Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-08-15
2004-12-28
Weber, Jon P. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C530S331000
Reexamination Certificate
active
06835714
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel heterocyclic compound being useful as a medicament, especially exhibiting a human neutrophilic elastase inhibitory activity, intermediates thereof, and a human neutrophilic elastase inhibitor containing as the active ingredient said heterocyclic compound.
PRIOR ART
Human neutrophilic elastase (hereinafter, occasionally simply referred to as elastase) is a kind of serine proteases being massively released from the granules of neutrophile, which appear in the cases of infections or inflammatory diseases. Elastase is an enzyme hydrolyzing proteins such as elastin, collagen, proteoglycan, fibronectin, etc. which constitute the interstitum of intravital connective tissues such as lung, cartilage, vascular wall, skin, etc. In addition, it has been clarified that elastase acts on other proteins or cells as well.
In the living body, elastase keeps the homeostasis of the living body while the activities thereof are controlled by endogenous inhibitor proteins such as &agr;
1
-protease inhibitor, &agr;
2
-macrogloblin, secretory leukocyte protease inhibitor, etc. However, when a balance between elastase and the endogenous inhibitors is lost by the excessive release of elastase in the inflammation site or by the lowering in the inhibitor level, the control of elastase activities cannot be kept, by which tissues are injured.
Diseases in which elastase may participate are, for example, pulmonary emphysema, adult respiratory distress syndrome (ARDS), idiopathic interstitial pneumonia (IIP), cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinopulmonary infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, joint scleroma, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection against organ transplant, premature amniorrhexis, bullous dermatosis, shock, sepsis, systemic lupus erythematosus (SLE), Cróhn's disease, disseminated intracapillary coagulation (DIC), tissue injury after ischemia-reperfusion, formation of cornea cicatricial tissue, myelitis, etc.
Therefore, an elastase inhibitor can be expected to be useful in the prophylaxis or treatment of these diseases. Under these expectations, various elastase inhibitors have been reported.
For example, European Patent Publication No. 189305 (hereinafter, occasionally referred to as Ref. 1) discloses a compound of the following formula (A-1), and it discloses that said compound (A-1) is useful as an elastase inhibitor.
wherein R
1
is a lower alkyl having 1 to 5 carbon atoms, R
2
is a lower alkyl having 1 to 10 carbon atoms, etc., R
4
is a hydrogen atom, etc., A is —CO—, etc., and n is 0, 1 or 2.
Within the above formula, the compound of the following formula is included.
R
3
of the above formula (A-2) represents various substituents, but it does not mean the specific substituents included within the present compounds as mentioned below.
In addition, European Patent Publication No. 291234 (hereinafter, occasionally referred to as Ref. 2) discloses a compound of the following formula (B-1), and it also discloses that said compound (B-1) exhibits a leukocyte elastase inhibitory activity.
wherein Q is an orthophenylene group optionally having a substituent such as a halogen, etc., X is an oxygen atom or a sulfur atom, A is —CO—, etc., L is a phenylene, a (C
1
-C
6
) alkanediyl, etc., and R
6
is an acylsulfonamide, etc.
Moreover, the following compound (a) is disclosed in Example 2(63) of U.S. Pat. No. 5,017,610 (hereinafter, occasionally referred to as Ref. 3). The chemical structure of said compound (a) is completely different from the chemical structure of the present compounds. However, said compound (a) should be noted because it has been most developed and studied as a water-soluble elastase inhibitor.
DISCLUSORE OF INVENTION
An object of the present invention is to provide a novel heterocyclic compound having a potent elastase inhibitory activity and an intermediate thereof.
The present invention relates to a novel heterocyclic compound of the following formula (I-a), its ester, and a salt thereof.
wherein * means that the carbon atom marked with * is an asymmetric carbon atom,
A and B are the same or different and each is a lower alkylene group being optionally substituted by an oxo group,
D is a heteromonocyclic or heterobicyclic group of the following formula:
wherein D
1
is a methylene group or an ethylene group, and these groups may optionally be substituted by an oxo group, Ring G is a 5- to 14-membered, saturated or unsaturated, heteromonocyclic or heterobicyclic group optionally having other heteroatoms selected from a nitrogen atom, an oxygen atom and/or a sulfur atom, and said heterocyclic group being optionally substituted by a substituent T
1
, in which T
1
is the same or different 1 to 3 groups selected from
(i) an oxo group,
(ii) a substituted or unsubstituted lower alkyl group,
(iii) a substituted or unsubstituted amino group,
(iv) a substituted or unsubstituted carbamoyl group,
(v) a carboxyl group or a lower alkoxycarbonyl group,
(vi) a phenyl group being optionally substituted by a halogen atom, a lower alkoxy group or a lower alkyl group, and
(vii) a substituted or unsubstituted lower alkylcarbonyl group,
R
1
and R
2
are the same or different and each is a lower alkyl group,
R
3
and R
4
are different from each other, and each is a hydrogen atom or a hydroxy group, or both combine together to form an oxo group,
R
5
is a group of the formula:
wherein X
1
and X
2
are a halogen atom, Y
1
is a hydrogen atom, a halogen atom, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an aralkylaminocarbonyl group, an aralkyloxycarbonyl group, a lower alkylcarbonyl group, or an aralkylcarbonyl group, or a group of the following formula:
wherein U is an oxygen atom or a sulfur atom, Q is a vinylene group or an orthophenylene group being optionally substituted by T
2
, T
2
is 1 to 3 groups selected from a halogen-substituted or unsubstituted lower alkyl group, a lower alkoxy group, a lower alkylsulfonyl group, a lower alkylcarbonyloxy group and an amino group being optionally substituted by a lower alkyl group,
n is 0, 1 or 2, and
m is an integer of 0 to 5.
Hereinafter, the present compounds (I-a) are explained in more detail.
Among the compounds of the above formula (I-a), the compound (I-a) wherein R
3
and R
4
combine together to form an oxo group (hereinafter, occasionally referred to the ketone compound) exhibits an excellent elastase inhibitory activity. The partial structure of the formula (I-a) represented by HOOC-A-D-B- greatly contributes so that to exhibit such excellent properties of the present compound (I-a). In addition, the present compounds can be distinguished from the above mentioned known compounds in this specific partial structure.
Therefore, the primary characteristic of the chemical structure of the present compounds (I-a) is the above-mentioned specific partial structure. The secondary characteristic of the chemical structure of the present compounds (I-a) is a combination of the above-mentioned specific partial structure and the rest of the structure.
Among the compounds of the above formula (I-a), the compound (I-a) wherein R
3
and R
4
are different from each other and each is a hydrogen atom or a hydroxy group (hereinafter, referred to the OH compound) is useful as an intermediate for directly preparing the above compound (the ketone compound) which is an elastase inhibitor.
The definition for each substituent is explained below.
The term “lower” means that a group accompanied by this term is a group having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified. Therefore, the “lower alkyl group” is a straight chain or branched chain hydrocarbon having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, etc. The “lower alkylene group” is a group wherein one hydrogen atom is removed from the above-mentioned l
Honda Seiji
Inoue Yasunao
Komiya Masanobu
Omodani Tomoki
Sato Fuminori
Dainippon Pharmaceutical Co., Ltd.
Lukton David
Weber Jon P.
LandOfFree
Heterocyclic compounds, intermediates thereof and elastase... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heterocyclic compounds, intermediates thereof and elastase..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heterocyclic compounds, intermediates thereof and elastase... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3291848