Anthranilic acid derivatives

• US 5,716,993 A
• Filed: 09/14/1995
• Issued: 02/10/1998
• Est. Priority Date: 12/27/1993
• Status: Expired due to Term

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai Company Limited (Eisai Medical Research Incorporated)
• Inventors: Ishibashi, Keiji, Ozaki, Fumihiro, Ikuta, Hironori, Ishihara, Hiroki, Souda, Shigeru
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/507,476
• Time in Patent Office: 880 Days
• Field of Search: 549/441, 514/351, 514/466, 514/253, 514/321, 514/337, 514/329, 514/428, 514/406, 514/468, 514/603, 514/619, 546/300, 546/197, 546/226, 546/283.7, 546/284.1, 548/568, 548/364.4, 564/184, 564/86, 564/168, 544/337
• US Class Current: 514/619
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 229/56 with amino and carboxyl groups bound in ortho-position
• CPC Class Codes: C07C 229/64 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/30 having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/32 having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
• CPC Class Codes: C07C 237/40 having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 237/44 having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07C 255/58 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 311/39 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/40 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 311/51 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/81 : Amides; Imides
• 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 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 265/26 : Two oxygen atoms, e.g. isatoic anhydride
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/33 : in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 317/48 : Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides an anthranilic acid derivative having a cGMP-PDE inhibitory activity.

An anthranilic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof: ##STR1## wherein R¹, R², R³ and R⁴ represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, a nitro group, a hydroxyalkyl group, a cyano group or the like; R⁵ and R⁶ represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group or the like;

W represents a group of the formula: --N═ or --CH═; R⁷ and R⁸ represent the same or different from each other, a hydrogen atom, an optionally halogenated lower alkyl group or the like;

A represents a hydrogen atom, an optionally halogenated lower alkyl group or the like;

Y represents an oxygen atom or a sulfur atom; and

n is an integer of 0 to 6!.

Claims

1. An anthranilic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof:

##STR218## wherein R¹, R², R³ and R⁴ represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, a nitro group, a hydroxyalkyl group, a cyano group, a group of the formula;

##STR219## wherein R⁹ and R¹⁰ represent the same or different from each other, a hydrogen atom, an optionally halogenated lower alkyl group, an arylalkyl group, a heteroarylalkyl group, an acyl group or an optionally protected carboxyl group, or alternatively R⁹ and R¹⁰ together with the nitrogen atom to which they are bonded may form a ring which may be substituted; and

p is an integer of 0 to 6, an optionally substituted tetrazolyl group, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted pyrazolyl group, an optionally substituted imidazolyl group, a group of the formula;

##STR220## (wherein R¹³ represents a hydrogen group or an optionally halogenated lower alkyl group; and

q is an integer of 0 to 2, or alternatively two substituents selected from among R¹, R², R³ and R⁴ which are adjacent to each other may form a ring together with the carbon atoms to which they are bonded respectively;

R⁵ and R⁶ represent the same or different from each other, a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally halogenated lower alkyl group or an optionally halogenated lower alkoxy group, or alternatively R⁵ and R⁶ together with the carbon atoms to which they are bonded respectively may form a cycloalkyl ring, an oxolane ring, a 1,3-dioxolane ring or a 1,4-dioxane ring;

W represents a group of the formula;

--N= or --CH=;

R⁷ and R⁸ represent the same or different from each other, a hydrogen atom or an optionally halogenated lower alkyl group, or alternatively R¹ and R⁷ together with the carbon atoms to which they are bonded respectively may form a ring which may contain a nitrogen atom, an oxygen atom or a sulfur atom and which may be substituted;

A represents a hydrogen atom, an optionally halogenated lower alkyl group or a group of the formula;

--X--(CH₂)_m --Z wherein X represents --CO--, --CS--, --CH₂ -- or --S(O)₂ --;

Z represents a hydroxy group, an optionally halogenated lower alkoxy group, a cyano group, a halogen atom, an optionally protected carbamoyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyloxy group, a group of the formula;

--NR¹¹ R¹² wherein R¹¹ and R¹² represent the same or different from each other, a hydrogen atom, an optionally halogenated lower alkyl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an acyl group, an optionally protected carboxy group or an optionally substituted carbamoyl group, or alternatively R¹¹ and R¹² together with the nitrogen atom to which they are bonded may form a ring which may be substituted, or an optionally substituted cycloalkyl group; and

m is an integer of 0 to 6;

Y represents an oxygen atom or a sulfur atom; and

n is an integer of 0 to 6.

2. An anthranilic acid derivative or pharmacologically acceptable salt thereof as set forth in claim 1, wherein Y is an oxygen atom.

3. A preventive and therapeutic agent for diseases wherein a phosphodiesterase inhibitory action is efficacious, which comprises an anthranilic acid derivative or pharmacologically acceptable salt thereof as set forth in claim 1 as an active ingredient.

4. A preventive and therapeutic agent for diseases wherein a cyclic GMP phosphodiesterase inhibitory action is efficacious, which comprises an anthranilic acid derivative or pharmacologically acceptable salt thereof as set forth in claim 1 as an active ingredient.

5. A preventive and therapeutic agent as set forth in claim 4, wherein said diseases include ischemic heart diseases, angina pectoris, hypertension, pulmonary hypertension, heart failure and asthma.

6. A drug composition comprising a pharmacologically effective amount of an anthranilic acid derivative or pharmacologically acceptable salt thereof as set forth in claim 1, and a pharmacologically acceptable carrier.

7. A method for the prevention and treatment of diseases, which comprises administering a pharmacologically effective amount of an anthranilic acid derivative or pharmacologically acceptable salt thereof as set forth in claim 1 to inhibit phosphodiesterase.