KR100552925B1 - 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivatives and the use thereof - Google Patents

Abstract

The present invention relates to novel compounds of formula [1] useful for inhibiting tumor necrosis factor-α (TNF-α) or cyclic AMP phosphodiesterase IV (PDE 4). More specifically, the present invention provides a novel method of preparing compounds of formula [1], and pharmaceutically acceptable salts thereof, and biologically important therapeutic efficacy against inflammatory and autoimmune diseases associated with harmful excess TNF-α. It relates to a pharmaceutical composition having a.

Description

3-Cyclopentyloxy-4-methoxyphenyl-isoindolinone derivatives and uses thereof {3-CYCLOPENTYLOXY-4-METHOXYPHENYL-ISOINDOLINONE DERIVATIVES AND THE USE THEREOF}

The present invention relates to novel compounds of formula [1] useful for inhibiting tumor necrosis factor-α (TNF-α) or cyclic AMP phosphodiesterase IV (PDE 4). These compounds include arthritis, bronchial asthma, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn's disease, sepsis, septic shock, other inflammatory diseases such as cachexia, transplant rejection, multiple sclerosis It may be useful for preventing or treating systemic lupus erythematosus. The invention also relates to the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for use as drugs thereof.

TNF-α is a primary cytokine secreted by monocytes stimulated by several immune activators. In humans or animals these factors are known to induce acute infection, shock, inflammation, fever, hemolysis, coagulation and acute reactions.

If TNF-α is excessive or poorly controlled, many diseases such as endotoxemia, toxin shock syndrome (Nature 330.662-664 (1987)) or cachexia [Lancet 335 (1990), 662 (1990)] This onset. Inhibiting the production and action of TNF-α is expected to be a good treatment for inflammatory, infectious, and immune diseases. Inhibition of the production and action of TNF-α is septic shock, sepsis, endotoxins, sepsis syndrome, malaria mycobacterium infection, encephalomyelitis, psoriasis, cachexia, transplant rejection, asthma, cancer, autoimmune disease, rheumatism It can be inferred that diseases such as arthritis, osteoarthritis, Crohn's disease, multiple sclerosis and systemic lupus erythematosus can be treated.

Therefore, TNF-α inhibitors are currently being intensively studied as therapeutic agents for the disease. Recently, soluble receptors for TNF-α and anti-TNF antibodies have been recognized by the FDA and their efficacy in human rheumatoid arthritis patients has been remarkable [Science 234. 470-474 (1985), W09211383, Clinical and Experimental Rheumatoid 5173). -5175 (1993), PNAS 9784-9788 (1992), Annals of Rh Disease 480-486 (1990). Xanthine compounds such as pentoxifylline inhibit TNF-α, but their efficacy is known to be weak [Circulatory Shock 44.188-195 (1994)]. Loriphram causes CNS side effects such as nausea and vomiting (Drugs of the Future 28.793-803 (1995)), but is a novel derivative for inhibiting TNF-α, an active pharmacophore currently under investigation. (W09212961, W09503794, W09402465, W09505386, W09509624, W09620926).

Disease states associated with pathological abnormalities associated with secondary cell messengers are regulated by inhibiting enzymes such as PDE-4 (an important enzyme that regulates cyclic AMP levels to regulate other important biological responses), and also in accordance with the present invention. Can be treated. Thus, the ability to modulate PDE, including PDE 4, means that it is possible to treat related biological abnormalities.

In particular, PDE 4 inhibitors refer to bronchodilators, asthma-prophylactic agents, eosinophil accumulation inhibitors, and other diseases and conditions for the treatment of pathological eosinophil accumulation. In addition, PDE 4 inhibitors are involved in the treatment of abnormalities associated with inflammatory diseases, proliferative diseases and brain metabolism inhibition.

US patent application US 5,635,517 describes that isoindolinone compounds of the formula show TNF-α reducing activity. US 5,635,517 does not describe or suggest compounds in which the isoindolinone moiety is bound to the phenyl moiety:

Where

One of X and Y is C═O and the other of X and Y is C═O or CH ₂ .

US patent application US 6,020,358 discloses that isoindolinone compounds of the formula show TNF-α reducing activity. US 5,635,517 does not describe or suggest compounds in which the isoindolinone moiety is directly bonded to the 3,4-dialkoxyphenyl moiety:

Where

Y is C═O, CH ₂ , SO ₂ , or CH ₂ C═O.

Although the prior patent WO 98/42666 describes a 3,4-dialkoxyphenyl derivative as an inhibitor of TNF-α release, it is not described or suggested that the compound inhibits PDE 4:

R ₆ is a substituted isoindolinone ring.

Therefore, it is predicted that compounds having inhibitory activity against PDE 4 or TNF-α are of pharmaceutical value and there is a need for the development of new compounds which always inhibit PDE 4 and TNF-α.

The object of the invention relates to compounds which inhibit PDE 4 and TNF-α.

Disclosure of the Invention

The present inventors have intensively studied to solve the problems with the previous PDE 4 or TNF-α inhibitors. As a result, a novel 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative of formula [1] has been proposed as a selective and potent PDE 4 and TNF-α inhibitor. The present inventors explained that there are no side effects such as nausea or vomiting and have a long half-life in vivo. Thus, the present invention has been achieved.

It is a first object of the present invention to provide a novel compound of formula [1] having PDE 4 and TNF-α inhibitory activity.

It is a second object of the present invention to provide a novel 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative of formula [1] and a method for synthesizing its salts.

A third object of the present invention is the novel 3- of formula [1] for use in joint inflammation, rheumatoid arthritis, osteoarthritis, sepsis, septic shock, asthma, transplant rejection, psoriasis, allergic inflammation, and autoimmune diseases. It is to provide a pharmaceutical composition of PDE 4 and TNF-α inhibitor comprising a cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative and salts thereof.

The present invention provides a novel compound of formula [1], 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative and its pharmaceutically acceptable salts:

Where

R ₁ is lower alkyl, cycloalkyl, hydroxycycloalkyl, arylalkyl, cycloalkylalkyl, bicycloalkyl;

R ₂ is hydrogen, hydroxy, oxo, halogen, lower alkyl, and amino;

R ₃ is hydrogen, hydroxy, oxo, halogen, lower alkyl, and amino;

R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, lower alkyl, lower alkoxy, amino, lower alkylamino, cyano, aldehyde, aldehyde oxime, -COR ₅ ;

R ₅ is hydroxy, —NHNH ₂ , lower alkyl;

X is oxygen or carbon, carbonyl, imine, amide;

A, B, C, and D are independently carbon, nitrogen or N-oxides.

As used herein above and in the specification, the following terms should be understood to have the following meanings unless stated otherwise.

Justice

"Halogen" means fluoro, chloro, or bromo. Preferred are fluoro and chloro.

"Lower alkyl" means an aliphatic hydrocarbon group having 1 to 6 carbon atoms in the chain, such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Preferably, it means a straight or branched chain hydrocarbon having 1 to 4 carbon atoms.

"Lower alkoxy" refers to alkyl oxo groups which may be straight or branched chain having 1 to 4 carbon atoms in the chain, such as methoxy, ethoxy, propoxy and butoxy.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system having 3 to 8 carbon atoms in the chain, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and adamantyl. Preferably, it means a hydrocarbon having 3 to 6 carbon atoms.

