NL1028569C2 - Use of a coumarin group comprising derivatives for the preparation of an antiviral agent, as well as cat food. - Google Patents

Description

Use of a coumarin group comprising derivatives for the preparation of an antiviral agent, as well as cat food

The present invention relates to the use of a coumarin group comprising 1,4-dihydropyridine-5-carboxylic acid ester derivatives and pyridine-5-carboxylic acid ester derivatives for the preparation of an antiviral agent.

The use of a coumarin group comprising 1.4-10 dihydropyridine-5-carboxylic acid ester derivatives as antiviral agents is known from the international patent application WO 01/14370 (Rephar-tox B.V.). The virus diseases can be such virus diseases caused by: 1 Adenovirus type 2 15 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) Herpes simplex virus-2 (G; 196; Lyons) 6 HIV-1 7 HIV-2

8 Influenza virus A

9 Influenza virus B

10 Parainfluenza-3 virus 25 11 Polio virus-1 12 Reovirus 13 Respiratory syncytial virus 14 Semliki forest virus 15 Sindbis virus 30 16 Vaccinia virus 17 Varicella zoster virus (TK + OKA strain; TK + YS strain; TK-07/1 strain; TK- YS / R strain; 18 Vesicular stomatitis virus.

The present invention has for its object to provide a new application.

Therefore, the present invention relates to the use of a coumarin group comprising compounds of the general formula (I) or (II) 1028569 2 (I) (II) ^ R4> ^ R4 → R1 → J-R1 0 ° r. JL r. X.

^ 1 R2> | R 2, R 3, R 3, R 3, R 3, wherein R represents hydrogen, CN, NO 2, or a -COOR 'group, wherein R' is a linear or branched (C 1-6) alkyl group; R 1 has a meaning as defined for R 4 or is hydrogen, fluoro, chloro, bromo, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, whether or not esterified with a linear or branched (C 1-6) alkanol, carboxamide; R 2 represents OH, linear or branched (C 1-6) alkoxy or has a meaning as defined for R 4 with the exception of hydrogen; R 3, R 3 'independently represent H or independently have a meaning as defined for R 4; R 4 represents H or a coumarinyl group of formula III (III) -CO * wherein X represents a single bond, - (CH 2) n-O-, or - (CH 2) m Y - (CH 2) k ~ 0, wherein n ranges from 1 to 6, m and k are each greater than or equal to 1 and the sum of m and k is less than or equal to 4; and 1 nPft.RRQ 3 Y represents phenylene, (C 3-6) cycloalkylene, or a carbon atom substituted with 1 or 2 (C 1 -C 2) alkyl groups; R 5 represents hydrogen, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene may or may not be substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, and nitro; With the proviso that at least 1 of the groups R 1, R 2, R 3, R 3 ', and R 4 is selected from, optionally substituted, coumarin-4-yl and coumarin-7-yl, as well as the N-oxide, stereoisomers and / or addition salts thereof with a pharmaceutically acceptable acid or base for the preparation of a medicament for the prevention and / or treatment of Feline Infectious Peritonitis Syndrome.

It is noted that more than 1 R 1 and R 5 groups may be present.

In the present application, an optionally present alkyl group, alkanol group or alkoxy group preferably has 1 or 2 carbon atoms. An alkanol is an alkyl group substituted with a hydroxyl group.

In the present application, the term cycloalkyl is understood to mean a cycloalkyl group with 3 to 8 carbon atoms.

Halogen is understood to be a halogen atom selected from the group consisting of fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The largest group of anti-viral compounds known in the art include the nucleoside analogs. A major disadvantage of this is that 30 virus strains increasingly develop resistance to it. For this reason there is a great need for new compounds with an anti-viral effect.

The compounds of formulas (I) and (II), which are not nucleoside analogues, have been found to exhibit excellent anti-viral activity against the ethiological agent of Feline Infectious Peritonitis Syndrome (Feline Infectious Peritonitis, FIPV). The importance of an effective anti-FIPV agent is important since no effective treatment is known. For prophylactic treatment, it is recommended to do this prior to stressful situations such as sterilization / castration, vaccination, and relocation, and preferably continue this until the cat is back to its old state. For certain types of cat, in particular FIPV sensitive, such as Burmese, it is preferable to treat them continuously prophylactically.

The same applies to cats that already suffer from another viral disease (Feline leukemia Virus, or Feline Immunodeficiency Virus) that are known to be at increased risk of FIPV.

