CA2136183A1 - Spiro-oxetanes, processes for their production and pharmaceutical agents - Google Patents
Spiro-oxetanes, processes for their production and pharmaceutical agentsInfo
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- CA2136183A1 CA2136183A1 CA002136183A CA2136183A CA2136183A1 CA 2136183 A1 CA2136183 A1 CA 2136183A1 CA 002136183 A CA002136183 A CA 002136183A CA 2136183 A CA2136183 A CA 2136183A CA 2136183 A1 CA2136183 A1 CA 2136183A1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract Pharmaceutical agents containing a compound of formula I
in addition to the conventional carrier and auxiliary substances
in addition to the conventional carrier and auxiliary substances
Description
-` 2136183 Boehringer Mannheim GmbH
Spiro-oxetanes Processes for their production and Pharmaceutical aqents The present invention concerns pharmaceutical agents which contain spiro-oxetane derivatives, processes for their production as well as new spiro-oxetane derivatives. ~ :
The invention concerns pharmaceutical agents which contain spiro-oxetane derivatives of the general ~
formula I :~ .
B ~
in which :
;
A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or .
Cl-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or ` :~
X denotes the group -CH20- and Y is a valency bond and R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C3-C6 lactone residue their enantiomers, diastereomers and racemates.
The compounds of the general formula I have valuable pharmacological properties, they can in particular inhibit the activity of phospholipases. They are therefore suitable for treating acute and chronic allergic, non-allergic and traumatic inflammatory diseases such as for example rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis and inflammatory respiratory tract diseases.
Some spiro-oxetanes are known from Liebigs Ann. Chem.
1988, 869 without, however, a statement regarding a pharmaceutical action.
The invention therefore also concerns new spiro-oxetanes of the general formula I
:
AB ~ ~ (I) in which ., A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH20- and Y is a valency bond and ~ -:
R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C5-C6 lactone residue their enantiomers, diastereomers and racemates.
Furthermore the invention concerns new spiro-oxetanes of formula I in which :~
A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, Cl-C6 alkyl or C1-C6 alkoxy, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH20- and Y is a valency bond and.
R denotes a spiro-linked C3 or C4 lactone residue .
, ~''' `.. : ;: `
,, .
their enantiomers, diastereomers and racemates as well as the compound 1,5-dioxadispiro[3.1.5.1]dodeca-7,10-dien-9-one.
The alkyl residues in the aforementioned groups can be straight-chained or branched. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl and 3-pentyl residues.
Alkoxy preferably denotes methoxy, ethoxy, propoxy or butoxy.
Halogen atoms are in particular fluorine, chlorine and bromine.
Cycloalkyl residues preferably denote cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
~-Propiolactone, ~-butyrolactone, ~-valerolactone and ~-caprolactone come into consideration as the lactone residue.
Apart from the compounds mentioned in the examples, all substances are in particular a subject matter of the invention which have every possible combination of the substituents mentioned in the examples.
The process according to the invention for the production of compounds of formula I is characterized in that either :. ~ ' - . ~ ' !
~"~,. . .
`' ~ . ~ ' . ' ' ' :. '`,, ~ '. ~ ' ' :' a) a compound of the general formula II
= (II), B/
in which A and B have the above-mentioned meaning .: :' ;
is reacted with a compound of the general formula III :~
~ .
H2C= ~ (III), in which ~ has the meaning stated above or b) a compound of the general formula IV
'~' A
\ =CH2 (IV), B
in which A and B have the meaning stated above is reacted with a compound of the general formula V
O= (~) (V), ", ~
in which ~ has the meaning stated above, the reaction mixture obtained is processed, the compounds of formula I are isolated and subsequently if .:,., : : . .
,, ~ .~ .
;., :, .. .
,~ ., ' desired the compounds I obtained are resolved into their enantiomers or diastereomers.
It is expedient to react compounds of formula II with compounds of formula III or compounds of formula IV with compounds of formula V in a solvent such as for example a halogenated hydrocarbon such as dichloromethane, chloroform, tetrachloromethane or trichloroethane with exposure to light such as for example sunlight, incandescent light, W light or W/VIS laser light.
The resolution of racemates into enantiomers or diastereomers can be carried out chromatographically on suitable optically active phases with common eluting agents. Optically active polyacrylamides or polymethacrylamides and to a certain extent also silica gel (e.g. ChiraSpher~ from Merck, Chiralpak~ OT/OP from Baker), cellulose esters/carbamates (e.g. Chiracel~
OB/OY from Baker/Daicel), phases based on cyclodextrin or crown ethers (e.g. Crownpak~ from Daicel) or microcrystalline cellulose triacetate (Merck) are for example suitable as the optically active phases.
