Catechol derivatives

• US 5,236,952 A
• Filed: 04/16/1991
• Issued: 08/17/1993
• 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: DaPrada, Mose, Bruderer, Hans, Borgulya, Janos, Zurcher, Gerhard, Bernauer, Karl
• Primary Examiner(s): Reamer, James H.
• Application Number:
  US07/686,210
• Time in Patent Office: 854 Days
• Field of Search: 568/306, 558/415, 558/520, 558/525, 514/676, 514/523
• US Class Current: 514/520
• 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-adensoylmethionine 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, extraneuornal 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 the group CO--R¹¹ wherein R¹¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl, 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 situated in the p-position 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 1, 3,4-Dihydroxy-5-nitrobenzophenone.

7. A compound, according to claim 1, 2'"'"'-Fluoro-3,4-dihydroxy-5-nitrobenzophenone.

14. A compound according to claim 1, wherein said compound is 4-dihydroxy-5'"'"'-methyl-5-nitrobenzophenone.

8. A pharmaceutical composition comprising a compound of the formula ##STR25## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is CO--R¹ wherein R¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl or an ester or ether derivative thereof which if hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier material.

9. A pharmaceutical composition, according to claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrobenzophenone.

10. A pharmaceutical composition, according to claim 8, wherein the compound of formula Ia is 2'"'"'-fluoro-3,4-dihydroxy-5-nitrobenzophenone.

15. A pharmaceutical composition according to claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-4'"'"'-methyl-5-nitrobenzophenone.

22. A pharmaceutical composition according to claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-4'"'"'-methyl-5-nitrobenzophenone.

11. A pharmaceutical composition comprising L-dopa, peripheral decarboxylase inhibitor, a compound of the formula ##STR26## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is the group CO--R¹ wherein R¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl or an ester or ether derivative thereof which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier material.

12. A pharmaceutical composition, according to claim 11, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrobenzophenone.

13. A pharmaceutical composition, according to claim 11, wherein the compound of formula Ia is 2'"'"'-fluoro-3,4-dihydroxy-5-nitrobenzophenone.

16. A pharmaceutical composition according to claim 11, wherein the compound of formula Ia is 3,4-dihydroxy-4'"'"'-methyl-5-nitrobenzophenone.

17. A pharmaceutical composition for treating depression comprising an effective amount of a compound of the formula ##STR27## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is CO--R¹ wherein R¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl or an ester or ether derivative thereof which if hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier material.

18. A pharmaceutical composition according to claim 17, wherein the compound of formula Ia is 3,4-dihydroxy-4'"'"'-methyl-5-nitrobenzophenone.

19. A pharmaceutical composition for treating Parkinson'"'"'s disease comprising L-dopa, a peripheral decarboxylase inhibitor, a compound of the formula ##STR28## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is CO--R¹ wherein R¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl or an ester or ether derivative thereof which if hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier material.

20. A pharmaceutical composition according to claim 19, wherein the compound of formula Ia is 3,4-dihydroxy-4'"'"'-methyl-5-nitrobenzophenone.

21. A pharmaceutical composition for inhibiting catechol-O-methyl-transferase, said composition comprising a catechol-O-methyl transferase inhibiting amount of a compound of the formula ##STR29## wherein Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is CO--R¹ wherein R¹ is a phenyl group optionally mono- or disubstituted by halogen, cyano, hydroxy or lower alkyl or an ester or ether derivative thereof which if hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier material.