US4172132A
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US
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1,3,5(10),6,8,14-19-Nor-pregnahexaenes, their use as anti-psoriatic agents, and pharmaceutical formulations useful therefor
Assignee: Merck Sharp & Dohme LLC
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Filing: 1978-07-18
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Granted: 1979-10-23
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Expires: 1998-07-18
Abstract
Abstract 1,3,5(10),6,8,14-19 Nor-pregnahexaene-20-ones exhibit anti-mitotic activity with minimal or no hormonal activity. They are particularly useful in the treatment and control of psoriasis when applied topically, a preferred anti-psoriatic compound being 16 alpha -methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17 alpha ,21-triol-20-one 21-acetate.
Inventors
- 👤 Richard W. Draper
- 👤 Charles J. Casmer
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 04:24
CPC Classifications
C; C07; C07J; C07J5/00; C07J5/0046; C07J5/0053; C07J21/00; C07J21/005; C07J5/0061; C07J5/0069; C07J5/0076
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
221 words
The method of eliciting a mitotic inhibitory response in a warm-blooded animal having a disease characterized by rapid cell proliferation which comprises administering to said animal a non-toxic, mitotic inhibitory effective amount of a 19-nor-pregnahexaene-20-one of the following formula I: ##STR3## wherein A is hydrogen, lower alkyl, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl; R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; Y is (H,H), (H,OH), or oxygen; W is (H,H); (H, lower alkyl); (Hα hydroxy); (H-α OR 1 ), wherein R 1 is an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or ═CHT wherein T is hydrogen, lower alkyl, fluorine, or chlorine; Q is OR 2 wherein R 2 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; hydrogen provided W is (H,H), or (H, lower alkyl); or Q and W together is a 16α,17α-lower alkylidenedioxy; Z is hydrogen, chlorine or bromine; R 3 is hydrogen or an acyl radical of a hydrocarbon-carboxylic acid having up to 20 carbon atoms; or OR 3 together with Q is a member selected from the group consisting of alkylidenedioxy and alkylorthoalkanoate; and when Q is hydroxy and R 3 is hydrogen, the 17α,20;20,21-bismethylenedioxy derivatives thereof; together with a non-toxic pharmaceutically acceptable carrier.
Claim 2
Independent Claim
221 words
The method of eliciting a mitotic inhibitory response in a warm-blooded animal having a disease characterized by rapid cell proliferation which comprises administering to said animal a non-toxic, mitotic inhibitory effective amount of a 19-nor-pregnahexaene-20-one of the following formula I: ##STR3## wherein A is hydrogen, lower alkyl, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl; R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; Y is (H,H), (H,OH), or oxygen; W is (H,H); (H, lower alkyl); (Hα hydroxy); (H-α OR 1 ), wherein R 1 is an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or ═CHT wherein T is hydrogen, lower alkyl, fluorine, or chlorine; Q is OR 2 wherein R 2 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; hydrogen provided W is (H,H), or (H, lower alkyl); or Q and W together is a 16α,17α-lower alkylidenedioxy; Z is hydrogen, chlorine or bromine; R 3 is hydrogen or an acyl radical of a hydrocarbon-carboxylic acid having up to 20 carbon atoms; or OR 3 together with Q is a member selected from the group consisting of alkylidenedioxy and alkylorthoalkanoate; and when Q is hydroxy and R 3 is hydrogen, the 17α,20;20,21-bismethylenedioxy derivatives thereof; together with a non-toxic pharmaceutically acceptable carrier.
Claim 3
Dependent Claim
17 words
The method of claim 1 wherein said disease is a skin disease characterized by rapid cell proliferation.
Claim 4
Dependent Claim
63 words
The method of claim 2 when said 19-nor-pregnahexaene-20-one is administered topically, which is the method of reducing epidermal mitosis in a warm-blooded animal having a skin disease characterized by rapid cell proliferation which comprises applying topically to the affected area in a concentration effective for reducing epidermal mitrosis, a 19-nor-pregnahexaene-20-one of formula I in claim 1, together with a non-toxic, pharmaceutically acceptable carrier.
Claim 5
Dependent Claim
52 words
The method of claim 3 wherein said skin disease is psoriasis, which is the method of treating and controlling psoriasis which comprises applying topically to the affected area in a concentration effective for the treatment of psoriasis, a 19-nor-pregnahexaene-20-one of formula I in claim 1, together with a non-toxic, pharmaceutically acceptable carrier.
Claim 6
Dependent Claim
21 words
The method of claim 4 when carried out with a 1,3,5(10), 6,8,14-19-nor-pregnahexaene-20-one of formula I wherein W is (H, lower alkyl).
Claim 7
Dependent Claim
58 words
The method of claim 5 when carried out with a compound of structural formula II: ##STR4## wherein R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms; R 2 and R 3 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms.
Claim 8
Dependent Claim
31 words
The method of claim 6 when carried out with a 1,3,5(10), 6,8,14-19-nor-pregnahexaene-20-one of formula II wherein R 2 is hydrogen, R 3 is acetyl, and R is hydrogen, acetyl or benzoyl.
Claim 9
Dependent Claim
11 words
The method of claim 6 when carried out with 16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17α,21-triol-20-one 21-acetate.
Claim 10
Dependent Claim
29 words
A pharmaceutical composition for the treatment of psoriasis comprising an anti-psoriatically effective amount of a 19-nor-pregnahexaene-20-one of formula I in claim 1, together with a non-toxic pharmaceutically acceptable carrier.
