Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-13
2003-09-16
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S329000
Reexamination Certificate
active
06620817
ABSTRACT:
This application is a 371 of PCT/JP00/07854, filed Nov. 9, 2000.
TECHNICAL FIELD
The present invention relates to a novel [5-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]acetamide derivative being useful as an agent in the treatment of immuno inflammatory diseases, a process for preparing the same, a pharmaceutical composition containing the same, and an intermediate for preparing said acetamide derivative.
BACKGROUND ART
WO-96/32383 and JP-A-10-130150 disclose that the acetamide derivative of the following formula selectively acts on benzodiazepine &ohgr;
3
receptors, and exhibits anti-anxiety activity and anti-rheumatoid activity, and is useful in the treatment of anxiety-related diseases and immune diseases.
wherein X is —O— or —NR
4
—,
R
1
is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cyclolalkyl-lower alkyl group,
R
2
is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl group, etc.,
R
3
is a hydrogen atom, a lower alkyl group or a hydroxy-lower alkyl group,
R
4
is a hydrogen atom, a lower alkyl group, etc.,
R
5
is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy-lower alkyl group, a substituted or unsubstituted benzyloxy-lower alkyl group, an acyloxy-lower alkyl group, a lower alkoxy-lower alkyl group, a trifluoromethyl group, a halogen atom, an amino group, a mono- or di-lower alkylamino group, an acylamino group, an amino-lower alkyl group, a nitro group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, a carboxyl group, a protected carboxyl group, a carboxy-lower alkyl group or a protected carboxy-lower alkyl group,
R
6
is a hydrogen atom, a lower alkyl group, a trifluoromethyl group, or a substituted or unsubstituted phenyl group, or R
5
and R
6
may optionally combine to form —(CH
2
)
n
—(n is 3, 4, 5 or 6),
R
7
is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group or a nitro group,
R
8
is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.
The above WO 96/32383 discloses as a compound having a 4-trifluoromethylphenyl group at the 2-position of the pyrimidine ring, and exhibiting anti-rheumatoid activity the compound of the following formula (A) (the compound of Example 6 of said publication).
In addition, the above JP-A-10-130150 discloses, in addition to the compound of the above formula (A), as a compound having a 4-trifluoromethylphenyl group at the 2-position of the pyrimidine ring and exhibiting anti-rheumatoid activity the compound of the following formula (B) (the compound of Example 206 of said publication).
The compounds of the present invention of the formula (I) as mentioned below are conceptually included within the scope of the claims of said WO 96/32383, but said publication never concretely disclose the present compound. Then, as compared the structures of the compounds of the formulae (A) and (B) with that of the compound of the present invention as mentioned below, the former compounds have a 4-trifluoromethyl group at the 2-position of the pyrimidine ring but both the 5-position and the 6-position of the pyrimidine ring are methyl groups, and hence, they are structurally quite different from the latter compound (the compound of the present invention) in which the 5-position of the pyrimidine ring is substituted by a chlorine atom, and the 6-position thereof is a phenyl group.
WO 98/09960 discloses that a 2,4-disubstituted pyrimidine derivative of the following formula selectively acts on benzodiazepine 6)3 receptors like the compound of the above WO 96/32383.
wherein A is a heteroaryl group, etc., and the definitions for the other substituents are omitted, but either one of A and R
2
should be a heteroaryl group.
The compound of the present invention of the following formula (I) is apparently distinguished from the compound of the above formula in which at least one of the substituent (A) at the 2-position of the pyrimidine ring and R
2
is a heteroaryl group.
Immuno inflammatory diseases such as rheumatoid arthritis (hereinafter, occasionally referred to as rheumatism), Sjögren syndrome, Behcet disease, ankylosing spondylitis, etc. are differentiated in terms of being systemic crisis or being local crisis at a specific organ, but all of these diseases are intractable and cryptogenic diseases. Therefore, it is a present situation that the treatment of these diseases should be relied on non-specific anti-inflammatory therapy or immunosuppressive therapy. For example, non-steroid anti-inflammatory agents or steroidal agents have been used in the treatment of rheumatism so far. However, since it was recently found that immune-response abnormality is participated in the rheumatism, an immunosuppressive agent (e.g., methotrexate, mizoribine, etc.) or an immuno modulating agent (e.g., sulfasalazine, D-penicillamine, oral gold agents, etc.) has been positively used in the treatment of rheumatism. However, such drugs have serious side effects, respectively, and it is therapeutically very important to monitor the side effects in its course of treatment after the administration of these drugs. In addition, many of immuno modulating agents have a problem, that is, when they are continuously administered, the pharmacological effects thereof become weak or even disappear, which is a clinically very serious problem. Under the above-mentioned circumstances, it has been strongly desired to develop a therapeutic agent for immuno inflammatory diseases or an immuno modulating agent, with a high efficiency and a high safety.
The present inventors have intensively studied and tried on various pharmaceutical activities of the compounds selectively acting on benzodiazepine &ohgr;
3
receptors, and during the process thereof, they have found the compounds exhibiting effects on immuno inflammatory diseases such as anti-rheumatoid activity, etc., and filed a patent application (the above WO 96/32383 and JP-A-10-130150). In the above publications, there is disclosed a compound having a 4-trifluroromethyl group as the substituent on the phenyl group attached to the 2-position of the pyrimidine ring. For example, the compound of the above formula (A) disclosed in WO 96/32383 exhibits a rather potent anti-rheumatoid activity, but the efficacy thereof is not sufficient enough. In addition, JP-A-10-130150 discloses the compound of the above formula (B) exhibiting a more potent anti-rheumatoid activity, but by the research thereafter, it was found that the compound of the formula (B) has a much influence on liver and kidney, and this compound is not suitable as a medicament in terms of the safety.
DISCLOSURE OF INVENTION
The present inventors have intensively studied in order to obtain a [2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]acetamide derivative having an anti-rheumatoid activity as potent as the compound of the above formula (B) and a high safety, and being useful as an agent for treatment or prophylaxis of immuno inflammatory diseases, and have found that a compound having a chloro substituent at the 5-position and a phenyl substituent at the 6-position of pyrimidine ring, i.e., a specific [5-chloro-6-phenyl-2-(4-trifluoromethyl-phenyl)-4-pyrimidinylamino]acetamide derivative of the formula (I) as shown below (hereinafter, occasionally referred to as the present compound) has unexpectedly a potent anti-rheumatoid activity but hardly has an influence on liver, etc., and finally have accomplished the present invention.
An object of the present invention is to provide a [5-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]acetamide derivative having a potent anti-rheumatoid activity and a high safety, and being useful in the prophylaxis or treatment of immuno inflammatory diseases. Another object of the present invention is to provide a process for preparing said compound. Still further ob
Itoh Mari
Murata Teruya
Ohno Kazunori
Tanaka Masayasu
Dainippon Pharmaceutical Co., Ltd.
Ford John M.
Wenderoth , Lind & Ponack, L.L.P.
LandOfFree
[5-CHLORO-6-PHENYL-2-(4-TRIFLUOROMETHYLPHENYL)-4-PYRIMI... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with [5-CHLORO-6-PHENYL-2-(4-TRIFLUOROMETHYLPHENYL)-4-PYRIMI..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and [5-CHLORO-6-PHENYL-2-(4-TRIFLUOROMETHYLPHENYL)-4-PYRIMI... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3077049