US5196437A
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US
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Method for treating hepatic diseases and regenerating liver tissue using FK 506 and related compounds
Assignee: Astellas Pharma Inc
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Filing: 1990-12-18
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Granted: 1993-03-23
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Expires: 2010-12-18
Abstract
Abstract Macrolide compounds having the structure shown below <IMAGE> (I) wherein R1 is hydroxy or protected hydroxy, R2 is hydrogen, hydroxy or protected hydroxy, R3 is methyl, ethyl, propyl or allyl, R4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted is a single bond or a double bond, provided that R2 is not protected hydroxy where R4 is hydroxy or oxo are used to treat hepatic disease and regenerate liver tissue by facilitating hypertrophy and hyperplasia of hepatocytes.
Inventors
- 👤 Thomas E. Starzl
- 👤 Satoru Todo
- 👤 Antonio Francavilla
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-01 15:24
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/70
Claims Analysis
Total Claims: 36
Claim 1
Independent Claim
138 words
A method of regenerating mammal liver tissue, comprising administering to a mammal in need thereof a regeneration effective amount of a macrolide of formula I: ##STR4## where R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 2
Independent Claim
138 words
A method of regenerating mammal liver tissue, comprising administering to a mammal in need thereof a regeneration effective amount of a macrolide of formula I: ##STR4## where R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 3
Dependent Claim
14 words
The method of claim 1, wherein R 1 and R 2 are each hydroxy.
Claim 4
Dependent Claim
10 words
The method of claim 2, wherein R 3 is allyl.
Claim 5
Dependent Claim
10 words
The method of claim 1, wherein R 3 is ethyl.
Claim 6
Dependent Claim
10 words
The method of claim 1, wherein R 3 is methyl.
Claim 7
Dependent Claim
10 words
The method of claim 1, wherein R 4 is hydroxy.
Claim 8
Dependent Claim
10 words
The method of claim 1, wherein R 4 is methoxy.
Claim 9
Dependent Claim
10 words
The method of claim 1, wherein R 4 is oxo.
Claim 10
Dependent Claim
11 words
The method of claim 3, wherein the macrolide is FK 506.
Claim 11
Dependent Claim
11 words
The method of claim 1, wherein said administering is oral administration.
Claim 12
Independent Claim
138 words
A method of stimulating hypertrophy and hyperplasis of hepatocytes, comprising contacting mammalian hepatocytes with an effective amount of a macrolide of the formula shown below: ##STR5## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutially acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically accceptable organic carbamic acyloxy, and salts thereof.
Claim 13
Independent Claim
138 words
A method of stimulating hypertrophy and hyperplasis of hepatocytes, comprising contacting mammalian hepatocytes with an effective amount of a macrolide of the formula shown below: ##STR5## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutially acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically accceptable organic carbamic acyloxy, and salts thereof.
Claim 14
Dependent Claim
14 words
The method of claim 11, wherein R 1 and R 2 are each hydroxy.
Claim 15
Dependent Claim
10 words
The method of claim 12, wherein R 3 is allyl.
Claim 16
Dependent Claim
10 words
The method of claim 11, wherein R 3 is ethyl.
Claim 17
Dependent Claim
10 words
The method of claim 11, wherein R 3 is methyl.
Claim 18
Dependent Claim
10 words
The method of claim 11, wherein R 4 is hydroxy.
Claim 19
Dependent Claim
10 words
The method of claim 11, wherein R 4 is methoxy.
Claim 20
Dependent Claim
10 words
The method of claim 11, wherein R 4 is oxo.
Claim 21
Dependent Claim
11 words
The method of claim 13, wherein the macrolide is FK 506.
Claim 22
Independent Claim
145 words
A method for treating hepatic disease or liver resection by regenerating liver tissue, comprising administering to a mammal in need thereof, an effective amount of a macrolide of the formula shown below, ##STR6## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 23
Independent Claim
145 words
A method for treating hepatic disease or liver resection by regenerating liver tissue, comprising administering to a mammal in need thereof, an effective amount of a macrolide of the formula shown below, ##STR6## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 24
Dependent Claim
13 words
The method of claim 20, wherein said hepatic disease is an immunogenic disease.
Claim 25
Dependent Claim
16 words
The method of claim 21, wherein said hepatic immunogenic disease is a chronic autoimmune liver disease.