"Arylalkyl" means a phenyl alkyl group having 3 to 10 carbon atoms in the chain, such as phenylethyl, phenylpropyl, phenylbutyl and phenylpentyl. Preferably, it means a hydrocarbon having 3 to 8 carbon atoms.

"Cycloalkylalkyl" means a cycloalkylalkyl group wherein cycloalkyl is as previously defined and alkyl is methyl and ethyl. Preferably, cycloalkylalkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclopentylethyl.

"Bicycloalkyl" means an indanyl group, such as 1-indanyl and 2-indanyl.

"N-oxide" means a moiety of the structure:

According to an aspect of the compound of the present invention,

R ₁ is C ₁ -C ₄ lower alkyl, C ₃ -C ₆ cycloalkyl, hydroxy C ₃ -C ₆ cycloalkyl, aryl C ₃ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl C ₁ -C ₂ alkyl , Indanyl;

R ₂ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₂ lower alkyl, and amino;

R ₃ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₂ lower alkyl, and amino;

R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, C ₁ -C ₂ lower alkyl, C ₁ -C ₂ lower alkoxy, amino, C ₁ -C ₂ lower alkylamino, cyano, aldehyde, aldehyde oxime, -COR ₅ ;

R ₅ is hydroxy, —NHNH ₂ , C ₁ -C ₂ lower alkyl;

X is oxygen or carbon, carbonyl, imine, amide;

Preferred are the compounds described in formula [1], or a pharmaceutically acceptable salt thereof, wherein A, B, C, and D are independently carbon, nitrogen or N-oxide.

According to an aspect of the compound of the present invention,

R ₁ is C ₁ -C ₂ lower alkyl, C ₃ -C ₆ cycloalkyl, hydroxy C ₃ -C ₆ cycloalkyl, aryl C ₃ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl C ₁ -C ₂ alkyl , 1-indanyl or 2-indanyl;

R ₂ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₂ lower alkyl, and amino;

R ₃ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₂ lower alkyl, and amino;

R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, methyl, methoxy, amino, methylamino, cyano, aldehyde, aldehyde oxime, -COR ₅ ;

R ₅ is hydroxy, —NHNH ₂ , C ₁ -C ₂ lower alkyl;

X is oxygen or carbon, carbonyl, imine, amide;

More preferred are the compounds described in formula [1], or a pharmaceutically acceptable salt thereof, wherein A, B, C, and D are carbon, nitrogen or N-oxides.

Preferred compounds for use according to the invention are selected from:

2- (3-cyclopentyloxy-4-methoxyphenyl) -6- (1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -1-isoindolinone

2- (3-cyclopentyloxy-4-methoxyphenyl) -6- (6-hydroxy-1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -1-isoindoli Paddy field

6-[(6-amino-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [3 (cyclopentyloxy) -4-methoxyphenyl] -1-iso Indolinone

2- [3-cyclopentyloxy-4-methoxyphenyl] -6-[(6-fluoro-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -1-iso Indolinone

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-5-isoin Dolinecarboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-5-isoin Doline carboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-oxo-5-isoin Doline carbohydrazide

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6- [6- (hydroxymethyl) -1-oxo-2,3-dihydro-1H-2-isoindolyl] methyl- 1-isoindolinone

2-[(4-methoxyphenyl) -3- (1-methyl-3-phenylpropoxy) phenyl] -6- (1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -1-isoindolinone

6-{[6-hydroxymethyl] -1-oxo-2,3-dihydro-1H-2-isoindolyl} methyl} -2- [4-methoxy-3- (1-methyl-3- Phenylpropoxy) phenyl] -1-isoindolinone

6- (6-amino-1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -2-[(4-methoxyphenyl) -3- (1-methyl-3-phenylprop Foxy) phenyl] -1-isoindolinone

6-[(6-fluoro-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [4-methoxy-3- (1-methyl-3-phenylprop Foxy) phenyl] -1-isoindolinone

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl)- 3-oxo-5-isoindolincarboxylic acid

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl)- 3-oxo-5-isoindolincarboximideamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} Methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl } Methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-methyl) -3-oxo -2,3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2-{[2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-methyl) -3- Oxo-2,3-dihydro-1H-5-isoindolyl] aminoacetamide

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-methyl) -3-oxo-5- Isoindolin carbohydrazide

6-{[6- (hydroxymethyl) -1-oxo-2,3-dihydro-1H-2-isoindolyl] methyl} -2- [4-methoxy-3- (1-methyl-3 -Phenylpropoxy) phenyl] -1-isoindolinone

2- (3-cyclopentyloxy-4-methoxyphenyl) -3-methyl-6- (1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -1-isoindolinone

2- (3-cyclopentyloxy-4-methoxyphenyl) -6- (6-hydroxy-1-oxo-2,3-dihydro-1H-2-isoindolylmethyl) -3-methyl-1 Isoindolinone

6-[(6-amino-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [3 (cyclopentyloxy) -4-methoxyphenyl] -3-methyl -1-isoindolinone

2- [3-cyclopentyloxy-4-methoxyphenyl] -6-[(6-fluoro-1-oxo-2,3-dihydro-1 H-2-isoindolyl) methyl] -3-methyl -1-isoindolinone

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl) -3- Oxo-5-isoindolincarboxylic acid

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -3-oxo -5-isoindolinecarboximideamide

N1- [2-({2- [3-cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl]- 3-oxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-methyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-methyl) -3-oxo-2 , 3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2- [2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] amino} acetamide

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl) -3- Oxo-5-isoindolincarbohydrazide

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6-{[6- (hydroxymethyl) -1-oxo-2,3-dihydro-1H-2-isoindolyl] methyl } -3-methyl-1-isoindolinone

2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-methyl-6-[(1-oxo-2,3-dihydro-1H-2-isoindolyl ) Methyl] -1-isoindolinone

6-[(6-hydroxy-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [4-methoxy-3 (1-methyl-3-phenylpropoxy ) Phenyl] -3-methyl-1-isoindolinone

6-[(6-amino-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [4-methoxy-3phenylpropoxy] phenyl] -3-methyl- 1-isoindolinone

6-[(6-fluoro-1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -2- [4-methoxy-3- (1-methyl-3-phenylprop Foxy) phenyl] -3-methyl-1-isoindolinone

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl } Methyl) -3-oxo-5-isoindolincarboxylic acid

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-methyl) -3- Oxo-5-isoindolincarboximideamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5- Isoindolylmethyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5- Isoindolyl} methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2-{[2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolyl} methyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl] amino} acetamide

2-({2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -3-oxo-5-isoindolin carbohydrazide

6-{[6- (hydroxymethyl) -1-oxo-2,3-dihydro-1H-2-isoindolyl] methyl} -2- [4-methoxy-3- (1-methyl-3 -Phenylpropoxy) phenyl] -3-methyl-1-isoindolinone

2- [2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl] -1,3-isoindolindione

2- [2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl] -5-hydroxy-1,3-iso Indolindione

5-amino-2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl) -1, 3-isoindolindione

2-({2- [3-cyclopentyloxy-4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl) -5-fluoro-1,3 Isoindolin Dione

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -1,3-dioxo- 5-isoindolincarboxylic acid

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -1,3-dioxo- 5-isoindolinecarboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-di Oxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -1,3- Dioxo-2,3-dihydro-1H-5-isoindolyl) ethanediamide

N1- [2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -1,3- Dioxo-2,3-dihydro-1H-5-isoindolyl) -2-aminoacetamide

