WO1992005788A1 - New phosphonate derivatives as lipase agents inhibiting - Google Patents

New phosphonate derivatives as lipase agents inhibiting Download PDF

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Publication number
WO1992005788A1
WO1992005788A1 PCT/DK1991/000307 DK9100307W WO9205788A1 WO 1992005788 A1 WO1992005788 A1 WO 1992005788A1 DK 9100307 W DK9100307 W DK 9100307W WO 9205788 A1 WO9205788 A1 WO 9205788A1
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Prior art keywords
carbon atoms
alkyl group
stated
halogen
nitro
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PCT/DK1991/000307
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French (fr)
Inventor
Fredrik Björkling
Shamkant Anant Patkar
Original Assignee
Novo Nordisk A/S
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Publication of WO1992005788A1 publication Critical patent/WO1992005788A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/42—Halides thereof
    • C07F9/425—Acid or estermonohalides thereof, e.g. RP(=X)(YR)(Hal) (X, Y = O, S; R = H, or hydrocarbon group)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds

Definitions

  • This invention relates to the use of compounds of formula I stated in Claim 1 below as lipase inhibiting agents, for example as medicaments.
  • Phospholipid analogues containing a fluorinated ketone as a replacement for the ester are potent phospho ⁇ lipase A 2 inhibitors, vide J.Am.Chem.Soc. 109 (1987), 8071.
  • a class of phospholipid analogues containing a phosphonated group in place of the ester at the 2-position of the glycerol backbone were shown to be binding inhibitors of phospholipase A 2 from cobra venom, vide J.A .Che .Soc. 110 (1988), 2665.
  • Phospholipase A 2 and lipases are mechanistically very different.
  • This invention relates to the use of compounds of formula I stated in Claim 1 below as lipase inhibiting agents. It is surprising that these compounds have interest- ing properties such as lipase inhibiting action. For example, some compounds of formula I have about 100 to 1000 times better efficacy than the known bis-p-nitrophenyl- ethylphosphonate.
  • lipase inhibiting com ⁇ pounds can be used to determine the active center of a lipase in question, which is import ⁇ ant for the further development of improved lipases.
  • lipase inhibiting compounds can be added to detergents con- taining lipases in order to improve the stability of such detergents during the storage thereof.
  • examples of icro- bial, fungal, bacterial and yeast as well as human lipases which can be inhibited by the compounds of this invention are lipases from Mucor M. , Pseudomonas C. , Candida A. and Humicola L.
  • the lipase inhibiting compounds of this invention may, for example, be used in the treatment of acne, or to regulate the uptake of fat by inhibition of the gastric lipases.
  • Such medical preparations are prepared by methods which are known per se by the skilled art ⁇ >rker.
  • Examples of specific, interesting compounds of for ⁇ mula I are as follows: butylphosphonochloridate methyl ester, butylphosphonochloridate ethyl ester, butylphosphono ⁇ chloridate propyl ester, butylphosphonochloridate butyl ester, hexylphosphonochloridate methyl ester, hexylphospho ⁇ utilizatloridate ethyl ester, hexylphosphonochloridate propyl ester, hexylphosphonochloridate butyl ester, octylphosphono- chloridate methyl ester, octylphosphonochloridate ethyl ester, octylphosphonochloridate propyl ester, octylphospho- istloridate butyl ester, decylphosphonochloridate methyl ester, decylphosphonochloridate ethyl ester, decylphosphono- chlor
  • Compounds of formula I are effective in the treat ⁇ ment of acne and as antilipemic agents.
  • the compounds of formula I may be administered orally or parenterally in a single dose or divided doses of, for example, from 1 mg to 1 g, preferably from 20 mg to 200 mg, a day for oral administration or from 1 mg to 100 mg, preferably from 1 mg to 10 mg, for parenteral adminstration.
  • the compounds of formula I may be ad- ministered topically.
  • Such administration may be in the form of a powder, a cream, an ointment, a suspension, a gel or a solution, for example, in a base cream.
  • Such preparations are prepared analogously to the preparation of similar preparations, vide, for example, German Offenle ⁇ un ⁇ sschrift No. 3,018,114 and British Patent Application No. 8136777, the content of which is both incorporated by reference.
  • Medical preparations containing a compound of for ⁇ mula I are to be administered as prescribed by the physician similarly with the administation of similar medicaments. Any novel feature or combination of features de ⁇ scribed herein is considered essential to this invention.
  • Lipase from the C.antarctica B component was in- cubated with a varying concentration of the inhibitor, where the enzyme concentration was 20 ⁇ M.
  • the lipase activity was measured with glycerine tributyrine as substrate in the emulsion.
  • the esterase activity was measured with p-nitro- phenyl acetate as substrate. The results appear from the following table.
  • Example 3 Analogously as described in Example 3, the six different microbial lipases mentioned below were investigated and all six lipases were inhibited with n-hexylchlorophosphonate ethyl ester.
  • H.lanuqinosa f 2) M.miehei. 3) C.cylindracea. 4) P.cepacia. 5) C.antarctica A component and 6) C.antarctica B component.
  • Octanoyl, decanoyl and dodecanoyl chlorophosphonate ethyl ester inhibit all the lipases.
  • dodecanoylchlorophosphonate ethyl ester using M.miehei lipase.
  • concentration of M.miehei lipase during the incubation with the inhibitor was 25 ⁇ M and the inhibi ⁇ tor concentration was varied.
  • n-hexylchlorophosphonate ethyl ester did not inhibit phospholipase A 2 whereas p-bromophenacyl bromide inhibited phospholipases A 2 activity measured by titrimetric assay using chicken egg yolk as substrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of the formula R-(R2=)P(X)-OR1 wherein R is an optionally substituted alkyl group, R1 is an optionally substituted alkyl group or an optionally substituted phenyl group, R2 is oxygen or sulphur, and X is a leaving group, can be used as lipase inhibiting agents.