The starting compounds II, III, IV and V are substances known from the literature or can be produced analogously to processes known from the literature.
For the production of pharmaceutical agents, the ``
compounds of the general formula I are mixed in a well-known manner with suitable pharmaceutical carrier substances, aroma substances, flavourings and dyes and are for examples formed into tablets or coated tablets or are suspended or dissolved in water or oil such as e.g. olive oil with addition of appropriate auxiliary ~ .. . . . .
, ~ -. . . -,, ~.. . .
.~, ........................... .
., ~, .
substances.
The substances of the general formula I can be administered orally and parenterally in a liquid or solid form. Water is preferably used as an injection medium which contains the usual stabilizers, solubilizers andtor buffers for injection solutions.
Such additives are e.g. tartrate or borate buffer, ethanol, dimethylsulfoxide, complexing agents (such as ethylenediamine tetraacetic acid), high molecular polymers tsuch as liquid polyethylene oxide) to regulate viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier substances are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular polymers (such as polyethylene glycols).
Suitable preparations for oral administration can if desired, contain flavourings and sweeteners. For external application the substances I according to the invention can also be used in the form of powders and ~ ;
ointments. For this they are for example mixed with physiologically tolerated diluents in the form of powders or with common ointment bases.
The administered dose depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments that may be going on at the same time, the frequency of treatments and the type of desired effect. Usually the daily dose of the active ~ ~-compound is 0.1 to 50 mg/kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg/kg/day in one or several administrations per day are effective in order to obtain the desired results.
Apart from the substances mentioned in the examples the following compounds are preferred within the sense of the present invention:
6-oxadispiro[4.1.5.1]trideca-8,11-dien-10-one 2,6-dioxadispiro[4.1.5.1]trideca-8,11-dien-1,10-dione 2,2-di-~4-methoxy-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-methoxy-phenyl)-2,5-dioxaspiro[3.4]octan-6-one 2,2-di-(4-methyl-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-methyl-phenyl)-2,5-dioxaspiro[3.4]octan-6-one 2,2-di-(4-chloro-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-chloro-phenyl)-2,5-dioxaspiro[3.4]octan-6-one ., ":, . .:
.. ~., ., , . ::
. :
ExamPle 1.6-dioxadisPiror4.1.5.1ltrideca-8.11-dien-2.10-dione A solution of 6 ml (66 mmol) methylene- -butyrolactone and 7.2 g (66 mmol) p-benzoquinone in 400 ml tetra-chloromethane is irradiated at 0 to 5C for 7 hours with - -W light. The supernatant is removed by filtration and purified on silica gel (eluting agent isohexane:ethyl acetate 3:1). After triturating with ether, 2.2 g of the title compound (16 % of theory) remains with a melting point of 156 - 158C.
Example 2 :
In an analogous manner to that described in example 1 the following are obtained from p-benzoquinone and the ~
respective methylene compound : ~`
Name Yield Melting point C ~ ,~
% (solvent) ; : . ~, a) 4-oxadispiro[2.1.5.1]undeca- 11 oil 6,9-dien-8-one _ (fraction 1) as well as b) 10-oxadispiro~2Ø5.2lundeca- 9 oil 5,8-dien-7-one (fraction 2) from methylenecyclopropane , ., c) 5-oxadispiro[3.1.5.1]dodeca- 8 oil 7,10-dien-9-one from methylenecyclobutane . , , ~ -i d) l,5-dioxadispirot3.1.5.1]- 12 70-72 dodeca-7,10-dien-2,9-dione from diketene ~-. . .
Example 3 In an analogous manner to that described in example 1 2,2-diphenyl-1,5-dioxaspiro[3.4]-octan-6-one of melting point 130 - 132C in a yield of 11 % and l,l-diphenyl-2,5-dioxaspiro[3.4]octan-6-one of melting point 138 -140C in a yield of 14 % are obtained from benzophenone and methylene- -butyrolactone.
.., .; - ~
i .":: : :
, .
Pharmacoloqical tests Effects of spiro-oxetanes The present invention concerns pharmaceutical agents for the treatment of acute and chronic diseases of inflammatory, immunological, allergic, non-allergic or traumatic origin.
Since phospholipase A2 (PLA2) is a key enzyme in the genesis of these diseases, these diseases are effectively controlled by its inhibition.