2-{[2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-2,3-dihydro-1H-5-isoindolyl] amino} acetamide

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl} -1,3-dioxo- 5-isoindolin carbohydrazide

2-({2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl} methyl-5- (hydroxymethyl) -1,3-isoindolindione

2- {2-[(4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl) -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl] -1 , 3-isoindolindione

5-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -1,3-isoindolindione

5-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-isoindolindione

5-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2.3-dihydro-1H-5-isoindolylmethyl) -1,3-isoindolindione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-5-isoindolincarboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-5-isoindolincarboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] aminoacetamide

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-5-isoindolincarbohydrazide

5- (hydroxymethyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5- Isoindoleylmethyl) -1,3-isoindolindione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Isoindolindione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -5-hydroxy -1,3-isoindolindione

5-amino-2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl)- 1,3-isoindolindione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -5-fluoro -1,3-isoindolindione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-5-isoindolincarboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-5-isoindolincarboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-5-isoindolyl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-5-isoindolincarbohydrazide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -5- (hydr Oxymethyl) -1,3-isoindolindione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-isoindolindione

5-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolinylmethyl) -1,3-isoindolindione

5-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5- Isoindoleylmethyl) -1,3-isoindolindione

5-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl 3-oxo-2,3-dihydro-1H-5- Isoindoleylmethyl) -1,3-isoindolindione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-dioxo-5-isoindolincarboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-dioxo-5-isoindolinecarboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-5-isoindolyl] aminoacetamide

5- (1-hydrazinovinyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3- Dihydro-1H-5-isoindolinylmethyl) -1,3-isoindolindione

5- (hydroxymethyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro- 1H-5-isoindolinylmethyl) -1,3-isoindolindione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3-dihydro-1H -Pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-hydroxy-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-amino-2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3- Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-fluoro-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3- Dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3- Dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2.3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3- Dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6- (hydroxymethyl)- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one
2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1- Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1- Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1- Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

6- (hydroxymethyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5- Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-S-isoindolylmethyl) -2,3- Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-hydroxy -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-amino-2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl)- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-fluoro -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 -Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 -Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 -Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 -Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1-oxo- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6- (hydr Oxymethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1methyl-3-oxo-2,3-dihydro-1H-5- Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5- Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

 2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1-oxo-2,3-dihydro-1H-pyrrolo [34-c] pyridine-6-carboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

6- (hydroxymethyl) -2- (2 [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H -5-isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3-dihydro-1H -Pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-hydroxy-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-amino-2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3- Dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-fluoro-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentytoxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2, 3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-di Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-di Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-di Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-di Oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6- (hydroxymethyl)- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1, 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

6- (hydroxymethyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] 3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3-cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3-di Hydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H 5-isoindolylmethyl) -6-hydroxy- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-amino-2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl)- 2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6-fluoro -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1 , 3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -1,3- Dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -6- (hydr Oxymethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-amino-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5- Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

6-fluoro-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboxylic acid

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carboximideamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] acetamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] ethanediamide

N1- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] -2-aminoacetamide

2- [2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-6-yl] aminoacetamide

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylmethyl ) -1,3-dioxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-6-carbohydrazide

6- (hydroxymethyl) -2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro- 1H-5-isoindolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6-[(1-oxo-2,3-dihydro-1H-2-isoindoleyl) carbonyl] -1-isoindoli Paddy field

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2,3-dihydro- 1H-pyrrolo [3. 4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -3-hydroxy-1- Isoindolinone

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -3-hydroxy-2, 3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -1,3-isoindolin Dion

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2,3-dihydro- 1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-methyl-6-[(1-oxo-2,3-dihydro 1H-2-isoindolyl) carbonyl] -1- Isoindolinone

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6-[(1-hydroxy-3-oxo-2,3-dihydro-1 H-2-isoindolyl) carbonyl]- 3-methyl-1-isoindolinone

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -3-hydro Roxy-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -1,3 Isoindolin Dione

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -6-[(1-oxo-2,3-dihydro-1H-2-isoindolyl) carbonyl] -1-isoindolinone

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

3-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Carbonyl) -1-isoindolinone

3-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolyl Carbonyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -2 , 3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylcarbonyl) -1 , 3-isoindolindione

2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -3-methyl-6-[(1-oxo-2,3-dihydro-1H-2-isoindolyl ) Carbonyl] -1-isoindolinone

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl carbo Yl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

6-[(1-hydroxy-3-oxo-2,3-dihydro-1H-2-isoindolyl) carbonyl] -2- [4-methoxy3- (1-methyl-3-phenylprop Foxy) phenyl] -3-methyl-1-isoindolinone

3-hydroxy-2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5 Isoindolylcarbonyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl carbo Nil) -1,3-isoindolindione

2- (2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-5-isoindolyl carbo Nil) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione.

The compounds of the present invention are useful in the form of acids, or in the form of their N-oxides or pharmaceutically acceptable salts thereof. All forms are within the scope of the present invention. Pharmaceutically acceptable salts within the scope of the present invention are derived from the following acids; Inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; Organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toloenesulfonic acid, cyclohexylsulfonic acid, chinic acid and the like.

The present invention relates to a process for the synthesis and preparation of novel 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivatives. According to the invention, the compound of formula [3] is prepared by reacting the compound of formula [4] synthesized by WO patent application No. 98/42666 with [5] or [6]. The compound of formula [3] is then reduced to yield the compound of formula [2]. The compound of formula [2] is dehydroxylated to prepare the compound of formula [1], wherein R 3 is hydrogen and one of C and D is nitrogen. By this method, 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative can be produced.

Where

A, B, C, D, X, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above.

In the present invention, the process for preparing the compound of formula [1] can be described in the following scheme.

Scheme 1

Where

A, B, C, D, X, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as defined above.

In the following, the preparation method of 3-cyclopentyloxy-4-methoxyphenylisoindolinone derivative of formula [1] is described in detail.

According to the preceding WO patent application No. 98/42666, a 1-amino-3,4-dialkoxypentyl derivative is reacted with an isobenzofuran-1,3-dione derivative or phthaloyl dichloride derivative to formula [4] To prepare a compound. The reaction product, 2- (3,4-dimethoxy-phenyl) -isoindole-1,3-dione derivative, is reacted with a) Grignard reagent to react with 2- (3,4-dimethoxy-phenyl) -3-hydroxy Prepare 3--3-methyl-2,3-dihydro-isoindol-1-one derivatives, or b) reduce with sodium borohydride to reduce N- (3,4-dimethoxy-phenyl) -2-hydro Obtain oxymethyl-benzamide derivatives. Depending on the amount of reducing agent, two forms of reducing products are obtained. The compound is cyclized by intramolecular mltzunobu reactions or dehydroxylated using triethylsilane and trifluoroacetic acid.

The newly synthesized compound of formula [1] is prepared by a method similar to that described above. In a different manner the compound of formula [3] is prepared by reacting an amine or hydroxy compound of formula [4] with formula [6] or [5] in reaction A. In the case of the amine compound, the reaction of Chemical Formulas [4] and [6] is carried out by refluxing with an acidic catalyst in a non-reactive solvent. Inorganic catalysts or organic catalysts are used for this purpose. The inorganic catalyst is hydrochloric acid, sulfuric acid, or nitric acid, and the organic catalyst is acetic acid or trifluoroacetic acid. Acetic acid is most preferably used among these catalysts. Non-reactive solvents such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran, benzene and toluene can be preferably used and chloroform is the most preferred of these solvents. This reaction is carried out for 4-48 hours at a temperature in the range of 60-70 ° C. In another case, the hydroxy compound of formula [4] is reacted with formula [5] by intramolecular mltzunobu reaction. More specifically, the compound of formula [4] is reacted with triphenylphosphine and diethylazodicarboxylate in dichloromethane solvent. This reaction is usually carried out for 1-2 hours at a temperature of 0 to 100 ° C., preferably at room temperature (room temperature).

