Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-01-15
2001-10-09
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S011000, C560S012000, C560S014000, C549S447000, C562S429000, C562S430000, C562S431000, C564S162000, C546S342000
Reexamination Certificate
active
06300514
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to aryl (sulfide, sulfoxide, sulfone) derivatives, processes for the preparation thereof, and matrix metalloproteinases inhibitors containing them as active ingredient.
More particularly, this invention relates to matrix metalloproteinases inhibitors containing aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (I)
(wherein all the symbols are the same meanings as hereinafter described.), non-toxic salts thereof, as active ingredient, and the above-mentioned novel aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (I), non-toxic salts thereof, and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
The matrix metalloproteinases (hereinafter abbreviated as MMP) are neutral metalloproteinases and zinc (hereinafter abbreviated as Zn
2+
) is essential in the active site for their activation They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and, therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMP which differ in primary structure are identified.
As common characteristics of these enzymes, MMP
(1) have Zn
2+
in the active site and the activity depends on calcium (Ca
2+
),
(2) are secreted as an inactive proenzyme and activated outside of cells,
(3) have high homology on amino acid sequence,
(4) have an ability to degrade various extracellular matrix components in vivo,
(5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMP.
MMP inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression or excess activation of MMP. Such diseases are, for example, rheumatoid diseases, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cells, autoimmune diseases (e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascular emigration or infiltration of leukocytes, arterialization etc.
Some compounds possessing inhibitory activity against matrix metalloproteinases are known. A sequence in the vicinity of the cleavage site of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinity for collagenase. Much research and development on substrate analogous matrix metalloproteinases inhibitors, which are chemically modified so as to have zinc affinity groups on a cleavage site of the substrate, has energetically been carried out [Inhibitors of matrix metalloproteinases (MMP's), Nigel RA Beeley, Phillip R J Ansell, Andrew J P Docherty et al., Curr. Opin. Ther. Patents, 4, 7-16 (1994), Current Drugs Ltd ISSN 0962-2594]. However, these substrate-analogous inhibitors might have various problems. Therefore, it is desired to obtain a non-peptide inhibitor and some compounds are reported.
For example, (1) in the specification of EP 606046, arylsulfonamide derivatives of the formula (X)
(wherein (a) Ar
X
is carbocyclic or heterocyclic aryl; R
X
is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R
1X
is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R
2X
is hydrogen, lower alkyl; or (b) R
X
and R
1X
taken together with the chain to which they are attached form 1,2,3,4-tetrahydro-isoquinoline, piperidine etc.; Ar
X
and R
2X
are as defined in (a); or (c) R
1X
and R
2X
taken together with the carbon to which they are attached form C3-7 cycloalkane, oxa-cyclohexane, thia-cyclohexane etc. which is unsubstituted or substituted by lower alkyl; and Ar
X
and R
2X
are as defined in (a).) are disclosed to have inhibitory activity against matrix metalloproteinase.
(2) In the specification of WO 9535276, the compounds of the formula (Y)
(wherein X
Y
is COOH, CONHOH; R
1Y
is &agr;-amino acid; R
2Y
is Z
1Y
Q
Y
W
Y
; Z
1Y
is hydrogen, aryl etc.; (i) Q
Y
W
Y
together form bond, (ii) Q
Y
is O, S, W
Y
is C1-20 alkyl etc., (iii) Q
Y
is bond, W
Y
is C9-20 alkyl etc., (iv) Q
Y
is bond, W
Y
is C1-8 alkyl; Y
Y
is SO
2
; Z
Y
is aryl, heteroaryl.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
(3) In the specification of WO 9615096, the compounds of the formula (Z)
(T
Z
)x
Z
A
Z
-B
Z
-D
Z
E
Z
G
Z
(Z)
(wherein (T
Z
)x
Z
A
Z
is unsubstituted or substituted various aromatic ring or aromatic hetero ring; B
Z
is various aromatic ring or aromatic hetero ring; D
Z
is —CO—, —CH(OH)—, —CH
2
— etc.; E
Z
is Cn carbon chain optionally having R
6Z
(in which R
6Z
is —(CH
2
)v
Z
Z
Z
R
8Z
(in which v
Z
is 0, integer of 1≠4; Z
Z
is —S—, —SO—, —SO
2
— etc.; R
8Z
is optionally substituted C6-10 aryl etc.)); G
Z
is carboxyl, alkoxycarbonyl.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
(4) In the specification of WO 9509841, the compounds of the formula (E)
(wherein R
1E
is phenyl optionally having substituent etc.; R
2E
is hydrogen, C1-6 alkyl etc.; R
3E
is amino acid residue optionally having substituent; R
4E
is hydrogen, C1-6 alkyl etc.; R
5E
is hydrogen, methyl; n
E
is 0, 1, 2; A
E
is C1-6 hydrocarbon chain.)