Other coumarin derivatives with antiviral activity have also been described in the literature. For example, International Patent Application WO92 / 18123 describes coumarin derivatives and as most related compounds alkoxycoumarin derivatives. These compounds are indicated to be suitable for inhibiting the replication of retroviruses.

Preferred compounds are those wherein R 3 and / or R 3 'is an optionally substituted coumarin-4-yl group.

Furthermore, R2 is preferably an optionally substituted coumarin-7-yl group.

Advantageously, R 4 is hydrogen.

Partly from a pharmacokinetic point of view, the presence of 1 coumarinyl group appears to be preferred.

A preferred compound for use in the present invention is 2-methyl-6- (4-methyl-2-oxo-2H-chromium-7-yloxymethyl) -4- (3-nitrophenyl) -1,4-dihydropyridine -3,5-dicarboxylic acid diisopropyl ester (compound 48).

The present invention also relates to cat food containing a coumarin-group-containing compound selected from 1,4-dihydropyridine-5-carboxylic acid ester derivatives and pyridine-5-carboxylic acid ester derivatives 1,4-dihydropyridine-5-carboxylic acid ester derivatives of the general formula (I) or (II) · 35 :: Γ 102 8569_5 (I) (II)> R4> vR4> 2 ~ R1 → J-R1 ii o R. / -L R.

YV R2 R2

R a 'R 3 R 3' R 3 wherein R represents hydrogen, CN, NO 2 or a -COOR 'group, wherein R' is a linear or branched (C 1-6) alkyl group; R 1 has a meaning as defined for R 4 or hydrogen, fluorine, chlorine, bromine, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, whether esterified or not with a linear or branched (C 1-6) alkanol, carboxamide; R 2 represents OH, linear or branched (C 1-6) alkoxy or has a meaning as defined for R 4 with the exception of hydrogen; R 3, R 3 'independently represent H or independently have a meaning as defined for R 4; R 4 represents H or a coumarinyl group of formula III 20 (III) CC CC £ where 25 X represents a single bond, - (CH 2) n-O-, or - (CH 2) 4, - Y- (CH 2) k - 0, where n ranges from 1 to 6, m and k are each greater than or equal to 1 and the sum of m and k is less than or equal to 4; and 1 028569 6 Y represents phenylene, (C 3-6) cycloalkylene, or a carbon atom substituted with 1 or 2 (C 1 -C 2) alkyl groups; R 5 represents hydrogen, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene may or may not be substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, and nitro; With the proviso that at least 1 of the groups R 1, R 2, R 3 and R 3 ', and R 4 is selected from optionally substituted, coumarin-4-yl and coumarin-7-yl, as well as the N-oxide, stereoisomers and / or addition salts thereof. The cat food can be either liquid or solid cat food, for example cat milk, wet cat food (such as canned food) and dry cat food (for example kibble or sweets). Thus the agent can be administered to the cat in a simple manner.

The present invention will now be illustrated with reference to the following embodiments and in vivo experiments. Starting materials are either commercially available or easily analogous to known compounds for those skilled in the art to prepare. Known starting materials are described in PCT WO 94/12488.

The invention will now be elucidated with reference to the following examples.

25

EXAMPLES

I) Preparation of compounds

The compounds were prepared using Methods A to C as described in International Patent Application WO 01/14370, and Methods D and E as described below.

Ia) Method D

which comprises the steps of a) subjecting 2,6-dimethyldihydropyridine derivative of the formula 1028569 L. __ 7

Ch "" N "1 R 3, H R 3 wherein R represents hydrogen, CN, NO 2 or a -COOR 'group, wherein R' is a linear or branched (C 1-6) alkyl group; R 1 has a meaning as defined for R 4 or is hydrogen, fluorine, chlorine, bromine, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, whether or not esterified with a linear or branched (Ca-6) alkanol, carboxamide; R2 represents OH, linear or branched (C1-1) alkoxy or has a meaning as defined for R4 with the exception of hydrogen; R 3, R 3 'represent hydrogen; R 4 represents H or a coumarinyl group of formula III (III) -cos where X represents a single bond, - (CH 2) n-O-, or - (CH 2) ra-Y- (CH 2) k-O / wherein n is different from 1 to 6, m and 25 k are each greater than or equal to 1 and the sum of m and k is less than or equal to 4; and Y represents phenylene, (C 3-6) cycloalkylene, or a carbon atom substituted with 1 or 2 (C 1 -C 2) alkyl groups; R 5 represents hydrogen, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene may or may not be substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, and nitro; to a bromination yielding the preparation of 2-bromomethyl derivatives and bis-2-bromomethyl derivatives of the formulas 10 (IV) (V) R 4 R 4 (y-R 1, y-R 1 ° R, R>. "

