K-252 derivatives which enhance neurotrophin-induced activity
AssigneesCephalon, Inc., Kyowa Hakko Kogyo Co., Ltd.
InventorsMarcie A. Glicksman, Robert L. Hudkins, David P. Rotella, Nicola T. Neff, Chikara Murakata
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Abstract
Disclosed are derivatives of the indolocarbazole alkaloid K-252a of the Formulae I-VI, useful for enhancing neurotrophin-induced activity of neurotrophin responsive cells. A particularly preferred neurotrophin is NT-3, and a particularly preferred neurotrophin responsive cell is one which comprises a trk receptor. The enhanced neurotrophin-induced activity occasioned by the disclosed K-252a derivatives may be determined by the following assays: ChAT activity; DRG neuronal survival; or cell division (mitogenesis).
Claims9
A method for enhancing a neurotrophin-induced activity of a neurotrophin responsive cell, said method comprising contacting said cell with a K-252a derivative of the formula:
- ##STR11## wherein:
- a) Z.sup.1 and Z.sup.2 together represent O;
- each R.sup.1, R.sup.2, R.sup.5, and R.sup.6 independently is H, F, Cl, Br, I, NO.sub.2, CN, alkyl of 1-6 carbons or NR.sup.13 R.sup.14 independently is H or n-alkyl of 1-6 carbons;
- Y is H, OH, NH.sub.2, n-alkyl of 1-6 carbons, CHO, OCONH.sub.2 benzyl,
- O-n-alkyl of 1-6 carbons, (CH.sub.2).sub.n OH or (CH.sub.2).sub.n NH.sub.2 where n is an integer of 1-6;
- then either
- 1) R is OH, OCONH.sub.2, or O-n-alkyl of 1-6 carbons;
- and
- X is CH.sub.2 OH, CH.sub.2 NH.sub.2, (or an acid salt thereof;) CH.sub.2 O-n-alkyl of 2-7 carbons CO.sub.2 R.sup.7 where R.sup.7 is H or alkyl of 1-6 carbons, CONHOR.sup.8, CONH(CH.sub.2).sub.n OR.sup.8 where n is an integer of 1-6 and R.sup.8 is H or an acyl derivative group, or CONHR.sup.9 where R.sup.9 is alkyl of 1-3 carbons;
- or
- 2) R and X are combined to form a linking group of the formula --CH.sub.2 OCR.sup.10 R.sup.11 O-- where each R.sup.10 and R.sup.11 independently is H or alkyl of 1-3 carbons;
- or --CH.sub.2 NR.sup.12 CO.sub.2 -- where R.sup.12 is H or alkyl of 1-3 carbons;
- or
- b) Z.sup.1 is H and Z.sup.2 is OH;
- Y is H or CHO;
- R is OH;
- and
- X is CONH(CH.sub.2).sub.2 OH, CO.sub.2 CH.sub.3, or CH.sub.2 OH;
- and
- R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are as defined in a);
- or
- c) Z.sup.1 and Z.sup.2 are both H and R, Y and X are as defined in b), except that X cannot be CO.sub.2 CH.sub.3 ;
- and when R.sup.1 is Br, X cannot be CH.sub.2 OH;
- and R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are as defined in a);
- or
- d) Z.sup.1 is H and Z.sup.2 is SR.sup.15 where R.sup.15 is n-alkyl of 1-3 carbons;
- and Y, R and X are defined as in b), except that when R.sup.15 is C.sub.2 H.sub.5, X cannot be CH.sub.2 OH;
- and R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are as defined in a).
A method for enhancing a neurotrophin-induced activity of a neurotrophin responsive cell, said method comprising contacting said cell with a K-252a derivative of the formula:
- ##STR12## wherein:
- a) when Z.sup.1 and Z.sup.2 together represent O, then either
- 1) each R.sup.1, R.sup.2, R.sup.5, and R.sup.6 independently is H, F, Cl, Br, I, NO.sub.2, CN, alkyl of 1-6 carbons, or NR.sup.13 R.sup.14 where each R.sup.13 and R.sup.14, independently, is H or n-alkyl of 1-6 carbons;
- and
- Y is H, OH, NH.sub.2, n-alkyl of 1-6 carbons, CHO, benzyl, O-n-alkyl of 1-6 carbons, (CH.sub.2).sub.n OH or (CH.sub.2).sub.n NH.sub.2 where n is an integer of 1-6;
- and each R.sup.3 and R.sup.4 independently is H or (CH.sub.2).sub.n CH(OH)CH.sub.2 OH, where n is an integer of 1-6;
- or
- 2) each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently is H;
- and Y is as defined in a) 1), except that Y cannot be benzyl;
- or
- b) Z.sup.1 is H and Z.sup.2 is H, OH, or SR.sup.15, where R.sup.15 is n-alkyl of 1-3 carbons;
- Y is H or CHO;
- and
- each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 is H.
A method for enhancing a neurotrophin-induced activity of a neurotrophin responsive cell, said method comprising contacting said cell with a K-252a derivative of the formula:
- ##STR13## wherein:
- a) each P1 and P2 is H or P1 and P2 together represent O;
- and each W1 and W2 is H or W1 and W2 together represent O;
- provided that each P1 and P2 is different from W1 and W2.
Dependencies are inferred from the claim text.