US4435388A
Expired / Lapsed
US
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Tylosin 20-imino-20-deoxo-4"-acyl derivatives, pharmaceutical compositions and method of use
Assignee: Merck Sharp & Dohme LLC
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Filing: 1982-06-10
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Granted: 1984-03-06
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Expires: 2002-06-10
Abstract
Abstract There are disclosed 20-imino-20-deoxo-4''-acyl derivatives of the antibiotic tylosin which have higher serum levels and better absorption than the parent tylosins. Methods of preparation of the compounds are also disclosed.
Inventors
- 👤 Ashit K. Ganguly
- 👤 Allan K. Mallams
- 👤 Yi-Tsung Liu
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-03 21:47
CPC Classifications
C; C07; C07H; C07H17/00; C07H17/04; C07H17/08
Claims Analysis
Total Claims: 47
Claim 1
Independent Claim
257 words
A compound of the formula ##STR10## wherein R 1 is hydrogen or an acyl group selected from alkanoyl of 2 to 5 carbon atoms, palmityl, stearyl, lauryl, oleyl, chloroacetyl, benzoyl, adamantanecarbonyl, cyclopropanecarbonyl, cyclohexanecarbonyl, β-cyclohexylpropionyl, phenylacetyl, phenoxyacetyl, mandelyl, 2-thienylacetyl, alkyl-, aryl- and aralkylsulfonyl, substituted aryl- and aralkylsulfonyl, wherein the substituents on the aryl portions are halogen, nitro and alkoxy groups, succinyl, maleyl, fumaryl, malonyl and phthalyl; R 2 is acyl, wherein acyl is as defined in R 1 ; R 3 is hydrogen or acyl, wherein acyl is as defined in R 1 ; or R 2 and R 3 are together a carbonyl group linking the 3"-and 4"-hydroxyl groups; R 4 is hydrogen or acyl, wherein acyl is as defined in R 1 ; R 5 is selected from the group consisting of ##STR11## wherein n is 0-2, and Q is selected from the gorup consisting of CH 2 , CR 6 R 7 , CHR 6 , CHR 7 , NH,NR 6 , O, S, SO 2 , CHOH, CHOR 6 , CHOR 7 , ##STR12## CHCOOH, CHCOOR 6 , CHCONH 2 , and CHCONR 6 R 7 , wherein R 6 and R 7 may be the same or different each being a member of the group consisting of (C 1-C 6 )alkyl, (C 7-C 10 )aralkyl and (C 6-C 10 )aryl including X-substituted aryl and aralkyl, wherein X is halogen, trifluoromethyl, (C 1-C 6 ) alkoxy, or (C 1-C 6 ) alkylcarbonyl; N--NH--aralkyl, and ##STR13## and the non-toxic pharmaceutically acceptable acid addition salts thereof.
Claim 2
Dependent Claim
257 words
A compound of the formula ##STR10## wherein R 1 is hydrogen or an acyl group selected from alkanoyl of 2 to 5 carbon atoms, palmityl, stearyl, lauryl, oleyl, chloroacetyl, benzoyl, adamantanecarbonyl, cyclopropanecarbonyl, cyclohexanecarbonyl, β-cyclohexylpropionyl, phenylacetyl, phenoxyacetyl, mandelyl, 2-thienylacetyl, alkyl-, aryl- and aralkylsulfonyl, substituted aryl- and aralkylsulfonyl, wherein the substituents on the aryl portions are halogen, nitro and alkoxy groups, succinyl, maleyl, fumaryl, malonyl and phthalyl; R 2 is acyl, wherein acyl is as defined in R 1 ; R 3 is hydrogen or acyl, wherein acyl is as defined in R 1 ; or R 2 and R 3 are together a carbonyl group linking the 3"-and 4"-hydroxyl groups; R 4 is hydrogen or acyl, wherein acyl is as defined in R 1 ; R 5 is selected from the group consisting of ##STR11## wherein n is 0-2, and Q is selected from the gorup consisting of CH 2 , CR 6 R 7 , CHR 6 , CHR 7 , NH,NR 6 , O, S, SO 2 , CHOH, CHOR 6 , CHOR 7 , ##STR12## CHCOOH, CHCOOR 6 , CHCONH 2 , and CHCONR 6 R 7 , wherein R 6 and R 7 may be the same or different each being a member of the group consisting of (C 1-C 6 )alkyl, (C 7-C 10 )aralkyl and (C 6-C 10 )aryl including X-substituted aryl and aralkyl, wherein X is halogen, trifluoromethyl, (C 1-C 6 ) alkoxy, or (C 1-C 6 ) alkylcarbonyl; N--NH--aralkyl, and ##STR13## and the non-toxic pharmaceutically acceptable acid addition salts thereof.
Claim 3
Dependent Claim
16 words
A compound according to claim 1 wherein R 5 is a group of the formula ##STR14##
Claim 4
Dependent Claim
37 words
A compound according to claim 1 or 2 wherein R 1 , R 3 and R 4 are hydrogen and R 2 is an acyl group selected from the group consisting of acetyl, propionyl, n-butyryl and iso-valeryl.
Claim 5
Dependent Claim
38 words
A compound according to claim 1 or 2 wherein R 1 is acetyl, R 3 and R 4 are hydrogen and R 2 is an acyl group selected from the group consisting of acetyl, propionyl, n-butyryl and iso-valeryl.
