EP0494622A1
Expired / Lapsed
EP
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Bridged cyclic ketal derivatives
Assignee: Glaxo Group Ltd
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Filing: 1992-01-07
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Granted: —
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Expires: 2012-01-07
Abstract
Abstract Compounds are described of the formula wherein R¹ represents a hydrogen atom or a hydroxyl, acyloxy, carbonate, carbamate or ether group; R² represents a hydrogen atom, a hydroxyl group, a group -OCOR⁷ or a group -OCO₂R⁷ (where R⁷ is a group selected from C₁₋₈alkyl, aryl, arylC₁₋₄alkyl and C₃₋₈cycloalkyl); R³ represents a group selected from (where the dotted line represents the absence or presence of a single bond, R⁸ represents a hydrogen atom or a hydroxyl, acyloxy, C₁₋₆alkoxy or C₁₋₄alkyl group, R⁹ represents a hydrogen atom and R¹⁰ represents a hydrogen atom or a hydroxyl, C₁₋₆alkoxy or acyloxy group or CR⁹R¹⁰ forms a group C=0, R¹¹ represents a hydrogen atom or a C₁₋₄alkyl group, R¹² represents a hydrogen atom or a methyl group, R¹³ represents a hydrogen atom or a hydroxyl group, m represents 1 or 2 and n represents zero or 1); R⁴ and R⁵ may each independently represent a hydrogen atom or a methyl group; R⁶ represents a hydrogen atom or a hydroxymethyl group; and salts thereof; with the proviso R¹ and R² cannot both represent hydrogen atoms. These compounds inhibit the enzyme squalene synthase and/or are intermediates for the preparation of compounds which inhibit the enzyme squalene synthase. Compounds of the invention may be formulated for use in a variety of conditions where a lowering of the level of blood plasma cholesterol in animals would be beneficial and for use in combating fungal infections in animals.
Inventors
- 👤 Philip James Sidebottom
- 👤 Charles David Hartley
- 👤 Panayiotis Alexandrou Procopiou
- 👤 Michael George Lester
- 👤 Nigel Stephen Watson
- 👤 Barrie Edward Kirk
- 👤 Brian Cox
- 👤 Suzanne Elaine Roberts
- 👤 Barry Clive Ross
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-22 23:03
CPC Classifications
C; C07; C07D; C07D493/00; C07D493/02; C07D493/08; A; A61; A61P; A61P3/00; A61P3/06; C07H; C07H19/00; C07H19/01; C07H9/00; C07H9/02; C07H9/04; C12; C12P; C12P17/00; C12P17/18; C12P17/181
Claims Analysis
Total Claims: 26
Claim 1
Independent Claim
177 words
Compounds having the formula(I) wherein R¹ represents a hydrogen atom or a hydroxyl, acyloxy, carbonate, carbamate or ether group; R² represents a hydrogen atom, a hydroxyl group, a group -OCOR⁷ or a group -OCO₂R⁷ (where R⁷ is a group selected from C₁₋₈alkyl, aryl, arylC₁₋₄alkyl and C₃₋₈cycloalkyl); R³ represents a group selected from (where the dotted line represents the absence or presence of a single bond, R⁸ represents a hydrogen atom or a hydroxyl, acyloxy, C₁₋₆alkoxy or C₁₋₄alkyl group, R⁹ represents a hydrogen atom and R¹⁰ represents a hydrogen atom or a hydroxyl, C₁₋₆alkoxy or acyloxy group or CR⁹R¹⁰ forms a group C=0, R¹¹ represents a hydrogen atom or a C₁₋₄alkyl group, R¹² represents a hydrogen atom or a methyl group, R¹³ represents a hydrogen atom or a hydroxyl group, m represents 1 or 2 and n represents zero or 1); R⁴ and R⁵ may each independently represent a hydrogen atom or a methyl group; R⁶ represents a hydrogen atom or a hydroxymethyl group; and salts thereof; with the proviso R¹ and R² cannot both represent hydrogen atoms.
