US4283394A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Cytotoxic nucleoside-corticosteroid phosphodiesters
Assignee: Research Corp
•
Filing: 1979-08-06
•
Granted: 1981-08-11
•
Expires: 1999-08-06
Abstract
Abstract Nucleotides of nucleosides or bases having known cytotoxic activity are reacted with steroids, preferably corticosteroids, to form corresponding cytotoxic nucleoside-corticosteroid phosphodiester analogues of the formula: ##STR1## wherein: steroid is the residue formed by removal of a hydroxyl hydrogen atom from a natural or synthetic adrenal corticosteroid containing the characteristic cyclopentanophenanthrene nucleus which is esterified to the phosphate moiety at the 21-position; sugar is a naturally occurring pentose or deoxypentose in the furanose form, preferably ribose, deoxyribose, lyxose, xylose or arabinose and especially ribose, deoxyribose or arabinose, which is esterified to the phosphate moiety at the 5'-position and covalently bonded to the heterocycle moiety at the 1'-position to form a nucleoside; and heterocycle is a purine, pyrimidine, hydrogenated pyrimidine, triazolopurine or similar nucleoside base. The conjugates exhibit an enhanced therapeutic index as compared to the parent nucleoside or base compounds, and are thus useful cytotoxic, antiviral and antineoplastic agents.
Inventors
- 👤 Charles R. West
- 👤 Chung I. Hong
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-25 04:15
CPC Classifications
C; C07; C07H; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07H19/10; C07J; C07J51/00
Claims Analysis
Total Claims: 22
Claim 1
Independent Claim
106 words
A compound selected from the group consisting of compounds of the formula: ##STR3## wherein: steroid is a 21-hydroxy-1,4-pregnadiene-3,20-dione; 21-hydroxy-1,4-pregnadiene-3,11,20-trione; 21-hydroxy-4-pregnene-3,20-dione or 21-hydroxy-4-pregnene-3,11,20-trione which is unsubstituted or substituted by 1-3 hydroxy, methyl or fluoro groups at the 2α, 6α, 9α, 11, 16α, 17 or 18 positions and which is esterified to the phosphate moiety at the 21-position; sugar is ribose, deoxyribose, lyxose, xylose or arabinose which is esterified to the phosphate moiety at the 5'-position and covalently bonded to the heterocycle moiety at the 1'-position to form a nucleoside; and heterocycle is a purine, pyrimidine, hydrogenated pyrimidine or triazolopurine nucleoside base; and the physiologically acceptable salts thereof.
Claim 2
Dependent Claim
106 words
A compound selected from the group consisting of compounds of the formula: ##STR3## wherein: steroid is a 21-hydroxy-1,4-pregnadiene-3,20-dione; 21-hydroxy-1,4-pregnadiene-3,11,20-trione; 21-hydroxy-4-pregnene-3,20-dione or 21-hydroxy-4-pregnene-3,11,20-trione which is unsubstituted or substituted by 1-3 hydroxy, methyl or fluoro groups at the 2α, 6α, 9α, 11, 16α, 17 or 18 positions and which is esterified to the phosphate moiety at the 21-position; sugar is ribose, deoxyribose, lyxose, xylose or arabinose which is esterified to the phosphate moiety at the 5'-position and covalently bonded to the heterocycle moiety at the 1'-position to form a nucleoside; and heterocycle is a purine, pyrimidine, hydrogenated pyrimidine or triazolopurine nucleoside base; and the physiologically acceptable salts thereof.
Claim 3
Dependent Claim
37 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of betamethasone, chloroprednisone, corticosterone, cortisone, desoxycorticosterone, dexamethasone, dichlorisone acetate, fluocinolone acetonide, fluorohydrocortisone, fluorometholone, fluprednisolone, flurandrenolone, hydrocortisone, methylprednisolone, paramethasone, prednisolone, prednisone and triamcinolone.
Claim 4
Dependent Claim
17 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of: 11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione;
Claim 5
Dependent Claim
7 words
1α . 21-dihydroxy-1,4-pregnadiene-3,11,20-trione; 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione; 11β,17α,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione; and 11β,17α,21-trihydroxy-4-pregnene-3,20-dione.
Claim 6
Dependent Claim
7 words
1α . 21-dihydroxy-1,4-pregnadiene-3,11,20-trione; 9α-fluoro-11β,17α,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione; 11β,17α,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione; and 11β,17α,21-trihydroxy-4-pregnene-3,20-dione.