Reaction B is used to reduce the compound of formula [3] to afford the compound of formula [2]. Reducing agents preferably used in Reaction B are sodium borohydride, lithium borohydride, or lithium aluminum hydride, with sodium borohydride being most preferred among them. One equivalent of reducing agent is used together with one equivalent of the compound of formula [3] to obtain a compound of formula [2]. Reaction B is preferably carried out in alcohol solvent. Alcohol solvents such as methanol, ethanol, propanol, butanol, isopropyl alcohol may be preferred and ethanol, methanol may be most preferred. In Reaction B, the compound of formula [2] is prepared at -10-0 占 폚 for 1-2 hours.

The compound of formula [2] obtained from reaction B is dehydroxylated by the following reaction C to give a compound of formula [1] wherein R3 is hydrogen and one or two of A, B, C and D is nitrogen. ). Triethylsilane and trifluoroacetic acid can be used to dehydroxylize at room temperature for 1-2 hours.

Compound 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone of formula [1] prepared from the above method can be isolated and purified by conventional methods, such as column chromatography, or recrystallization.

In the present invention, the compound 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone of the formula [1] inhibits the action of a harmful excess of TNF-α so that joint inflammation, rheumatoid arthritis, osteoarthritis, sepsis, septic shock It can prevent and treat a variety of diseases such as asthma, transplant rejection, psoriasis, allergic inflammation and autoimmune diseases. Representative compounds of the present invention, such as compounds 12, 13, and 16 in Table 1, show an oral median dose of at least 3.5 kg per kilogram of body weight in Table 4, which suggests that these compounds are pharmaceutically non-toxic as pharmaceuticals. Therefore, in order to use the compound of formula [1] or a pharmaceutically acceptable salt thereof for therapeutic purposes, it will generally be formulated into a pharmaceutical composition according to standard pharmaceutical practice. Accordingly, the present invention also relates to pharmaceutical compositions comprising an effective non-toxic amount of a compound of formula [1] and a pharmaceutically acceptable carrier or diluent.

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The composition of the present invention is mixed with a pharmaceutically acceptable carrier in a conventional pharmaceutical preparation method for oral administration such as tablets, capsules, granules, powders, solutions or suspensions; For injection, such as injectable solutions, suspensions; Useful pharmaceutical preparations for topical administration such as suppositories, ointments, creams, gels, sprays and patches can be obtained.

The product according to the invention may exist in a form which allows it to be administered by the most suitable route and the invention also relates to a pharmaceutical composition comprising at least one product according to the invention, suitable for use in the medical or veterinary arts. . These compositions can be prepared according to conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include in particular diluents, sterile aqueous media and various non-toxic solvents. The composition may be in the form of tablets, pills, granules, powders, aqueous solutions or injectables, elixirs or syrups, and at least one selected from stabilizers, colorants, flavors, sweeteners to obtain pharmaceutically acceptable agents. It may include a medicament. Carrier selection and the amount of active substance in the carrier are usually determined by the solubility and chemical properties of the worm, the particular mode of administration, and the regulations followed in the pharmaceutical industry. For example, excipients such as lactose, sodium citrate, calcium carbonate, calcium diphosphate and disintegrants such as starch, alginic acid and glidants such as magnesium stearate, sodium lauryl sulfate and talc, for example Certain complex silicates may be used to make tablets. It is advantageous to use lactose and high molecular polyethylene glycols to prepare capsules. If an aqueous suspending agent is used, it may include an emulsifier or a medicament for promoting the suspending agent. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used. For parenteral administration, solutions of the products according to the invention in vegetable oils such as sesame oil, peanut oil or olive oil, or aqueous organic solutions such as water and propylene glycol, injectable esters such as ethyl oleate, Suspensions or emulsions, and sterile aqueous solutions of pharmaceutically acceptable salts are used. Salt solutions of the products according to the invention are particularly useful for intramuscular or subcutaneous injection administration. In addition, an aqueous solution comprising a salt solution in pure distilled water, provided that its pH is appropriately adjusted, properly buffered, isotonicized with a sufficient amount of glucose or sodium chloride and is sterilized by heat treatment, irradiation or microfiltration, It can be used for my administration. Suitable compositions comprising the compounds of the present invention can be prepared by conventional methods. For example, the compounds of the present invention can be dissolved or suspended in nebulizers or suspending agents or suitable carriers for liquid aerosols, or they can be inhaled or adsorbed onto suitable solid carriers for dry powder inhalers. Solid compositions for rectal administration include suppositories prepared according to known methods and comprising at least one compound of formula [1]. The dosage used will be determined by the physician and depends on the desired therapeutic effect, route of administration and duration of treatment, and the condition of the patient. For adults, the dosage is usually 0.001 to 50, preferably 0.001 to 5 mg / kg (body weight) per day for inhalation administration, 0.01 to 100, preferably 0.1 to 70, more particularly 0.5 to 10 mg / kg per day for oral administration (Body weight), and 0.001 to 10, preferably 0.01 to 1 mg / kg body weight per day upon intravenous administration. In each particular case, the dosage will depend on the particular factors in the subject to be treated, such as age, weight, general health and other properties that may affect the efficacy of the pharmaceutical product. The product according to the invention can be administered as many times as necessary to obtain the desired therapeutic efficacy. Depending on the physiological requirements of each particular patient, it may be necessary to treat for prolonged periods of 1 to 4 doses per day. Typically, the active product can be administered orally 1 to 4 times per day.

The following examples illustrate the invention but the invention is not limited to these examples.

Reference Example 1

3-cyclopentyloxy-4-methoxynitrobenzene

To a solution of 2-methoxy-5-nitrophenol (3.0 g, 17.74 mmol) in DMF (30 ml) was added cyclopentyl bromide (4.0 g, 26.61 mmol) and potassium carbonate (5 g, 35.48 mmol). The reaction mixture was stirred at 60 ° C. for 15 h, cooled to rt, treated with distilled water (20 ml) and extracted twice with ether. The ether layer was dried over MgSO _4, filtered and concentrated under reduced pressure to afford the title compound (4 g, 95%) as a pale yellow solid.

Reference Example 2

3-cyclopentyloxy-4-methoxyaniline

To a solution of 3-cyclopentyloxy-4-methoxynitrobenzene (4.2 g, 17.73 mmol) in methanol (30 ml) was added ammonium formate (3.5 g, 53.21 mmol) and 10% Pd-C (0.3 g). The reaction mixture was refluxed for 2 hours, cooled to room temperature, filtered through celite and evaporated in vacuo to remove solvent. The residue was dissolved in ether, washed twice with distilled water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (3 g, 81%) as a pale brown liquid.

Reference Example 3

N- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1,3-dione

Phthalic anhydride (0.36 g, 2.43 mmol) was added to a solution of 3-cyclopentyloxy-4-methoxyaniline (0.52 g, 2.42 mmol) in chloroform (10 ml). The reaction mixture was stirred for 0.5 h at rt, treated with acetic acid (10 ml), refluxed for 4 h, cooled to rt and concentrated under reduced pressure to remove chloroform and acetic acid. The residue was crystallized from methanol to give the title compound (0.75 g, 91%) as a white solid.                 

Reference Example 4

3-methyl-3-hydroxy-2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1-one

3.0 M methylmagnesium bromide (0.2 ml, 4.44 mmol) in a solution of 2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1,3-dione (0.5 g, 1.48 mmol) in dry THF (10 ml) ) Was added slowly at 0 ° C. The reaction mixture was allowed to warm to room temperature, stirred for 20 minutes, quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The organic layer was washed with distilled water, dried over MgSO ₄ , filtered and concentrated in vacuo. Ether was added to the residue, stirred at rt and filtered to give the title compound (0.35 g, 67%) as a white solid.

Reference Example 5

3-methyl-2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1-one

To a solution of 3-methyl-3-hydroxy-2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1-one (0.52 g, 1.48 mmol) in dichloromethane (10 ml), triethylsilane ( 1.29 ml, 1.78 mmol) and trifluoroacetic acid (0.14 ml, 1.78 mmol) were added. The reaction mixture was stirred for 4 hours at room temperature, evaporated in vacuo and diluted with ethyl acetate. The organic layer was washed with distilled water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (0.46 g, 92%) as a white solid.

Reference Example 6

3-hydroxy-2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1-one

Sodium borohydride (0.06 g, 1.48) in a solution of 2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1,3-dione (0.5 g, 1.48 mmol) in methanol (10 ml) at 0 ° C. mmol) was added. The reaction mixture was treated with ice water, extracted with ethyl acetate, dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.48 g, 96%) as a white solid.

Reference Example 7

2- (3-cyclopentyloxy-4-methoxyphenyl) -2,3-dihydro-isoindolin-1-one

Triethylsilane (0.31 ml, 1.48) in a solution of 3-hydroxy-2- (3-cyclopentyloxy-4-methoxyphenyl) isoindolin-1-one (0.5 g, 1.47 mmol) in dichloromethane (10 ml) mmol) and trifluoroacetic acid (0.34 ml, 4.42 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at rt for 2 h, quenched with saturated sodium bicarbonate solution, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.45 g, 95%) as a white solid.

Reference Example 8

2- (3-cyclopentyloxy-4-methoxyphenyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione

Thionyl chloride (3.45 g, 28.95 mmol) was added to a solution of pyridine-3,4-dicarboxylic acid (1.62 g, 9.65 mmol) in toluene (10 ml). The reaction mixture was refluxed for 4 hours and evaporated in vacuo to remove thionyl chloride. Dichloromethane (10 ml), 3-cyclopentyloxy-4-methoxyaniline (2 g, 9.65 mmol) and triethylamine (2.44 g, 25.13 mmol) were added to the residue, which was stirred for 6 hours at room temperature and then in vacuo. Concentrated. The resulting mixture was treated with chloroform (10 ml) and acetic acid (2 ml), refluxed for 48 hours, cooled to room temperature, concentrated under reduced pressure to remove chloroform and acetic acid, ethanol was added and stirred at room temperature. The resulting solid was filtered to give the title compound (2.8 g, 86%) as a yellow solid.

Reference Example 9

N4- (3-cyclopentyloxy-4-methoxyphenyl) -3- (hydroxymethyl) isonicotinamide

2- (3-cyclopentyloxy-4-methoxyphenyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione (0.5 in methanol) at room temperature g, 1.48 mmol) was slowly added sodium borohydride (0.28 g, 7.41 mmol). The reaction mixture was stirred for 1 h at rt, evaporated in vacuo, distilled water (10 ml) was added and extracted twice with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give the title compound (0.25 g, 50%) as a white solid.

Reference Example 10

2- (3-cyclopentyloxy-4-methoxyphenyl) -2,3-dihydro-pyrrolo [3,4-c] pyridin-1-one

Triphenylphosphine (0.37) in a solution of N4- (3-cyclopentyloxy-4-methoxyphenyl) -3- (hydroxymethyl) -isonicotinamide (0.4 g, 1.17 mmol) in dry THF (10 ml) at room temperature. g, 1.41 mmol) and diethylazodicarboxylate (0.25 g, 1.41 mmol) were added. The reaction mixture was stirred at rt for 1 h, evaporated in vacuo, treated with 6N HCl solution (10 ml) and extracted with ethyl acetate. The aqueous layer was basified to pH 8-9 with 6N NaOH solution and extracted with ethyl acetate. The resulting organic layer was then dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.34 g, 89%) as a white solid.

Reference Example 11

2- (3-cyclopentyloxy-4-methoxyphenyl) -3-methylene-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

2- (3-cyclopentyloxy-4-methoxyphenyl) -3-hydroxy-3-methyl-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine- in benzene (10 ml) To the 1-one (0.52 g, 1.48 mmol) solution was added p-toluenesulfonic acid (0.28 g, 1.48 mmol). The reaction mixture was stirred for 4 hours at room temperature and diluted with ethyl acetate. The organic layer was washed with distilled water, dried over MgSO ₄ , filtered and evaporated in vacuo to remove solvent. The residue was purified by flash chromatography on silica gel to give the title compound (0.45 g, 91%) as a white solid.

Reference Example 12

2- (3-cyclopentyloxy-4-methoxyphenyl) -3-methyl-2,3-dihydropyrrolo [3,4-c] pyridin-1-one

2- (3-cyclopentyloxy-4-methoxyphenyl) -3-methylene-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one in methanol (30 ml) (0.5) g, 1.48 mmol) was added ammonium formate (0.3 g, 4.44 mmol) and 10% Pd-C (0.1 g). The reaction mixture was stirred at rt for 1 h, filtered through celite and evaporated in vacuo to remove methanol. The residue was diluted with ethyl acetate, washed twice with distilled water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.36 g, 94%) as a white solid.

Reference Example 13

Ethyl 2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-5-isoindolin carboxylate

2- (3-cyclopentyloxy-4-methoxyphenyl) -1,3-dioxo-5-isoindolin carboxylic acid (0.92 g) prepared according to the method described in Reference Example 3 in anhydrous acetone (10 ml). , 2.42 mmol) was slowly added triethylamine (1 ml, 7.26 mmol). The reaction mixture was stirred at rt for 10 min and treated with iodoethane (1.13 g, 7.26 mmol), cooled to rt for 10 h, evaporated in vacuo and methanol was added. The resulting solid was filtered to give ethyl 2- (3-cyclopentyloxy-4-methoxyphenyl) -1,3-dioxo-5-isoindolin carboxylate (0.94 g, 95%) as a pale yellow solid. Obtained. The title compound was obtained as a white solid (0.36 g, 40%) as described in Reference Examples 6 and 7.

Reference Example 14

2- (3-cyclopentyloxy-4-methoxyphenyl) -6-hydroxymethyl-1-isoindolinone

Lithium borohydride (0.08) in a solution of ethyl-2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-5-isoindolin carboxylate (0.96 g, 2.42 mmol) in anhydrous THE (10 ml) g, 3.63 mmol) was added. The reaction mixture was stirred for 1 h at rt, evaporated in vacuo, diluted with ethyl acetate and washed twice with distilled water. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.83 g, 97%) as a white solid.

