the formula (I) and (II), to a method for the preparation thereof as well as to pharmaceutical compositions containing said compounds of the formula (I) or (II).

Description

Use of derivatives comprising a coumarin group for the preparation of an antiviral agent, derivatives comprising a coumarin group, a method for the preparation thereof, and pharmaceutical compositions containing them
The present invention relates to the use of 1,4- dihydropyridine-5-carboxylic acid derivatives comprising a coumarin group and pyridine-5-carboxylic acid derivatives comprising a coumarin group for the preparation of an anti-viral agent. The use of 1, 4-dihydropyridine-5-carboxylic acid ester derivatives comprising a coumarin group as anti-viral agents is known from the International patent application WO 01/14370 (Rephartox B. V.). The virus diseases may be those virus diseases caused by: 1 Adenovirus type 2 2 Coxsackie virus B4
3 Cytomegalovirus (AD-169 strain; Davis strain)
4 Herpes simplex virus 1 (KOS; F; Mclntyre; TK-B2006; TK-VMW1837; TK-Cheng C158/77; TK-Field C137/101)
5 Herpes simplex virus-2 (G; 196; Lyons) 6 HIV-I
7 HIV-2
8 Influenza virus A
9 Influenza virus B
10 Parainfluenza-3 virus 11 Polio virus-1
12 Reovirus
13 Respiratory syncytial virus
14 Semliki forest virus
15 Sindbis virus 16 Vaccinia virus
17 Varicella zoster virus (TK+ OKA strain; TK+ YS strain; TK- 07/1 strain; TK- YS/R strain;
18 Vesicular stomatitus virus.
The object of the present invention is to provide a new use. Thus, the present invention relates to the use of compounds comprising a coumarin group of the general formula (I) or (II)
Figure imgf000003_0001
wherein
R is hydrogen, CN, NO2 or a -COOR' -group, wherein R' represents a linear or branched (Ci_6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci-β) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_e) alkanol, carbox- amide;
R2 represents OH, linear or branched (Ci_6) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
[HI)
Figure imgf000003_0002
wherein
X represents a single bond, - (CH2) n-O-, or - (CH2) ra-Y-
(CH2) k~0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C3-β) cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C2) alkyl groups ;
R5 represents hydrogen, linear or branched (C1-^) alkyl, linear or branched (Ci_6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base for the preparation of a drug for the prevention of and/or treatment of Severe Acute Respiratory Syndrome (SARS) .
It is noted that more than 1 Rl- or R5-groups may be present. If there are more than 1 Rl (or R5) groups, these may optionally be different. R5 may be present on any carbon atom of the backbone of the coumarin ring system. In the present application an optionally present alkyl group, alkanol group or alkoxy group, preferably has 1 or 2 carbon atoms. Alkanol is an alkylgroup substituted with an hydroxyl group.
In the present application the term cycloalkyl is understood to mean a cycloalkyl group having 3 to 8 carbon atoms. Halogen is understood to mean a halogen atom chosen from the group consisting of fluoro, chloro, bromo or iode, preferably fluoro or chloro.
SARS is caused by a virus named SARS-CoV (SARS associated corona virus) . The largest group of anti-viral compounds known in the art include nucleoside-analogues . The disadvantage is that virus strains are increasingly becoming resistant to these analogues. For this reason there is a strong need for new compounds having an anti-viral activity. It has been found that the compounds of the formulas (I) and (II) , which are not nucleoside-analogues, show excellent anti-viral activity against SARS. The importance of an effective medicine against SARS cannot be emphasized enough. Literature also discloses other coumarine derivatives having anti-viral activity. For example, the International patent application WO92/18123 discloses coumarine derivatives, and as most related compounds alkoxy coumarine derivatives. These compounds are indicated to be suitable for inhibiting the replication of retrovirusses .
In "Synthesis of new dihydropyridine derivates" in Huaxue Yan- jiu Yu Yingyong, April 2002, 14_(2), p. 233-234, Deng et al disclose compounds containing ester bond coupled coumarine groups.