are disclosed to have inhibitory activity against the liberation of TNF, and inhibitory activity against matrix metalloproteinase.
(5) In the specification of WO 9324449, the compounds of the formula (F)
(wherein RF is —CONHOH, carboxyl, esterified carboxyl etc.; R
1F
is hydrogen, optionally substituted alkyl, alkenyl, aryl, aralky, heteroaralkyl, heteroarylthioalkyl; R
2F
is optionally substituted arylthio, arylthioalkyl etc.; R
3F
is hydrogen, alkyl; R
4F
is hydrogen, alkyl; R
5F
is optionally substituted alkyl etc.) are disclosed to have inhibitory activity against matrix metalloproteinase.
(6) In the specification of WO 9616027, the compounds of the formula (G)
(wherein R
1G
is —CONHOH, carboxyl, alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl etc.; R
2G
is aryl etc.; R
3G
is alkyl etc.; R
7G
is aryl etc.; X
G
is —(CH
2
)m
G
Y
G
(CH
2
)n
G
(in which Y
G
is S etc.; m
G
, n
G
, p
G
is 0~4.)
are disclosed to have inhibitory activity against matrix metalloproteinase.
Also, (7) in the specification of Japanese Patent Kokai No. 4-226939 and (8) Japanese Patent Kokai No. 4-293576, each of the compound of the formula (W-1)
(wherein R
1W-1
, R
2W-1
is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or together form methylene, ethylene, polymethylene; R
3W-1
is hydrogen, halogen, haloalkyl, C1-12 alkyl, C1-12 alkoxy etc.; R
4W-1
is hydrogen, halogen, nitro, —C(O)CH
3
, S(O)
p
R
9W-1
(in which p is 0, 1, 2, R
9w-1
is hydroxy, —ONa, optionally substituted C1-12 alkyl, cycloalkyl)),
and the compounds of the formula (W-2)
(wherein R
1W-2
, R
2W-2
is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, or together form methylene, ethylene, polymethylene; Ar
W-2
is optionally substituted phenyl; HET
W-2
is hetero ring containing nitrogen, sulfur or oxygen atom over 1 atom.) are disclosed to have inhibitory activity against elastase.
(9) In the specification of EP 0173516, the compounds of the formula (J)
(wherein B
J
is —SCH
2
— etc.; T
J
is oxygen etc.; R
1J
is optionally substituted phenyl, naphthyl by R
5J
, R
6J
, or C1-20 alkyl, alkenyl, alkynyl; R
2J
is hydrogen, C1-6 alkyl; R
3J
is hydrogen, alkyl etc.; R
4J
is —(CH
2
)p
J
—COOR
8J
(in which p
J
is 0~10; R
8J
is hydrogen, C1-6 alkyl.)
are disclosed to have SRS antagonistic activity or 5a-reductase inhibitory activity.
(10) In the specification of British Patent 2031408, the compounds of the formula (K)
(wherein R
K
is hydrogen, alkyl; A
1K
, A
2K
is alkylene, alkenylene; m
K
is 0, 1; Z
K
is
etc.; R
1K
, R
2K
is hydrogen, alkyl.)
are disclosed to have inhibitory activity against TXA
2
synthetase.
(11) In the specification of British Patent 2039903, the compounds of the formula (L)
(wherein A
L
is C1-5 alkylene optionally substituted by hydroxy; E
L
is
etc.; B
L
is sulfur etc.; Z
L
is bond, C≡C,
D
L
is bond, C1-5 al
Sugiura Tsuneyuki
Takahashi Kanji
Ono Pharmaceutical Co. Ltd.
Owens Amelia
Stevens Davis Miller & Moshner, L.L.P.
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