Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-22
2002-01-15
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S053000, C536S029100, C536S029110, C536S029130
Reexamination Certificate
active
06339064
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of substituted benzylglycosylamides 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,
1993, Jun. 28, 27).
WO 96/14325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors. The compounds of the present invention differ in that (a) the carbohydrate posesses an anomeric amide, (b) the substituents on the carbohydrate backbone are substantually different and, (c) the activity against smooth muscle cell proliferation is greater.
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 posesses an anomeric amide, (b) the substituents on the benzyl groups are different and (c) the use (smooth muscle antiproliferation) is different.
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.
Drag 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 benzylglycosylamides which bear no structural resemblance to heparin, sulfated cyclodextrins, or to sulfated lactobionic acid dimers, (b) contain no more than two contiguous sugar residues (disaccharide), (c) are of a defined structure, (d) and are not sulfated.
DESCRIPTION OF THE INVENTION
This invention provides benzylglycosylamides of formula I
wherein
Y is C or N;
where n is 0-3;
X is
R
1
, and R
2
are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF
3
, CN, OH, NO
2
, NH
2
, alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms;
R
3
is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms;
R
4
, R
5
, R
6
, R
7
, and R
8
are each, independently, acyl of 1 to 6 carbon atoms, benzyl substituted with R
1
, and R
2
; or benzoyl substituted with R
1
and R
2
;
R
9
and R
10
are each, independently, acyl of 1 to 6 carbon atoms, or the R
9
and R
10
groups on the 4′ and 6′ positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R
1
, phenyl substituted with R
1
, benzyl substituted with R
1
, 2-phenylethyl substituted with R
1
, or 3-phenylpropyl substituted with R
1
;
with the provisio that when R
1
or R
2
are cyanoalkoxy of 2-7 carbon atoms, R
3
is not acylamide, and further provided that when R
1
, R
2
, or R
3
are alkoxy of 1-6 carbon atoms, at least one of R
1
, R
2
, R
3
, or R
4
are not hydrogen;
or a pharmaceutically acceptable salt thereof.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. When Y is nitrogen, it is preferred that the pyridine carboxamide is pyridine 3-carboxamide.
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 Y is nitrogen or 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 formula I of this invention are those in which
n is 0-1;
R
1
, and R
2
are each independently, hydrogen, halogen, CF
3
, OH, NO
2
, NH
2
, methoxy, butoxy, or butoxynitrile;
R
3
is hydrogen, acetamide, or methoxy;
R
4
, R
5
, R
6
, R
7
, and R
8
are each, independently, hydrogen, an acyl of 1-6 carbon atoms, or benzoyl;
R
9
and R
10
are each, independently, acyl of 1-6 carbon atoms, or the R
9
and R
10
groups on the 4′ and 6′ positions of the maltose are taken together form a benzylidene ring;
or a pharmaceutically acceptable salt thereof, with all other substituents as defined above.
More preferred compounds of formula I are those in which
n is 0;
R
1
, and R
2
are each independently, hydrogen or halogen;
R
3
is hydrogen;
R
4
, R
5
, R
6
, R
7
, and R
8
are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, or benzoyl;
R
9
and R
Adebayo Folake O.
McDevitt Robert E.
American Home Products Corporation
Fonda Kathleen K.
Maier Leigh C.
Nagy Michael R.
LandOfFree
Benzylglycosylamides as inhibitors of smooth muscle cell... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzylglycosylamides as inhibitors of smooth muscle cell..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzylglycosylamides as inhibitors of smooth muscle cell... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2846584