ILL

"η I I Η I

Br Br Br 15 where R, R 1, R 2 and R 4 are as defined above b) subjecting the product of step a) to a reaction with a hydroxycoumarin corresponding to the formula (VI) (VI) h ° -xOC 2 R 5 wherein X and R 5 are as defined above, yielding a compound of the formula II (II) 1028569 9> sR 4 | 1 [-R 1]

FL

Μl R2

I Η I

R3 "R3 where R, R1, R2, R3, R3" and R4 are as defined above, provided that at least 1 of R3 and R3 "is an optionally substituted coumarinyl group.

The process for the preparation of the 2-bromoethyldihydropyridine derivative, obtained after step a), is analogous to that described by D. Alker et al in: Tetrahedron Letter, 31, pages 1479-1482, 1990.

Solid pyridinium bromide perbromide (15 mmol) was added portionwise to a stirred ice-cold solution of a dihydropyridine (10 mmol) in CH 2 Cl 2. After complete addition, the mixture was stirred for an additional 15 minutes, washed with ice-cold 2 M HCl, dried over MgSO 4 and evaporated without heating.

The remaining material was dissolved in DMF together with 15 mmol of a hydroxy-15 coumarin corresponding to formula (III) and 20 mmol of K 2 CO 3. The mixture was heated at 60 ° C for 6 hours, cooled to room temperature and poured into water. The precipitate was filtered off, dissolved in CH 2 Cl 2 and placed on a silica gel column. Elution with ethyl acetate and crystallization 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 scheme of the single drawing, wherein 1: pyridinium bromide perbromide in CH 2 Cl 2, 0 ° C 2: hydroxycoumarin, K 2 CO 3, DMF, 60 ° C

Ib) Method E

1028589 10

The process for the preparation of the pyridine derivatives according to the invention is analogous to that described by Kang-Hyeok Lee and Kwang-Youn Ko in Bull. Korean Chem. Soc., 2, pp. 1505-1506, 2002. According to the invention, a compound of the formula (II) is used as the starting material.

A mixture of 10 inmol 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 with 1 M bicarbonate. The organic solution was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica (eluent: ethyl acetate or a mixture of ethyl acetate and hexane).

15

Using methods A to E, starting from the appropriate starting compounds, the following compounds were prepared (Table 1). The mass (M + H) of the prepared compounds was measured by ESI (electron spray impact) mass spectrometry via continuous flow injection with an LCQ Deca (Finnigan).

