Iridoid derivatives and neovascularization inhibitors containing the same as active ingredient

• US 6,225,478 B1
• Filed: 09/13/1999
• Issued: 05/01/2001
• Est. Priority Date: 03/05/1997
• Status: Expired due to Fees

• Current Assignee: Tsumura & Company
• Original Assignee: Tsumura & Company
• Inventors: Yamazaki, Yousuke, Sakakibara, Chiaki, Morishige, Hideaki, Kigawa, Masaharu, Kurita, Yukiko
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): Solola, Taofiq A.
• Application Number:
  US09/394,510
• Time in Patent Office: 596 Days
• Field of Search: 549/332, 549/387, 549/553, 549/562
• US Class Current: 549/332
• CPC Class Codes: C07D 311/94 condensed with rings other than six-membered or with ring systems containing such rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

Novel iridoid derivatives represented by general formula (I):

and a vascularization inhibitor having for its active ingredient said derivative are disclosed. This vascularization inhibitor has remarkable vascularization inhibitory effects unaccompanied by serious adverse side effects, which is useful for the treatment and prevention of various diseases accompanied by abnormal acceleration of vascularization.

Claims

1. A compound represented by the following general formula (I):

wherein;

X represents a C_1-5 alkyl group or —

COR¹, and R¹ is;

(a) a hydroxyl group or —

OM, wherein —

OM is a pharmacologically allowable salt or M is an alkali metal atom,

(b) a C_1-10 alkoxyl group, C_2-10 alkenyloxyl group or C_4-15 alkedienyloxyl group and wherein each may or may not be substituted with a phenyl group,

(c) a furfuryloxyl group, phenoxyl group or C_3-10 cycloalkyloxyl group, or

(d) —

NR⁴R⁵ wherein R⁴ and R⁵ may be respectively identical or different, and each represents

a hydrogen atom,

C_3-10 cycloalkyl group,

phenyl group,

a five-membered or six-membered ring system containing one or more heteroatoms selected from

nitrogen,

oxygen or

sulfur atoms,

C_1-10 alkyl group which may or may not be substituted with a

mercapto group,

—

CO₂R⁶ wherein R⁶ is a C_1-5 alkyl group,

phenyl group or

nitrogen-containing aromatic group;

or

R⁴ and R⁵ are bonded to form a heterocycloalkyl group, and said heterocycloalkyl group is a five-membered or six-membered ring system that contains as a heteroatom only the nitrogen atom at which R⁴ and R⁵ are bonded, or which contains a different nitrogen atom or oxygen atom, and said heterocycloalkyl group may or may not be substituted with a C_1-5 alkyl group which may or may not be substituted with a hydroxyl group or —

OCONH—

R⁷ wherein R⁷ is a hydrogen atom or C_1-5 alkyl group;

Y represents a hydrogen atom or the following formula;

wherein R² and R³ may be respectively identical or different, and each represents;

(a) a hydrogen atom, C_1-10 alkyl group which may be a straight or branched chain, C_2-10 alkenyl group, C_3-10 cycloalkyl group, C_1-10 alkylamino group, C_1-10 alkoxyl group, C_3-10 heterocycloalkyl group, phenyl group, phenyl C_1-5 alkyl group, naphthyl group, or cyclic amino group containing a heteroatom selected from nitrogen, oxygen or sulfur atoms, wherein each of said groups may or may not be substituted with a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, —

SO₂NH₂ group, hydroxy C_1-5 alkoxyl group, C_1-5 alkylamino group, C_1-5 alkylcarbonyl group, C_1-5 alkylthio group, benzylthio group, halogenated C_1-5 alkyl group, halogenated C_1-5 alkoxy group and —

CO₂R⁸

wherein R⁸ is a C_1-5 alkyl group, C_3-10 cycloalkyl group or five-membered or six membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms;

