Silanol enzyme inhibitors

Details Silanol enzyme inhibitors Silanol enzyme inhibitors

1998-12-17

2002-08-27

Low, Christopher S. F. (Department: 1653)

Organic compounds -- part of the class 532-570 series

Organic compounds

Silicon containing

56, 56, 56, 56, 56, 56, C562S553000, C514S063000

Reexamination Certificate

active

06441212

ABSTRACT:

BACKGROUND OF THE INVENTION
Protease enzymes mediate many biological processes, e.g., by editing a polypeptide to a shorter, active form, or by terminating biological activity through degradation of an active polypeptide. Other protease enzymes are concerned with tissue remodeling.
Proteases hydrolyze the amide backbone of polypeptides and during this hydrolysis, a tetrahedral intermediate is formed as part of the enzyme substrate complex. Some analogs of the tetrahedral intermediate can inhibit protease enzymes. Elements other than carbon, specifically, phosphorous and boron, have been used to prepare transition state analogs. Phosphorous: Kam, C. -M.; Nishino, N.; Powers, J. C., “Inhibition of Thermolysin and Carboxypeptidase A by Phosphoramidates”, Biochemistry 18, 3032-3038 (1979). Boron: Amiri, P.; Lindquist, R. N.; Matteson, D. S.; Sadhu, K. M. “Benzamidomethaneboronic Acid: Synthesis and Inhibition of Chymmotrypsin”, Arch. Biochem. Biophys. 234, 531-536 (1984). There has been only one attempt, however, to utilize silanols in transition state analogs because silanediols have a strong proclivity to self condense and form siloxanes or silicones. The simplest silanediol, dimethylsilanediol, was tested as an inhibitor of angiotensin-converting enzyme and found to be inactive. Galardy, R. E.; Kortylewicz, Z. P. “Inhibitors of angiotensin-converting enzyme containing a tetrahedral arsenic atom”, Biochem. J. 226, 447-454 (1985). In addition, known silanediols are virtually all dialkyl or diaryl homologues. Lickiss, P. D., “The Synthesis and Structure of Organosilanols”, Adv. Inorg. Chem. 42, 147-262 (1995). Therefore, organic silanols have been absent from the field of protease inhibition.
It is an object of the invention to provide silicon—containing enzyme inhibitors.
It is a further object of the invention to provide silanols and silanediols and their siloxane oligomers as bioactive molecules, particularly as inhibitors of hydrolase enzymes.
It is a still further object of the invention to provide a process for the synthesis of silanol and silanediol—based peptide mimics as well as their siloxane oligomers.
It is yet another object to provide a method for inhibiting proteases using silicon-containing peptide analogs.
SUMMARY OF THE INVENTION
The silicon—containing compounds of the invention are represented by formula I, formula II or formula III.
wherein X is OH;
Y is OH, H, lower alkyl of one to six carbons with said alkyl preferably methyl, or F;
Z and Z′ are independently H, lower alkyl with said alkyl preferably methyl or ethyl, or Q
3
Si where Q is lower alkyl with said alkyl preferably methyl or ethyl, or Q is aryl of four to ten carbons with said aryl preferably containing phenyl;
n is preferably 3-50, more preferably 3-10, most preferably 3-5;
n′ is preferably 2-50, more preferably 2-10, most preferably 2-5;
A and B are independently
a) alkyl of one to ten carbons or heteroatoms, preferably three to ten carbons or heteroatoms and said alkyl can be further substituted with aryl;
b) aryl of four to ten carbons or heteroatoms and said aryl can be further substituted with inorganic or organic groups as described below;
c) cyclic of three to ten carbons or heteroatoms;
 in d, e, and f, CH is bonded to silicon;
R
1
-R
11
groups are each independently hydrogen, alkyl of one to ten carbons or heteroatoms, aryl of four to fourteen carbons or heteroatoms, arylalkyl of five to twenty carbons or heteroatoms; substituted carbonyl or unsubstituted carbonyl.
Heteroatoms are nitrogen, oxygen, silicon or sulfur.
R
3
, R
4
, R
6
, R
7
, R
10
and R
11
independently can be one or more naturally-occurring amino acids, e.g., alanine, asparagine, aspartic acid, cysteine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, serine, threonine, valine, tryptophan and tyrosine. Derivatives of these amino acids, as are known in the art, can also be used.
