US4110432A
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Conjugates of prostaglandins, analogs, formulations and their use
Assignee: SmithKline Beecham Corp
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Filing: 1975-06-03
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Granted: 1978-08-29
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Expires: 1995-06-03
Abstract
Abstract Immunogenic conjugates of prostaglandins of the A, B, D and E series and their structural analogues of value in the proplylaxis or therapy in mammals of pathological conditions in which prostaglandins are involved. Also provided are pharmaceutical formulations comprising the conjugates together with a carrier therefor and methods for the treatment of mammals comprising the administration thereto of a conjugate or formulation thereof.
Inventors
- 👤 Samuel Wilkinson
- 👤 Roderick J. Flower
- 👤 Sergio H. Ferreira
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 14:10
CPC Classifications
A; A61; A61K; A61K39/00; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6835; A61K47/6883; C; C01; C01F; C01F11/00; C01F11/46; A61K2039/60; A61K2039/6031; A61K2039/6081
Claims Analysis
Total Claims: 24
Claim 1
Independent Claim
266 words
A conjugate of formula (I) ##STR5## wherein (M) is that part of the macromolecule other than the reactive free amino group of an immunogenic macromolecule of the formula (M)-- NH 2 : (pg) is the residue of a prostaglandin or analogue thereof of the formula (PG)-COOH selected from prostaglandins of the A, B, D and E series and those analogues thereof wherein there is retained the characteristic cyclopentane or cyclopentene group or wherein this group is replaced by a cyclohexane group; Y is selected from (i) --NH(CH 2 ) a NH-- where a is 2 to 6; (ii) --NH(CH 2 ) b 1.Z.(CH 2 ) b 2.NH-- where b 1 and b 2 are the same or different and each is 1 to 4 and Z is --O--, --NH-- or --CH(OH)--; (iii) --W.CO.CH 2 .W 1 -- where W and W 1 are the same or different and each is a group defined in (i) or (ii) above; or (iv) --NH.CH 2 .CONH.CH 2 .CO.W 2 -- where W 2 is a group defined in (i) or (ii) above; x is 2 to 4; m is at least 1 and is not greater than the number of free amino groups in the parent macromolecule of the group (M) available for acylation; p is 1; and n is 0 or an integer not greater than the number of carboxyl groups in the parent macromolecule of the group (M) available for reaction with the bis-amine H-Y-H; and where, when the sum of m and n is greater than 1 the groups (PG) may be the same or different.
Claim 2
Dependent Claim
266 words
A conjugate of formula (I) ##STR5## wherein (M) is that part of the macromolecule other than the reactive free amino group of an immunogenic macromolecule of the formula (M)-- NH 2 : (pg) is the residue of a prostaglandin or analogue thereof of the formula (PG)-COOH selected from prostaglandins of the A, B, D and E series and those analogues thereof wherein there is retained the characteristic cyclopentane or cyclopentene group or wherein this group is replaced by a cyclohexane group; Y is selected from (i) --NH(CH 2 ) a NH-- where a is 2 to 6; (ii) --NH(CH 2 ) b 1.Z.(CH 2 ) b 2.NH-- where b 1 and b 2 are the same or different and each is 1 to 4 and Z is --O--, --NH-- or --CH(OH)--; (iii) --W.CO.CH 2 .W 1 -- where W and W 1 are the same or different and each is a group defined in (i) or (ii) above; or (iv) --NH.CH 2 .CONH.CH 2 .CO.W 2 -- where W 2 is a group defined in (i) or (ii) above; x is 2 to 4; m is at least 1 and is not greater than the number of free amino groups in the parent macromolecule of the group (M) available for acylation; p is 1; and n is 0 or an integer not greater than the number of carboxyl groups in the parent macromolecule of the group (M) available for reaction with the bis-amine H-Y-H; and where, when the sum of m and n is greater than 1 the groups (PG) may be the same or different.
Claim 3
Dependent Claim
53 words
A conjugate according to claim 1, wherein Y is --NH(CH 2 ) b 1.Z.(CH 2 ) b 2.NH-- where Z is --NH-- and b 1 and b 2 are the same or different and each is 2 to 4, or Y is --NH(CH 2 ) a NH-- where a is 2 to 4.
Claim 4
Dependent Claim
100 words
A conjugate according to claim 1 wherein (PG) is derived from a compound of the formula ##STR6## wherein R 1 is hydrogen or hydroxy and R 2 is hydrogen, or R 1 and R 2 together form a bond; R 3 and R 4 together form a bond when R 1 is hydrogen and are otherwise both hydrogen; and one of R 5 and R 6 is a group --X 1 .COOH and the other is a group --X 2 .CH.sub. 3 where X 1 and X 2 are the same or different and are each a carbon atom chain.
Claim 5
Dependent Claim
32 words
A conjugate according to claim 3, wherein (PG) is derived from a compound defined in claim 3 wherein X 1 and X 2 are each 2 to 8 carbon atoms in length.
Claim 6
Dependent Claim
28 words
A conjugate according to claim 3, wherein (PG) is defined in claim 3 wherein X 1 and X 2 are each 6 or 7 carbon atoms in length.
Claim 7
Dependent Claim
18 words
A conjugate according to claim 1, wherein (M) is derived from a protein fraction of a mammalian serum.
Claim 8
Dependent Claim
17 words
A conjugate according to claim 1, wherein (M) is derived from a protein fraction of human serum.
Claim 9
Dependent Claim
14 words
A conjugate according to claim 1 wherein (M) is derived from human serum albumin.
Claim 10
Dependent Claim
10 words
A conjugate according to claim 1, wherein x is 2.
