Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same

• US 4,963,590 A
• Filed: 11/27/1987
• Issued: 10/16/1990
• Est. Priority Date: 11/28/1986
• Status: Expired due to Term

• Current Assignee: Orion Corporation (Smiths Group International Holdings Ltd.)
• Original Assignee: Orion-Yhtyma OY
• Inventors: Mannisto, Pekka T., Heinola, Kalevi E., Pohto, Pentti, Backstrom, Reijo J., Honkanen, Erkki J., Pippuri, Aino K., Nissinen, Erkki A. O., Kaakkola, Seppo K., Pystynen, Jarmo J., Kairisalo, Pekka J., Linden, Inge-Britt Y.
• Primary Examiner(s): FRIEDMAN, STANLEY
• Application Number:
  US07/126,911
• Time in Patent Office: 1,054 Days
• Field of Search: 514/678
• US Class Current: 514/678
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 205/22 having one nitro groups bound to the ring
• CPC Class Codes: C07C 205/23 having two nitro groups bound to the ring
• CPC Class Codes: C07C 205/26 and being further substituted by halogen atoms
• CPC Class Codes: C07C 205/34 having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
• 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 205/45 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 205/57 having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 255/00 Carboxylic acid nitriles cyanogen or compounds thereof C01C3/00
• CPC Class Codes: C07C 317/00 Sulfones; Sulfoxides
• CPC Class Codes: C07C 323/00 Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 45/565 by reaction with hexamethylene-tetramine
• CPC Class Codes: C07C 45/673 : by change of size of the carbon skeleton
• CPC Class Codes: C07C 45/74 : combined with dehydration
• 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 49/835 : having unsaturation outside an aromatic ring
• CPC Class Codes: C07C 49/84 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/56 : containing halogen
• CPC Class Codes: C07C 59/64 : containing six-membered aromatic rings
• CPC Class Codes: C07C 59/68 : the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 207/333 : Radicals substituted by oxygen or sulfur atoms
• CPC Class Codes: C07D 211/32 : by oxygen atoms
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 215/14 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 317/62 : 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 atoms of the carbocyclic ring
• CPC Class Codes: C07D 319/24 : [b,e]-condensed with two six-membered rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Pharmacologically active catechol derivatives of formula I ##STR1## wherein R₁ and R₂ independently comprise hydrogen, alkyl, acyl, optionally substituted aroyl, lower alkylsulfonyl or alkylcabamoyl or taken together form a lower alkylidene or cycloalkylidene, X comprises an electronegative substituent such as halogen, nitro, cyano, lower alkylsulfonyl, sulfonamido, aldehyde, caboxyl or trifluoromethyl and R₃ comprises hydrogen, halogen, hydroxy alkyl, amino, nitro, cyano, trifluoromethyl, lower alkylsulfonyl, sulfonamide, aldehyde, alkyl carbonyl, aralkylidene carbonyl or carboxyl or a group selected from ##STR2## wherein R₄ comprises hydrogen, alkyl, cyano, carboxyl or acyl and R₅ comprises hydrogen, cyano, carboxyl, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, optionally substituted aroyl or heteroaroyl, hydroxyalkyl or carboxyalkyl or R₄ and R₅ together form a five to seven membered substituted cycloalkanone ring;

--(CO).sub.n (CH.sub.2).sub.m --COR

wherein n is 0-1 and m is 0-7 and R comprises hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino; ##STR3## wherein R₈ and R₉ independently comprise hydrogen or one of the following optionally substituted groups; alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or together form an optionally substituted piperidyl group;

--NH--CO--R.sub.10

wherein R₁₀ comprises a substituted alkyl group.

Claims

1. A pharmaceutical composition for inhibiting catechol-O-methyl-transferase, said composition comprising a catechol-O-methyl-transferase inhibiting amount of a compound having the formula I ##STR54## wherein R₁ and R₂ independently represent hydrogen or alkylcarbonyl of 2 to 5 carbon atoms, X represents nitro or cyano and R₃ represents ##STR55## wherein R₄ represents cyano or alkylcarbonyl of 2 to 5 carbon atoms and R₅ represents cyano;

alkylcarbonyl of 2 to 5 carbon atoms;

alkoxycarbonyl of 2 to 9 carbon atoms;

or carbamoyl which is unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, or hydroxyalkyl of 1 to 8 carbon atoms, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition as claimed in claim 1, wherein X is nitro.

3. The pharmaceutical composition as claimed in claim 1, wherein R₄ and R₅ are both alkylcarbonyl of 2 to 3 carbon atoms.

5. A pharmaceutical composition as claimed in claim 1, wherein R₄ represents cyano and R₅ represents carbamoyl which is unsubstituted or substituted with alkyl of 1 to 8 carbon atoms or hydroxyalkyl of 1 to 8 carbon atoms.

6. The pharmaceutical composition as claimed in claim 5, wherein R₅ represents carbamoyl which is substituted with methyl, ethyl, isopropyl or hydroxypropyl.

4. A pharmaceutical composition for inhibiting catechol-O-methyl-transferase, said composition comprising a catechol-O-methyl-transferase inhibiting amount of 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition for inhibiting catechol-O-methyl-transferase, said composition comprising a catechol-O-methyl-transferase inhibiting amount of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, and a pharmaceutically acceptable carrier.

8. A method for inhibiting catechol-O-methyl-transferase in a patient, said method comprising administering a catechol-O-methyl-transferase inhibiting amount of a compound having the formula I ##STR56## wherein R₁ and R₂ independently represent hydrogen or alkylcarbonyl of 2 to 5 carbon atoms, X represents nitro or cyano and R₃ represents ##STR57## wherein R₄ represents cyano or alkylcarbonyl of 2 to 5 carbon atoms and R₅ represents cyano;

alkylcarbonyl of 2 to 5 carbon atoms;

alkoxycarbonyl of 2 to 9 carbon atoms;

or carbamoyl which is unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, or hydroxyalkyl of 1 to 8 carbon atoms, to a patient in need of such treatment.

9. The method as claimed in claim 8, wherein X is nitro.

10. The method as claimed in claim 8, wherein R₄ and R₅ are both alkylcarbonyl of 2 to 3 carbon atoms.

12. A method as claimed in claim 8, wherein R₄ represents cyano and R₅ represents carbamoyl which is unsubstituted or substituted with alkyl of 1 to 8 carbon atoms or hydroxyalkyl of 1 to 8 carbon atoms.

13. The method as claimed in claim 12, wherein R₅ represents carbamoyl which is substituted with methyl, ethyl, isopropyl or hydroxypropyl.

11. A method for inhibiting catechol-O-methyl-transferase in a patient, said method comprising administering a catechol-O-methyl-transferase inhibiting amount of 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione, to a patient in need of such treatment.

14. A method for inhibiting catechol-O-methyl-transferase in a patient, said method comprising administering a catechol-O-methyl-transferase inhibiting amount of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, to a patient in need of such treatment.