,-The spiro-oxetanes are PLA2 inhibitors which are superior in their profile of action to the introduced -~
and therapeutically reliable cyclooxygenase inhibitors.
For comparison a typical CO inhibitor was selected i.e.
indomethacin. -~
1) Inhibition of PLA2 --~ Human recombinant type II PLA2 (= synovial PLA2) -was used for testing as a typical PLA2 representative.
Table 1 contains the percentage in-vitro inhibition of this enzyme by the compound of example 1, a spiro-oxetane representative. The enzyme is inhibited dose-dependently by up to 93 ~.
Compared to this one can see in Table 1 that indomethacin also inhibits the enzyme, however, only by 52 % at the highest concentration. This already documents a superiority.
2) Inhibition of collaqen-induced AA releas~ from human thrombocytes Inhibition of AA release from thrombocytes also serves as a further indicator for PLA2 inhibition.
For this purpose thrombocytes are incubated with 3H-AA. This added radioactive arachidonic acid is incorporated into membrane phospholipids.
Subsequently thrombocytic PLA2 is activated by means of the collagen receptor and in this manner 3H-AA is again released from the phospholipids into the medium in which it can be quantified.
Table 1 shows that the collagen-induced release of AA is inhibited dose-dependently by the compound of example 1, in which case the inhibition was complete at 100 % at the highest concentration of the inhibitor. In contrast indomethacin only shows a 23 % inhibition at the highest concentration.
The lower inhibition of rh sPLA2 as well as of AA
release by indomethacin already illustrates that this structure does not have a significant PLA2 inhibitory action. In contrast the spiro-oxetane representative completely inhibits the enzyme and AA release and is therefore superior.
_ ... . ... . .
.......... ., ~
: . :- . -. .
.
Tab. 1 Comparison of the spectrum of action of the compound of example 1 and indomethacin Substance PLA2 a) AA b) in % in % .
Example 1 100 ~g/ml 93 100 - -10 ~g/ml 37 86 1 ~g/ml 11 42 .. ,,~
Indomethacin 100 ~g/ml 52 23 10 ~g/ml 10 18 1 ~g/ml 0 6 :
a) Inhibition of the enzyme activity (human recombinant type II PLA2) b) Inhibition of collagen-induced arachidonic acid release -::~
Spiro-oxetanes Processes for their production and Pharmaceutical aqents The present invention concerns pharmaceutical agents which contain spiro-oxetane derivatives, processes for their production as well as new spiro-oxetane derivatives. ~ :
The invention concerns pharmaceutical agents which contain spiro-oxetane derivatives of the general ~
formula I :~ .
B ~
in which :
;
A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or .
Cl-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or ` :~
X denotes the group -CH20- and Y is a valency bond and R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C3-C6 lactone residue their enantiomers, diastereomers and racemates.
The compounds of the general formula I have valuable pharmacological properties, they can in particular inhibit the activity of phospholipases. They are therefore suitable for treating acute and chronic allergic, non-allergic and traumatic inflammatory diseases such as for example rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis and inflammatory respiratory tract diseases.
Some spiro-oxetanes are known from Liebigs Ann. Chem.
1988, 869 without, however, a statement regarding a pharmaceutical action.
The invention therefore also concerns new spiro-oxetanes of the general formula I
:
AB ~ ~ (I) in which ., A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH20- and Y is a valency bond and ~ -:
R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C5-C6 lactone residue their enantiomers, diastereomers and racemates.
Furthermore the invention concerns new spiro-oxetanes of formula I in which :~
A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, Cl-C6 alkyl or C1-C6 alkoxy, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH20- and Y is a valency bond and.
R denotes a spiro-linked C3 or C4 lactone residue .
, ~''' `.. : ;: `
,, .
their enantiomers, diastereomers and racemates as well as the compound 1,5-dioxadispiro[3.1.5.1]dodeca-7,10-dien-9-one.
The alkyl residues in the aforementioned groups can be straight-chained or branched. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl and 3-pentyl residues.
Alkoxy preferably denotes methoxy, ethoxy, propoxy or butoxy.
Halogen atoms are in particular fluorine, chlorine and bromine.
Cycloalkyl residues preferably denote cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
~-Propiolactone, ~-butyrolactone, ~-valerolactone and ~-caprolactone come into consideration as the lactone residue.
Apart from the compounds mentioned in the examples, all substances are in particular a subject matter of the invention which have every possible combination of the substituents mentioned in the examples.