(b) —

COR⁹ wherein R⁹ is a phenyl group or a C_1-5 alkyl group which may or may not be substituted with a halogen atom;

or

(c) R² and R³ are bonded to form a heterocycloalkyl group or heterocycloalkenyl group, and said heterocycloalkyl group or heterocycloalkenyl group is a four-membered, five-membered or six-membered ring system that may be condensed with a benzene ring, and contains as a heteroatom only the nitrogen atom at which R² and R³ are bonded, or which contains a different nitrogen atom, oxygen atom or sulfur atom, wherein said ring system may or may not be substituted with a C_1-5 alkyl group, hydroxy C_1-5 alkyl group, phenyl group, phenyl C_1-5 alkyl group, halogenated phenyl group, C_1-5 alkoxyphenyl group or halogenated C_1-5 alkylphenyl group; and

A represents an oxygen atom or sulfur atom; and

Z represents a C_1-10 alkyl group which may or may not be substituted with a hydroxyl group, halogen atom, —

O—

R¹⁰, —

OCOR¹¹, —

OCOO—

R¹² or OCONH—

R¹³

wherein R¹⁰ through R¹³ may be a hydrogen atom or C_1-5 alkyl group that may be substituted with a halogen atom;

or

wherein the C_1-10 alkyl group may or may not be substituted with —

CO—

R¹⁴ or —

CH₂—

S—

R¹⁵,

wherein R¹⁴ and R¹⁵ each represents a five-membered or six-membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms, or a hydroxy C_1-5 alkyl group.

2. A compound represented by the following general formula (V):

wherein;

X represents a C_1-5 alkyl group or —

COR¹, and R¹ is;

(a) a hydroxyl group or —

OM, wherein —

OM is a pharmacologically allowable salt or

M is an alkali metal atom,

(b) a C_1-10 alkoxyl group, C_2-10 alkenyloxyl group or C_4-15 alkedienyloxyl group and wherein each may or may not be substituted with a phenyl group,

(c) a furfuryloxyl group, phenoxyl group or C_3-10 cycloalkyloxyl group, or

(d) —

NR⁴R⁵ wherein R⁴ and R⁵ may be respectively identical or different, and each represents

a hydrogen atom,

C_3-10 cycloalkyl group,

phenyl group,

a five-membered or six-membered ring system containing one or more heteroatoms selected from

nitrogen,

oxygen or

sulfur atoms,

C_1-10 alkyl group which may or may not be substituted with a

mercapto group,

—

CO₂R⁶ wherein R⁶ is a C_1-5 alkyl group,

phenyl group or

nitrogen-containing aromatic group;

or

R⁴ and R⁵ are bonded to form a heterocycloalkyl group, and said heterocycloalkyl group is a five-membered or six-membered ring system that contains as a heteroatom only the nitrogen atom at which R⁴ and R⁵ are bonded, or which contains a different nitrogen atom or oxygen atom, and said heterocycloalkyl group may or may not be substituted with C_1-5 alkyl group which may or may not be substituted with a hydroxyl group or —

OCONH—

R⁷ wherein R⁷ is a hydrogen atom or C_1-5 alkyl group;

Y represents a hydrogen atom or the following formula;

wherein R² and R³ may be respectively identical or different, and each represents;

(a) a hydrogen atom, C_1-10 alkyl group which may be a straight or branched chain, C_2-10 alkenyl group, C_3-10 cycloalkyl group, C_1-10 alkylamino group, C_1-10 alkoxyl group, C_3-10 heterocycloalkyl group, phenyl group, phenyl C_1-5 alkyl group, naphthyl group, or cyclic amino group containing a heteroatom selected from nitrogen, oxygen or sulfur atoms, wherein each of said groups may or may not be substituted with a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, —

SO₂NH₂ group, hydroxy C_1-5 alkoxyl group, C_1-5 alkylamino group, C_1-5 alkylcarbonyl group, C_1-5 alkylthio group, benzylthio group, halogenated C_1-5 alkyl group, halogenated C_1-5 alkoxy group and —