Table 1

Rep For- Name of work- M + H

The method is 001 ~ 31 2,6-Dimethyl-4- {4- [2- (2-oxo-2H-C 534 chrome-7-yloxy) ethoxy] phenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester 004 ~ 32 2,6-Dimethyl-4- {4- [2- (2-oxo-4-propyl-C 576 2H-chromium-7-yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3, 5-dicarboxylic acid diethyl ester "" 007 33 4 - {4- [2 - (6, 7-Dimethyl-2-oxo-2 H -C 562 chrome-4-yloxy) ethoxy] phenyl} -2,6-dimethyl- 1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 1028569 11 O10 34 2,6-Dimethyl-4- [4- (2-oxo-2H-chromium-C 490-4-yloxy) phenyl] -1,4-dihydropyridine -3,5-carboxylic acid diethyl ester 012 35 4 - {4 - [2 - (7-Methoxy-2-oxo-2H-chromium C 564 4-yloxy) ethoxy] phenyl} -2,6-dimethyl-1,4-dihydropyridine- 3,5-carboxylic acid diethyl ester 013 36 2,6-Dimethyl-4- [3- (2-oxo-2H-chromium-C 490-4-yloxy) phenyl] -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 019 37 2,6 -Dimethyl-4- {3- [2- (2-oxo-2H-C 534-chromium-4-yloxy) -ethoxy] -phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 025 38 2-Methyl-4 - (3-nitrophenyl) -6- (2-oxo-E 535 4a, 8a-di hydro-2 H-chromium-4-yloxymethyl) -pyridine-3,5-carboxylic acid diethyl ester 030 39 2-Methyl-4- (2-nitrophenyl) -6- (2-oxo-B 535 2 H-chromium-4-yloxymethyl) - 1,4-dihydropyridine-3,4-carboxylic acid diethyl ester 031 40 2-Methyl-6- (4-methyl-2-oxo-2H-B 549 chromium-6-yloxyraethyl) -4- (2-nitrophenyl) -1.4 -dihydropyridine-3,5-carboxylic acid diethyl estericarboxylic acid diethyl ester 20- 41 2,6-Dimethyl-4-phenyl-1,4-A 564 106 dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5— (2— (2— (2— (2 - - [2- (2-oxo-2H-chromium-4-yloxy) ethoxy] -ethoxy} -ethyl) ester 041 42 2-Methyl-4- (2-nitrophenyl) -6- (2-oxo-B 535 2H -chromes-7-yloxymethyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 044 43 2, 6-Dimethyl-4-phenyl-1,4-A 504 dihydropyridine-3,5-dicarboxylic acid 1 028569 12 3-ethyl ester 5 - [2- (4-methyl-2-oxo-2H-chromium-7-yloxy) ethyl] ester 045 44 2,6-Dimethyl-4-phenyl-1,4-A 490 dihydropyridine-3,5-dicarboxylic acid 3- ethyl ester 5- [2- (2-oxo-2H-chrome-7-yloxy) ethyl] ester 046 45 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-A 535 dihydropy ridin-3,5-dicarboxylic acid 3-ethyl ester 5- [2- (2-oxo-2H-chromium-7-yloxy) ethyl] ester 047 46 2, 6-Dimethyl-4- (3-nitrophenyl) -1, 4- A 549 dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5- [2- (4-methyl-2-oxo-2H-chromium-6-yloxy) ethyl] ester 049 47 2,6-Bis- (2- oxo-2H-chromen-4-D 718 yloxymethyl) -4- (4-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 056 48 2-Methyl-6- (4-methyl-2-oxo-2H - B 577 chromium-7-yloxymethyl) -4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester 057 49 2, 6-Bis- (4-raethyl-2-oxo-2H-) chromium-7-D 751 yloxymethyl) -4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester 002 50 2, 6-Dimethyl-4- {4- [2- (4-methyl -2-oxo-C 548 2 H-chromium-6-yloxy) ethoxy] phenyl] -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 003 ~ 5I 2,6-Dimethyl-4- {4- [2- (4 -methyl-2-oxo-C 548 2 H-chromium-7-yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3,5-006 52 2, 6-Dimethyl-4- {4- [2- (2 -OXO-2H-C 534 chromium-4-yloxy) ethoxy] phenyl> -1,4-dihydropyridine-3,5-dicarbon acid 009 53 2, 6-Dimethyl-4- {4- [2- (oxo C 602 1 02 85 69 - 13 trifluoromethyl-2H-chromium-7-yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3 5-carboxylic acid diethyl ester 011 54 2,6-Dimethyl-4- {4- (2- (3,4,8-C 576-trimethyl-2-oxo-2H-chrome-7-yloxy) ethoxy] phenyl} -1 1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 014 55 2,6-Dimethyl-4- {2- [2- (2-oxo-2H-C 534 chrome-4-yloxy) ethoxy] phenyl) -1,4 dihydropyridine-3,5-carboxylic acid diethyl ester 015 56 2,6-Dimethyl-4- {2- [2- (3,4,8-C 578 trimethyl-2-oxo-4a, 5-dihydro-2H-chromium-7-) yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 017 57 2,6-Dimethyl-4- {2- [2- (2-oxo-4-propyl) C 576 2H-chromium-7 -yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 018 58 2,6-Dimethyl-4- {2- [2- (4-methyl-2-oxo) C 548 2 H-chromium- 6-yloxy) ethoxy] phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 020 59 2,6-Dimethyl-4- {3- [2- (2-oxo-4-propyl) C 576 2 H-chromiums -7-yloxy) -ethoxy] -phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester. methyl 4- {3- [2- (2-ΟΧΟ-2Η-C-534-chromium-7-yloxy) -ethoxy] -phenyl} -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 022 61 2,6-Dimethyl- 4- {3- [2- (4-methyl-2-oxo-C 548 2 H-chromium-6-yloxy) ethoxy] phenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 1028569 14 023 62 2-Methyl -4- (3-nitrophenyl) -6- (2-oxo-B 535 2H-chromium-7-yloxymethyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 024 63 4- (2-Cyclohexylmethoxyphenyl) -2- B 574 methyl 6- (2-oxo-2 H-chromium-7-yloxymethyl) -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 20-66 2,6-Dimethyl-4- {2- [4- (2 -oxo-2H-Tc 534 130 chrome-4-yloxy) -butoxy] phenyl} -1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 032 68 2-Methyl-4- (4-nitrophenyl) -6- (2- oxo-B 535 2 H-chromium-4-yloxymethyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 033 "69 2-Methyl-6- (4-methyl-2-oxo-2 H-B 549 chromium-6- yloxymethyl) -4- (4-nitrophenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 034 70 2-Methyl-6- (2-oxo-2H-chromium-7- B 558 yloxymethyl) -4- (2 trifluoromethylphenyl) -1,4-dih ydropyridine-3,5-carboxylic acid diethyl ester-036 71 2-Methyl-6- (4-methyl-2-oxo-2H-D 572 chrome-6-yloxymethyl) -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3, 5-carboxylic acid diethyl ester 035 72 ~ 2,6-Bis- (2-oxo-2H-chromium-7-D 718 yloxymethyl) -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3, 5-carboxylic acid diethyl ester 02 02 8569 15 037 73 2,6-Bis- (4-methyl-2-oxo-2 H-chromium-6-D 746 yloxymethyl) -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 038 74 2-Methyl-6- (4-methyl-2-oxo-2H-D 572 chrome-7-yloxymethyl) -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 039 75 2.6 -Bis- (4-methyl-2-oxo-2H-chromium-7-D 746 yloxymethyl) -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 040 76 2, 6-Bis- (4-methyl-2-oxo-2H-chromium-6-D 723 yloxymethyl) -4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 043 77 2, 6-Dimethyl-4-phenyl-1 4- A 504 dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5- [2- (4-methyl-2-oxo-2H-chromos-6-yl) oxy) ethyl] ester 027 78 2-Methyl-4- (4-nitrophenyl) -6- (2-oxo-D 535 2 H-chromium-7-yloxymethyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 029 79 4- (4-Nitrophenyl) -2,6-bis- (2-oxo-2H-D 695 chromium-4-yloxymethyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 042 80 4- (2-Nitrophenyl) -2,6-bis- (2-oxo-2H-D 695 chromium-7-yloxymethyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 052 ~ 8 2-Methyl-6- (2-oxo-2H -chromes-7- B 558 (yloxymethyl) -4- (4-trifluoromethylphenyl) -1,4-1028569 1 --- - 16 dihydropyridine-3,5-carboxylic acid diethyl ester 028 82 4- (4-Nitrophenyl) -2.6 -bis- (2-oxo-2H-D 695 chromium-7-yloxymethyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 050 83 2-Methyl-6- (4-methyl-2-oxo-2H-B 572 chromium-6-yloxymethyl) -4- (4-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 053 84 2, 6-Bis- (2-oxo-2H-chromium-7- D 718 yloxymethyl) -4- (4-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 055 85 2,6-Bis- (4-methyl-2-oxo-2H-chromium-7-D 746 yloxymethyl ) -4- (4-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 051 86 2, 6-Bis- (4-methyl-2-oxo-2H-chromium-6-D 746 yloxymethyl) -4 - (4-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 054 87 2-Methyl-6- (4-methyl-2-oxo-2H-D 572 chromium-7-yloxymethyl) -4- (4 -trifluoromethylphenyl) -1,4-dihydropyridine-3,5-carboxylic acid diethyl ester 048 88 2-Methyl-6- (2-oxo-2H-chromium-4- D 558 yloxymethyl) -4- (4-trifluoromethylphenyl) -1.4 dihydropyridine 3,4-carboxylic acid diethyl ester 028569 17