The process according to the invention for the production of compounds of formula I is characterized in that either :. ~ ' - . ~ ' !
~"~,. . .
`' ~ . ~ ' . ' ' ' :. '`,, ~ '. ~ ' ' :' a) a compound of the general formula II
= (II), B/
in which A and B have the above-mentioned meaning .: :' ;
is reacted with a compound of the general formula III :~
~ .
H2C= ~ (III), in which ~ has the meaning stated above or b) a compound of the general formula IV
'~' A
\ =CH2 (IV), B
in which A and B have the meaning stated above is reacted with a compound of the general formula V
O= (~) (V), ", ~
in which ~ has the meaning stated above, the reaction mixture obtained is processed, the compounds of formula I are isolated and subsequently if .:,., : : . .
,, ~ .~ .
;., :, .. .
,~ ., ' desired the compounds I obtained are resolved into their enantiomers or diastereomers.
It is expedient to react compounds of formula II with compounds of formula III or compounds of formula IV with compounds of formula V in a solvent such as for example a halogenated hydrocarbon such as dichloromethane, chloroform, tetrachloromethane or trichloroethane with exposure to light such as for example sunlight, incandescent light, W light or W/VIS laser light.
The resolution of racemates into enantiomers or diastereomers can be carried out chromatographically on suitable optically active phases with common eluting agents. Optically active polyacrylamides or polymethacrylamides and to a certain extent also silica gel (e.g. ChiraSpher~ from Merck, Chiralpak~ OT/OP from Baker), cellulose esters/carbamates (e.g. Chiracel~
OB/OY from Baker/Daicel), phases based on cyclodextrin or crown ethers (e.g. Crownpak~ from Daicel) or microcrystalline cellulose triacetate (Merck) are for example suitable as the optically active phases.
The starting compounds II, III, IV and V are substances known from the literature or can be produced analogously to processes known from the literature.
For the production of pharmaceutical agents, the ``
compounds of the general formula I are mixed in a well-known manner with suitable pharmaceutical carrier substances, aroma substances, flavourings and dyes and are for examples formed into tablets or coated tablets or are suspended or dissolved in water or oil such as e.g. olive oil with addition of appropriate auxiliary ~ .. . . . .
, ~ -. . . -,, ~.. . .
.~, ........................... .
., ~, .
substances.
The substances of the general formula I can be administered orally and parenterally in a liquid or solid form. Water is preferably used as an injection medium which contains the usual stabilizers, solubilizers andtor buffers for injection solutions.
Such additives are e.g. tartrate or borate buffer, ethanol, dimethylsulfoxide, complexing agents (such as ethylenediamine tetraacetic acid), high molecular polymers tsuch as liquid polyethylene oxide) to regulate viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier substances are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular polymers (such as polyethylene glycols).
Suitable preparations for oral administration can if desired, contain flavourings and sweeteners. For external application the substances I according to the invention can also be used in the form of powders and ~ ;
ointments. For this they are for example mixed with physiologically tolerated diluents in the form of powders or with common ointment bases.
The administered dose depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments that may be going on at the same time, the frequency of treatments and the type of desired effect. Usually the daily dose of the active ~ ~-compound is 0.1 to 50 mg/kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg/kg/day in one or several administrations per day are effective in order to obtain the desired results.
Apart from the substances mentioned in the examples the following compounds are preferred within the sense of the present invention:
6-oxadispiro[4.1.5.1]trideca-8,11-dien-10-one 2,6-dioxadispiro[4.1.5.1]trideca-8,11-dien-1,10-dione 2,2-di-~4-methoxy-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-methoxy-phenyl)-2,5-dioxaspiro[3.4]octan-6-one 2,2-di-(4-methyl-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-methyl-phenyl)-2,5-dioxaspiro[3.4]octan-6-one 2,2-di-(4-chloro-phenyl)-1,5-dioxaspiro[3.4]octan-6-one 1,1-di-(4-chloro-phenyl)-2,5-dioxaspiro[3.4]octan-6-one ., ":, . .:
.. ~., ., , . ::
. :
ExamPle 1.6-dioxadisPiror4.1.5.1ltrideca-8.11-dien-2.10-dione A solution of 6 ml (66 mmol) methylene- -butyrolactone and 7.2 g (66 mmol) p-benzoquinone in 400 ml tetra-chloromethane is irradiated at 0 to 5C for 7 hours with - -W light. The supernatant is removed by filtration and purified on silica gel (eluting agent isohexane:ethyl acetate 3:1). After triturating with ether, 2.2 g of the title compound (16 % of theory) remains with a melting point of 156 - 158C.
