Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents

DESCRIPTION

[0015]

• • [0016] wherein
  • [0017] A is a non-aromatic ring system containing 4 to 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring can be replaced by a group X, wherein X is selected from the group consisting of S, O, N, NR⁴, SO, CO or SO₂;
  • [0018] D is O, S, SO₂, NR⁴ or CH₂;
  • [0019] Z¹ and Z² are independent from each other O, S, or NR⁵;
  • [0020] R¹ is independently —CO₂R″, —SO₃H, —CONR*R″, —CR″O, —SO₂—NR*R″, —NO₂, —SO₂—R″, —SO—R*, —CN, alkoxy, —OH, —SH, alkylthio, —NR″—CO₂—R′, —NR″—CO—R*, —NR″—SO₂R′, —O—CO—R*, —O—CO₂—R*, —O—CO—NR*R″; cycloalkyl, alkylamino, hydroxyalkylamino, aryl, or heteroaryl;
  • [0021] R⁹ is independently H, halogen, haloalkyl, haloalkyloxy or alkyl;
  • [0022] R* is independently H: alkyl, cycloalkyl, aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • [0023] R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • [0024] R² is H, OR⁶, or NHR⁷;
  • [0025] R³ is H, alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, O-aryl; O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl, or S-cycloalkyl;
  • [0026] R⁴ is H, alkyl, cycloalkyl, aryl, or heteroaryl;
  • [0027] R⁵ is H, OH, alkoxy, O-aryl, alkyl, or aryl;
  • [0028] R⁶ is H, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylaryl, alkoxyalkyl, acylmethyl, (acyloxy)alkyl, non-symmetrical (acyloxy)alkyldiester, or dialkylphosphate;
  • [0029] R⁷ is H, alkyl, aryl, alkoxy, O-aryl, cycloalkyl, or O-cycloalkyl;
  • [0030] R⁸ is hydrogen or alkyl;
  • [0031] E is an alkyl or cycloalkyl group which is substituted by [D_m-(CHR₃)_n]_q or a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring;

[0032]

• • [0033] m is 0 or 1;
  • [0034] n is 0 or 1;
  • [0035] p is 0 or 1;
  • [0036] r is 0 or 1;
  • [0037] q is 0 or 1;
  • [0038] t is 1 to 3; and
  • [0039] v is 0 to 3;

[0041]

• • [0042] wherein
  • [0043] A is a non-aromatic ring system containing 4, 5, 6, 7 or 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring can be replaced by a group X, wherein X is selected from the group consisting of S, O, N, NR⁴, SO, CO or SO₂;
  • [0044] D is O, S, SO₂, NR⁴, or CH₂;
  • [0045] Z¹ and Z² are independent from each other O, S, or NR⁵;
  • [0046] R¹ is independently H, halogen, haloalkyl, haloalkyloxy —CO₂R″, —SO₃H, —OH —CONR*R″, —CR″O, —SO₂—NR*R″, —NO₂, —SO₂—R″, —SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO₂—R′, —NR″—CO—R*, —NR″—SO₂—R′, —O—CO—R*, —O—CO₂—R*, —O—CO—NR*R″; cycloalkyl, alkylamino, hydroxyalkylamino, —SH, heteroaryl, or alkyl;
  • [0047] R* is independently H, alkyl, cycloalkyl, aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • [0048] R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • [0049] R² is NHOH or R² together with the nitrogen atom which is attached to R⁸ form a 5 or 6 membered heterocyclic ring with the proviso that R² is —[CH₂]₈ and R⁸ is absent;
  • [0050] R³ is H, alkyl, cycloalkyl, aryl alkoxy, O-aryl; O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl; S-cycloalkyl, arylalkyl or haloalkyl;
  • [0051] R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;
  • [0052] R⁵ is H, OH, alkoxy, O-aryl, alkyl or aryl; R⁸ is hydrogen, or alkyl;
  • [0053] E is an alkyl or cycloalkyl group which is substituted by [D_m-(CHR₃)_n]_qY or a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring;
  • [0054] Y is hydrogen halogen, haloalkyl, haloalkyloxy, alkyl, cycloalkyl, a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring or

[0055]