Claim 7
Dependent Claim
22 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of: 17α,21-dihydroxy-4-pregnene-3,11,20-trione; 11β,21-dihydroxy-4-pregnene-3,20-dione; 4-pregnen-21-ol-3,20-dione; 21-hydroxy-4-pregnene-3,20-dione; and 9α-fluoro-11β,17α,21-trihydroxy-4-pregnene-3,20-dione.
Claim 8
Dependent Claim
23 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of: 11β,21-Dihydroxy-3,20-dioxo-pregn-4-en-18-ol; 21-Hydroxy-pregna-4,6-diene-3,20 dione; 21-Hydroxy-2α-methyl-pregn-4-ene 3,20-dione; and 11β,21-Dihydroxy-pregn-1,4-diene-3,20-dione.
Claim 9
Dependent Claim
22 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of 16α-Methyl-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione; 11β,21-Dihydroxy-16α-methyl-pregna-1,4-diene-3,20-dione; 9α-Fluoro-11β,17α,21-trihydroxy-16α-methyl-pregn-4-ene-3,20-dione; 9α-Fluoro-11β,17α,21-trihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione; and 9α-Fluoro-11β,17α,21-trihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione.
Claim 10
Dependent Claim
23 words
A compound according to claim 1, wherein the steroid is selected from the group consisting of α -Fluoro-11β,21-dihydroxy-16α,17α-[1-methylethylidene-bis(oxy)]-pregna-1,4-diene-3,20-dione; 9α-Fluoro-11β,21-dihydroxy-16α-methyl-pregna-1,4-diene-3,20-dione; 9α-Fluoro-11β,21-dihydroxy-16α-methyl-pregn-4-ene-3,20-dione; 6α,9α-Difluoro-11β,21-dihydroxy-16α-methyl-pregn-4-ene-3,20-dione; and 9α,11β-Dichloro-21-hydroxy-16α-methyl-pregna-1,4-diene-3,20-dione.
Claim 11
Dependent Claim
14 words
A compound according to claim 1, wherein the sugar is ribose, deoxyribose or arabinose.
Claim 12
Dependent Claim
14 words
A compound according to claim 8, wherein the heterocycle is a purine or pyrimidine.
Claim 13
Dependent Claim
38 words
A compound according to claim 8, wherein the heterocycle is selected from the group consisting of cytosine, uracil, thymine, adenine, guanine, dihydrouracil, 5-fluorouracil, 5-azauracil, 6-azauracil, 5-azacytosine, 6-azacytosine, tetrahydropyridine dione, 2-amino tetrahydropyridine dione, 6-mercaptopurine, thioguanine, selenoguanine, 8-azaadenine-7-carboxyamide and N-methyl-2-amino-1,2,4-triazolopurine.
Claim 14
Dependent Claim
30 words
A compound according to claim 8, wherein the sugar and the heterocycle together form a nucleoside selected from the group consisting of 1-β-D-arabinofuranosylcytosine; 5-fluorodeoxyuridine; 5-azacytidine; 1-β-D-arabinofuranosyladenine; 6-mercaptopurine ribonucleoside; and tubercidin.
Claim 15
Dependent Claim
7 words
A compound according to claim 1, 5'-(prednisolone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 16
Dependent Claim
7 words
A compound according to claim 1, 5'-(prednisone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 17
Dependent Claim
7 words
A compound according to claim 1, 5'-(dexamethasone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 18
Dependent Claim
7 words
A compound according to claim 1, 5'-(6α-methylprednisolone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 19
Dependent Claim
7 words
A compound according to claim 1, 5'-(cortisol-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 20
Dependent Claim
7 words
A compound according to claim 1, 5'-(cortisone-21-phosphoryl)-1-β-D-arabinofuranosylcytosine.
Claim 21
Dependent Claim
29 words
A pharmaceutical composition comprising a safe and cytotoxically effective amount of a compound according to any one of claims 12 thru 17 in combination with a pharmaceutically acceptable carrier.
Claim 22
Independent Claim
43 words
A method for inhibiting the growth of cancer cells in a living body, which comprises administering a safe and cytotoxically effective amount of a compound according to any one of claims 12 thru 17 to a living test animal afflicted with cancer susceptible.
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) | 1984-08-10 | 1985-02-09 | 1985-08-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1988-08-10 | 1989-02-09 | 1989-08-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1992-08-10 | 1993-02-09 | 1993-08-11 | $7700.00 | Window Closed / Lapsed |