Tricyclic compound having acyloxymethoxycarbonyl side chain

Details Tricyclic compound having acyloxymethoxycarbonyl side chain Tricyclic compound having acyloxymethoxycarbonyl side chain

2001-12-03

2004-07-20

Desai, Rita (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S257000, C546S261000, C546S300000, C514S345000, C514S336000

Reexamination Certificate

active

06765096

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel compound which is useful as a prodrug, a pharmaceutical composition containing the same and an intermediate therefor. More particularly, the present invention relates to a novel tricyclic compound having an acyloxymethoxycarbonyl side chain, an immunosuppressant and an antiallergic agent containing the same as well as a novel tricyclic compound having the immunosuppressive activity and the antiallergic activity and an intermediate therefor.
BACKGROUND ART
Making of prodrugs for pharmaceutical active substances is studied in many cases for the purpose of improving the physical properties such as the crystallizability, the stability, the water-solubility and the like, the bioavailability, and duration of the pharmacological activity. In particular, although it is desirable to convert amine compounds into a prodrug for the purpose of enhancing the absorbability and the stability, simple amidated prodrugs can not be returned to amines in the living body and it is said that procedures for converting into a prodrug require elaboration.
In WO97/39999 and WO98/04508, it is disclosed that para-terphenyl derivatives are effective as an immunosuppressant and an antiallergic agent. In particular, WO98/04508 refers to prodrugs and, more particularly, describes conversion of hydroxy compounds into a prodrug.
In JP-A23359/1985, JP-A18747/1986 and WO96/18605, described is a method of making a prodrug by substituting primary or secondary amines with —COOCR
1
R
2
OCOR
3
(R
3
=alkyl, carboxyalkyl, haloalkyl, carbamylalkyl etc.). In addition, in JP-A503925/1993 and Synthesis (December, 1990, 1159-1166), there are described R
2
SCOOCH
2
OCOR
1
(Compound A) and ClCOOCH
2
OCOR
1
(Compound B) as an intermediate for synthesizing a prodrug. However, it is clearly described therein that Compound B can not be synthesized from Compound A (wherein R
1
is hydroxyethyl or acetylaminomethyl, and R
2
is ethyl) according to those methods.
Compounds having the similar skeleton to that of the present compound and having the immunosuppressive activity or the antiallergic activity are described in WO94/27980, WO95/13067, WO96/15123, WO95/15318, WO96/40659, WO96/40143, WO96/38412, WO96/10012, WO97/24356, WO97/27181, WO97/24324, WO97/44333, WO97/46524, WO98/04508, WO98/24766, WO98/24782, WO98/56785, FR2301250, U.S. Pat. No. 5,593,991, JP-B7368/1972, JP-A91259/1976, JP-A3163/1996, JP-A124571/1997, JP-A71564/1997, JP-A124571/1997, JP-A79993/1999, Bioorganic & Medicinal Chemistry Letters, Vol.5, No.18, p2143-2146(1995), J. Med. Chem., 1974, Vol.17, NO.11, 1177-1181 and the like.
Additionally, liquid crystalline compounds having the similar skeleton to that of the present compound are disclosed in JP-A121225/1983, JP-A87253/1997, JP-A253065/1988, JP-A106864/1986, JP-A106871/1986, JP-A83346/1990, JP-A48760/1997, JP-A31063/1997, WO88/07992 and the like, compounds having the insecticidal or miticidal activity in JP-A193067/1996, compounds having the circulatory disease and psychosis-treating activity in EP0600717A1, and compounds having the central nervous disease-treating activity in WO95/15954.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a novel prodrug of a compound having the immunosuppressive activity and/or the antiallergic activity.
The present invention provides the following compounds or pharmaceutically acceptable salts thereof or prodrugs thereof.
[1] A compound represented by the formula (I):
(hereinafter, referred to as compound (I))
wherein one of X and X′ is —N(COOCR
3
R
2
