Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-18
2004-04-13
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S131000
Reexamination Certificate
active
06720343
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition containing a sulfonamide derivative having an oxadiazole ring as an active ingredient for treating or preventing cancer.
BACKGROUND ART
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active site, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 to MMP-23, have been reported.
An MMP inhibitor has been developed as an anticancer agent as described in Chem. Rev. 1999, 99, 2735-2776, Current Pharmaceutical Design, 1999, 5, 787-819, etc.
It is described in CANCER RESEARCH 53, 878-883, 1993, CANCER RESEARCH 53, 5365-5369, 1993, etc. that an activity of MMP-2 and MMP-9 is enhanced in cancer patients.
It is well-known that MMP-9 is produced from immune cells such as macrophages and lymphocytes, and its production is controlled by cytokines in The Journal of Immunology 4159-4165, 1996 and The Journal of Immunology 2327-2333, 1997. This MMP-9 is thought to participate when a cell such as macrophage and lymphocyte destroys an extracellular matrix to wander around inflammation or tumor sites. Accordingly, it is supposed that a strong inhibition of MMP-9 may decrease immune response.
A sulfonamide derivative having an oxadiazole ring exhibits an MMP inhibitory activity as described in WO99/04780.
Further, there are other sulfonamide derivatives exhibiting an MMP inhibitory effect.
DISCLOSURE OF INVENTION
As described above, compounds exhibiting an MMP inhibitory activity are under development as an anticancer agent. However, the development of MMP inhibitor having more safety and high efficacy as medicaments has been desired.
In the above situation, the inventors of the present invention have found that certain sulfonamide derivatives having an oxadiazole ring are useful as an anticancer agent with safety and high efficacy.
The present invention relates to:
1) A pharmaceutical composition for treating or preventing cancer containing a compound of the general formula (I), a prodorug, a pharmaceutically acceptable salt, or a solvate thereof as an active ingredient:
wherein
R
1
is NHOH, hydroxy, or lower alkyloxy;
R
2
is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R
3
is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R
4
is optionally substituted arylene or optionally substituted heteroarylene;
R
5
is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted non-aromatic heterocyclic group.
In more detail, the invention relates to the following 2) to 6).
2) A compound of the formula (I′):
wherein
R
6
is NHOH, hydroxy, or lower alkyloxy;
R
7
is hydrogen, methyl, isopropyl, isobutyl, benzyl, or indol-3-ylmethyl;
R
8
is hydrogen or optionally substituted lower alkyl;
R
9
is phenylene or 2,5-thiophene-diyl;
R
10
is optionally substituted thienyl, optionally substituted furyl, or optionally substituted pyridyl;
a prodorug, or a pharmaceutically acceptable salt, or a solvate thereof.
3) A compound of the following formula:
a prodrug, or a pharmaceutically acceptable salt, or a solvate thereof.
4) A parmaceutical composition which contains a compound as described in 2) or 3) as an active ingredient.
5) A parmaceutical composition of 4) as an agent for treating or preventing cancer.
6) A parmaceutical composition of 4) as an agent for preventing metastasis.
7) Use of a compound of 2) or 3) for the preparation of medicine for treating cancer.
8) A method for treating a mammal cancer by administering to a mammal, including human, a therapeutic effective amount of the compound as described in 2) or 3).
In the present specification, the term “lower alkyl” employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
In the present specification, the term “lower alkenyl” means a straight- or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bond. Examples of the alkenyl include vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like. C2 to C6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.
In the present specification, the term “lower alkynyl” means a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bond. The alkynyl may contain (a) double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2 to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.
In the present specification, the term “cycloalkyl” includes cycloalkyl group having 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C3 to C6 cycloalkyl is preferred.
In the present specification, the term “aryl” employed alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Examples include phenyl, 1-naphtyl, 2-naphtyl, anthryl, and the like.
In the present specification, the term “aralkyl” herein used means the above mentioned “lower alkyl” substituted one or more with the above mentioned “aryl” at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl), and the like. Benzyl and phenylethy are preferred.
Preferable is benzyl as “aralkyl” for R
2
or R
3
.
In the present specification, the term “heteroaryl” employed alone or in combination with other terms includes a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with cycloalkyl, aryl, non-aromatic heterocyclic group, and other heteroaryl at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl(e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g., 2-indolizinyl, 6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), puriyl (e.g., 8-puriyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 3-quinolyl, 5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g., 2-naphthyridinyl), quinolanyl (e.g., 2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofu
Maekawa Ryuji
Watanabe Fumihiko
Yoshioka Takayuki
Lambkin Deborah C.
Shionogi & Co. Ltd.
Wenderoth Lind & Ponack LLP
Wright Tonya
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