Description

New phosphonate derivatives as Lipase agents inhibiting.
This invention relates to the use of compounds of formula I stated in Claim 1 below as lipase inhibiting agents, for example as medicaments.
BACKGROUND OF THIS INVENTION
The design of specific inhibitors of various classes of enzymes, such as lipases, is a topic of intense biochemical as well as medical interest.
Phospholipid analogues containing a fluorinated ketone as a replacement for the ester are potent phospho¬ lipase A2 inhibitors, vide J.Am.Chem.Soc. 109 (1987), 8071. A class of phospholipid analogues containing a phosphonated group in place of the ester at the 2-position of the glycerol backbone were shown to be binding inhibitors of phospholipase A2 from cobra venom, vide J.A .Che .Soc. 110 (1988), 2665. Phospholipase A2 and lipases (for example tri- acylglycerollipases) are mechanistically very different.
Very few lipase inhibiting compounds are known. Compounds inhibiting pancreas lipase are known from European patent application No. 84106420.7 (publication No. 129,748) such compounds being lipstatin and tetrahydrolipstatin (formamidomethylvaleryloxylhexylhydroxyhexadecanoic acid lactone) .
According to Bioorσanic Chemistry 14 (1986), 357, the stereochemical dependency of reactivity of agents with stereocenters at phosphorus has been studied in case of the protease chymotrypsin with (CH3)3C-C(CH3)H-0-PO(F)-CH3. According to Biochemistry 2. (1963), 72 - 76, the inactiva- tion of chymotrypsin, trypsin and acetylcholine esterase has been studied with a series of p-nitrophenyl alkyl- and phenylalk lphosphonates.
According to FEBS LETTERS 184 (1985), 193, bis-p- nitrophenylmethylphosphonate is known to inhibit lipases. However, the activity of this compound is very low. BRIEF STATEMENT OF THIS INVENTION
This invention relates to the use of compounds of formula I stated in Claim 1 below as lipase inhibiting agents. It is surprising that these compounds have interest- ing properties such as lipase inhibiting action. For example, some compounds of formula I have about 100 to 1000 times better efficacy than the known bis-p-nitrophenyl- ethylphosphonate.
DETAILED PRACTICE OF THIS INVENTION There are several uses of lipase inhibiting com¬ pounds. For example, such compounds can be used to determine the active center of a lipase in question, which is import¬ ant for the further development of improved lipases. Also, lipase inhibiting compounds can be added to detergents con- taining lipases in order to improve the stability of such detergents during the storage thereof. Examples of icro- bial, fungal, bacterial and yeast as well as human lipases which can be inhibited by the compounds of this invention are lipases from Mucor M. , Pseudomonas C. , Candida A. and Humicola L.
As medicaments, the lipase inhibiting compounds of this invention may, for example, be used in the treatment of acne, or to regulate the uptake of fat by inhibition of the gastric lipases. Such medical preparations are prepared by methods which are known per se by the skilled art \ >rker.
Examples of specific, interesting compounds of for¬ mula I are as follows: butylphosphonochloridate methyl ester, butylphosphonochloridate ethyl ester, butylphosphono¬ chloridate propyl ester, butylphosphonochloridate butyl ester, hexylphosphonochloridate methyl ester, hexylphospho¬ nochloridate ethyl ester, hexylphosphonochloridate propyl ester, hexylphosphonochloridate butyl ester, octylphosphono- chloridate methyl ester, octylphosphonochloridate ethyl ester, octylphosphonochloridate propyl ester, octylphospho- nochloridate butyl ester, decylphosphonochloridate methyl ester, decylphosphonochloridate ethyl ester, decylphosphono- chloridate propyl ester, decylphosphonochloridate butyl ester, dodecylphosphonochloridate methyl ester, dodecylphos- phonochloridate ethyl ester, dodecylphosphonochloridate propyl ester, dodecylphosphonochloridate butyl ester and butylphosphonochloridate 2,3-dibutoxy-l-propyl ester.
Some compounds of formula I are known and the re¬ maining compounds of formula I can be prepared by processes which are analogous to known processes, vide, for example, J.Am.Chem.Soc. 81 (1959), 372. This invention relates to the use of the compounds of formula I in the different stereoisomer forms thereof.
Compounds of formula I are effective in the treat¬ ment of acne and as antilipemic agents.
