Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-07-11
2002-09-17
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S056000, C514S061000
Reexamination Certificate
active
06451767
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of substituted benzylmaltotriosides as smooth muscle cell proliferation inhibitors and as therapeutic compositions for treating diseases and conditions which are characterized by excessive smooth muscle proliferation such as restenosis.
All forms of vascular reconstruction such as angioplasty and vein bypass procedures effect a response to injury that ultimately leads to smooth muscle cell (SMC) proliferation and subsequently, deposition of profuse amounts of extracellular matrix (Clowes, A. W.; Reidy, M. A.
J. Vasc. Surg
1991, 13, 885). These events are also central processes in the pathogenesis of atherosclerosis (Raines E. W.; Ross R.
Br. Heart J.
1993, 69 (Supplement), S. 30) as well as transplant arteriosclerosis (Isik, F. F.; McDonald, T. O.; Ferguson, M.; Yamanaka, E.; Gordon
Am. J. Pathol.
1992, 141, 1139). In the case of restenosis following angioplasty, clinically relevant solutions for controlling SMC proliferation through pharmacological intervention have remained elusive to date (Herrman, J. P. R.; Hermans, W. R. M.; Vos, J.; Serruys P. W.
Drugs
1993, 4, 18 and 249). Any successful approach to selective SMC proliferation inhibition must not interfere with endothelial cell repair or the normal proliferation and function of other cells (Weissberg, P. L.; Grainger, D. J.; Shanahan C. M.; Metcalfe, J. C.
Cardiovascular Res.
1993, 27, 1191).
The glycosaminoglycans heparin and heparan sulfate are endogenous inhibitors of SMC proliferation, yet are able to promote endothelial cell growth (Castellot, J. J. Jr.; Wright, T. C.; Karnovsky, M. J.
Seminars in Thrombosis and Hemostasis
1987, 13, 489). However, the full clinical benefits of heparin, heparin fragments, chemically modified heparin, low molecular weight heparins, and other heparin mimicking anionic polysaccharides may be compromised due to other pharmacological liabilities (excessive bleeding arising from anticoagulation effects, in particular) coupled with heterogeneity of the various preparations (Borman, S.
Chemical and Engineering News,
Jun. 28, 27, 1993).
WO 96/14325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors. The compounds of the present invention differ in that (a) the carbohydrate moiety is maltotriose and (b) the substituents on the carbohydrate backbone are substantially different.
Zehavi, U., in
Carbohyd. Res.
1986, 151, 371, disclosed 4-carboxy-2-nitrobenzyl 4-O-&agr;-D-glucopyranosyl-&bgr;-D-glucopyranoside which is attached to a polymer for study as an acceptor in the glycogen synthase reaction. The compounds of the present invention differ in that (a) the carbohydrate moiety is maltotriose, (b) the substituents on the benzyl groups are different and (c) the use (smooth muscle antiproliferation) is different.
Patent numbers U.S. Pat. No. 5,498,775, WO96/14324, and U.S. Pat. No. 5,464,827 describe polyanionic benzylglycosides or cyclodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions which are characterized by excessive smooth muscle proliferation. &bgr;-cyclodextrin tetradecasulfate has been described as a smooth muscle cell proliferation inhibitor and as an effective inhibitor of restenosis (Reilly, C. F.; Fujita, T.; McFall, R. C.; Stabilito, I. I.; Wai-se E.; Johnson, R. G.
Drug Development Research
1993, 29, 137). U.S. Pat. No. 5,019,562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with undesirable cell or tissue growth. WO 93/09790 discloses antiproliferative polyanionic derivatives of cyclodextrins bearing at least 2 anionic residues per carbohydrate residues. Meinetsberger (EP 312087 A2 and EP 312086 A2) describes the antithrombotic and anticoagulant properties of sulfated bis-aldonic acid amides. U.S. Pat. No. 4,431,637 discloses polysulfated phenolic glycosides as modulators of the complement system. The compounds of the present invention differ from all of the prior art in that the compounds (a) are benzylmaltotriosides which bear no structural resemblance to heparin, sulfated cyclodextrins, or to sulfated lactobionic acid dimers, (b) contain no more than three contiguous sugar residues (trisaccharide) and (c) are of a defined structure.
DESCRIPTION OF THE INVENTION
This invention provides benzylmaltotriosides of formula I
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
, are each, independently, hydrogen, acyl of 2-7 carbon atoms, perfluoroacyl of 2-10 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, benzoyl, benzyl or —SO
3
M;
M is hydrogen, lithium, sodium, potassium or ammonium;
R
11
is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, nitrile, nitro, or alkoxy of 1-6 carbon atoms;
R
12
is hydrogen, nitro, amino, acylamino of 2-7 carbon atoms, perfluoroacylamino of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, perfluoroalkylamino of 1-6 carbon atoms, dialklylamino where each alkyl chain is independently 1-6 carbon atoms, perfluorodialklylamino where each alkyl chain is independently 1-6 carbon atoms alkylsulfonylamino of 1-6 carbon atoms, perfluoroalkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino of 6-10 carbon atoms or arylsulfonylamino substituted with halo of 6-10 carbon atoms;
or a pharmaceutically acceptable salt thereof.
Alkyl, alkoxy, alkylsulfonylamino, acylamino and acyl includes both straight chain as well as branched moieties optionally substituted with fluorine. Halogen means bromine, chlorine, fluorine, and iodine. Aryl is defined as a fully unsaturated carbocyclic radical containing one or more rings having 6-10 carbon atoms optionally substituted with fluorine; with phenyl and naphthyl radicals being preferred.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium. Acid addition salts can be prepared when the compound of formula I contains a basic nitrogen, and base addition salts can typically be prepared when the compound of formula I contains a hydroxyl group.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention are benzylmaltosides of formula I
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
, are each, independently, hydrogen, acyl of 2-7 carbon atoms, or —SO
3
M;
M is lithium, sodium, potassium or ammonium;
R
11
is halogen;
R
12
is nitro, amino, or acylamino of 2-7 carbon atoms;
or a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are benzylmaltosides of formula I
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
and R
10
, are each, independently, hydrogen, acetyl, or —SO
3
M;
M is lithium, sodium, potassium or ammonium;
R
11
is chloro;
R
12
is hydrogen, nitro, amino, or acetylamino;
or a pharmaceutically acceptable salt thereof.
Specifically preferred compounds of this invention are:
5-(Deca-O-acetyl-&bgr;-D-maltotriosyloxymethyl)-2-chloro-1-nitrobenzene or a pharmaceutically acceptable salt thereof;
N-[5-(Deca-O-acetyl-&bgr;-D-maltotriosyloxymethyl)-2-chloro-phenyl]-acetamide or a pharmaceutically acceptable salt thereof;
N-[5-(&
Maier Leigh
Nagy Michael
Wilson James O.
Wyeth
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