• • • [0056] m is 0 or 1;
    • [0057] n is 0 or 1;
    • [0058] p is 0 or 1;
    • [0059] r is 0 or 1;
    • [0060] q is 0 or 1;
    • [0061] s is 0 to 2; and
    • [0062] t is 0 to 3;
  • [0063] with the proviso that the following compounds are excluded:
  • [0064] compounds wherein ring A is an unsubstituted carbocycle containing six carbon atoms and one double bond between the CZ¹ and CZ²-substituents, Z¹=Z²=O, and s is 0; 1,3,5-Tribenzyl-2,4,6-trioxopyrrolo[3,4-d]imidazole, 1,3-Dibenzyl-5-(4-methoxy-benzyl)-2,4,6-trioxopyrrolo[3,4-d]imidazole, 1,3-Bis-(4-methoxybenzyl)-5-benzyl-2,4,6-trioxopyrrolo[3,4-d]imidazole, and 1,3-Tris-(4-methoxybenzyl)-2,4,6-trioxo-pyrrolo[3,4-d]imidazole.

[0066]

• • [0067] wherein
  • [0068] the bond between G and M is a single or double bond;
  • [0069] A is a non-aromatic ring system containing 4, 5, 6, 7 or 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring can be replace by a group X, wherein X is selected from the group consisting of S, O, N, NR⁴, SO, CO or SO₂;
  • [0070] D is O, S, SO₂, NR⁴, or CH₂;
  • [0071] G is O, S, SO₂, CO, N, NR⁴, CR¹ or CHR¹;
  • [0072] L is N or CR¹;
  • [0073] M is N or CR⁵;
  • [0074] Z¹ is O, S, or NR⁵; NR⁴CONR⁴, CONR⁴, or CO;
  • [0075] R¹ is independently H, halogen, haloalkyl, haloalkyloxy —CO₂R″, —SO₃H, —OH, —CONR*R″, —CR″O, —SO₂—NR*R″, —NO₂, —SO₂—R″, —SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO₂—R′, —NR″CO—R*, —NR″—SO₂—R′, —O—CO—R*, O—CO₂—R*, —O—CO—NR*R″; cycloalkyl, alkylamino, hydroxyalkylamino, —SH, heteroaryl, or alkyl;
  • [0076] R* is independently H, alkyl, cycloalkyl, aminoalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
  • [0077] R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
  • [0078] R³ is H, alkyl, cycloalkyl, aryl, alkoxy, O-aryl; O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl; S-cycloalkyl, arylalkyl, or haloalkyl;
  • [0079] R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;
  • [0080] R⁵ is H, OH, alkoxy, O-aryl, alkyl or aryl;
  • [0081] R⁷ is H, OH, alkyl, aryl, alkoxy, O-aryl, cycloalkyl, or O-cycloalkyl;
  • [0082] R⁸ is hydrogen, or alkyl;
  • [0083] E is an alkyl or cycloalkyl group which is substituted by [D_m-(CHR₃)_n]_qY or a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring;
  • [0084] Y is hydrogen, halogen, haloalkyl, haloalkyloxy, alkyl, cycloalkyl, a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring or

[0085]

• • • [0086] m is 0 or 1;
    • [0087] n is 0 or 1;
    • [0088] p is 0 or 1;
    • [0089] r is 0 or 1;
    • [0090] q is 0 or 1; and
    • [0091] t is 0 to 3;

[0093]

