Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-30
2001-04-10
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S419000, C548S490000, C548S491000
Reexamination Certificate
active
06214856
ABSTRACT:
SUMMARY OF THE INVENTION
This invention relates to novel chemical compounds which are indolecarboxamides. The claimed pharmaceutical compositions and methods use those compounds as active ingredients to inhibit calpain and thus are useful in the treatment of, for example, neurodegenerative disorders, strokes and traumatic brain injury.
BACKGROUND OF THE INVENTION
Calpains are calcium—dependent cysteine proteases present in a variety of tissues and cells. Excessive activation of calpain provides a molecular link between ischaemia or injury induced by increases in intraneuronal calcium and pathological neuronal degeneration. If the elevated calcium levels are left uncontrolled, serious structural damage to neurons may result. Recent research has suggested that calpain activation may represent a final common pathway in many types of brain damage. Selective inhibition of calpain would, therefore, be an attractive therapeutic approach in the treatment of neurodegenerative diseases. Exemplary of these diseases would be myocardial ischaemia, cerebral ischaemia, muscular dystrophy, stroke, Alzheimer's disease, or traumatic brain injury. The compounds of this invention may also be useful in the treatment of cataracts and platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
The compounds which are the active ingredients of the pharmaceutical compositions and methods of this invention are represented by the following formula:
in which:
R
1
is CH
2
Ph, CH
2
CH(CH
3
)
2
, or CH
2
CH
2
CH
2
CH
2
NR
6
,R
7
;
Z is CHO, COCH
2
F, COCOOH, COCONH-alkyl, COCOO-alkyl, COCO(CH
2
)
n
-aryl, COCONHCH(R
1
)COOH, or COCH
2
O-(3-phenylisoxazol-5-yl);
n=1-6;
R
2
is H, CH
3
, CH
2
Ph, CH
2
-pyridine, CH
3
SO
2
, CF
3
SO
2
, or PhSO
2
;
R
3
is H, CH
3
, or lower alkyl;
R
4
and R
5
are independently H, halo, lower alkyl, lower alkoxy, or benzyloxy;
R
6
is COOCH
2
Ph, COOCH
2
-pyridine, CO-aryl, SO
2
CH
3
, SO
2
CF
3
, SO
2
-aryl, H, or lower alkyl; and
R
7
is H, or lower alkyl, provided that when Z is CHO and R
3
is other than H, then R
2
is not H, or a pharmaceutically acceptable salt thereof.
Preferred compounds are those where the sterochemistry at the R
1
group corresponds to that of the naturally occurring amino acids. Also preferred are those compounds where R
1
is CH
2
Ph and Z is CHO.
The following preferred compounds are representative of the compounds of the invention:
(S)-N-(1-formyl-2-phenylethyl)1-methyl-2-indolecarboxamide;
(S)-N-(1-formyl-2-phenylethyl)-2-indolecaboxamide;
(S)-N-(1-formyl-2-phenylethyl)-5-methoxy-6-(phenylmethoxy)-2-indolecarboxamide;
(S)-5-bromo-N-(1-formyl-2-phenylethyl)-2-indolecarboxamide;
(S)-N-(1-formyl-2-phenylethyl)-1-(methylsulfonyl)-2-indolecarboxamide;
(S)-N-(1-formyl-2-phenylethyl)-1-phenylmethyl)-2-indolecarboxamide;
(S)-N-(1-formyl-2-phenylethyl)-6-methoxy-2-indolecarboxamide; and
(S)-N-(1-formyl-2-phenylethyl)-3-methyl-1-(phenylmethyl)-2-indolecarboxamide.
Compounds of Formula I are prepared by the methods illustrated in Schemes 1 and 2.
The indole-2-carboxylic acids 1 (Scheme 1), whether prepared or commercially obtained, are converted to the amide alcohols 2 by standard coupling conditions (e.g., (S)-(−)-2-amino-3-phenylpropanol, 1-hydroxybenzotriazole hydrate (HOBT), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), N-methylmorpholine (NMM), methylene chloride). Oxidation of 2 (the Dess-Martin reagent in methylene chloride is preferred, but not limiting) affords the aldehydes 3. This procedure can be repeated with a wide variety of substituted indole-2-carboxylic acids and with a wide variety of amino alcohol derivatives to obtain compounds with varying R
1
substituents.
Compounds of Formula I wherein the indole carboxylic acid is not commercially available are prepared by the method described in Scheme 2.
