Method of treating disorders related to protease-activated...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S415000

Reexamination Certificate

active

06387942

ABSTRACT:

BACKGROUND OF THE INVENTION
Thrombin, a coagulation protease, activates G protein-coupled protease-activated receptors (PARs) which in turn induce cell activation such as platelet aggregation and proliferation of vascular smooth vessel cells. See Coughlin, Proc. Natl. Acad. Sci. USA, 1999, 96: 11023-11027. Aggregation of the activated platelets contributes to pathogenesis of many diseases, e.g., atherosclerosis, myocardial infarction, unstable angina pectoris, and thrombosis. It is therefore desirable to discover a drug which can treat such diseases by specifically inhibiting the activation of PARs, e.g., by means of inhibiting thrombin.
SUMMARY OF THE INVENTION
This invention relates to a method of treating a disorder related to PAR-induced platelet aggregation. The method includes administering to a subject -n need thereof a compound having a pyrazolyl core and three aryl groups: (1) a first aryl group, via an alkylene linker, bonded to 1-N of the pyrazolyl core, (2) a second aryl group fused at 4-C and 5-C of the pyrazolyl core, and (3) a third aryl group bonded directly to 3-C of the pyrazolyl core. Each of these three aryl groups, independently, is phenyl, thienyl, furyl, or pyrrolyl, which is optionally mono-substituted or multi-substituted with halo (e.g., —Cl), alkyl (e.g., —C
5
H
11
), carboxyl, alkoxycarbonyl [e.g., —(C═O)—O—C
5
H
11
], thiocarbonyl [e.g., —(C═O)—S—C
4
H
9
], aminocarbonyl [e.g., —(C═O)—N(C
3
H
7
)
2
], hydroxyalkyl (e.g., —C
6
H
12
OH), alkoxyalkyl (e.g., —C
3
H
6
—O—
i
C
4
H
9
), amino, aminoalkyl [e.g., —C
3
H
6
N(C
3
H
7
)
2
], thioalkyl (e.g., —C
4
H
8
SC
4
H
9
), or oxyalkoxy (e.g., —OCH
2
CH
2
O— as a disubstituent). The compound is administered to the subject in an amount effective for treating the disorder,
Shown below is a formula which encompasses a number of the fused pyrazolyl compounds described above:
Formula (I) includes a pyrazolyl core and three aryl groups, i.e., Ar
1
, Ar
2
, and Ar
3
, as the three aryl groups described above. Each of Ar
1
, Ar
2
, and Ar
3
, independently, is phenyl, thienyl, furyl, or pyrrolyl; each of R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
, independently, is H, halo, —R, —C(═O)OH, —C(═O)OR, —C(═O)SH, —C(═O)SR, —C(═O)NRR′, —ROH, —ROR′, —RSH, —OR, —OH, —SR, —SH, —NRR′, —NHR, —RNR′R″, —RNHR′, or —RSR′, or R
1
and R
2
together, R
3
and R
4
together, or R
5
and R
6
together, are —ORO—, wherein each of R, R′, and R″, independently, is C
1-4
alkyl; and n is 1, or 2, or 3.
A subset of the compounds of formula (I) are featured by that n is 1, Ar
3
is phenyl, and each of R
5
and R
6
, independently, is H, halo, —R, —C(═O)OH, —C(═O)OR, —C(═O)SH, —C(═O)SR, —C(═O)NRR′, —ROH, —ROR′, —RSH, —NRR′, —NHR, —RNR′R″, —RNHR′, or —RSR′, or R
5
and R
6
together are —ORO—.
Another subset of the compounds of formula (I) are featured by that n is 1, Ar
3
is furyl, and each of R
5
and R
6
, independently, is H, halo, —R, —C(═O)OH, —C(═O)OR, —C(═O)SH, —C(═O)SR, —C(═O)NRR′, —ROH, —ROR′, —RSH, —NRR′, —NHR, —RNR′R″, —RNHR′, or —RSR′, or R
5
and R
6
together are —ORO—.
Set forth below are some specific examples of the compounds which can be used to practice the method of this invention: 1-benzyl-3-(3′-ethoxycarbonyl)phenyl-indazole, 1-benzyl-3-(3′-hydroxymethyl)phenyl-indazole, 1-benzyl-3-(5′-diethylaminomethyl)-furyl-indazole, 1-benzyl-3-(5′-methoxymethyl)furyl-indazole, 1-benzyl-3-(5′-hydroxymethyl)furyl-6-methyl-indazole, 1-benzyl-3-(5′-hydroxymethyl)-furyl-indazole, 1-benzyl-3-(5′-hydroxymethyl)-furyl-6-fluoro-indazole, 1-benzyl-3-(5′-hydroxymethyl)-furyl-6-methoxy-indazole, and 1-benzyl-3-(5′-hydroxymethyl)-furyl-5, 6-methylenedioxo-indazole.