Preferred compounds are those wherein R4 is an optionally substituted coumarin-4-yl-group.
Furthermore, it is preferred that R2 and R3, R3' are chosen from an optionally substituted coumarin-4-yl-group and an optionally substituted coumarin-7-yl-group.
The present invention also relates to a pyridine-5-carboxylic acid ester derivative comprising a coumarine group, of the formula I
(i:
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Ci-6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, an optionally esterified linear or branched (Ci_6) alkanol, carboxamide;
R2 represents OH, linear or branched (Ci-ε) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4; R4 represents H or a coumarinyl group of the formula III
;iii;
Figure imgf000006_0001
wherein
X represents a single bond, - (CH2) n-O-, or - (CH2) ra-Y-
(CH2) k~0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and
Y represents phenylene, (C3_8) cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C2) alkyl groups ; R5 represents hydrogen, linear or branched (Ci-ε) alkyl, linear or branched (Ci_6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base. If there is more than 1 Rl group, these may optionally be different.
The present invention also relates to a method for the preparation of a compound of the formula (I) (i;
Figure imgf000007_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Ci_6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci-β) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, an optionally esterified linear or branched (Cx-g) alkanol, carboxamide;
R2 represents OH, linear or branched (Ci-β) alkoxy or has a meaning as defined for R4 with the exception of hydrogen; R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(III)
Figure imgf000007_0002
wherein
X represents a single bond, -(CHa)n-O-, or - (CH2) m~Y~ (CH2Jk-O, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C3_8) cycloalkylene, or represents a carbon atom substituted with 1 or 2 (C1-C2) alkyl groups;
R5 represents hydrogen, linear or branched (Ci_6) alkyl, linear or branched (Ci-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, by subjecting a compound of the formula (II),
Figure imgf000008_0001
wherein R, Rl, R2, R3, R3' and R4 are as defined before, to an oxidation yielding the coumarine derivative of the formula (I).
Suitable oxidizing agents are, for example, 3-chloroperbenzoic acid, hydrogen peroxide, silver oxide, hydroxy (tosyloxy) iodobenzene .
Compounds of the formula II can be prepared as disclosed in WO 01/14370.
In addition, the present invention relates to new coumarine derivatives of the formula (II'), a subset of the compounds of the formula II ( II '
Figure imgf000009_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Cχ-6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_6) alkanol, carbox- amide;
R2 represents OH, linear or branched (Ci_6) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(III)
Figure imgf000009_0002
wherein
X represents a single bond, - (CH2) n-0~, or - (CH2) m-Y- (CH2) k-0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C3_8) cycloalkylene, or a carbon atom._ sυb.At.itjα.te.d..._with 1 or 2 (Ci-C2) alkyl groups;
R5 represents hydrogen, linear or branched (Ci_6) alkyl, linear or branched (Ci_6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2 , R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base, with the exception of those compounds of the formula (II) wherein R = CN, NO2 or a -COOR' -group, wherein R' is a (Ci-C6) alkyl group;
Rl = Rβ or R4; R2 = (Ci-C6) alkoxy or R4; R3 = H or R4; R4 = a coumarine group of the formula III;
R5 = H, (Ci-C6) alkyl, (Ci-C5) alkoxy, halogen, nitro, hydroxyl, or amino;
R6 = H, (Ci-C6) alkyl, (Ci-C6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a (Ci-C6) alkanol, carboxamide, optionally substituted with 1-2 (Ci-C6) alkyl groups ;
X = a single bond, -(CH2Jn-O-, or - (CH2 J1n-Y- (CH2) k-0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y = phenylene, cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C2) -alkyl groups; wherein (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, in particular, chlσro or fluoro, and nitro; with the provisio that at least 1 of the groups Rl, R2 and R3 is the same as of R4, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base, wherein more than 1 Rl- and R6-groups may be present, the (Ci- C6) alkyl and (Ci-C6) alkoxy are linear or branched, the term cycloalkyl is understood to mean a cycloalkyl group having 3 to 8 carbon atoms, and halogen is understood to mean a halogen atom chosen from the group containing fluoro, chloro, bromo or iodo.