At least one of A or B, or both A and B, are d), e), or f).
By “independently” is meant that within formulas I-III, all moieties for the variables such as A, B, R
1
to R
11
, Z and Z′ need not be the same for each variable but may be different moieties within the same compound.
It will also be understood that the compounds have a stable configuration, so that, for example, a destabilizing excess of heteroatoms is not present, and sufficient hydrogens are present to form a stable molecule.
The alkyl groups for A or B may be branched or unbranched and are typically methyl, ethyl, n-butyl, n-propyl, iso-propyl, iso-butyl, iso-pentyl, neo-pentyl, 1-pentyl, 2-pentyl, 3-pentyl, cyclopropylmethyl, and the alkyl groups can be substituted, e.g., with aryl, such as 3-phenyl-1-propyl. The aryl groups for A or B are typically phenyl, phenylmethyl, 1-phenylethyl, 2-phenylethyl, but may also be any other aryl group, for example, pyrrolyl, furanyl, thiophenyl, pyridyl, thiazoyl, imidazoyl, oxazoyl, pyrazinoyl, etc., as well as aryl groups with two or more rings, for example, naphthalenyl, quinolinoyl, isoquinolinoyl, benzothiazoyl, benzofuranyl, etc. The aryl group may also be substituted by an inorganic, alkyl or other aryl group. The cyclic groups for A or B are typically cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl or cycloheptyl.
The alkyl groups for R
1
to R
11
may be branched or unbranched and contain one to ten members including carbon atoms and optional heteroatoms, preferably three to six members including carbon atoms and optional heteroatoms. Some examples of the alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, heptyl, octyl, nonyl and decyl. The alkyl groups may, in whole or in part, be in the form of rings such as cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, pyrrolindinyl, oxazolindinyl, isoxazolidinyl, etc.
Aryl groups for R
1
-R
11
typically include phenyl, but may also be any other aryl group, for example, pyrrolyl, furanyl, thiophenyl, pyridyl, thiazoyl, imidazoyl, oxazoyl, pyrazinoyl, etc., as well as aryl groups with two or more rings, for example, naphthalenyl, quinolinoyl, isoquinolinoyl, benzothiazoyl, benzofuranyl, etc. The aryl group may also be substituted by an inorganic, alkyl or other aryl group.
The arylalkyl groups for R
1
-R
11
may be any combination of the alkyl and aryl groups described above. These groups may be further substituted. Carbonyl groups for R
1
-R
11
can also be substituted, e.g., with alkyl, aryl, or substitute heteroatoms including oxygen, nitrogen and sulfur.
Alkyl, aryl and cyclic groups in all cases (A, B, R, Z and Z′) can contain one or more double or triple bonds; and/or their hydrogens may be substituted for by inorganic groups such as amino, thio, halo, doubly bonded oxygen (carbonyl) or singly bonded oxygen (hydroxy) or may be substituted for by organic groups such as alkyl, alkenyl or aryl as described herein.
The compounds are stable and can be stored for weeks or longer at room temperature without noticeable decomposition in either solid or solution form. In addition, there is no intrinsic toxicity associated with silicon (Friedberg, K. D. and Schiller, E., Handbook on Toxicity of Inorganic Compounds, Eds. Seiler H. G., and Sigel, H.; Marcel Dekker, New York, 1988, pp. 595-617).
A process is also provided for preparing the compounds of formulas I-III. Preparation of the compounds will generally require a protecting group for the silanol or silanediol that will avoid self condensation. The protecting group must be stable and yet readily removed. Synthesis of the protected silanediol involves formation of silicon—carbon bonds using one or more types of reactions such as those which are described below, followed by deprotection to yield a silanol or silanediol through a reaction generally involving hydrolysis.
The compounds of the invention exhibit pharmaceutical activity and are therefore useful as pharmaceuticals. The compounds of

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