The compounds of formula I may be administered orally or parenterally in a single dose or divided doses of, for example, from 1 mg to 1 g, preferably from 20 mg to 200 mg, a day for oral administration or from 1 mg to 100 mg, preferably from 1 mg to 10 mg, for parenteral adminstration.
In addition, the compounds of formula I may be ad- ministered topically. Such administration may be in the form of a powder, a cream, an ointment, a suspension, a gel or a solution, for example, in a base cream. Such preparations are prepared analogously to the preparation of similar preparations, vide, for example, German Offenleσunσsschrift No. 3,018,114 and British Patent Application No. 8136777, the content of which is both incorporated by reference.
Medical preparations containing a compound of for¬ mula I are to be administered as prescribed by the physician similarly with the administation of similar medicaments. Any novel feature or combination of features de¬ scribed herein is considered essential to this invention.
This invention is further illustrated in the fol¬ lowing examples which, however, are not to be interpreted as limiting to the scope of protection. Example l
a) Preparation of diethyl hexylphophonat. 1-Hexanylbromide (10 g, 60.6 mmol) and triethyl- phosphite (20.1 g, 121 mmol) were heated overnight at 160°C. The reaction mixture was then distilled in vacuo giving the product in a yield of 68%. b) Preparation of hexylphosphonochloridate ethyl ester (CgH13-POCl-OC2H5) .
To diethyl hexylphosphonat (6.0 g, 27 mmol) in CC14 (20 ml), PC15 (5.6 g, 27 mmol) was added. The mixture was refluxed overnight. After removal of the solvent, the mix¬ ture was distilled giving the product in a yield of 50%. Boiling point 92 - 95°C/0.2 mbar. --H NMR (400 MHz, CDC13) : δ = 4.4 - 4.27 (m, 1H) , 4.27 - 4.15 (m, 1H) , 2.2 - 2.1 (m, 2H) , 1.8 - 1.68 (m, 2H) , 1.45 -1.25 (mm, 9H) , 0.91 (t, 3H) .
Example 2
Inhibition of C.antarctica B lipase with n-hexylchloro- phosphate ethyl ester.
Lipase from the C.antarctica B component was in- cubated with a varying concentration of the inhibitor, where the enzyme concentration was 20 μM. The lipase activity was measured with glycerine tributyrine as substrate in the emulsion. The esterase activity was measured with p-nitro- phenyl acetate as substrate. The results appear from the following table.
Figure imgf000007_0001
Example 3
Analogously as described in Example 3, the six different microbial lipases mentioned below were investigated and all six lipases were inhibited with n-hexylchlorophosphonate ethyl ester.
1) H.lanuqinosaf 2) M.miehei. 3) C.cylindracea. 4) P.cepacia. 5) C.antarctica A component and 6) C.antarctica B component.
Example 4
Using the procedure of Example 3 and exchanging the chloro leaving group in n-hexylchlorophosphonate ethyl ester with p-nitrophenyl, also inhibition of the lipases was achieved, which appears from the following table.
Figure imgf000008_0001
Example 5
Effect of the long chain R group on inhibition of M.miehei lipase.
Octanoyl, decanoyl and dodecanoyl chlorophosphonate ethyl ester inhibit all the lipases. Below, an example is given for dodecanoylchlorophosphonate ethyl ester using M.miehei lipase. The concentration of M.miehei lipase during the incubation with the inhibitor was 25 μM and the inhibi¬ tor concentration was varied.
Figure imgf000008_0002
Example 6
To check the specificity of the n-hexylchlorophosphonate ethyl ester, the effect of the inhibitor on phospholipase A2 from Naja Naja venom from (Sigma) was determined. n-Hexyl- chlorophosphonate ethyl ester did not inhibit phospholipase A2 whereas p-bromophenacyl bromide inhibited phospholipases A2 activity measured by titrimetric assay using chicken egg yolk as substrate.
Example 7
Selective inhibition of lipases.
To a mixture of Rhizomucor miehei lipase (0.5 mg/ml) and chymotrypsin (0.5 mg/ml) in phosphate buffer (pH value: 7.4), 2 mol equivalents based upon the lipase inhibi¬ tor used (dodecylphosphonochloridate ethyl ester) , a selec¬ tive inhibition of the lipase occured as determined by standard enzyme activity analysis.
Example 8
Utility of p-nitrophenyldodecanoylphosphonate ethyl ester as active site titrating agent for lipases.
One milligram per milliliter lipase was dissolved in 50 mM tris buffer (pH 7) and incubated with an excess of p-nitrophenyldodecanoylphosphonate ethyl ester with p-nitro- phenol as leaving group for 15 to 30 minutes at room tem¬ perature. p-Nitrophenol liberated was assayed spectrophoto- metrically.