In Vitro activity

The biological activity was tested for anti-FIPV activity through standard experiments by the Rega Institute (Leuven, Belgium). The results (anti-viral activity and cytotoxicity) are shown in Table 2.

Table 2 anti-FIPV activity Compound IC50 CC50 44 678> 100 45 O 66 49 33> 100 48 02> ÖÖÖ 10 IC50: Concentration of the test substance with virus production inhibited by 50% CC50: Concentration of the test chemical is needed to reduce cell growth by 50%. 1028569

Claims (5)

R 1, R 3, R 3, H R 3, 3 where R is hydrogen, CN, NO 2 or a -COOR 'group, where R' is a linear or is branched (C 1-6 alkyl group); R 1 has a meaning as defined for R 4 or is hydrogen, fluorine, chlorine, bromine, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, esterified or not with a linear or branched (C 1-6) alkanol, carboxamide; R 2 represents OH, linear or branched (C 1-6) alkoxy or has a meaning as defined for R 4 with the exception of hydrogen; R 3, R 3 'independently represent H or independently have a meaning as defined for R 4; R 4 represents H or a coumarinyl group of formula III (III) 1028569 wherein X represents a single bond, - (CH 2) n-O-, or - (CH 2) m Y - (CH 2 j k-0, where n varies from 1 up to 6, m and 5 k are each greater than or equal to 1 and the sum of m and k is less than or equal to 4, and Y is phenylene, (C 3-8) cycloalkylene, or one substituted by 1 or 2 (C 1 -C 2) alkyl groups represents a carbon atom; R 5 represents hydrogen, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene may or may not be substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, and nitro; with the proviso that at least 1 of the groups R 1, R 2, R 3 and R 3 'and R 4 is selected from, optionally substituted, coumarin-4-yl and coumarin-7-yl, as well as the N-oxide, stereoisomers and / or addition salts thereof with a pharmaceutically acceptable acid or base for the preparation of a medicament for the prevention and / or treatment of Feline Infectious Peritonitis Syndrome (FIPV). Use of a coumarin group comprising 1,4-5 dihydropyridine-5-carboxylic acid ester derivatives and pyridine-5-carboxylic acid ester derivatives 1,4-dihydropyridine-5-carboxylic acid ester derivatives of the general formula (I) or (II) (I) ( II) R4 R4 Use according to claim 1, characterized in that R 3 and / or R 3 'is an optionally substituted coumarin-4-yl group. Use according to claim 1 or 2, characterized in that R 2 is an optionally substituted coumarin-7-yl group. Use according to any one of the preceding claims, characterized in that 2-methyl-6- (4-methyl-2-oxo-2H-chromium-7-yloxymethyl) -4- (3-nitrophenyl) -1,4- dihydropyridine-3,5-dicarboxylic acid diisopropyl ester is used. A cat food containing a coumarin group-comprising compound selected from 1,4-dihydropyridine-5-carboxylic acid ester derivatives and pyridine-5-carboxylic acid ester derivatives 1,4-dihydropyridine-5-carboxylic acid ester derivatives of the general formula (I) or (II) 1 02 85 69 (I) (II) J J R R1 J J-R1 fl fl R. Jl. R. Js. JL J1 R2 J1X R2 Ra 'R3 R3' H R3 where R represents hydrogen, CN, NO2 or a -COOR 'group, where R' is a linear or branched (C1-6) alkyl group; R 1 has a meaning as defined for R 4 or is hydrogen, fluoro, chloro, bromo, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, benzyloxy, cyano, nitro, carboxylic acid, whether or not esterified with a linear or branched (C 1-6) alkanol, carboxamide; R 2 represents OH, linear or branched (C 1-6) alkoxy or has a meaning as defined for R 4 with the exception of hydrogen; R 3, R 3 'independently represent H or independently have a meaning as defined for R 4; R 4 represents H or a coumarinyl group of formula III (III) wherein X represents a single bond, - (CH 2) 0 - 0, or - (CH 2) m -25 Y- (CH 2) k-0, where n varies from 1 to 6, m and k are each greater than or equal to 1 and the sum of m and k is less than or equal to 4; and 028569 Y represents phenylene, (C 3-8) cycloalkylene, or a carbon atom substituted with 1 or 2 (C 1 -C 2) alkyl groups; R 5 represents hydrogen, linear or branched (C 1-6) alkyl, linear or branched (C 1-6) alkoxy, halogen, nitro, hydroxyl, or amino; wherein alkyl, alkoxy, alkanol, benzyloxy, phenylene and cycloalkylene may or may not be substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, and nitro; With the proviso that at least 1 of the groups R 1, R 2, R 3, R 3 and R 4 is selected from, optionally substituted, coumarin-4-yl and coumarin-7-yl, as well as the N-oxide, stereoisomers and / or addition salts of it. 102 8569_