Example 2 :
In an analogous manner to that described in example 1 the following are obtained from p-benzoquinone and the ~
respective methylene compound : ~`
Name Yield Melting point C ~ ,~
% (solvent) ; : . ~, a) 4-oxadispiro[2.1.5.1]undeca- 11 oil 6,9-dien-8-one _ (fraction 1) as well as b) 10-oxadispiro~2Ø5.2lundeca- 9 oil 5,8-dien-7-one (fraction 2) from methylenecyclopropane , ., c) 5-oxadispiro[3.1.5.1]dodeca- 8 oil 7,10-dien-9-one from methylenecyclobutane . , , ~ -i d) l,5-dioxadispirot3.1.5.1]- 12 70-72 dodeca-7,10-dien-2,9-dione from diketene ~-. . .
Example 3 In an analogous manner to that described in example 1 2,2-diphenyl-1,5-dioxaspiro[3.4]-octan-6-one of melting point 130 - 132C in a yield of 11 % and l,l-diphenyl-2,5-dioxaspiro[3.4]octan-6-one of melting point 138 -140C in a yield of 14 % are obtained from benzophenone and methylene- -butyrolactone.
.., .; - ~
i .":: : :
, .
Pharmacoloqical tests Effects of spiro-oxetanes The present invention concerns pharmaceutical agents for the treatment of acute and chronic diseases of inflammatory, immunological, allergic, non-allergic or traumatic origin.
Since phospholipase A2 (PLA2) is a key enzyme in the genesis of these diseases, these diseases are effectively controlled by its inhibition.
,-The spiro-oxetanes are PLA2 inhibitors which are superior in their profile of action to the introduced -~
and therapeutically reliable cyclooxygenase inhibitors.
For comparison a typical CO inhibitor was selected i.e.
indomethacin. -~
1) Inhibition of PLA2 --~ Human recombinant type II PLA2 (= synovial PLA2) -was used for testing as a typical PLA2 representative.
Table 1 contains the percentage in-vitro inhibition of this enzyme by the compound of example 1, a spiro-oxetane representative. The enzyme is inhibited dose-dependently by up to 93 ~.
Compared to this one can see in Table 1 that indomethacin also inhibits the enzyme, however, only by 52 % at the highest concentration. This already documents a superiority.
2) Inhibition of collaqen-induced AA releas~ from human thrombocytes Inhibition of AA release from thrombocytes also serves as a further indicator for PLA2 inhibition.
For this purpose thrombocytes are incubated with 3H-AA. This added radioactive arachidonic acid is incorporated into membrane phospholipids.
Subsequently thrombocytic PLA2 is activated by means of the collagen receptor and in this manner 3H-AA is again released from the phospholipids into the medium in which it can be quantified.
Table 1 shows that the collagen-induced release of AA is inhibited dose-dependently by the compound of example 1, in which case the inhibition was complete at 100 % at the highest concentration of the inhibitor. In contrast indomethacin only shows a 23 % inhibition at the highest concentration.
The lower inhibition of rh sPLA2 as well as of AA
release by indomethacin already illustrates that this structure does not have a significant PLA2 inhibitory action. In contrast the spiro-oxetane representative completely inhibits the enzyme and AA release and is therefore superior.
_ ... . ... . .
.......... ., ~
: . :- . -. .
.
Tab. 1 Comparison of the spectrum of action of the compound of example 1 and indomethacin Substance PLA2 a) AA b) in % in % .
Example 1 100 ~g/ml 93 100 - -10 ~g/ml 37 86 1 ~g/ml 11 42 .. ,,~
Indomethacin 100 ~g/ml 52 23 10 ~g/ml 10 18 1 ~g/ml 0 6 :
a) Inhibition of the enzyme activity (human recombinant type II PLA2) b) Inhibition of collagen-induced arachidonic acid release -::~
Claims (6)
1. Pharmaceutical agents containing a compound of formula I in addition to conventional carrier and auxiliary substances (I) in which A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH2O- and Y is a valency bond and R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C3-C6 lactone residue, their enantiomers, diastereomers and racemates.
2. Use of compounds of formula I as claimed in claim 1 for the treatment of acute and chronic allergic, non-allergic and traumatic inflammatory diseases.
3. Compounds of formula I
(I) in which A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH2O- and Y is a valency bond and R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C5 or C6 lactone residue, their enantiomers, diastereomers and racemates.