Reference Example 15

6- (aminomethyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) -1-isoindolinone

Methane sulfonyl chloride (0.33 g, in 2- (3-cyclopentyloxy-4-methoxyphenyl) -6-hydroxymethyl-1-iso-indolinone (0.86 g, 2.42 mmol) in dichloromethane (10 ml) 2.90 mmol) and triethylamine (0.37 g, 3.63 mmol) were added slowly at 0 ° C. The reaction mixture was stirred for 0.5 h at room temperature, washed twice with distilled water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to [2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo- 2,3-dihydro-1H-5-isoindolyl] methyl ethanesulfonate (0.96 g, 96%) was obtained as a white solid.

[2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3-dihydro-1H-5-isoindolinyl] methyl methanesulfonate (1 g, 2.42 in DMF (10 ml) mmol) was added sodium azide (0.47 g, 7.26 mmol). The reaction mixture was stirred for 2 h at 60 ° C., cooled to rt, ethyl acetate was added, washed three times with distilled water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 6- (azidomethyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) -1-isoindolinone (0.9 g, 97%) was obtained as a white solid.

Triphenylphosphine (0.7) in a solution of 6- (azidomethyl) -2- (3-cyclopentyloxy-4-methoxyphenyl) -1-iso-indolinone (0.92 g, 2.42 mmol) in THF (10 ml) g, 2.66 mmol) was added. The reaction mixture was stirred for 20 minutes, distilled water (1 ml) was added, stirred for 8 hours at room temperature, 1N HCl solution was added and extracted with ethyl acetate. The aqueous layer was basified to pH 8-9 with 2N NaOH solution and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title compound (0.79 g, 92%) as a white solid.

Example 1

1-methoxy-2- (1-methyl-3-phenyl-propoxy) -4-nitrobenzene

The title compound was obtained as a pale yellow solid (1.64 g, 92%) using 4-phenyl-butan-2-ol (0.89 g, 5.92 mmol) according to the method described in Reference Example 1.

Example 2

4-methoxy-3- (1-methyl-3-phenyl-propoxy) aniline

The title compound was pale yellow solid using 1-methoxy-2- (1-methyl-3-phenyl-propoxy) -4-nitrobenzene (1.5 g, 4.98 mmol) according to the method described in Reference Example 2. As (1.09 g, 81%).

Example 3

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -isoindole-1,3-dione

The title compound was prepared as a white solid (1.30 g, using 4-methoxy-3- (1-methyl-3-phenyl-propoxy) aniline (1.Og, 3.69 mmol) according to the method described in Reference Example 3. 91%).

Example 4

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-methyl-2,3-dihydro-isoindol-1-one

The title compound was prepared according to the method described in Reference Examples 4, 5, and Example 3, 2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) -phenyl] -isoindole-1, White solid (1.Og, 62%) was prepared using 3-dione (1.0 g, 2.58 mmol).

Example 5

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -2,3-dihydroisoindol-1-one

The title compound was prepared according to the method described in Reference Example 7, 2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -isoindole-1,3-dione (1.0, 2.58 mmol) to prepare a white solid (0.83 g, 86%).

Example 6

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -pyrrolo [3,4-c] pyridine-1,3-dione

The title compound was prepared using 4-methoxy-3- (1-methyl-3-phenyl-propoxy) aniline (2.48 g, 9.65 mmol) and pyridine-3,4-dicarboxylic acid according to the method described in Reference Example 8. 1.62 g, 9.65 mmol) was prepared as a white solid (3.18 g, 85%).

Example 7

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-methyl-2,3-dihydro-pyrrolo [3,4-c] pyridine-1- On

The title compound was prepared according to the method described in Reference Examples 11 and 12, 2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -pyrrolo [3,4-c]. Prepared as a white solid (0.47 g, 87%) using pyridine-1,3-dione (1.Og, 2.58 mmol).

Example 8

2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -2,3-dihydropyrrolo [3,4-c] pyridin-1-one

The title compound was prepared according to the method described in Reference Examples 8 and 9, 2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -pyrrolo [3,4-c]. Prepared as a white solid (0.83 g, 86%) using pyridine-1 3-dione (1.Og, 2.58 mmol).

Example 9

6-hydroxymethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl-2,3-dihydro-isoindol-1-one

The title compound was prepared according to the method described in Reference Example 14, 2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-oxo-2,3-dihydro- Prepared as a white solid (0.77 g, 85%) using 1H-isoindole-5-carboxylic acid ethyl ester (1.0 g, 2.18 mmol).

Example 10

6-aminomethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] 2,3-dihydro-isoindol-1-one

Refer to the title compound in the manner described in Reference Example 15 6-azidomethyl-2- [4-methoxy-3- (1-methyl-3-phenylpropoxy) -phenyl] -2,3-dihydro Prepared as a white solid (0.86 g, 91%) using isoindole-1-one (1.0 g, 2.26 mmol).

Example 11

2- [2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl] -1,3-isoindolindione

2- [3- (cyclopentyloxy-4-methoxyphenyl)]-6 (hydroxymethyl) -1-isoindolinone (0.5 g, 1.41 mmol) and phthalimide in dry THF (10 ml) at room temperature Triphenylphosphine (0.56 g, 2.12 mmol) and diethylazodicarboxylate (0.38 g, 2.12 mmol) were added to the (0.21 g, 1.41 mmol) solution. The reaction mixture was stirred for 40 minutes at room temperature. The reaction mixture was evaporated in vacuo and recrystallized from methanol to give the title compound (0.57 g, 85%) as a white solid.                 

Example 12

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-hydroxy-1-iso Indolinone

Refer to the title compound according to the method described in Reference Example 6 2- [2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3-dihydro-1H-5-isoindolyl Methyl] -1,3-isoindolindione (0.5 g, 1.04 mmol) was used as a white solid (0.46 g, 92%).

Example 13

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6- [1-oxo-2,3-dihydro-1H-2-isoindolyl) methyl] -1-isoindolinone

Refer to the title compound according to the method described in Reference Example 7 2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-iso Obtained as a white solid (0.25 g, 85%) using indolylmethyl) -3-hydroxy-1-isoindolinone (0.3 g, 0.62 mmol).

Example 14

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -2,3-dihydro-1H -Pyrrolo [3,4-c] pyridine-1,3-dione

The title compound was purified using 2- [3- (cyclopentyloxy-4-methoxyphenyl)]-6- (hydroxymethyl) -1-isoindolinone (0.5 g, 1.41 mmol) according to the method described in Example 11. ) And phthalimide (0.21 g, 1.41 mmol) and pyrrolo [3,4-c] pyridine-1,3-dione (0.22 g, 1.49 mmol) to prepare as a yellow solid (0.55 g, 80%) It was.

Example 15

2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-isoindolylmethyl) -3-hydroxy-2,3 -Dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

Refer to the title compound according to the method described in Reference Example 6 2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-iso Indolylmethyl) -2,3-dihydro-1H-pyrrolo [3,4-c] pyridine-1,3-dione (0.5 g, 1.03 mmol) as a white solid (0.45 g, 90%) Prepared.

Example 16

2- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -2,3-dihydro-py Rolo [3,4-c] pyridin-1-one

Refer to the title compound according to the method described in Reference Example 7 2- (2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-oxo-2,3-dihydro-1H-5-iso White solid (0.23 g, 78) using indolylmethyl) -3-hydroxy-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one (0.3 g, 0.62 mmol) %).

