Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-02
1999-07-20
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514295, 540456, 540457, A01N 4342, C07D26722
Patent
active
059256494
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel ascomycins having pharmaceutical, e.g, antiinflammatory, activity. The invention also provides processes for making these novel compounds and pharmaceutical compositions comprising the same.
Ascomycins, of which FK-506 and Ascomycin itself are the best known, comprise a class of lactam macrolides, many of which have potent immunosuppressive or antiinflammatory activity. FK506 is a macrolide immunosuppressant produceable by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in the appendix to the Merck Index, 11th ed. (1989) as item A5. Ascomycin is described, e.g., in U.S. Pat. No. 3,244,592. A large number of related compounds which retain the basic structure of FK506 and Ascomycin are also known. These compounds are described in various publications, for example EP 184162, EP 315973, EP 323042, EP 423714, EP 427680, EP 465426, EP 474126, WO 91/02736, WO 91/13899, WO 91/19495, EP 484936, EP 532088, EP 532089, WO 93/5059 and the like. Ascomycin, FK-506 and their structurally similar analogues and derivatives are termed collectively "ascomycins" in this specification.
As a class, ascomycins are potent immunosuppressive and anti-inflammatory compounds, but their pharmaceutical utility is limited by their toxicity. FK-506, for example, may be toxic to the kidneys, liver, and central nervous system at pharmaceutically relevant dosages. Additionally, while systemic immunosuppression may be desirable for some conditions, e.g., graft rejection, it is generally undesirable for the treatment of local inflammatory conditions, e.g., asthma or dermatitis.
It has now surprisingly been discovered that certain ascomycins bearing one or more physiologically hydrolyzable and acceptable oxycarbonyl moieties are highly effective locally active anti-inflammatory agents, e.g., on the skin and airways, but are "soft" drugs, that is they are rapidly transformed in vivo to ascomycins bearing unprotected carboxy groups, which compounds are not systemically active. It is further surprisingly discovered that the corresponding ascomycins bearing unprotected carboxy groups, although much less intrinsically active than the physiologically hydrolyzable oxycarbonyl moieties, nevertheless are highly potent topically, especially dermally. Both the acid and ester forms of the ascomycins described herein are well tolerated and, unlike currently available ascomycins, they do not produce systemic immunosuppression or significant systemic side effects at pharmacologically active dosages.
An ascomycin of the invention is thus an ascomycin bearing one or more physiologically hydrolyzable and acceptable oxycarbonyl moieties or one or more carboxy moieties, which is useful in the manufacture of a systemically nonimmunosuppressive, locally active medicament for topical application, e.g., to the skin or airways, e.g., a compound of formula I, Ia, or Ib, as described and exemplified below.
The physiologically hydrolyzable and acceptable oxycarbonyl or carboxy moiety or moieties are suitably linked to the ascomycin through a non-metabolically labile spacer of from 1 to 18 carbon units in length, preferably 6-8 carbon units, and optionally comprising a cyclic (e.g. aromatic) or branched structure and/or one or more heteroatoms, e.g., nitrogen, oxygen or sulfur. Preferably, the spacer comprises an arylene moiety, e.g., a phenylene moiety. In measuring the length of the spacer moiety, it is understood that the length is the length of longest consecutive chain of atoms in the moiety, not counting side chains or the bridge portion of cyclic structures. Thus, a p-phenylcarbamoyl spacer, for example, would be considered to have a length of 6 carbon units--four for the p-phenylene, one for the nitrogen and one for the carbonyl. This spacer is suitably attached to the ascomycin via the hydroxy at the 4-position on the cyclohexyl ring of the ascomycin (i.e., position 28, using the standard numbering for FK-506), e.g., by an O-carbamate or O-thiocarbamate coupling. For example, the invention includes a 28-O-carbamoy
REFERENCES:
patent: 3244592 (1966-04-01), Arai
patent: 4929611 (1990-05-01), Okuhara et al.
Chemical Abstracts, vol. 109, No. 23, Abstract No. 210803, p. 640, 1988.
J. Funk, et al., J. Am. Acad. Dermatol., vol. 31, 1994, pp. 999-1014.
T. Fukuda, et al., Int. Arch. Allergy Appl. Immunol., vol. 94, 1991, pp. 259-261.
Hersperger Rene
Naef Reto
Loeschorn Carol A.
Ngo Tamthom T.
Novartis AG
Raymond Richard L.
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