CO₂R⁸

wherein R⁸ is a C_1-5 alkyl group, C_3-10 cycloalkyl group or five-membered or six membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms;

(b) —

COR⁹ wherein R⁹ is a phenyl group or a C_1-5 alkyl group which may or may not be substituted with a halogen atom;

or

(c) R² and R³ are bonded to form a heterocycloalkyl group or heterocycloalkenyl group, and said heterocycloalkyl group or heterocycloalkenyl group is a four-membered, five-membered or six-membered ring system that may be condensed with a benzene ring, and contains as a heteroatom only the nitrogen atom at which R² and R³ are bonded, or which contains a different nitrogen atom, oxygen atom or sulfur atom, wherein said ring system may or may not be substituted with a C_1-5 alkyl group, hydroxy C_1-5 alkyl group, phenyl group, phenyl C_1-5 alkyl group, halogenated phenyl group, C_1-5 alkoxyphenyl group or halogenated C_1-5 alkylphenyl group; and

A represents an oxygen atom or sulfur atom.

3. A compound represented by the following general formula (VII):

wherein;

X represents a C_1-5 alkyl group or —

COR₁, and R¹ is;

(a) a hydroxyl group or —

OM, wherein —

OM is a pharmacologically allowable salt or M is an alkali metal atom,

(b) a C_1-10 alkoxyl group, C_2-10 alkenyloxyl group or C_4-15 alkedienyloxyl group and wherein each may or may not be substituted with a phenyl group,

(c) a furfuryloxyl group, phenoxyl group or C_3-10 cycloalkyloxyl group, or

(d) —

NR⁴R⁵ wherein R⁴ and R⁵ may be respectively identical or different, and each represents

a hydrogen atom,

C_3-10 cycloalkyl group,

phenyl group,

a five-membered or six-membered ring system containing one or more heteroatoms selected from

nitrogen,

oxygen or

sulfur atoms,

C_1-10 alkyl group which may or may not be substituted with a mercapto group,

—

CO₂R⁶ wherein R⁶ is a C_1-5 alkyl group,

phenyl group or

nitrogen-containing aromatic group;

or

R⁴ and R⁵ are bonded to form a heterocycloalkyl group, and said heterocycloalkyl group is a five-membered or six-membered ring system that contains as a heteroatom only the nitrogen atom at which R⁴ and R ⁵ are bonded, or which contains a different nitrogen atom or oxygen atom, and said heterocycloalkyl group may or may not be substituted with a C_1-5 alkyl group which may or may not be substituted with a hydroxyl group or —

OCONH—

R⁷ wherein R⁷ is a hydrogen atom or C_1-5 alkyl group;

Y represents a hydrogen atom or the following formula;

wherein R² and R³ may be respectively identical or different, and each represents;

(a) a hydrogen atom, C_1-10 alkyl group which may be a straight or branched chain, C_2-10 alkenyl group, C_3-10 cycloalkyl group, C_1-10 alkylamino group, C_1-10 alkoxyl group, C_3-10 heterocycloalkyl group, phenyl group, phenyl C_1-5 alkyl group, naphthyl group, or cyclic amino group containing a heteroatom selected from nitrogen, oxygen or sulfur atoms, wherein each of said groups may or may not be substituted with a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, —

SO₂NH₂ group, hydroxy C_1-5 alkoxyl group, C_1-5 alkylamino group, C_1-5 alkylcarbonyl group, C_1-5 alkylthio group, benzylthio group, halogenated C_1-5 alkyl group, halogenated C_1-5 alkoxy group and —

CO₂R⁸

wherein R⁸ is a C_1-5 alkyl group, C_3-10 cycloalkyl group or five-membered or six membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms;