• • [0094] wherein
  • [0095] A is a non-aromatic ring system containing 4, 5, 6, 7 or 8 carbon atoms, wherein the ring system comprises at least one double bond and wherein one or more of the carbon atoms in the ring can be replaced by a group X, wherein X is selected from the group consisting of S, O, N, NR⁴, SO, CO or SO₂;
  • [0096] D is O, S, SO₂, NR⁴, or CH₂;
  • [0097] Z¹ and Z² are independent from each other O, S, or NR⁵,
  • [0098] R¹ is independently H, halogen, haloalkyl, haloalkyloxy —CO₂R″, —SO₃H, —OH, —CONR*R″, —CR″O, —SO₂—NR*R″, —NO₂, —SO₂—R″, —SO—R*, —CN, alkoxy, alkylthio, aryl, —NR″—CO₂—R′, —NR″—CO—R*, —NR″—SO₂—R′, —O—CO—R*, —O—CO₂—R*, —O—CO—NR*R″; cycloalkyl, alkylamino, hydroxyalkylamino, heteroaryl, —SH, or alkyl;
  • [0099] R² is H or OR⁶, NHR⁷, NR⁷OR⁷ or R² togehter with the nitrogen atom which is attached to R⁸ form a 6 membered heteroyclic ring with the proviso that R² is —[CH₂]₈ and R⁸ is absent;
  • [0100] R³ is H, alkyl, cycloalkyl, aryl, alkoxy, O-aryl; O-cycloalkyl, halogen, aminoalkyl, alkylamino, hydroxylamino, hydroxylalkyl, haloalkyloxy, heteroaryl, alkylthio, S-aryl; S-cycloalkyl, arylalkyl, or haloalkyl;
  • [0101] R⁴ is H, alkyl, cycloalkyl, aryl or heteroaryl;
  • [0102] R⁵ is H, OH, alkoxy, O-aryl, alkyl or aryl;
  • [0103] R⁶ is H, alkyl cycloalkyl aryl, arylalkyl, heteroaryl, alkylaryl alkoxyalkyl, acylmethyl, (acyloxy)alkyl, non-symmetrical (acyloxy)alkyldiester, or dialkylphosphate;
  • [0104] R⁷ is H, OH, alkyl, aryl, alkoxy, O-aryl, cycloalkyl, or O-cycloalkyl;
  • [0105] R⁸ is hydrogen, or alkyl;
  • [0106] E is an alkyl or cycloalkyl group which is substituted by [D_m-(CHR₃)_n]_qY or a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring;
  • [0107] Y is hydrogen, halogen, haloalkyl, haloalkyloxy, alkyl, cycloalkyl, a monocyclic or polycyclic substituted or unsubstituted ring system which may contain one or more groups X and which contains at least one aromatic ring or

[0108]

• • • [0109] m is 0 or 1;
    • [0110] n is 0 or 1;
    • [0111] p is 0 or 1;
    • [0112] q is 0 or 1;
    • [0113] s is 0 to 2;
    • [0114] t is 0 to 3;
  • [0115] with the proviso that the following compounds are excluded: 5,5-Dimethyl-4-phenyl-2-(3-phenyl-ureido)-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Chlorophenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Methoxylphenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 2[3-(4-Methylphenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-caboxylic acid methyl ester, 2[3-(4-Nitrophenyl-ureido)]-5,5-dimethyl-4-phenyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-5,5-dimethyl-2-(3-phenyl-ureido)-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-chlorophenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-methoxyphenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, 4-(4-Chlorophenyl)-2[3-(4-methylphenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-carboxylic acid methyl ester, or 4-(4-Chlorophenyl)-2[3-(4-nitrophenyl-ureido)]-5,5-dimethyl-4,5-dihydro-furan-3-caboxylic acid methyl ester,
• [0116] an alkyl group, if not stated otherwise, denotes a linear or branched C₁–C₆-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C₁–C₆-alkenyl or a linear or branched C₁–C₆ alkinyl group, which can optionally be substituted by one or more substituents R′, preferably by halogen;
• [0117] the C₁–C₆-alkyl, C₁–C₆-alkenyl and C₁–C₆-alkinyl residue may be selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃, —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —C₆H₁₃, —C(R′)₃, —C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃, —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—CH₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅, CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂, —C(CH₃)═CH—CH═CH₂, —CH═C(C₃)—CH═C₂, —CH═CH—C(CH₃)═CH₂, —CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C═CH, —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃, —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH, —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH, —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂, —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—(CH₃)₃, —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃, —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂, —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆C≡C—CH₃, —CH₂C≡C—C₃H₇, —C₂H₄C≡C₂H₅;
• [0118] R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″, —NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl, —SO₂-alkyl, —NR″—CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl arylalkyl or heteroaryl;
• [0119] R″ is independently hydrogen, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
• [0120] a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group X, X being as defined above; the C₃–C₈-cycloalkyl residue may be selected from the group comprising -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃, -cyclo-C₈H₁₅;
• [0121] an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
• [0122] an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above,
• [0123] an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^10′)₂, —CR¹⁰(R^10′)R^10″, —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^10′)₂, —CH₂—CR¹⁰(R^10′)R^10″, —C₃(R¹⁰)₇ or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^10′, R^10″ represent F, Cl, Br or I, preferably F;
• [0124] a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above;
• [0125] an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃, —OCR¹⁰(R^10′)₂, —OCR¹⁰(R^10′)R^10″, —OC₂(R¹⁰)₅, —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R^10′)₂, —OCH₂—CR¹⁰(R^10′)R^10″, —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^10′, R^10″ represent F, Cl, Br or I, preferably F;
• [0126] a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group or HO-alkyl-NH— group, the alkyl group being as defined above;
• [0127] an alkyl no group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
• [0128] a halogen group is chlorine, bromine, fluorine or iodine, fluorine being preferred;
• [0129] an aryl group preferably denotes an aromatic group having five to fifteen carbon atoms, which can optionally be substituted by one or more substituents R′, where R′ is as defined above; the aryl group is preferably a phenyl group, —CH₂Ph, —C₂H₄Ph, —CH═CH—Ph, —C≡C—Ph, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′, -o-CH₂—C₆H₄—R′, -m-CH₂—C₆H₄—R′, -p-CH₂—C₆H₄—R′;
• [0130] a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S. This heterocyclic group ran be fused to another rig. For example, this group can be selected from a thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, indolyl, indolinyl, benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl benzothiazolyl, quinazolinyl, quinoxazolinyl; or preferably quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoqulnolinyl group. This heterocyclic group can optionally be substituted by one or more substituents R′, where R′ is as defined above.