Example 17

2- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -1,3-dioxo-2 , 3-dihydro-1H-isoindole-5-carboxylic acid

The title compound was prepared in 6-aminomethyl-2- (3-cyclopentyloxy-4-methoxy-phenyl) -2,3-dihydro-isoindol-1-one (0.5) according to the method described in Reference Example 3. g, 1.42 mmol) and 1, 2, 4-benzenetricarboxyl anhydride (0.27 g, 1.42 mmol) were prepared as brown solids (0.74 g, 95%).

Example 18

2- (3-Cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (1,3-dioxo-1,3-dihydro Isoindol-2-yl) -amide

An excess of hydrazine solution was added to a solution of ethyl-2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-5-isoindolin carboxylate (0.96 g, 2.42 mmol) in ethanol (10 ml). . The reaction mixture was stirred at rt for 24 h, evaporated in vacuo and distilled water was added. The resulting solid was filtered to afford 2- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-5-isoindolinecarbo hydrazide (0.48 g, 48%) as a white solid.

The title compound was prepared according to the method described in Reference Example 3, 2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid high Prepared as a white solid (0.42 g, 62%) using drazide (0.5 g, 1.31 mmol).

Example 19

2-{[2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindol-5-ylmethylene-amino} -isoindole-1, 3-dion

2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindole in CH ₂ Cl ₂ (5 ml), methanol (8 ml) and water (2 ml) Pyrrolo [3,4-c] pyridine-1,3-dione (0.25 g, 1.42 mmol) was added to a -5-carbaldehyde (0.5 g, 1.42 mmol) solution. The reaction mixture was stirred for 3 days at room temperature and then concentrated in vacuo. The title compound was prepared as a yellow solid (0.57 g, 82%) by plate chromatography on silica gel.

Example 20

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-methyl-6-[(1-oxo-2,3-dihydro-1 H-2-isoindolyl) methyl] -1- Isoindolinone

The title compound was prepared according to the method described in Examples 10, 6 and 7, 2- [3- (cyclopentyloxy-4-methoxyphenyl)]-6- (hydroxymethyl) -1-isoindolinone (0.5 g, 1.41 mmol) as a white solid (0.43 g, 64%).

Example 21

2- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -1-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -2,3- Dihydro-pyrrolo [3,4-c] pyridin-1-one

The title compound was prepared according to the method described in Reference Examples 11, 12 and 13, 2- (3-cyclopentyloxy-4-methoxyphenyl) -6-hydroxymethyl-3-methyl-2,3-dihydro- Prepared as a white solid (0.36 g, 55%) using isoindole-1-one (0.5 g, 1.36 mmol).

Example 22

2- (3-cyclopentyloxy-4-methoxy-phenyl) -6- (1-oxo-1,3-dihydro-isoindol-2-ylmethyl) -2,3-dihydro-pyrrolo [ 3,4-c] pyridin-1-one

The title compound was converted to 6-aminomethyl-2- (3-cyclopentyloxy-4-hydroxy-phenyl) -2,3-dihydro-pyrrolo [3,4-c according to the method described in Reference Example 20. ] Was prepared as a white solid (0.35 g, 54%) using pyridin-1-one (0.5 g, 1.36 mmol).

Example 23

2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-methyl-6- (1-oxo-1,3-dihydroisoindol-2-ylmethyl) -2,3-dihydro- Pyrrolo [3,4-c] pyridin-1-one

The title compound was converted to 6-aminomethyl-2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-methyl-2,3-dihydro-pyrrolo [3] according to the method described in Reference Example 20. , 4-c] pyridin-1-one (0.5 g, 1.36 mmol) was obtained as a white solid (0.36 g, 51%).

Example 24

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -6-[(1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-2-yl) Methyl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

The title compound was converted to 6-aminomethyl-2- (4-methoxy-3-propoxy-phenyl) -2,3-dihydro-1H-pyrrolo [3,4- according to the method described in Reference Example 21. c] pyridin-1-one (0.5 g, 1.41 mmol) was obtained as a yellow solid (0.34 g, 51%).

Example 25

2- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-methyl-6-[(1-oxo-2,3-dihydro-1 H-pyrrolo [3,4-c] pyridine- 2-yl) methyl] -2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-1-one

The title compound was converted to 6-aminomethyl-2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-methyl-2,3-dihydro-pyrrolo [3] according to the method described in Reference Example 21. , 4-c] pyridin-1-one (0.5 g, 1.36 mmol) was obtained as a yellow solid (0.32 g, 48%).

Example 26

2- {2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-oxo-2,3-dihydro-1 H-isoindol-5-ylmethyl} Isoindole-1,3-dione

Refer to the title compound in the manner described in Reference Example 11 6-hydroxymethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -2,3-di Hydro-isoindol-1-one (0.5 g, 1.20 mmol) was obtained as a white solid (0.52 g, 80%).

Example 27

2- {2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -1-methyl-3-oxo-2,3-dihydro-1H-isoindole-5 -Ylmethyl} -isoindole-1,3-dione

Refer to the title compound according to the method described in Reference Example 11 6-hydroxymethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-methyl-2 , 3-dihydro-isoindol-1-one (0.5 g, 1.16 mmol) was obtained as a white solid (0.51 g, 78%).

Example 28

2- {2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -1-oxo-2,3-dihydro-1 H-pyrrolo [3,4-c ] Pyridin-6-ylmethyl} -isoindole-1,3-dione

The title compound was prepared according to the method described in Reference Example 11, 6-aminomethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) phenyl] -2,3-dihydro- Pyrrolo [3,4-c] pyridin-1-one (0.59 g, 1.41 mmol) was obtained as a white solid (0.61 g, 79%).

Example 29

2- {2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-methyl-1-oxo-2,3-dihydro-1 H-pyrrolo [3 , 4-c] pyridin-6-ylmethyl} -isoindole-1,3-dione

The title compound was converted into 6-aminomethyl-2- [4-methoxy-3- (1-methyl-3-phenyl-propoxy) -phenyl] -3-methyl-2, according to the method described in Reference Example 11. 3-Dihydro-pyrrolo [3,4-c] pyridin-1-one (0.5 g, 1.16 mmol) was obtained as a white solid (0.50 g, 77%).

The pharmaceutical compositions of the present invention will be described through the following composition examples.

Composition Example 1

2- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl for 30 minutes on a mechanical shaker / mixer ] -2,3-dihydro-pyrrolo [3,4-c] pyridin-1-one (1 g) (average particle size 3.5 microns) and lactose (99 g) (average particle size 72 microns) together Mixed. The resulting blend was No. The product was prepared as appropriate for a dry powder inhaler, for example, by filling until 3 mg of the hard gelatin capsule was filled.

Composition Example 2

No. each containing the following. 2 sizes of gelatin capsules:

2- [2- (3-cyclopentyloxy-4-methoxy-phenyl) -3-oxo

-2,3-dihydro-1H-isoindol-5-ylmethyl] -2,3-

Dihydro-pyrrolo [3,4-c] pyridin-1-one 20 mg

Lactose 100mg

Starch 60mg

Dextrin 40mg

Magnesium Stearate 1mg

Was prepared according to the conventional method.

Compositions similar to the above were prepared from other compounds of formula [1].