Claims

1. The use of a compound of the general formula I
R-(R2=)P(X)-OR1 (I)
wherein R represents an alkyl group preferably containing 2 - 20 carbon atoms, optionally substituted by hydroxy, halogen or nitro, R1 represents an alkyl group preferably containing not more than 20 carbon atoms optionally sub¬ stituted by hydroxy, halogen, nitro, alkoxy (preferably con¬ taining not more than 6 carbon atoms) or acyl (preferably containing not more than 14 carbon atoms) or phenyl optio¬ nally substituted by hydroxy, halogen, nitro or alkyl (pre¬ ferably containing not more than 6 carbon atoms) , R2 repre¬ sents oxygen or sulphur, and X represents a leaving group, as lipase inhibiting agent.
2. The use, according to Claim 1, characterized in that the alkyl group in R contains 4 - 10 carbon atoms.
3. The use, according to Claim 1 or 2, characterized in that R is ethyl, propyl or butyl.
4. The use, according to any one of the preceding claims, characterized in that the alkyl group in R1 contains below 10 carbon atoms.
5. The use, according to any one of the preceding claims, characterized in that the group R1 is butyl, hexyl, oσtyl, decyl or dodeσyl.
6. The use, according to any one of the preceding claims, characterized in that R1 is alkyl substituted by alkoxy, preferably substituted two times by alkoxy, wherein said alkyl group preferably contains 2 or 3 carbon atoms, and wherein said alkoxy group, wherein the parent chain pre- ferably is a straight chain alkyl group, contains not more than 20 carbon atoms.
7. The use, according to any on of the preceding claims, characterized in that R1 is 2,3-dibutoxy-l-propyl.
8. The use, according to any one of the preceding claims, characterized in that R2 is oxygen.
9. The use, according to any one of the preceding claims, characterized in that X is halogen, preferably chloro, fluoro or bromo, phenol optionally substituted by nitro or halogen, or an activated alkyl group such as tri- chloro alkyl, preferably trichloroethyl.
10. The use of a compound of the above general- formula I stated in Claim 1 with the definition of the symbols stated in any one of Claims 1 through 9 or a phar aceutical- ly acceptable salt thereof for the manufacture of a medica¬ ment.
11. A compound of the above general formula I stated in Claim 1 with definition of the symbols stated in any one of Claims 1 through 9 or a pharmaceutically acceptable salt thereof for use in a method for treatment of the human or animal body or for use in a diagnostic method practiced on the human or animal body.
12. The use of a compound of the above general formula I stated in Claim 1 with the definition of the symbols stated in any one of Claims 1 through 9 or a pharmaceutical¬ ly acceptable salt thereof for the manufacture of a pharma¬ ceutical composition.
13. .Any novel feature or combination of features de¬ scribed herein.
PCT/DK1991/000307 1990-10-09 1991-10-09 New phosphonate derivatives as lipase agents inhibiting WO1992005788A1 (en)