[0169]
wherein A, X, R¹, R², R⁸, Z¹, Z² and p have the meaning as define above. Preferably Y is E and more preferably Y is an optionally substituted phenyl.

EXAMPLES

1. Synthesis of cyclopent-1-ene-1,2,3-tricarboxylic acid monoamide and cyclopent-1-ene-1,2,5-tricarboxylic acid monoamide and derivatives

2. Synthesis of cyclopent-1-ene-1,2-dicarboxylic acid 2-hydroxyamide 1-monoamide derivate

3. Synthesis of 3-hydroxy-cyclopentene-dicarboxylic acide-monoamide and 5-hydroxy-cyclopentene-dicarboxylic acide-monoamide

4. Synthesis cylopentenedicarboxylic acid 2-monoamide 1-alkyl ester

Example 1

3-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-cyclopent-2-ene-1,2-dicarboxylic acid LC/(+)-ESI-MS: m/z=400 [M+H]+

Example 2

2-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-cyclopent-1-ene-1,3-dicarboxylic acid LC/(+)-ESI-MS: m/z=400 [M+H]+

Example 3

2-(3-Fluoro-3′-methoxy-biphenyl 4-ylcarbamoyl)cyclopent-1-enecarboxylic acid methyl esterLC/(+)-ESI-MS: m/z=370 [M+H]+

Example 4

Cyclopent-1-ene-1,2-dicarboxylic acid 1-[(3-fluoro-3′-methoxy-biphenyl-4-yl)amide]2-hydroxyamide LC/(+)-ESI-MS: m/z 371 [M+H]+

Example 5

3-Hydroxy-2-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=480 [M+H]+

Example 6

5-Hydroxy-2-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=480 [M+H]+

Example 7

2-(3′-Ethoxy-3,5-difluoro-biphenyl-4-ylcarbamoyl)-3-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z 404 [M+H]+

Example 8

2-(3′-Ethoxy-3,5-difluoro-biphenyl-4-ylcarbamoyl)-5-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=404 [M+H]+

Example 9

2-(1′,3′-di-methoxy-3,5-difluoro-biphenyl-4-ylcarbamoyl)-3-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z 420 [M+H]+

Example 10

2-(1′,3′-di-methoxy-3,5-difluoro-biphenyl-4-ylcarbamoyl)-5-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z 420 [M+H]+

Example 11

3-Hydroxy-2-(3,5,2′-trifluoro-biphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z 378 [M+H]+

Example 12

5-Hydroxy-2-(3,5,2′-trifluoro-biphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=378 [M+H]+

Example 13

2-(2-Chloro-2′-methoxy-biphenyl-4-ylcarbamoyl)3-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=388 [M+H]+

Example 14

2-(2-Chloro-2′-methoxy-biphenyl-4-ylcarbamoyl)-5-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=388 [M+H]+

Example 15

2-(2′-Chloro-3,5-difluoro-biphenyl-4-ylcarbamoyl)-3-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z 394 [M+H]+

Example 16

2-(2′-Chloro-3,5-difluoro-biphenyl-4-ylcarbamoyl)-5-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=394 [M+H]+

Example 17

2-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-3-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=372 [M+H]+

Example 18

2-(3-Fluoro-3′-methoxy-biphenyl-4-ylcarbamoyl)-5-hydroxy-cyclopent-1-enecarboxylic acid LC/(+)-ESI-MS: m/z=372. [M+H]+