Catechol derivatives

• US 5,705,703 A
• Filed: 01/21/1997
• Issued: 01/06/1998
• Est. Priority Date: 03/11/1986
• Status: Expired due to Term

• Current Assignee: Valeant Global Acquisition Company Pte Limited
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Bruderer, Hans, Borgulya, Janos, Zurcher, Gerhard, Bernauer, Karl, Prada, Mose Da
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US08/784,554
• Time in Patent Office: 350 Days
• Field of Search: 558/414, 558/415, 558/416, 562/465, 562/473, 564/170, 568/306
• US Class Current: 568/306
• CPC Class Codes: C07C 205/23 having two nitro groups bound to the ring
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 205/43 to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
• CPC Class Codes: C07C 205/44 the carbon skeleton being further substituted by —CHO groups
• CPC Class Codes: C07C 205/45 the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• CPC Class Codes: C07C 205/56 having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 205/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 255/00 Carboxylic acid nitriles cyanogen or compounds thereof C01C3/00
• CPC Class Codes: C07C 255/53 containing cyano groups and hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 45/298 with manganese derivatives
• CPC Class Codes: C07C 45/30 with halogen containing compounds, e.g. hypohalogenation
• CPC Class Codes: C07C 45/305 with halogenochromate reagents, e.g. pyridinium chlorochromate
• CPC Class Codes: C07C 45/46 Friedel-Crafts reactions
• CPC Class Codes: C07C 45/673 by change of size of the carbon skeleton
• CPC Class Codes: C07C 47/565 all hydroxy groups bound to the ring
• CPC Class Codes: C07C 47/575 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/83 polycyclic
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 69/017 Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 217/16 : substituted by oxygen atoms
• CPC Class Codes: C07D 241/44 : 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 hetero ring
• CPC Class Codes: C07D 253/07 : 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
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/40 : Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 279/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 285/16 : Thiadiazines; Hydrogenated thiadiazines
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Catechol derivatives of the formula ##STR1## wherein Ra, Rb and Rc have the significance given herein. the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adenosylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuronal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure.

Formula Ia above embraces not only compounds which form part of the invention, but also known compounds: the compounds which form part of the invention can be prepared according to known methods.

Claims

1. A compound of the formula ##STR24## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc'"'"' is a) --CO--COR³¹ and R³¹ is hydroxy, amino, a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylimino group or a saturated, N-containing heterocyclic group attached via a ring nitrogen atom;

b) --COR²¹ and R²¹ is a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue;

or

c) --(A)_n --COR³¹ and A is vinylene unsubstituted or substituted by lower alkyl, n is 1, and R³¹ is amino, a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylamino group or a saturated, N-containing heterocyclic group attached via a ring nitrogen atom

or an ester or ether derivative thereof which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof.

2. A compound, according to claim 1, wherein Rb is para to Ra.

3. A compound, according to claim 2, wherein Ra is nitro.

4. A compound, according to claim 3, wherein Rb is hydrogen, chlorine or fluorine.

5. A compound, according to claim 4, wherein Rb is hydrogen.

6. A compound, according to claim 5, wherein Rc'"'"' is --CO--COR³¹ and R³¹ is hydroxy, amino, a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylimino group or a saturated, N-containing heterocyclic group attached via a ring nitrogen atom.

7. A compound, according to claim 6, wherein R³¹ is a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom.

8. A compound, according to claim 7, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is lower alkyl unsubstituted or substituted by lower cycloalkyl or cycloalkenyl groups, lower alkenyl unsubstituted or substituted by lower cycloalkyl or cycloalkenyl groups, C_3-7 cycloalkyl unsubstituted or substituted by lower alkyl groups, C_8-10 -bicycloalkyl unsubstituted or substituted by lower alkyl groups, or lower cycloalkenyl unsubstituted or substituted by lower alkyl groups.

9. A compound, according to claim 7, wherein the substituted or unsubstituted saturated or partially unsaturated lower hydrocarbon residue is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i-butyl or t-butyl.

10. A compound, according to claim 9, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is mono- or disubstituted with at least one of hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino, or lower alkylthio.

11. A compound, according to claim 9, ethyl 3,4-dihydroxy-5-nitrophenylglyoxalate.

12. A compound, according to claim 5, wherein Rc'"'"' is --COR²¹ and R²¹ is a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue.

13. A compound, according to claim 12, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is lower alkyl unsubstituted or substituted by lower cycloakyl or cycloalkenyl groups, lower alkenyl unsubstituted or substituted by lower cycloalkyl or cycloalkenyl groups, C_3-7 cycloalkyl unsubstituted or substituted by lower alkyl groups, C_8-10 -bicycloalkyl unsubstituted or substituted by lower alkyl groups, or lower cycloalkenyl unsubstituted or substituted by lower alkyl groups.

14. A compound, according to claim 13, wherein R²¹ is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i-butyl or t-butyl.

15. A compound, according to claim 14, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is mono- or disubstituted with at least one of hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino, or lower alkylthio.

16. A compound, according to claim 14, 3'"'"',4'"'"'-dihydroxy-5'"'"'-nitrobutyrophenone.

17. A compound, according to claim 5, wherein Rc'"'"' is --A_n--COR³¹ and A is vinylene unsubstituted or substituted by lower alkyl, n is l, and R³¹ is amino, a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom or an imino or lower alkylamino group or a saturated, N-containing heterocyclic group attached via a ring nitrogen atom.

18. A compound, according to claim 17, wherein R³¹ is a substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom.

19. A compound, according to claim 18, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is lower alkyl unsubstituted or unsubstituted by lower cycloalkyl or cycloalkenyl groups, lower alkenyl unsubstituted or substituted by lower cycloalkyl or cycloalkenyl groups, C_3-7 cycloalkyl unsubstituted or substituted by lower alkyl groups, C_8-10 -bicycloalkyl unsubstituted or substituted by lower alkyl groups, or lower cycloalkenyl unsubstituted or substituted by lower alkyl groups.

20. A compound, according to claim 19, wherein the saturated or partially unsaturated lower hydrocarbon residue is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i-butyl or t-butyl.

21. A compound, according to claim 20, wherein the substituted or unsubstituted, saturated or partially unsaturated lower hydrocarbon residue is mono- or disubstituted with at least one of hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino, or lower alkylthio.