The commercially available indole esters 4 are treated with a base such as NaH to form the indole anion. This is then reacted with either an alkylating agent such as, but not limited to, benzyl bromide or a sulfonylating agent such as, but not limited to, methanesulfonyl chloride to provide the N-protected compounds 5. The ester is then hydrolyzed under standard conditions using NaOH to provide the desired indole 2-carboxylic acids 1. The acids 1 are then converted to the desired final compounds according to Scheme 1. For the cases where the indole ester 5 is commercially available, these compounds are converted directly to the acids 1 as described above.
Although these methods illustrate the preparation of compounds for which Z is CHO, alternative “enzyme reactive groups” can be substituted as has been extensively described in the literature (
J. Med. Chem.,
1994, 37, 2918-2929;
J. Med. Chem.,
1993, 36, 3472-3480;
J. Med. Chem.,
1990, 33, 11-13;
Biochem. J.,
1986, 239, 633-640;
J. Med. Chem.,
1992, 35, 216-220). In addition, these methods are not intended to limit the scope of the possible R
1
groups which can be readily derived from any amino alcohol or amino acid by methods well known in the art.
Also included in the scope of the present invention are pharmaceutically acceptable salts of the compounds of Formula I. Preferred salts include, but are not limited to, hydrochloride, hydrobromide, citrate, tartrate, malate, maleate, lactate, gluctose 1,6-diphosphate, phosphate, succinate, sulfate, aspartate, adipate, methanesulfonate, lauryl sulfate, diguaiacyl phosphate, diacetyl sulfate, glutamate, edetate, ethylene diamine, sodium, potassium, calcium and ethanolamine salts. Such salts are prepared according to standard procedures well known in the art.
The pharmaceutical activity of the compounds of this invention is demonstrated by inhibition of calpain in vitro by the assay procedure described by Sasaki et al.,
J. Biol. Chem.
1984, 259, 12489-12494. The assays were performed using synthetic fluorogenic substrates. Inhibition of enzyme activity was calculated on the percent decrease in the rate of substrate hydrolysis in the presence of inhibitor relative to the rate in its absence. IC
50s
(nM) were calculated. Table 1 demonstrates the results of testing representative compounds of Formula I.
TABLE 1
R
1
Z
R
2
R
3
R
4
R
5
IC
50
(nM)
Ph
CHO
CH
3
H
H
H
500
Ph
CHO
H
H
H
H
600
Ph
CHO
H
H
CH
3
O
PhCH
2
O
135
Ph
CHO
H
H
Br
H
230
Ph
CHO
CH
3
SO
2
H
H
H
600
Ph
CHO
PhCH
2
H
H
H
500
Ph
CHO
H
H
H
CH
3
O
600
Ph
CHO
PhCH
2
CH
3
H
H
30
The above results clearly indicate that all compounds tested exhibited significant inhibition of calpain.
The pharmaceutical compositions of this invention employed to inhibit calpain comprise a pharmaceutical carrier and as the active ingredient a compound of Formula I. The active ingredient will be present in the compositions of this invention in an effective amount to inhibit calpain. Preferably, the compositions contain the active ingredient of Formula I in an amount of from about 0.1 mg to about 250 mg, advantageously from about 25 mg to about 150 mg per dosage unit.
The pharmaceutical carrier may be, for example, a solid or liquid. Exemplary of solid carriers are lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar or acacia. Exemplary of liquid carriers are syrups, peanut oil, olive oil, propylene glycol, polyethylene glycol and water.
A wide variety of pharmaceutical forms may be employed. Thus, if a solid carrier is used, the preparation can be tabletted or placed in a hard gelatin capsule. If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, placed in an ampule, a liquid suspension, syrup or suspension.
Preferably, parenteral solutions or suspensions are employed. They comprise the active compound in a sterile aqueous or oil carrier such as, for example, peanut oil, polyethylene glycol or polyvinyl pyrolidone. Preferably, such solutions contain the active compound in the range of 0.1 to 140 mg/kg of body weight of the patient to whom it will be administered. The sterile parenteral solutions may also contain additives such as, for example, preservatives such as benzyl alcohol and buffering agents
Daines Robert A
Sham Kelvin Kin-Cheong
Henderson Loretta J.
Jones Dwayne C.
Kerekes Zoltan
SmithKline Beecham Corporation
Venetianer Stephen
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