Claim 26
Dependent Claim
25 words
The method of claim 22, wherein said autoimmune liver disease is selected from the group consisting of autoimmune hepatitus, primary biliary cirrhosis and sclerosing cholangitis.
Claim 27
Dependent Claim
13 words
The method of claim 20, wherein said hepatic disease is acute liver necrosis.
Claim 28
Dependent Claim
20 words
The method of claim 24, wherein said acute liver necrosis is necrosis caused by toxins, viral hepatitis, shock or anoxia.
Claim 29
Dependent Claim
17 words
The method of claim 20, wherein said administering step is oral, parenteral, enteral, intramuscular or intravenous administration.
Claim 30
Dependent Claim
11 words
The method of claim 26 wherein said administering is oral administration.
Claim 31
Independent Claim
19 words
The method of any one of claims 20 to 25, 26 and 27, wherein the macrolide is FK 506.
Claim 32
Independent Claim
152 words
A method for treating hepatic disease selected from the group consisting of B-virus hepatitis, non-A/non-B hepatitis and cirrhosis, comprising administering to a mammal in need thereof, a liver regenerating effective amount of a macrolide of the formula shown below: ##STR7## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 33
Independent Claim
152 words
A method for treating hepatic disease selected from the group consisting of B-virus hepatitis, non-A/non-B hepatitis and cirrhosis, comprising administering to a mammal in need thereof, a liver regenerating effective amount of a macrolide of the formula shown below: ##STR7## wherein R 1 is hydroxy or pharmaceutically acceptable protected hydroxy, R 2 is hydrogen, hydroxy or pharmaceutically acceptable protected hydroxy, R 3 is methyl, ethyl, propyl or allyl, R 4 is hydroxy, methoxy or oxo, n is 1 or 2 and the symbol of a line and a dotted line is a single bond or a double bond, provided that R 2 is not pharmaceutically acceptable protected hydroxy where R 4 is hydroxy or oxo, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of 1-(lower alkylthio)(lower)alkoxy, tri(lower)alkylsilyloxy, lower alkyl-diphenylsilyloxy, pharmaceutically acceptable organic carboxylic acyloxy, pharmaceutically acceptable organic sulfonic acyloxy and pharmaceutically acceptable organic carbamic acyloxy, and salts thereof.
Claim 34
Dependent Claim
11 words
The method of claim 29, wherein said cirrhosis is alcoholic cirrhosis.
Claim 35
Dependent Claim
130 words
The method of claim 1, 11, 20 or 29, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of C 1 -C 4 -alkylthiomethyloxy, tri(C 1 -C 4 )alkoxysilyloxy, C 1 -C 4 -alkyldiphenylsilyloxy, C 1 -C 4 -alkanoyloxy, carboxy substituted (C 1 -C 4 ) alkanoyloxy, cyclo(C 5 -C 6 )-alkyloxy(C 1 -C 4 )alkanoyloxy having two C 1 -C 4 alkyl groups on the cycloalkyl moiety, camphorsulfonyloxy, carboxy(C 1 -C 4 )alkylcarbamoyloxy, tri(C 1 -C 4 )alkylsilyl(C 1 -C 4 )alkoxycarbonyl-(C 1 -C 4 )alkylcarbamoyloxy, benzoyloxy, benzoyloxy substituted with one or two nitro groups, benzenesulfonyloxy, halogen substituted benzenesulfonyloxy, phenyl(C 1 -C 4 )alkanoyloxy, and phenyl(C 1 -C 4 )alkanoyloxy substituted with C 1 -C 4 alkoxy or trihalo (C 1 -C 4 ) alkyl groups.
Claim 36
Dependent Claim
31 words
The method of claim 31, wherein said pharmaceutically acceptable protected hydroxy is selected from the group consisting of methylthiomethyloxy, tert-butyl-dimethylsilyloxy, tert-butyl-diphenylsilyloxy, acetyloxy, carboxypropionyloxy, menthyloxyacetyloxy, camphorsulfonyloxy, benzoyloxy, nitrobenzoyloxy, dinitrobenzoyloxy, iodobenzenesulfonyloxy and 2-trifluoromethyl-2-methoxy-2-phenylacetyloxy.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1996-03-22 | 1996-09-21 | 1997-03-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-03-22 | 2000-09-21 | 2001-03-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-03-22 | 2004-09-21 | 2005-03-23 | $7700.00 | Window Closed / Lapsed |