Claim 2
Dependent Claim
13 words
Compounds according to Claim 1 in which R⁴ and R⁵ represent hydrogen atoms.
Claim 3
Dependent Claim
15 words
Compounds according to Claim 1 or Claim 2 in which R¹ represents an acyloxy group.
Claim 4
Dependent Claim
15 words
Compounds according to Claim 3 in which R¹ represents a group selected from and alkanoyloxy.
Claim 5
Dependent Claim
16 words
Compounds according to any preceding claim in which R² represents a hydroxy, acetoxy or -OCO₂CH₃ group.
Claim 6
Dependent Claim
10 words
Compounds according to any preceding claim in which R³ represents
Claim 7
Dependent Claim
16 words
Compounds according to any preceding claim in which within R³ the group represents -CH₂CH(CH₃)- or -CH₂C(=0)-.
Claim 8
Dependent Claim
18 words
Compounds according to any preceding claim in which within R³ the group -CR⁹R¹⁰- represents -CH(OH)-, -CH₂- or -CH(OCOCH₃)-.
Claim 9
Dependent Claim
13 words
Compounds according to any preceding claim in which R⁶ represents a hydrogen atom.
Claim 10
Dependent Claim
16 words
Compounds according to any of Claims 1 to 8 in which R⁶ represents a hydroxymethyl group.
Claim 11
Dependent Claim
42 words
[1S-[1α(4R*,5S*),3α,4β,5α,6α(4S*,6R*),7β]] 1-(4-Hydroxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyloctanoate); [1S-[1α(4R*,5S*),4β,5α,6α(2E,4R*,6R*),7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-4,6,7-trihydroxy-2,8-dioxabicyclo [3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyl-2-octenoate); [1S-[1α(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyl-2-octenoate); [1S-[1α(4R*,5S*),3α,4β,5α,6α(4S*,6R*),7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyloctanoate); [1S-[1α(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β]] 1-(4-hydroxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyl-2-octenoate); [1S-[1α(4R*,5S*),3α,4β,5α,6α,7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-heptanoate; [1S-[1α(4R*,5S*),3α,4β,5α,6α,7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-nonanoate; [1S-[1α(4R*,5S*),3α,4β,5α,6α(4R*S*),7β]] 1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4-methyl)pentanoate; [1S-[1α(4R*,5S*),3α,4β,5α,6α(4S*,6R*),7β]] 1-(4-hydroxy-5-methyl-3-oxo-6-phenylhexyl)-3-hydroxymethyl-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylic acid, 6-(4,6-dimethyloctanoate); and physiologically acceptable salts thereof.
Claim 12
Dependent Claim
11 words
A compound according to any preceding claim for use in therapy.
Claim 13
Dependent Claim
31 words
A compound according to any preceding claim for use in the treatment of conditions where a lowering of the level of blood plasma cholesterol in animals, including humans, would be beneficial.
Claim 14
Dependent Claim
25 words
A compound according to any of Claims 1 to 12 for use in the treatment of fungal infections in a human or non-human animal patient.
Claim 15
Independent Claim
50 words
A method of treatment of the human or non-human animal body to combat diseases associated with hypercholesterolemia and/or hyperlipoproteinemia or to combat fungal diseases, which method comprises administering to said body an effective amount of a compound as claimed in any of Claims 1 to 12 which inhibits squalene synthase.
Claim 16
Dependent Claim
22 words
A pharmaceutical composition comprising a compound according to any of Claims 1 to 12 together with one or more carriers and/or excipients.
Claim 17
Dependent Claim
43 words
A pharmaceutical composition comprising an active amount of a compound as claimed in any of Claims 1 to 12 for use in the treatment of conditions where a lowering of the level of blood plasma cholesterol in animals, including humans, would be beneficial.
Claim 18
Dependent Claim
34 words
A pharmaceutical composition comprising an active amount of a compound as claimed in any of Claims 1 to 12 for use in the treatment of fungal infections in a human or non-human animal patient.