The disclaimer aims to exclude all compounds as disclosed in WO 01/14370 and in Dutch patent application NL1012886 on which it is based. The new compounds as claimed herein can be prepared using the method as disclosed in WO 01/14370 and NL1012886.
Finally, the present invention relates to a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient. The present invention will now be elucidated on the basis of the following embodiments and in vivo experiments. Starting materials can either be obtained commercially or can be easily prepared by those skilled in the art analogous to known compounds. Known starting materials are disclosed in PCT WO 94/12488. The invention will now be elucidated on the basis of the following examples.
EXAMPLES
I) Preparation of compounds
Known and new compounds were prepared using Methods A to C as disclosed in the International patent application WO 01/14370, and Methods D and E, as described below.
Ia) Method D which includes the steps of a) subjecting 2, 6-dimethyldihydropyridine derivative of the formula
Figure imgf000012_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Ci_6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Cχ-6) alkyl, linear or branched (Ci_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified a linear or branched (Cχ-β) alkanol, carboxamide;
R2 represents OH, linear or branched (Ci-ε) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent hydrogen;
R4 represents H or a coumarinyl group of the formula III
:iii)
Figure imgf000012_0002
wherein
X represents a single bond, - (CH2) n-0-, or - (CH2) m-Y- (CH2) k~0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and
Y represents phenylene, (C3_8) cycloalkylene, or a carbon atom substituted with 1 or 2 (C1-C2) alkyl groups ; R5 represents hydrogen, linear or branched (Ci_6) alkyl, linear or branched (Ci-β) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cy- cloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro;
to a bromination yielding 2-bromomethyl derivatives and bis-2- bromomethyl derivatives of the formulas
(IV) (V)
Figure imgf000013_0001
wherein R, Rl, R2 and R4 are as defined before b) subjecting the product of step a) to a reaction with a hy- droxycoumarine corresponding to the formula (VI)
(VI)
Figure imgf000013_0002
wherein X and R5 are as defined before,
yielding a compound of the formula II ( II )
Figure imgf000014_0001
wherein R, Rl, R2, R3, R3' and R4 are as defined before, with the provisio that at least 1 of R3 and R3' is an optionally substituted coumarinyl group.
Suitable bromination reagents for carrying out step a) are, for example, bromine, fosfortribromide, N-bromosuccinimide, pyridinium- bromideperbromide .
After step a) and/or b) a purification step may be carried out, for example, chromatography over silica or crystallisation, wherein the purified product can be used in the subsequent step. The method for the preparation of the 2-bromoethyl- dihydropyridine derivative, intermediate obtained after step a) , takes place analogous to that disclosed by D. Alker et al in: Tetrahedron Letter, 3JL' P- 1479-1482, 1990.
Solid pyridiniumbromideperbromide (15 mmol) was added portion- wise to a stirred ice-cold solution of a dihydropyridine (10 mmol) in CH2Cl2. After completing the addition, the mixture was stirred for another 15 minutes, washed with ice-cold 2 M HCl, dried over MgSO4 and concentrated by evaporation without heating.
The residue was dissolved in DMF together with 15 mmol of a hy- droxycoumarine corresponding to the formula (III) and 20 mmol of K2CO3. The mixture was heated for 6 hours at 60°C, cooled down to room temperature and poured into water. The precipitate was filtered off, dissolved in CH2Cl2 and applied onto a silica gel column. Elution with ethyl acetate and crystallisation from ethanol yielded the 2 compounds (a 2, 6-bis- (coumarinyloxymethyl) 1, 4-dihydropyridine-3, 5- carboxylic acid diethyl ester and a 2- (coumarinyloxymethyl) -1, 4- dihydropyridine-3, 5-carboxylic acid diethyl ester derivative).
