Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1997-09-16
2001-01-09
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S327000, C544S328000, C544S329000, C544S295000, C544S296000, C544S322000
Reexamination Certificate
active
06172227
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel 4,5-diaminopyrimidine derivatives useful in prevention or treatment of diseases implicated in respiratory system by inhibiting cyclic guanosine 3′,5′-monophosphate phosphodiesterase. In addition, the present invention relates to a process for producing the said compounds.
BACKGROUND OF THE INVENTION
It is known that cyclic guanosine 3′,5′-monophosphate (cGMP) induces an relaxation of cardiac muscle or smooth muscle and is implicated in the cellular growth of lymphocyte. However, there are reports in which cGMP is converted into inactive 5′GMP by cGMP phosphodiesterase, so the action of cGMP is lost. Therefore, compounds having inhibitory activity of cGMP phosphodiesterase will be able to maintain or increase level of cGMP and so will act as keeping a symmetrical metabolism. As such, the compounds can be effectively used in the prevention or treatment of hypertension, cardiagra, arteriosclerosis, respiratory system disease such as chronic bronchial asthma or bronchitis, etc.
U.S. Pat. No. 5,318,975 describes, as inhibitor of cGMP phosphodiesterase, 5-aminopyrimidine derivatives compounds of the following formula A:
wherein A
1
represents hydrogen or imidazole substituted with lower alkyl, A
2
represents hydrogen or lower alkyl and A
3
represents imidazolecarboxylamide substituted with lower alkyl.
EP 640,599 describes, as inhibitor of cGMP phosphodiesterase, 4-aminopyrimidine derivatives compound of the following formula B:
wherein B
1
represents 4-15 membered heterocyclic ring substituted with lower alkyl, lower alkoxy, halogen, etc., B
2
represents 4-15 membered heterocyclic ring substituted with lower alkyl, lower alkoxy, halogen, nitro, ester, etc. or hydroxy(lower alkoxy), B represents 4-15 membered heterocyclic ring substituted with lower alkyl, lower alkoxy, halogen, nitro, sulfone, etc.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides novel 4,5-diaminopyrimidine derivatives or physiologically acceptable salts, solvates or metabolically readily convertible ester thereof which have the inhibitory activity of cGMP phosphodiesterase. The compounds are represented as the general formula (I):
in which X is a direct bond, C
1-4
alkylene, C
1-4
alkyleneoxy, C
1-4
alkoxyphenyl or phenyl C
1-4
alkylene; Y is a direct bond or C
1-2
alkyl; R
1
is (i) 5-15 membered cyclic or branched chain heterocompound which includes one or two atoms selected from a group consisting of nitrogen, oxygen and sulfur and which is substituted with one or two substituent selected from a group consisting of hydrogen, halogen, nitro, hydroxy, C
1-6
alkyl, C
3-6
alkenyl and halogen C
1-4
alkoxy, (ii) C
4-10
carbocyclic compound or (iii) hydroxy C
1-4
alkoxy; R
2
is 5-15 membered cyclic or branched chain heterocompound which includes one or two atoms selected from a group consisting of nitrogen, oxygen and sulfur and which is substituted with one or two substituent selected from a group consisting of hydrogen, hydroxy, halogen, nitro, hydroxy C
1-5
alkyl, C
1-6
alkyl, C
3-6
alkenyl and halogen C
1-4
alkoxy; R
3
is hydrogen,
in which R
4
and R
5
are each independently selected from a group consisting of hydroxy, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen C
2-6
alkenyl and C
1-4
alkoxy or R
4
and R
5
represent each independently
in which R
6
is selected from a group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen, nitro and C
1-4
alkoxy.
The compound of the general formula I may be in the form of optical isomer or geometrical isomer. These isomers are included in the present invention.
The present invention provides a process for producing the compound of the general formula I which comprises (a) reacting a compound of the following structure III:
with a compound of the general formula III-a:
HN—X—R
1
(III-a)
in which X and R
1
represent the same as defined above, to give a compound of the general formula IV:
in which X and R
1
represent the same as defined above,
(b) reacting the compound IV with a compound of the general formula IV-a:
Y—R
2
(IV-a)
in which Y and R
2
represent the same as defined above, to give a compound of the general formula V:
in which X, R
1
and R
2
represent the same as defined above,
(c) reducing the compound V to give a compound of the general formula VI:
in which X, Y, R
1
, and R
2
represent the same as defined above,
(d-i) reacting the compound VI with a compound of the general formula (VI-1):
in which R
4
is selected from a group consisting of hydroxy, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen C
2-6
alkenyl and C
1-4
alkoxy or R
4
represents
in which R
6
is selected from a group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen, nitro and C
1-4
alkoxy to give the compound of the general formual I-A:
in which X, Y, R
1
, R
2
and R
4
are the same as defined above; or
(d-ii) reacting the compound VI with a compound of the general formula (VI-2):
in which R
5
is selected from a group consisting of hydroxy, C
1-6
alkyl, C
3-7
cycloalkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen C
2-6
alkenyl and C
1-4
alkoxy or R
5
represents
in which R
6
is selected from a group consisting of hydrogen, hydroxy, C
1-6
alkyl, C
3-6
alkenyl, halogen C
1-6
alkyl, halogen, nitro and C
1-4
alkoxy, to give the compound of the general formula I-B:
in which X, Y, R
1
, R
2
and R
5
are the same as defined above.
The compound III is described in WO 9510506 and, preferably, can be prepared by reacting the compound II with phosphorus oxychloride in the presence of a base. N,N-diethyl-aniline, N,N-dimethylaniline or N,N-diisopropylethylamine can be used as the base. As such, the reaction is carried out at a reflux temperature.
The compound IV can be prepared by reacting the compound III with the compound of the formula III-a: HN—X—R
1
in which R
1
is the same as defined above, preferably, using pyridine or triethylamine in solvent such as dichloromethane or acetonitrile at 0° C. to room temperature (J. Med. Chem. 1994, 37, 2106).
The compound V can be prepared by dissolving the compound IV in a polar solvent and reacting the solution with the compound of the formula IV-a: Y—R
2
in which R
2
is the same as defined above, at 0° C. to reflux temperature. Usually, the compound V is obtained as crystals in acetonitrile, ethanol or isopropanol.
The compound VI is obtained by reacting the compound V with iron and acid in polar solvent under reflux (WO 9518097) or by reacting the compound V with sodium borohydride and 5% palladium on activated carbon in solvent such as methanol or ethanol at 0° C. to 25° C. (
Synthesis,
1994, 1437).
The compound I-A is produced by reacting the compound VI with the compound VI-1:
in which R
4
is the same as defined above, using pyridine, triethylamine or N,N-diisopropylethylamine as a base in solvent such as acetonitrile, dichloromethane or tetrahydrofurane at 0° C. to reflux temperature.
The compound I-B is produced by reacting the compound VI with the compound VI-2:
in which R
5
is the same as defined above, using pyridine or N,N-diisopropylethylamine as a base in solvent such as acetonitrile, dichloromethane or tetrahydrofurane at 0° C. to 25° C.
REFERENCES:
patent: 5474996 (1995-12-01), Caille et al.
Robins et al., J. Am. Chem. Soc. 75 (1953) 263-266, 1953.*
Kim Young Gi
Lee Kwang Hyuk
Lee Youn Ha
Rhee Chung Keun
Suh Byoung Chool
Burns Doane Swecker & Mathis L.L.P.
Cheil Jedang Corporation
Ford John M.
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