Claim 19
Dependent Claim
38 words
A pharmaceutical composition according to any one of Claims 16 to 18 in a form suitable for oral, buccal, topical, parenteral, implant, rectal, ophthalmic or genito-urinary administration or in a form suitable for administration by inhalation or insufflation.
Claim 20
Dependent Claim
16 words
A pharmaceutical composition according to any one of Claims 16 to 19 in unit dosage form.
Claim 21
Dependent Claim
32 words
Use of a compound according to any of Claims 1 to 12 in the manufacture of a medicament for the treatment of hpercholesterolemia and/or hyperlipoproteinemia in a human or non-human animal patient.
Claim 22
Dependent Claim
31 words
Use of a compound according to any of Claims 1 to 12 in the manufacture of a medicament for the treatment of fungal infections in a human or non-human animal patient.
Claim 23
Dependent Claim
463 words
A process for the preparation of a compound as claimed in Claim 1 which comprises : (A) (in the preparation of compounds of formula (I) in which R⁶ represents a hydrogen atom) reacting a compound of formula (II) (wherein R¹, R² and R³ are as defined in Claim 1 and R 4a and R 5a are protecting groups) to remove the group t-BuO₃C by reduction under free radical conditions, followed by removal of the protecting groups present; (B) (in the preparation of compounds of formula (I) in which R⁶ represents a hydroxymethyl group) reacting a compound of formula (III) (wherein R¹, R², R³, R 4a and R 5a are as defined herein) to reduce the 3-carboxyl group to a hydroxymethyl group, followed by removal of the protecting groups present; (C) (in the preparation of compounds of formula (I) in which R³ represents a group -CH=CR⁸CR⁹R¹⁰CHR¹¹(CH₂) m Ph or a group -CH₂CR¹²=CR¹¹CR⁹R¹⁰CHR¹¹(CH₂) n Ph where R⁸ is hydrogen or C₁₋₄alkyl) reacting a compound of formula (V) (wherein R 3a represents CHO or CH₂COR¹² as appropriate, R¹ and R² are as defined in Claim 1, R 4a and R 5a are as defined for R⁴ and R⁵ in Claim 1 or are protecting groups and R 6a is as defined for R⁶ in Claim 1 or is a protected hydroxymethyl group) with a compound of formula (VIa) or (VIb) as appropriate (wherein R¹¹ is as defined in Claim 1, R⁸ is hydrogen or C₁₋₄alkyl, CR⁹R¹⁰ forms a group C=0 and R represents a C₁₋₆alkyl group or an aryl group), and thereafter removing any protecting groups present; (D) converting a compound of formula (I) or a protected derivative thereof to a different compound of formula (I) or a protected derivative thereof, followed, if necessary, by the removal of any protecting groups present; (E) (in the preparation of compounds of formula (I) in which R² represents a group -OCOR⁷ or -OCO₂R⁷) reacting a compound of formula (XII) (wherein R¹ is as defined in Claim 1, R 3b is as defined for R³ in Claim 1 or is a protected derivative thereof and R 4a , R 5a and R 6a are as defined herein) under conditions for ester or carbonate formation, followed by removal of the protecting groups present; or (F) (in the preparation of compounds of formula (I) in which R¹ represents an acyloxy, carbonate, carbamate or ether group) reacting a compound of formula (XIII) (wherein R 2a is as defined for R² in Claim 1 or is a protected hydroxyl group, R 3b and R 4a -R 6a are as defined herein and R¹⁸ is a hydroxyl group or a protected hydroxyl group) to convert the 6-position hydroxyl group to an acyloxy, carbonate, carbamate or ether group, followed by removal of any protecting groups present.
Claim 24
Dependent Claim
9 words
Compounds of formulae (II), (V) and (VII) to (XVI).
Claim 25
Dependent Claim
13 words
Compounds according to any of Claims 1 to 12 substantially as herein described.
Claim 26
Dependent Claim
14 words
Compositions according to any one of Claims 16 to 20 substantially as herein described.
References Cited (Backward Citations)
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