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EP0638317A1 (en) * 1993-08-05 1995-02-15 F. Hoffmann-La Roche Ag Pharmaceutical composition
US5562099A (en) * 1990-10-05 1996-10-08 Massachusetts Institute Of Technology Polymeric microparticles containing agents for imaging
WO1999034786A2 (en) * 1998-01-09 1999-07-15 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers

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EP0210545A2 (en) * 1985-07-24 1987-02-04 Merck & Co. Inc. Phosphorous containing enzyme inhibitors

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CHEMICAL ABSTRACTS, Volume 100, No. 23, 4 June 1984, (Columbus, Ohio, US), AAVIKSAAR, A. et al., "Specificity of subtilisin Carlsberg in the reaction with O-n-alkyl p-nitrophenyl methylphosphonates", see page 248, abstract 187879s; & EESTI NSV TEAD. AKAD. TOIM., KEEM. 1984, 33(1), 62-63. *
CHEMICAL ABSTRACTS, Volume 102, No. 9, 4 March 1985, (Columbus, Ohio, US), AAVIKSAAR, A. et al., "Specificities of subtilisin BPN and intracellular proteinase from Bacillus amyloliquefaciens in reaction with organophosphorus inhibitors", see page 230, abstract 74630b; & CHEM. BIOL. 1984, 3(3), 96-99. *
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J. AGR. FOOD. CHEM., Vol. 81, January 1959, T.R. FUKUTO et al., "The Effect of Structure on the Reactivity of Alkylphosphonate Esters", see page 372 - page 377. *
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5562099A (en) * 1990-10-05 1996-10-08 Massachusetts Institute Of Technology Polymeric microparticles containing agents for imaging
EP0638317A1 (en) * 1993-08-05 1995-02-15 F. Hoffmann-La Roche Ag Pharmaceutical composition
US5643874A (en) * 1993-08-05 1997-07-01 Hoffmann-La Roche Inc. Pharmaceutical composition comprising a glucosidase and/or amylase inhibitor, and a lipase inhibitor
WO1999034786A2 (en) * 1998-01-09 1999-07-15 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
WO1999034786A3 (en) * 1998-01-09 2000-02-03 Geltex Pharma Inc Lipase inhibiting polymers
US6267952B1 (en) 1998-01-09 2001-07-31 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
US6352692B1 (en) 1998-01-09 2002-03-05 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
US6558657B1 (en) 1998-01-09 2003-05-06 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
US6572850B1 (en) 1998-01-09 2003-06-03 Geltex Pharmaceuticals, Inc. Lipase inhibiting polymers
US6875428B2 (en) 1998-01-09 2005-04-05 Genzyme Corporation Lipase inhibiting polymers

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