Method D is visualized in the diagram of the sole figure, wherein 1: pyridiniumbromideperbromide in CH2Cl2, 0°C 2: hydroxycoumarine, K2CO3, DMF, 60°C
Ib) Method E
The method for the preparation of the pyridine derivatives ac- cording to the invention takes place analogous to that disclosed by
Kang-Hyeok Lee and Kwang-Youn Ko in Bull. Korean Chem. Soc, 2_3, p.
1505-1506, 2002. According to the invention a compound of the formula
(II) is used as a starting material.
A mixture of 10 mmol of a dihydropyridine of the formula (II) and 12 mmol of hydroxy (tosyloxy) iodobenzene as an oxidizing agent in dichloromethane was stirred for 5 minutes at room temperature and then washed using 1 M bicarbonate. The organic solution was dried over magnesium sulfate and concentrated by evaporation. The residue was purified using chromatography over silica (eluent: ethyl acetate or a mixture of ethyl acetate and hexane) .
Using the Methods A to E, starting from the suitable starting compounds, the following compounds were prepared (Table 1) . The mass
(M+H) of the prepared compounds was measured using ESI (electron spray impact) mass spectrometry via continue flow injection equipped with an LCQ Deca (Finnigan) .
Table 1
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
In Vitro activity
The biological activity was tested for anti-SARS activity by means of standard experiments by the Rega Instituut (Leuven, Belgium) . The results (anti-viral action and cytotoxicity) are shown in Table 2.
Table 2
Figure imgf000022_0002
IC50: Concentration of the substance to be tested at which the virus production is inhibited by 50 %.
CC50: Concentration of the substance to be tested required to reduce cell growth by 50%.

Claims

C L A I M S
1. The use of 1, 4-dihydropyridine-5-carboxylic acid derivatives comprising a coumarine group and pyridine-5-carboxylic acid derivatives 1, 4-dihydropyridine-5-carboxylic acid derivatives comprising a coumarine group of the general formula (I) or (II)
Figure imgf000023_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Cχ-β) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci-ε) alkanol, carbox- amide;
R2 represents OH, linear or branched (Ci_6) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(in:
Figure imgf000023_0002
wherein X represents a single bond, -(CH2Jn-O-, or - (CH2) ra-Y- (CH2) k-O, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the stun, of m and k is smaller than or equal to 4; and
Y represents phenylene, (C3-8) cycloalkylene, or a carbon atom substituted with 1 or 2 (Ci-C2) alkyl groups;
R5 represents hydrogen, linear or branched (Ci-β) alkyl, linear or branched (Ci-β) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base for the preparation of a drug for the prevention of and/or treatment of Severe Acute Respiratory Syndrome (SARS) .
2. Coumarine derivatives of the formula (I)
Figure imgf000024_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Ci-6) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Cχ_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_6) alkanol, carbox- amide;
R2 represents OH, linear or branched (C1-S) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(III)
Figure imgf000025_0001
wherein X represents a single bond, - (CH2) n-0-, or - (CH2) m-Y-
(CH2) k~O, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and
Y represents phenylene, (C3-8) cycloalkylene, or a car- bon atom substituted with 1 or 2 (Ci-C2) alkyl groups;
R5 represents hydrogen, linear or branched (Ci-ε) alkyl, linear or branched (Ci_6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cy- cloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base.
