Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-22
2003-12-16
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C514S025000, C514S042000, C536S001110, C536S004100, C536S017200, C536S017900, C536S029100, C536S053000, C536S054000, C536S116000, C536S118000, C536S123130, C536S018700
Reexamination Certificate
active
06664243
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of substituted benzyllactobionamides 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 anticoaguiation effects, in particular) coupled with heterogeneity of the various preparations (Borman, S.
Chemical and Engineering News
, Jun. 28, 27, 1993).
U.S. Pat. Nos. 5,296,588, 5,336,765, and EP 550106A1 describe an improved process of preparing N-substituted aldonamides. U.S. Pat. No. 5,310,542 and EP 551675-A1 also describe glycosides (specifically aldobionamides) being used in oral hygiene compositions to act as antimicrobial agents and inhibit formation and/or growth of bacteria responsible for dental plaque. U.S. Pat. No. 2,752,334 describes a process of preparing N-substituted lactobionamides and their use as emulsifying agents (specially for cheese) and antimycotic agents. The compounds of the present invention differ in that the compounds of this invention (a) are acetylated or sulfated benzyllactobionamides, (b) have substituents on the aromatic core that are different, and (c) are being used as smooth muscle cell antiproliferatives.
EP 312086 A2 and EP 312087 A2 describe polysulfate ester(s) of bis-aldonic acid amide derivatives as antiinflammatory and antithrombotic agents. The compounds of the present invention differ in that the compounds (a) are being used as smooth muscle cell antiproliferatives, (b) are not dimeric in nature, and (c) contain no more than two contiguous sugar residues (disaccharide).
(Klein, U.; Mohrs, K.; Wild, H.; Steglich, W.
Liebigs Ann. Chem.
1987, 485-489.) describes the use of peracetylated aldonamides to prepare 3-substituted pyrazoles. The compounds of the present invention differ in that the compounds (a) have substituents on the aromatic core that are different, (b) are not substituted at the benzylic position, (c) are being used as smooth muscle cell antiproliferatives, and (d) are not used as precursors to pyrazoles.
U.S. Pat. No. 5,498,775, WO 96/14324, and U.S. Pat. No. 5,464,827 describe polyanionic benzylglycosides or cylcodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions that 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-si 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 benzyllactobionamides which bear no structural resemblance to heparin or sulfated cyclodextrins, (b) are compounds which are not dimeric in nature, (c) contain no more than two contiguous sugar residues (disaccharide), and (d) are of defined structure.
WO 9614325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors. The compounds of the present invention differ in that (a) the saccharide backbone is different, (b) the open chain core has preparation advantages over the cyclic array, and (c) the substituents on the carbohydrate backbone are different.
(Zehavi, U.; Herchman, M.
Carbohyd. Res.
1986, 151, 371) discloses 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 from those of the Zehavi disclosure in that (a) the substituents on the benzyl groups are different and (b) the use (smooth muscle antiproliferation) is different.
DESCRIPTION OF THE INVENTION
This invention provides benzyllactobionamides of formula I
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
are each, independently, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl, or —SO
3
H;
R
9
is hydrogen, CN, NO
2
, halo, CF
3
, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
R
10
is hydrogen, —NO
2
, —NHR
11
, —NHR
13
, —N(R
13
)
2
, —NCH
3
R
13
, —NHCO
2
alkyl, wherein the alkyl moiety contains 1-6 carbon atoms, alkylsulfonamide of 1 to 4 carbon atoms,
Z is O or S;
R
11
is an &agr;-amino acid in which the &agr; carboxyl group forms an amide with the nitrogen of R
10
, wherein if said amino acid is glutamic acid or aspartic acid, the non-&agr; carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms;
R
12
is hydrogen, CN, NO
2
, halo, CF
3
, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or benzoyl;
R
13
is hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl;
or a pharmaceutically acceptable salt thereof.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. When R
11
is an &agr;-amino acid, the carboxyl moiety exists as an amide with the amide nitrogen being bonded to the phenyl ring of the compound of formula I. The following exemplifies the resulting structure when R
11
is alanine:
When the amino acid contains a second carboxyl moiety, the moiety is an alkyl ester of the free acid. The following example shows aspartic acid methyl ester.
Preferred amino acids include alanine, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. The amino acids defined by R
11
include both the D and L amino acids.
Pharmaceutic
Fonda Kathleen K.
Nagy Michael R.
Wyeth
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