(b) —

COR⁹ wherein R⁹ is a phenyl group or a C_1-5 alkyl group which may or may not be substituted with a halogen atom;

or

(c) R² and R³ are bonded to form a heterocycloalkyl group or heterocycloalkenyl group, and said heterocycloalkyl group or heterocycloalkenyl group is a four-membered, five-membered or six-membered ring system that may be condensed with a benzene ring, and contains as a heteroatom only the nitrogen atom at which R² and R³ are bonded, or which contains a different nitrogen atom, oxygen atom or sulfur atom, wherein said ring system may or may not be substituted with a C_1-5 alkyl group, hydroxy C_1-5 alkyl group, phenyl group, phenyl C_1-5 alkyl group, halogenated phenyl group, C_1-5 alkoxyphenyl group or halogenated C_1-5 alkylphenyl group; and

A represents an oxygen atom or sulfur atom; and

Z represents a C_1-10 alkyl group which may or may not be substituted with a hydroxyl group, halogen atom, —

O—

R¹⁰, —

OCOR¹¹, —

OCOO—

R¹² or OCONH—

R¹³

wherein R¹⁰ through R¹³ may be a hydrogen atom or C_1-5 alkyl group that may be substituted with a halogen atom;

or

wherein the C_1-10 alkyl group may or may not be substituted with —

CO—

R¹⁴ or —

CH₂—

S—

R¹⁵,

wherein R¹⁴ and R¹⁵ each represents a five-membered or six-membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms, or a hydroxy C_1-5 alkyl group.

4. A compound represented by the following general formula (VIII):

wherein;

R² and R³ may be respectively identical or different, and each represents;

(a) a hydrogen atom, C_1-10 alkyl group which may be a straight or branched chain, C_2-10 alkenyl group, C_3-10 cycloalkyl group, C_1-10 alkylamino group, C_1-10 alkoxyl group, C_3-10 heterocycloalkyl group, phenyl group, phenyl C_1-5 alkyl group, naphthyl group, or cyclic amino group containing a heteroatom selected from nitrogen, oxygen or sulfur atoms, wherein each of said groups may or may not be substituted with a halogen atom, hydroxyl group, mercapto group, nitro group, cyano group, —

SO₂NH₂ group, hydroxy C_1-5 alkoxyl group, C_1-5 alkylamino group, C_1-5 alkylcarbonyl group, C_1-5 alkylthio group, benzylthio group, halogenated C_1-5 alkyl group, halogenated C_1-5 alkoxy group and —

CO₂R⁸

wherein R⁸ is a C_1-5 alkyl group, C_3-10 cycloalkyl group or five-membered or six membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms;

(b) —

COR⁹ wherein R⁹ is a phenyl group or a C_1-5 alkyl group which may or may not be substituted with a halogen atom;

or

(c) R² and R³ are bonded to form a heterocycloalkyl group or heterocycloalkenyl group, and said heterocycloalkyl group or heterocycloalkenyl group is a four-membered, five-membered or six-membered ring system that may be condensed with a benzene ring, and contains as a heteroatom only the nitrogen atom at which R² and R³ are bonded, or which contains a different nitrogen atom, oxygen atom or sulfur atom, wherein said ring system may or may not be substituted with a C_1-5 alkyl group, hydroxy C_1-5 alkyl group, phenyl group, phenyl C_1-5 alkyl group, halogenated phenyl group, C_1-5 alkoxyphenyl group or halogenated C_1-5 alkylphenyl group; and

Z represents a C_1-10 alkyl group which may or may not be substituted with a hydroxyl group, halogen atom, —

O—

R¹⁰, —

OCOR¹¹, —

OCOO—

R¹² or OCONH—

R¹³

wherein R¹⁰ through R¹³ may be a hydrogen atom or C_1-5 alkyl group that may be substituted with a halogen atom;

or

wherein the C_1-10 alkyl group may or may not be substituted with —

CO—

R¹⁴ or —

CH₂—

S—

R¹⁵,

wherein R¹⁴ and R¹⁵ each represents a five-membered or six-membered ring system that may be condensed with a benzene ring and contains one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms, or a hydroxy C_1-5 alkyl group.