3. A method for the preparation of a coumarine derivative of the formula (I)
Figure imgf000026_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R1 is a linear or branched (Ci-β) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Ci-β) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci_6) alkanol, carbox- amide represents;
R2 represents OH, linear or branched (Ci~6) alkoxy or has a meaning as defined for R4 with the exception of hydrogen; R3, R3' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(III)
Figure imgf000026_0002
wherein
X represents a single bond, - (CH2) n-0-, or -(CH2)m-Y- (CH2) ij-0, wherein n ranges from 1 to 6, in and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C3-8) cycloalkylene, or a carbon atom substituted with 1 or 2 (C1-C2) alkyl groups ;
R5 represents hydrogen, linear or branched (Ci-β) alkyl, linear or branched (Ci-ε) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl,
by subjecting a compound of the formula (II]
Figure imgf000027_0001
wherein R, Rl, R2, R3, R3' and R4 are as defined in claim 1, to an oxidation yielding the coumarine derivative of the formula (I) .
4. Coumarine derivatives of the formula (II')
( H '
Figure imgf000028_0001
wherein
R represents hydrogen, CN, NO2 or a -COOR' -group, wherein R' is a linear or branched (Ci-β) alkyl group;
Rl has a meaning as defined for R4 or represents hydrogen, fluoro, chloro, bromo, linear or branched (Ci_6) alkyl, linear or branched (Cχ_6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a linear or branched (Ci-ε) alkanol, carbox- amide;
R2 represents OH, linear or branched (Ci_6) alkoxy or has a meaning as defined for R4 with the exception of hydrogen;
R3, R3 ' represent independently of each other H or independently of each other have a meaning as defined for R4;
R4 represents H or a coumarinyl group of the formula III
(III)
Figure imgf000028_0002
wherein
X represents a single bond, - (CH2) n~0~r or - (CH2) m-Y- (CH2)ic-O, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y represents phenylene, (C3_8) cycloalkylene, or a carbon atom substituted with 1 or 2 (C1-C2) alkyl groups;
R5 represents hydrogen, linear or branched (Ci_6) alkyl, linear or branched (Ci_5) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, and nitro; with the provisio that at least 1 of the groups Rl, R2, R3, R3' and R4 is chosen from, optionally substituted, coumarin-4-yl and cou- marin-7-yl, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base, with the exception of those compounds of the formula (II) wherein R = CN, NO2 or a -COOR' -group, wherein R' is a (Ci-C6) alkyl group;
Rl = R6 or R4; R2 = (Ci-C6) alkoxy or R4 ; R3 = H or R4; R4 = a coumarine group of the formula III;
R5 = H, (Ci-C6) alkyl, (Ci-C6) alkoxy, halogen, nitro, hydroxyl, or amino;
R6 = H, (Ci-C6) alkyl, (Ci-C6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a (Ci-C6) alkanol, carboxamide, optionally substituted with 1-2 (Ci-C6) alkyl groups;
X = a single bond, -(CH2)n-O-, or - (CH2 )m-Y- (CH2) k-0, wherein n ranges from 1 to 6, m and k each are equal to or larger than 1 and the sum of m and k is smaller than or equal to 4; and Y = phenylene, cycloalkylene, or is a carbon atom substituted with 1 or 2 (Ci-C2) -alkyl groups; wherein (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) alkanol, benzyloxy, phenylene and cycloalkylene are optionally substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, particularly chloro or fluoro, and nitro; with the provisio that at least 1 of the groups Rl, R2 and R3 is the same as R4, as well as the N-oxide, stereo isomers and/or addition salts thereof with a pharmaceutically acceptable acid or base, wherein more than 1 Rl- and Rβ-groups can be present, the (Ci- C6) alkyl and (C1-C6) alkoxy are linear or branched, the term cycloalkyl is understood to mean a cycloalkyl group having 3 to 8 carbon atoms, and halogen is understood to mean a halogen atom chosen from the group containing fluoro, chloro, bromo or iodo.
5. A pharmaceutical composition containing a compound according to claim 2 and/or claim 4 together with a pharmaceutically acceptable carrier or excipient.
PCT/NL2006/000142 2005-03-17 2006-03-17 Use of derivatives comprising a coumarin group for the preparation of an antiviral agent, derivatives comprising a coumarin group, a method for the preparation thereof, and pharmaceutical compositions containing them WO2006098620A1 (en)

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