(I) in which A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy or together denote the group -CH=CH-CO-CH=CH-, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH2O- and Y is a valency bond and R denotes a spiro-linked C3-C6 cycloalkane residue or a spiro-linked C5 or C6 lactone residue, their enantiomers, diastereomers and racemates.
4. Compounds of formula I
(I), in which A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH2O- and Y is a valency bond and R denotes a spiro-linked C3 or C4 lactone residue, their enantiomers, diastereomers and racemates.
(I), in which A and B which are the same or different, each denote a phenyl residue which is substituted if desired, by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy, X denotes oxygen and Y denotes a methylene group or X denotes the group -CH2O- and Y is a valency bond and R denotes a spiro-linked C3 or C4 lactone residue, their enantiomers, diastereomers and racemates.
5. 5-dioxadispiro[3.1.5.1]-dodeca-7,10-dien-2,9-dione.
6. Process for the production of compounds of formula I as claimed in one of the claims 3 to 5, wherein either a) a compound of the general formula II
(II), in which A and B have the above-mentioned meaning is reacted in a well-known manner with a compound of the general formula III
(III) in which ? has the meaning stated above or b) a compound of the general formula IV
(IV) in which A and B have the meaning stated above is reacted in a well-known manner with a compound of the general formula V
(V) in which ? has the meaning stated above, the reaction mixture obtained is processed, the compounds of formula I are isolated and subsequently if desired the compounds I obtained are resolved into their enantiomers or diastereomers.
(II), in which A and B have the above-mentioned meaning is reacted in a well-known manner with a compound of the general formula III
(III) in which ? has the meaning stated above or b) a compound of the general formula IV
(IV) in which A and B have the meaning stated above is reacted in a well-known manner with a compound of the general formula V
(V) in which ? has the meaning stated above, the reaction mixture obtained is processed, the compounds of formula I are isolated and subsequently if desired the compounds I obtained are resolved into their enantiomers or diastereomers.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4218096.1 | 1992-06-02 | ||
| DE4218096A DE4218096A1 (en) | 1992-06-02 | 1992-06-02 | Spiro-oxetanes, process for their preparation and medicines |
| PCT/EP1993/001356 WO1993024492A1 (en) | 1992-06-02 | 1993-05-29 | Spiro-oxetanes, process for preparing the same and medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2136183A1 true CA2136183A1 (en) | 1993-12-09 |
Family
ID=6460179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136183A Abandoned CA2136183A1 (en) | 1992-06-02 | 1993-05-29 | Spiro-oxetanes, processes for their production and pharmaceutical agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0643712B1 (en) |
| JP (1) | JPH08500337A (en) |
| AT (1) | ATE160568T1 (en) |
| AU (1) | AU4319893A (en) |
| CA (1) | CA2136183A1 (en) |
| DE (2) | DE4218096A1 (en) |
| WO (1) | WO1993024492A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999057100A1 (en) | 1998-05-01 | 1999-11-11 | Eli Lilly And Company | Spla2 inhibitor compounds for treatment of disease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH613699A5 (en) * | 1976-01-06 | 1979-10-15 | Givaudan & Cie Sa | Process for the preparation of theaspiron |
-
1992
- 1992-06-02 DE DE4218096A patent/DE4218096A1/en not_active Withdrawn
-
1993
- 1993-05-29 JP JP6500209A patent/JPH08500337A/en active Pending
- 1993-05-29 DE DE59307746T patent/DE59307746D1/en not_active Expired - Fee Related
- 1993-05-29 WO PCT/EP1993/001356 patent/WO1993024492A1/en active IP Right Grant
- 1993-05-29 AU AU43198/93A patent/AU4319893A/en not_active Abandoned
- 1993-05-29 CA CA002136183A patent/CA2136183A1/en not_active Abandoned
- 1993-05-29 AT AT93912829T patent/ATE160568T1/en not_active IP Right Cessation
- 1993-05-29 EP EP93912829A patent/EP0643712B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08500337A (en) | 1996-01-16 |
| DE59307746D1 (en) | 1998-01-08 |
| DE4218096A1 (en) | 1993-12-09 |
| EP0643712B1 (en) | 1997-11-26 |
| ATE160568T1 (en) | 1997-12-15 |
| WO1993024492A1 (en) | 1993-12-09 |
| EP0643712A1 (en) | 1995-03-22 |
| AU4319893A (en) | 1993-12-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |