Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV

• US 5,591,776 A
• Filed: 01/10/1995
• Issued: 01/07/1997
• Est. Priority Date: 06/24/1994
• Status: Expired due to Term

• Current Assignee: Euroceltique SA
• Original Assignee: Euroceltique SA
• Inventors: Dolby, Lloyd J., Chasin, Mark, Cavalla, David J.
• Primary Examiner(s): Gupta, Yogendra N.
• Application Number:
  US08/370,952
• Time in Patent Office: 728 Days
• Field of Search: 514/622, 564/174, 564/177
• US Class Current: 514/622
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 271/00 Derivatives of carbamic acids, i.e. compounds containing any of the groups , the nitrogen atom not being part of nitro or nitroso groups
• CPC Class Codes: C07C 45/30 with halogen containing compounds, e.g. hypohalogenation
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 213/73 Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/20 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/72 Two oxygen atoms, e.g. hydantoin
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 249/04 : 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/14 : Nitrogen atoms

Abstract

Rolipram-based PDE IV inhibitors containing phenyl- or benzyl-substituted moieties of the formula: ##STR1## wherein X₁ and X₂ may be the same or different and each is O or S;

R₁ is selected from the group consisting of hydrogen, saturated or unsaturated straight-chain or branched C_2-12 alkyl groups, cycloalkyl and cycloalkyl-alkyl groups containing from 3 to 10 carbon atoms in the cycloalkyl moiety;

R₂ =R₁ or --CH₃ ;

R₃ is hydrogen, halogen, or a saturated or unsaturated straight-chain or branched C_1-12 alkyl group, a cycloalkyl or cycloalkyl-alkyl groups containing from 3 to 7 carbon atoms in the cycloalkyl moiety;

Z is a linkage selected from --CH₂ CONH-- or --CH₂ NHCO--, and

R₄ is a phenyl or benzyl which may be unsubstituted or substituted with one or more halogen atoms, alkyl groups, hydroxyl groups, cyano groups, carboxyl groups, alkoxy groups, alkoxycarbonyl, amido, carboxamido, substituted or unsubstituted amino groups, cycloalkyl and cycloalkyl-alkyl groups containing from 3 to 10 carbon atoms in the cycloalkyl moiety, aryl or aralkyl groups preferably containing from about 6 to about 10 carbon atoms, or heterocyclic groups containing nitrogen, oxygen or sulfur in the ring; the alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, and aryl-alkyl groups being saturated or unsaturated, unsubstituted or substituted by halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, alkoxy groups, alkoxycarbonyl, carboxamido or substituted or unsubstituted amino groups, or one or more lower alkyl groups having from 1 to 3 carbon atoms;

provided that R₄ cannot be substituted with more than one methoxy group. compared to theophylline or rolipram as well as with improved selectivity with regard to PDE III inhibition. Pharmaceutical compositions containing the same and methods of treatment are also disclosed.

Claims

1. A compound of the formula:

##STR9## wherein;

X₁ and X₂ may be the same or different and each is O or S;

R₁ is selected from the group consisting of cycloalkyl and cycloalkyl-alkyl groups containing from 3 to 10 carbon atoms in the cycloalkyl moiety;

R₂ is R₁ or CH₃ ;

R₃ is hydrogen, halogen, or a saturated or unsaturated straight-chain or branched C_1-12 alkyl group, a cycloalkyl or cycloalkyl-alkyl groups containing from 3 to 7 carbon atoms in the cycloalkyl moiety;

Z is a linkage selected from --CH₂ CONH-- and --CH₂ NHCO--; and

R₄ is a phenyl or benzyl which may be unsubstituted or substituted with one or more halogen atoms, alkyl groups, hydroxyl groups, cyano groups, carboxyl groups, alkoxy groups, alkoxycarbonyl, amido, carboxamido, substituted or unsubstituted amino groups, cycloalkyl and cycloalkyl-alkyl groups containing from 3 to 10 carbon atoms in the cycloalkyl moiety, aryl or aralkyl groups preferably containing from about 6 to about 10 carbon atoms, or heterocyclic groups containing nitrogen, oxygen or sulfur in the ring;

said alkyl, alkoxy, cycloalkyl, cycloalkyl-alkyl, aryl, and aryl-alkyl groups being saturated or unsaturated, unsubstituted or substituted by halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, alkoxy groups, alkoxycarbonyl, carboxamido or substituted or unsubstituted amino groups, or one or more lower alkyl groups having from 1 to 3 carbon atoms;

provided that R₄ cannot be substituted with more than one methoxy group.

2. The compound of claim 1, wherein R₁ is a cycloalkyl of 3-6 carbon atoms, said cycloalkyl may be substituted by one or more alkyl groups or by one or more halogens, R₂ is hydrogen, or C_1-12 alkyl, and wherein R₃ is hydrogen, lower alkyl or halogen.

3. The compound of claim 2 wherein R₁ is cycloalkyl optionally substituted by one or more halogens.

4. The compound of claim 1 wherein R₂ is methyl or and wherein R₁ is cyclopentyl optionally substituted by R₅ as shown in the following structural formula:

##STR10## wherein R₅ is hydrogen or a saturated or unsaturated straight-chain lower alkyl group containing from about 1 to about 6 carbon atoms, unsubstituted or substituted with one or more halogen atoms, hydroxyl groups, cyano groups, nitro groups, carboxyl groups, alkoxy groups, alkoxycarbonyl, carboxamido or substituted or unsubstituted amino groups.

5. The compound of claim 2 wherein Z is a linkage selected from the group consisting of --CH₂ CONH--, --CH₂ NHCO--.

6. The compound of claim 2, wherein X₁ and X₂ are O.

7. The compound of claim 2 wherein R₄ is an unsubstituted or substituted phenyl or benzyl.

8. The compound of claim 6 wherein R₄ is a substituted phenyl having one of the following structures:

##STR11## wherein R₆ is an unsubstituted or substituted lower alkyl.

9. The compound of claim 1, selected from the group consisting of:

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline; and

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-hydroxy-3-allyl-5-chloroaniline.

10. A method of effecting selective PDE IV inhibition to a patient requiring the same, comprising administering an effective amount of the compound of claim 1.

11. The method of claim 10, wherein said compound is selected from the group consisting of:

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline; and

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-hydroxy-3-allyl-5-chloroaniline.

12. A pharmaceutical composition comprising the compound of claim 1.

13. The pharmaceutical composition of claim 12, wherein said compound is selected from the group consisting of:

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline; and

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-hydroxy-3-allyl-5-chloroaniline.

14. A method of treating a mammal suffering from a disease state selected from the group consisting of asthma, allergies, inflammation, depression, dementia, atopic diseases, rhinitis and disease states associated with abnormally high physiological levels of cytokine, comprising administering an effective amount of the compound of claim 1.

15. The method of claim 14, wherein said compound is selected from the group consisting of:

N-(3 -Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-allyloxy-5-chloroaniline; and

N-(3-Cyclopentyloxy-4-methoxyphenyl-acetyl)-2-hydroxy-3-allyl-5-chloroaniline.