OCOR
1
)—, the other is —(CH
2
)s- (wherein s is an integer of 0 to 2), —O—, —NR
A
— (wherein R
A
is hydrogen, optionally substituted lower alkyl, lower alkenyl or lower alkylcarbonyl), —N(COOCR
3
R
2
OCOR
1
)— or —S(O)p- (wherein p is an integer of 0 to 2),
R
1
is lower alkyl substituted with 1 or 2 groups selected from the group consisting of —CONH
2
, —CONHCH
3
, —CONHC
2
H
5
, —OCONH
2
, —OCONHCH
3
, —OCONHC
2
H
5
, —(NHCOCRR′)mNHCOCH
3
, —(NHCOCRR′)mNHCOC
2
H
5
, —CSNH
2
, —(OCH
2
CH
2
)nOH, —OCH
3
, —(OCH
2
CH
2
)nOCH
3
, —COCH
3
, —COC
2
H
5
, —OCOCH
3
, —OCOC
2
H
5
, —NHOH, —NHCONH
2
, —NHCSNH
2
, —NHSO
2
CH
3
, —N(SO
2
CH
3
)
2
, —O
2
NH
2
, —SOCH
3
, —SO
2
CH
3
, —OCH
2
CONH
2
, —OCH
2
CON(CH
3
)
2
, —SO
2
N(CH
3
)
2
, —PO(OCH
3
)
2
, —NHCSNHC
2
H
5
, —CH═NNHCONH
2
, —CH═NNHCSNH
2
, —CH═NNHSO
2
CH
3
, triazolyl and tetrazolyl (wherein R and R′ are each independently hydrogen or lower alkyl, m is an integer of 0 to 2, and n is an integer of 1 or 2),
R
2
and R
3
are each independently hydrogen or lower alkyl,
Y and Y′ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lower alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted aryl or optionally substituted 5-membered or 6-membered heterocycle,
when X is —CH
2
—, Y may be optionally substituted lower alkoxy,
when X′ is —CH
2
—, Y′ may be optionally substituted lower alkoxy,
when X is —O— or —NR
A
—, Y may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
when X′ is —O— or —NR
A
—, Y′ may be optionally substituted lower alkylsulfonyl or optionally substituted arylsulfonyl,
ring A, ring B and ring C are each independently optionally substituted aromatic carbocycle or optionally substituted 5-membered or 6-membered heterocycle which may be fused with a benzene ring,
when ring A, ring B and/or ring C are optionally substituted 5-membered-heterocycle, W
1
, W
2
and/or W
3
represent a bond,
one of V
1
and V
2
is a single bond, the other is a single bond, —O—, —NH—, —OCH
2
—, —CH
2
O—, —CH═CH—, —C≡C—, —CH(OR
B
)— (wherein R
B
is hydrogen or lower alkyl), —CO—, —NHCHR
C
— or —CHR
C
NH— (wherein R
C
is hydrogen or hydroxy),
when both V
1
and V
2
are a single bond, at least one of ring A, ring B and ring C is optionally substituted aromatic carbocycle, and at least one is optionally substituted 5-membered or 6-membered heterocycle which may be fused with a benzene ring,
[2] a compound represented by the formula (II):
(hereinafter, referred to as compound (II))
wherein one of X and X′ is —N(COOCR
3
R
2
OCOR
1
)—, and the other is —O—, —NH— or —N(COOCR
3
R
2
OCOR
1
)—,
Y and Y′ are each independently optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,
R
1
, R
2
and R
3
have the same meanings as those for [1],
ring A and ring C are each independently optionally substituted benzene ring or optionally substituted 6-membered heterocycle containing 1 or 2 heteroatoms, at least one of them being 6-membered heterocycle,
R
8
, R
9
, R
10
and R
11
are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, optionally substituted lower alkenyloxy, optionally substituted cycloalkyloxy, optionally substituted acyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted lower alkenyloxycarbonyl, optionally substituted lower alkylthio, optionally substituted lower alkenylthio, optionally substituted amino, optionally substituted carbamoyl, guanidino, nitro, optionally substituted lower alkylsulfonyl, optionally substituted lower alkylsulfonyloxy, optionally substituted arylsulfonyl or optionally substituted arylsulfonyloxy,
[3] a compound represented by the formula (III):
(hereinafter, referred to as compound (III))
wherein X is —NH— or —N(COOCR
3
R
2
OCOR
1
)—, X′ is —O—, —NH— or —N(COOCR
3
R
2
OCOR
1
)—, at least one of X and X′ being —N(COOCR
3
R
2
OCOR
1
)—,
Y and Y′ are each independently optionally substituted lower alkyl or optionally substituted lower alkenyl,
R
1
, R
2
and R
3
hav

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