Claim 11
Dependent Claim
17 words
A conjugate according to claim 1, wherein (PG) is derived from a prostaglandin of the E series.
Claim 12
Dependent Claim
23 words
A conjugate according to claim 1, wherein the sum of m and n is greater than 1 and the groups (PG) are different.
Claim 13
Dependent Claim
18 words
A conjugate according to claim 1, wherein Y is --NH(CH 2 ) 3 .NH.(CH 2 ) 3 NH--.
Claim 14
Dependent Claim
48 words
A pharmaceutical formulation suitable for parenteral administration in the prophylaxis or therapy in mammals of a pathological condition in which endogenous prostaglandins are involved, which comprises an effective prophylactic or therapeutic amount of a conjugate of formula (I) as defined in claim 1 together with an adjuvant therefor.
Claim 15
Dependent Claim
13 words
A formulation according to claim 13 wherein the adjuvant is acceptable in man.
Claim 16
Dependent Claim
13 words
A a formulation according to claim 13 wherein the adjuvant is aluminium hydroxide.
Claim 17
Dependent Claim
17 words
A formulation according to claim 13 which is a solution or suspension in an aqueous liquid medium.
Claim 18
Dependent Claim
16 words
A sealed ampoule containing a known unit dosage amount of a formulation according to claim 13.
Claim 19
Dependent Claim
14 words
An ampoule according to claim 17 wherein the contents are in the freeze-dried state.
Claim 20
Independent Claim
308 words
A method for the therapy or prophylaxis in a human of a pathological condition in which endogenous prostaglandins are involved, comprising parenteral administration to the human of an effective therapeutic or prophylactic amount of a conjugate of formula (I) ##STR7## wherein (M) is that part of the macromolecule other than the reactive free amino group of an immunogenic macromolecule of the formula (M)--NH 2 ; (pg) is the residue of a prostaglandin or analogue thereof of the formula (PG)-COOH selected from prostaglandins of the A, B, D and E series and those analogues thereof wherein there is retained the characteristic cyclopentane or cyclopentene group or wherein this group is replaced by a cyclohexane group; Y is selected from (i) --NH(CH 2 ) a NH-- where a is 2 to 6; (ii) --NH(CH 2 ) b 1.Z.(CH 2 ) b 2.NH-- where b 1 and b 2 are the same or different and each is 1 to 4 and Z is -O-, -NH- or --CH(OH)--; (iii) --W.CO.CH 2 .W 1 -- where W and W 1 are the same or different and each is a group defined in (i) or (ii) above; or (iv) --NH.CH 2 .CONH.CH 2 .CO.W 2 -- where W 2 is a group defined in (i) or (ii) above; x is 2 to 4; m is at least 1 and is not greater than the number of free amino groups in the parent macromolecule of the group (M) available for acylation; p is 0 or 1; and n is 0 or an integer not greater than the number of carboxyl groups in the parent macromolecule of the group (M) available for reaction with the bis-amine H--Y--H, and is 0 when p is 0; and where, when the sum of m and n is greater than 1 the groups (PG) may be the same or different.
Claim 21
Independent Claim
308 words
A method for the therapy or prophylaxis in a human of a pathological condition in which endogenous prostaglandins are involved, comprising parenteral administration to the human of an effective therapeutic or prophylactic amount of a conjugate of formula (I) ##STR7## wherein (M) is that part of the macromolecule other than the reactive free amino group of an immunogenic macromolecule of the formula (M)--NH 2 ; (pg) is the residue of a prostaglandin or analogue thereof of the formula (PG)-COOH selected from prostaglandins of the A, B, D and E series and those analogues thereof wherein there is retained the characteristic cyclopentane or cyclopentene group or wherein this group is replaced by a cyclohexane group; Y is selected from (i) --NH(CH 2 ) a NH-- where a is 2 to 6; (ii) --NH(CH 2 ) b 1.Z.(CH 2 ) b 2.NH-- where b 1 and b 2 are the same or different and each is 1 to 4 and Z is -O-, -NH- or --CH(OH)--; (iii) --W.CO.CH 2 .W 1 -- where W and W 1 are the same or different and each is a group defined in (i) or (ii) above; or (iv) --NH.CH 2 .CONH.CH 2 .CO.W 2 -- where W 2 is a group defined in (i) or (ii) above; x is 2 to 4; m is at least 1 and is not greater than the number of free amino groups in the parent macromolecule of the group (M) available for acylation; p is 0 or 1; and n is 0 or an integer not greater than the number of carboxyl groups in the parent macromolecule of the group (M) available for reaction with the bis-amine H--Y--H, and is 0 when p is 0; and where, when the sum of m and n is greater than 1 the groups (PG) may be the same or different.
Claim 22
Dependent Claim
35 words
A method according to claim 19 wherein the conjugate is administered to the human in an amount in the range (calculated as the prostaglandin moiety in the conjugate) 21 to 1000 μg per kilogram bodyweight.
Claim 23
Dependent Claim
36 words
A method for the therapy or prophylaxis of inflammation in a human comprising parenteral administration to the human of an effective inflammation therapeutic or prophylatic amount of a conjugate of formula (I) defined in claim 19.
Claim 24
Dependent Claim
29 words
A method of raising antibodies in a human comprising parenteral administration to the human of an effective antibody-raising amount of a conjugate of formula (I) defined in claim 19.
References Cited (Backward Citations)
US3690834A
Cited
US3935074A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-08-28 | 1982-02-27 | 1982-08-29 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-08-28 | 1986-02-27 | 1986-08-29 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-08-28 | 1990-02-27 | 1990-08-29 | $7700.00 | Window Closed / Lapsed |