Claim 11
Dependent Claim
12 words
The composition of claim 9 which is a composition for topical administration.
Claim 12
Dependent Claim
19 words
A topical pharmaceutical composition of claim 10 wherein said 19-nor-pregnahexaene-20-one is a 19-nor-pregnahexaene-20-one of formula II in claim 6.
Claim 13
Dependent Claim
25 words
A composition of claim 11 wherein said 19-nor-pregnahexaene-20-one of formula II in claim 6 is 16α-methyl-1,3,5(10), 6,8,14-19-nor-pregnahexaene-3,17α,21-triol-20-one, or the 21-acetate, 3,21-diacetate or 3-benzoate 21-acetate thereof.
Claim 14
Dependent Claim
20 words
The composition of claim 11 comprising an anti-psoriatically effective amount of 16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17α,21-triol-20-one 21-acetate together with a non-toxic, pharmaceutically acceptable carrier.
Claim 15
Dependent Claim
192 words
A 19-nor-pregnahexaene-20-one of the following formula: ##STR5## wherein A is hydrogen, lower alkyl, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl; R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; Y is (H,H), (H,OH) or oxygen; W is (H,H) provided at least one of Y and Z is other than hydrogen; (H, lower alkyl); (H-α hydroxy); (H-α OR 1 ), wherein R 1 is an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or ═CHT wherein T is hydrogen, lower alkyl, fluorine, or chlorine; Q is OR 2 wherein R 2 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; hydrogen provided W is (H,H), or (H, lower alkyl); or Q and W together is a 16α,17α-lower alkylidenedioxy; Z is hydrogen, chlorine or bromine; R 3 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or OR 3 together with Q is a member selected from the group consisting of alkylidenedioxy and alkylorthoalkanoate; and when Q is hydroxy and R 3 is hydrogen, the 17α,20;20,21-bismethylenedioxy derivatives thereof.
Claim 16
Dependent Claim
192 words
A 19-nor-pregnahexaene-20-one of the following formula: ##STR5## wherein A is hydrogen, lower alkyl, fluoro, fluoromethyl, difluoromethyl, or trifluoromethyl; R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; Y is (H,H), (H,OH) or oxygen; W is (H,H) provided at least one of Y and Z is other than hydrogen; (H, lower alkyl); (H-α hydroxy); (H-α OR 1 ), wherein R 1 is an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or ═CHT wherein T is hydrogen, lower alkyl, fluorine, or chlorine; Q is OR 2 wherein R 2 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; hydrogen provided W is (H,H), or (H, lower alkyl); or Q and W together is a 16α,17α-lower alkylidenedioxy; Z is hydrogen, chlorine or bromine; R 3 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 20 carbon atoms; or OR 3 together with Q is a member selected from the group consisting of alkylidenedioxy and alkylorthoalkanoate; and when Q is hydroxy and R 3 is hydrogen, the 17α,20;20,21-bismethylenedioxy derivatives thereof.
Claim 17
Dependent Claim
11 words
A compound of claim 14 wherein W is (H, lower alkyl).
Claim 18
Dependent Claim
18 words
A compound of claim 14 wherein Y is (H,H), W is (H, lower alkyl), and Z is hydrogen.
Claim 19
Dependent Claim
52 words
A compound of claim 16 of structural formula II: ##STR6## wherein R is hydrogen, lower alkyl, or an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms; R 2 and R 3 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms.
Claim 20
Dependent Claim
21 words
A compound of claim 17 wherein R 2 is hydrogen, R 3 is acetyl, and R is hydrogen, acetyl or benzoyl.
Claim 21
Dependent Claim
9 words
A compound of claim 18 which is 16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-20-one 21-acetate.
Claim 22
Dependent Claim
9 words
A compound of claim 14 which is 15-chloro-16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17.alpha.,21-triol-20-one 21-acetate.
Claim 23
Dependent Claim
57 words
The process for the preparation of a 15-halogeno-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17α,21-triol-20-one of claim 14 which comprises the reaction of the corresponding 15-unsubstituted-1,3,5(10),6,8-19-nor-pregnapentaene-3,17α,21-triol-20-one, in which any 21-hydroxyl group present is protected, in an aprotic solvent with at least two molar equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of at least a molar equivalent of hydrogen halide, said halide being chloride or bromide.
Claim 24
Dependent Claim
28 words
The process of claim 17 wherein any 21-hydroxyl group is protected by a lower alkanoate ester, said aprotic solvent is dioxane, and said hydrogen halide is hydrogen chloride.
Claim 25
Dependent Claim
35 words
The process for the preparation of 15-chloro-16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17.alpha.,21-triol-20-one 21-acetate, which comprises the reaction of 16α-methyl-1,3,5(10),6,8-19-nor-pregnapentaene-3,17α,21-triol-20-one 21-acetate in dioxane with at least two molar equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone and with at least a molar equivalent of hydrogen chloride.
Claim 26
Dependent Claim
35 words
The process for the preparation of 15-chloro-16α-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17.alpha.,21-triol-20-one 21-acetate, which comprises the reaction of 16α-methyl-1,3,5(10),6,8-19-nor-pregnapentaene-3,17α,21-triol-20-one 21-acetate in dioxane with at least two molar equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone and with at least a molar equivalent of hydrogen chloride.
References Cited (Backward Citations)
US3182075A
Cited
US3182057A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1982-10-22 | 1983-04-23 | 1983-10-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1986-10-22 | 1987-04-23 | 1987-10-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1990-10-22 | 1991-04-23 | 1991-10-23 | $7700.00 | Window Closed / Lapsed |