The structures of 1-benzyl-3-(3′-ethoxycarbonyl)phenyl-indazole and 1-benzyl-3-(5′-diethylaminomethyl)-furyl-indazole are shown below with the atoms on the aryl groups numbered:
For brevity, the fused pyrazolyl compounds described above include their pharmaceutically acceptable salts and prodrugs, if applicable. Such a salt can be formed between a positively charged substituent (e.g., amino) in a fused pyrazolyl compound and a negatively charged counterion (e.g., chloride, bromide, iodide, sulfate, nitrate, phosphate, or acetate). Likewise, a negatively charged substituent (e.g., carboxylate) in a fused pyrazolyl compound can form a salt with a positively charged ion (e.g., sodium ion, potassium ion, magnesium ion, calcium ion, or an ammonium cation such as tetramethylammonium ion). Examples of the salts that can be used in the method of this invention include a hydrochloride salt of 1-benzyl-3-(5′-aminomethyl)furyl-indazole and a sodium salt of 1-benzyl-3-(3′-carboxyl)phenyl-indazole. Examples of the prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing fused pyrazolyl compounds described above.
A fused pyrazolyl compound is formulated into a pharmaceutical composition before it is administered to a subject in need of treatment of a disorder related to PAR-induced cell activation (e.g., atherosclerosis, myocardial infarction, unstable angina pectoris and thrombosis). Thus, also within the scope of the invention is the composition which contains an effective amount of the compound (or its salt) and a pharmaceutically acceptable carrier for use in treating a disorder or disease aforementioned. Examples of the carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow# 10. The invention also relates to the use of such a composition for the manufacture of a medicament for the treatment of above-mentioned disorders or diseases.
It was unexpected that the method of this invention specifically inhibits PAR-induced cell activation, e.g., platelet aggregation, with no or little inhibitory effect on that induced by other platelet activators. Other advantages or features of the invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to using a fused pyrazolyl compound to treat a disorder caused by PAR-induced cell activation.
A method of synthesizing the fused pyrazolyl compound is as follows: An aryl aryl ketone is first prepared by coupling an arylcarbonyl chloride with another aryl compound. Each aryl compound is optionally mono- or multi-substituted. The ketone then reacts with an arylalkylhydrazine, the aryl group of which is also optionally mono- or multi-substituted, to form a hydrazone containing three aryl groups. The hydrazone is transformed into a fused pyrazolyl compound. In the fused pyrazolyl compound, an aryl group is connected to 1-N of the pyrazolyl core via an alkylene linker, another aryl group is fused at 4-C and 5-C of the pyrazolyl core, and the third aryl group is directly connected to 3-C of the pyrazolyl core. Derivatives of the fused pyrazolyl compound may be obtained by modifying the substituents on any of the aryl groups.
Synthesis of three types of fused pyrazolyl compounds, i.e., 1-benzyl-3-furyl-indazole, 1-benzyl-3-phenyl-indazole, and thienylpyrazole.
Shown in Scheme 1 below is a method of synthesizing five 1-benzyl-3-furyl-indazole compounds, indicated as (1)-(5), all of which can be used to practice the method of the invention.
As shown in Scheme 1,5′-methoxycarbonyl-2-furyl phenyl ketone, prepared by coupling methyl 2-furoate with benzoyl chloride, reacts with benzylhydrazine to form a benzylhydrazone as a mixture of E- and Z-form isomers. The isoform mixture is then treated with a mixture of Pb(OAc)
4
and BF
3
/Et
2
O in CH
2
Cl
2
at room temperature, via a same azo intermediate, to give compound (1). The methoxycarbonyl group in compou

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