Claim 6
Dependent Claim
36 words
A compound according to claim 1 or 2 wherein R 1 and R 3 are hydrogen and R 2 and R 4 are acyl groups selected from the group consisting of acetyl, propionyl, n-butyryl and iso-valeryl.
Claim 7
Dependent Claim
36 words
A compound according to claim 1 or 2 wherein R 1 and R 4 are hydrogen, and R 2 and R 3 are acyl groups selected from the group consisting of acetyl, propionyl, n-butyryl and iso-valeryl.
Claim 8
Dependent Claim
36 words
A compound according to claim 1 or 2 wherein R 1 is hydrogen and R 2 , R 3 and R 4 are acyl groups selected from the group consisting of acetyl, propionyl, n-butyryl and iso-valeryl.
Claim 9
Dependent Claim
19 words
A compound according to claim 1 or 2 wherein R 2 and R 3 are a bridging carbonyl group.
Claim 10
Dependent Claim
9 words
The compound according to claim 2 which is 20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 11
Dependent Claim
10 words
The compound according to claim 2 which is 4"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl) -imino]tylosin.
Claim 12
Dependent Claim
10 words
A compound according to claim 2 which is 2', 4"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]tylosin.
Claim 13
Dependent Claim
9 words
A compound according to claim 2 which is 2'-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]-4"-O-iso-valeryltylosin.
Claim 14
Dependent Claim
9 words
A compound according to claim 2 which is 4'-O-n-butyryl-20-deoxo-20[(4,4-dioxothiomorpholinyl)-imino]-3"-O-propionyltylosin.
Claim 15
Dependent Claim
9 words
A compound according to claim 2 which is 2'-O-acetyl-4"-O-n-butyryl-20-deoxo-20-[(4,4-dioxo-thiomorpholinyl)imino]-3"-O-propionyltylosin.
Claim 16
Dependent Claim
9 words
A compound according to claim 2 which is 3"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorphilinyl)-imino]-4"-O-iso-valeryltylosin.
Claim 17
Dependent Claim
10 words
A compound according to claim 2 which is 2', 3"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]-4"-O-iso-valeryltylosin.
Claim 18
Dependent Claim
10 words
A compound according to claim 2 which is 3", 4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]tylosin.
Claim 19
Dependent Claim
10 words
A compound according to claim 2 which is 2'-O-acetyl-3",4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl) imino]-tylosin.
Claim 20
Dependent Claim
1 words
20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]-tylosin.
Claim 21
Dependent Claim
1 words
20-deoxo-20-[(4,4-dioxothiomorpholinyl)-imino]-tylosin.
Claim 22
Dependent Claim
33 words
A method of eliciting an antibactrial response in a mammal having a gram positive bacterial infection which comprises administering to the mammal a therapeutically effective quantity of a compound according to claim 1.
Claim 23
Dependent Claim
11 words
A method according to claim 20 wherein R 5 is ##STR15##
Claim 24
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 4"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]tylosin.
Claim 25
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 20-deoxy-20-[(4,4-dioxothiomorpholinyl)-inino]4"-O-iso-valeryltylosin.
Claim 26
Dependent Claim
13 words
A method according to claim 21 wherein the compound utilized is 2', 4"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]tylosin.
Claim 27
Dependent Claim
11 words
A method according to claim 21 wherein the compoundutilized is 2'-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 28
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 4"-O-n-butyryl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-3"-O-propionyltylosin.
Claim 29
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 2'-O-acetyl-4"-O-n-butyryl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-3"-O-propionyltylosin.
Claim 30
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 3"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 31
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 2',3"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 32
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 3",4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 33
Dependent Claim
12 words
A method according to claim 21 wherein the compound utilized is 2'-O-acetyl-3",4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 34
Dependent Claim
39 words
A pharmaceutical composition adapted for the treatment of a mammal having a gram positive bacterial infection which comprises a therapeutically effective quantity of a compound according to claim 1 or 2 in admixture with a pharmaceutically acceptable carrier therefor.
Claim 35
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 4"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 36
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 37
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 2',4"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 38
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 2'-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 39
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 4"-O-n-butyryl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-3"-O-propionyltylosin.
Claim 40
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 2'-O-acetyl-4"-O-n-butyryl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-3"-O-propionyltylosin.
Claim 41
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 3"-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 42
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 2',3"-di-O-acetyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-4"-O-iso-valeryltylosin.
Claim 43
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 3",4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 44
Dependent Claim
10 words
A pharmaceutical composition according to claim 32 which comprises 2'-O-acetyl-3",4"-O-carbonyl-20-deoxo-20-[(4,4-dioxothiomorpholinyl)imino]-tylosin.
Claim 45
Dependent Claim
11 words
A pharmaceutical composition according to claim 32 adapted for oral administration.
Claim 46
Dependent Claim
11 words
A pharmaceutical composition according to claim 32 adapted for topical composition.
Claim 47
Dependent Claim
11 words
A pharmaceutical composition according to claim 32 adapted for injectable administration.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-03-06 | 1987-09-05 | 1988-03-06 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-03-06 | 1991-09-05 | 1992-03-06 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-03-06 | 1995-09-05 | 1996-03-06 | $7700.00 | Window Closed / Lapsed |