Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-04-14
2001-07-24
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S454000
Reexamination Certificate
active
06265572
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to pyrrolidinyl cyclic disulfide compounds which are useful therapeutic agents for the treatment of inflammatory diseases.
BACKGROUND OF THE INVENTION
Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated endothelium. The integrin VLA-4 (a
4
&bgr;
1
), is the principal receptor for VCAM-1. VLA-4 is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes. VCAM-1 also binds to a second integrin LPAM-1 (Peyer's patch adhesion molecule) with is expressed on B and T-cells. The integrin LPAM-1 can also bind with another cell adhesion molecule called mucosal addressing cell adhesion molecule (MadCAM). Binding of the integrins VLA-4 and LPAM-1 to cell adhesion molecules VCAM-1 or MadCAM normally allows the passage of macromolecules and circulating cells from blood to tissue. However, binding of integrins to cell adhesion molecules can result in undesirable inflammation wherein the above cell types infiltrate tissue and cause tissue damage.
Therefore, cell adhesion molecule/integrin antagonists which inhibit the binding of integrins to cell adhesion molecules are able to prevent undesirable inflammation. For example, such antagonists are needed to prevent tissue damage caused by inflammatory bowel disease, T-cell emigration in arthritis, eosinophil accumulation and bronchoconstriction in asthma, and prolongation of the survival time of tissue allografts.
SUMMARY OF THE INVENTION
In accordance with this invention, it has been discovered that compounds selected from the group consisting of cyclic disulfide compounds of the formula:
wherein R
2
and R
3
are each independently lower alkyl, or taken together with their attached carbon atom form an aliphatic carbocyclic ring containing 4 to 6 carbon atoms; R
5
is hydrogen, lower alkyl, R—SO
2
—, R
6
—(CH
2
)
m
—CO— or R
8
—X—(CH
2
)
y
—CO—; R is lower alkyl; R
6
and R
8
are hydrogen or lower alkyl; X is —O— or —NH—; m is an integer of from 1 to 7,
y is an integer of from 0 to 7, and n is an integer of from 1 to 3; with a, b,
c, and d denoting asymmetric carbon atoms; and hydrolyzable esters or ethers thereof.
The compounds of the present invention are effective anti-inflammatory agents. In accordance with the present invention, the cyclic disulfide compounds combat inflammation by inhibiting adhesion of &agr;4 integrin expressing cells to endothelium. The general mechanistic action of the cyclic disulfide compounds is the inhibition of binding of &agr;4 integrin expressing cells to cell adhesion molecules of the endothelium. This compounds may also inhibit local activation of such cells at the site of inflammation, such as in the lung. The compounds of the present invention are particularly useful for the treatment of inflammation such as inflammation associated with chronic inflammatory diseases which include pulmonary inflammation, asthma, rheumatoid arthritis, multiple sclerosis (MS), and inflammatory bowel disease (IBD).
DETAILED DESCRIPTION OF THE INVENTION
As used throughout this application, the term “lower alkyl” includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl and propyl, preferably methyl. As used herein, the term “lower alkoxy” comprehends a straight chain or branched-chain alkoxy group having from 1 to 7 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tertbutoxy and the like. As also used herein, the term “lower alkanoic acids” comprehends an alkanoic acid of 2 to 7 carbon atoms such as propionic acid and acetic acid. As further used herein, the term “halogen” or “halo”, unless otherwise stated, comprehends fluorine, chlorine, bromine and iodine.
The term “substituted lower alkyl” means a lower alkyl group substituted by one or more groups selected independently from hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and substituted amino. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 2,2,2,-trifluroethyl, cyanomethyl, and 2-nitropropyl.
The term “lower alkanoyl” or “acyl” denotes a radical derived from an aliphatic carboxylic acid of 2 to 7 carbon atoms, for example, acetyl, propionyl and the like. The term “acyl” besides meaning “lower alkanoyl” also includes aroyl such as benzoyl.
As also used herein, the term “aryl” signifies mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc., which can be unsubstituted or substituted in one or more positions with a lower alkylenedioxy, a halogen, a nitro, a lower alkyl or a lower alkoxy substituent, and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, azulyl, etc., which can be substituted with one or more of the aforementioned groups. The preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term “aralkyl” denotes an alkyl group, where alkyl is lower alkyl, in which one of the hydrogen atoms has been replaced by an aryl group, examples of aralkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chloro-benzyl, 4-methoxybenzyl and the like.
As used herein, the term “hydrolyzable ester or ether group” designates any ester or ether which can be hydrolyzed to yield a hydroxyl group and/or a carboxyl group. Exemplary ester groups useful for this purpose are those in which the acyl moiety is derived from a lower alkanoic, an aryl lower alkanoic, or a lower alkane dicarboxylic acid. Among the activated acids which can be utilized to form such ester groups are the acid anhydrides and the acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Examples of anhydrides include acetic anhydride, caproic anhydride, benzoic acid anhydrides, lower alkane dicarboxylic acid anhydrides, e.g., succinic anhydride. In addition, hydrolyzable esters can be formed from chloroformates, e.g., trichloroethylchloroformate.
A suitable ether protecting group is, for example, the tetrahydropyranyl ether or 4-methoxy-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers such as benzyl, benzhydryl, or trityl ethers or &agr;-lower alkoxy lower alkyl ether, for example, methoxymethyl or allylic ethers, or alkyl silyl ethers such as trimethyl silyl ether
Alternatively, the term “hydrolyzable ester group” designates an ester which can be hydrolyzed to yield a carboxyl group. Typically, the alkoxyl moiety is derived from a lower alkanol or substituted lower alkanol. Among the alkanols which can be utilized to form such ester groups are substituted or unsubstituted primary, secondary and tertiary alkanols, such as ethanol, methanol, iso-propanol, tert-butanol and 2-(dimethyl amino)ethanol.
The term “thio protecting group” designates any group which can be cleaved to yield a free thio group. Among the preferred thio protecting groups are tri-arylmethane, tri-alkylmethane, aralkyl groups such as benzyl. Preferred acyl groups are lower alkanoyl and aroyl, particularly, benzoyl. Generally, it is preferred to utilize an acid cleavable thio protecting group for example a tri-aryl methyl group such as a trityl group being especially preferred.
The term “amino protecting group” designates any group which can be cleaved to yield a free amino group. The amino protecting group can be any conventional amino protecting group utilized in peptide synthesis. Generally, preferred amino protecting groups are those which are cleavable under mildly acidic conditions of from about pH 2.0 to 3.0. Particularly, preferred amino protecting groups are tertiary lower alkyl, lower alkyl and tri-lower alkyl methyl groups.
The term “pharmaceutically acceptable salts” is used to include salts with both inorganic and organic pharmaceutically acceptable salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para toluene sulfonic a
Chen Li
Fotouhi Nader
Jackson David Young
Tilley Jefferson Wright
Epstein William H.
Hoffmann-La Roche Inc.
Johnston George W.
Kifle Bruck
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