Experimental Example 1

In vitro TNF-α assay (see Taffet S. M. et al., Cellular Immunology (1989) 120, 291-300);                 

Cancer cell lines of mouse macrophages (RAW264.7) were diluted with RPMI1640 medium (including 5% FCS) and plated in 24 well plates at 1 × 10 ⁶ cells / ml. The cultures were then incubated at 37 ° C. in 5% CO ₂ for 18 hours. 1 μM compound and 1 μg / ml lipopolysaccharide (LPS) were added to the plate and the cultures were incubated at 37 ° C. for 6 hours. After incubation, the culture was centrifuged and the supernatant was recovered. Supernatants were stored at -20 ° C until measurement. In-medium TNF-α measurements were performed using the mouse TNF-α kit (Amersham, UK). Proceed according to the guidance provided by Amersham. Inhibition rate of each compound was calculated by comparing the amount of TNF-α released in the wells treated with the compound to that in the untreated wells. The inhibitory activity of the compounds against in vitro TNF-α synthesis is listed in Table 1. The IC ₅₀ of the compound of formula [1] was 1 to 1000 nM.

Table 1

Experimental Example 2

TNF-α in vivo assay (Novogrodsky A. et al., Science (1994) 264, 319-322)

Compounds were suspended in 5% sodium carboxymethyl cellulose (CMC) and then orally administered to starving mice (C57BL / 6, 6 weeks old, males) at a volume of 0.1 ml per 10 g body weight. Two hours after compound administration, lipopolysaccharide (LPS) was intraperitoneally administered at a concentration of 1.5 mg / mouse. The control group was orally administered 5% Na CMC in a volume of 0.1 ml per 10 g body weight. After 1 hour and 30 minutes, mice were anesthetized with ether, blood was collected from the vena cava, centrifuged at 12,000 rpm for 5 minutes, and serum was recovered from the blood. The recovered serum was stored at −20 ° C. until TNF-α ELISA analysis. The amount of TNF-α in serum was measured using the mouse TNF-α kit (Amersham, UK). Proceed according to the guidance provided by Amersham. Inhibition rate of each compound was calculated by comparing the amount of TNF-α released in the wells treated with the compound to that in the untreated wells. The inhibitory activity of compounds on in vitro TNF-α synthesis is listed in Table 2.

TABLE 2

Compounds invented by the inventors showed high inhibitory activity against TNF-α synthesis in vitro and in vivo in Tables 1 and 2.

Experimental Example 3

Assay for PDE 4 Inhibitory Activity

PDE 4 activity was measured using PDE 4 partially purified from [ ³ H] -cAMP (1 μM) and human monosite (U937) as substrate. Human monosite PDE 4 was isolated as described by Torphy et al. (J. Pharmacol. Exp. Ther., 263, 1195-1205, 1992). Synthetic compounds and loriphram were tested in duplicate at 7 concentrations of 10 ⁻⁹ to 10 ⁻³ M. U937 and the substrate and test compound were incubated at 37 ° C. for 30 minutes. The reaction product ([ ³ H] 5'AMP) was eluted on a cation exchange column and the radioactivity was measured by a liquid scintillation counter (LS 1701, Beckman) using a liquid scintillation cocktail. IC ₅₀ values were determined by linear regression of competition curves. Table 3 shows the inhibitory activity of the compounds against PDE 4 in vitro.

TABLE 3

Experimental Example 4

Acute Toxicity Test (LD ₅₀ )

The compounds in Table 3 were orally administered to SPF ICR mice (20 ± 1 g body weight) at various doses. There were 5 animals in each group. The number of dead animals was checked 24 hours after administration. The condition of the animals and the number of dead animals were observed for 7 days. A lethal dose of 50% (LD ₅₀ ) was calculated according to the Litchfield-Wilcoxon method. The results are listed in Table 4.

Table 4

* Refers to after oral administration

Claims (7)

Compound of formula [1] or a pharmaceutically acceptable salt thereof:

Where R ₁ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, hydroxyC ₃ -C ₈ cycloalkyl, phenylC ₃ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkylC ₁ -C ₂ alkyl or Indanyl group; R ₂ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₆ alkyl or amino; R ₃ is hydrogen, hydroxy, oxo, halogen, C ₁ -C ₆ alkyl or amino; R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, amino, C ₁ -C ₆ alkylamino, cyano, aldehyde, aldehyde oxime or -COR ₅ ; R ₅ is hydroxy, —NHNH ₂ or C ₁ -C ₆ alkyl; X is oxygen, carbon, carbonyl, imine or amide; A, B, C, and D are independently carbon, nitrogen or N-oxides. The method of claim 1, R ₁ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, hydroxy-C ₃ -C ₆ cycloalkyl, phenyl-C ₃ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl-C ₁ -C ₂ alkyl, 1-indanyl or 2-indanyl; R ₂ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₃ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, amino, C ₁ -C ₄ alkylamino, cyano, aldehyde, aldehyde oxime or -COR ₅ ; R ₅ is hydroxy, —NHNH ₂ or C ₁ -C ₄ alkyl; X is oxygen, carbon, carbonyl, imine or amide; A, B, C, and D are independently carbon, nitrogen or N-oxide, or a pharmaceutically acceptable salt thereof. The method of claim 2, R ₁ is methyl, ethyl, propyl, C ₃ -C ₆ cycloalkyl, hydroxy-C ₃ -C ₆ cycloalkyl, phenyl-C ₃ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl-C ₁ -C ₂ Alkyl, 1-indanyl or 2-indanyl; R ₂ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₃ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, methyl, methoxy, amino, methylamino, cyano, aldehyde, aldehyde oxime or -COR ₅ ; R ₅ is hydroxy, —NHNH ₂ , methyl or ethyl; X is carbon, carbonyl, imine or amide; A, B, C, and D are carbon, nitrogen, or N-oxides, or a pharmaceutically acceptable salt thereof. The compound of formula [4] is reacted with the compound of formula [5] or the compound of [6] to prepare the compound of formula [3], and the compound of formula [3] is reduced to give the compound of formula [2]. And 3-cyclopentyloxy-4-methoxyphenyl-isoindolinone derivative of formula [1], which comprises dehydroxylating the compound of formula [2] to produce the compound of formula [1]. Wherein R ₃ is hydrogen and one of C and D is nitrogen:

Where R ₁ is methyl, ethyl, propyl, C ₃ -C ₆ cycloalkyl, hydroxy-C ₃ -C ₆ cycloalkyl, phenyl-C ₃ -C ₆ alkyl, C ₃ -C ₅ cycloalkyl-C ₁ -C ₂ Alkyl, 1-indanyl or 2-indanyl; R ₂ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₃ is hydrogen, hydroxy, oxo, halogen, methyl, ethyl or amino; R ₄ is hydrogen, halogen, hydroxy, methylhydroxy, methyl, methoxy, amino, methylamino, cyano, aldehyde, aldehyde oxime or -COR ₅ ; R ₅ is hydroxy, —NHNH ₂ , methyl or ethyl; X is carbon, carbonyl, imine or amide; A, B, C, and D are carbon, nitrogen or N-oxides. A composition for treating an inflammatory disease or an autoimmune disease comprising the compound of claim 1 and a pharmaceutically acceptable carrier. delete The method of claim 5, wherein the disease is arthritis, rheumatoid arthritis, osteoarthritis, sepsis, septic shock, asthma, transplant rejection, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, multiple sclerosis, insulin dependent diabetes mellitus, chronic glomeruli Nephritis, and inflammatory bowel disease.