EP0590083A1 - Nouveau compose hypocholesterolemiant - Google Patents

Nouveau compose hypocholesterolemiant

Info

Publication number
EP0590083A1
EP0590083A1 EP92914946A EP92914946A EP0590083A1 EP 0590083 A1 EP0590083 A1 EP 0590083A1 EP 92914946 A EP92914946 A EP 92914946A EP 92914946 A EP92914946 A EP 92914946A EP 0590083 A1 EP0590083 A1 EP 0590083A1
Authority
EP
European Patent Office
Prior art keywords
compound
atcc
ppm
mhz
measured
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92914946A
Other languages
German (de)
English (en)
Other versions
EP0590083A4 (fr
Inventor
Laszlo R. Treiber
Leeyuan Huang
Shieh-Shung Tom Chen
Byron H. Arison
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0590083A1 publication Critical patent/EP0590083A1/fr
Publication of EP0590083A4 publication Critical patent/EP0590083A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/06—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using actinomycetales
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

Definitions

  • Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Biie acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e., several grams at a time and they are not very palatable.
  • MEVACOR (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
  • Squalene synthetase is the enzyme involved in the first committed step of the d_e_ novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
  • the present invention is directed to a bio- transformed analog of the above-noted natural products.
  • This invention is concerned with a Compound I or a pharmaceutically acceptable salt thereof which is useful as a cholesterol lowering agent.
  • the Compound I is prepared by a biotransformation of a solution of the compound of structural formula II in DMSO:
  • Compound I is formed from Compound II via a precursor, Compound III, which is spontaneously formed upon dissolving II in DMSO and allowing the solution to stand at room temperature for about 4 to 12 months.
  • Compound III or a previously prepared DMSO solution of Compound II is incubated with Streptomyces sp. in a nutrient medium, Compound I is formed.
  • the preferred Streptomyces species is Streptomyces rimosus and the preferred strain of the Streptomyces sp. is deposited in the culture collection of Merck & Co. Inc., Rahway, New Jersey as MA6817. A sample of this microorganism has been deposited under the terms of the Budapest Treaty with the American Type Culture Collection at 1230, Parklawn Drive, Rockville Maryland 20852 and has been # assigned accession number ATCC 55189.
  • Compound I is prepared in an aerobic fermentation procedure employing the novel culture, MA6817.
  • Mutants of MA6817 are also capable of producing the compounds of this invention and are included within the scope of this invention.
  • the culture employed and described herein is isolated from and substantially free from its soil contaminants and free of deleterious viable contaminating microorganisms. That is, the culture is free of contaminating microorganisms that are deleterious on the reaction which produces Compound I.
  • the organism was isolated from a soil sample 20 km east of Mount Olga Montana.
  • Cell wall analysis revealed a peptidoglycan containing L-diaminopimelic acid, and whole cell sugar analysis revealed glucose and ribose.
  • the organism MA6817 grows moderately well on Yeast Malt extract amd glycerol asparagine and well on inorganic salts-starch, oatmeal and trypticase soy agars. It grows at 27 ⁇ C and 37°C and grows well in liquid media such as yeast dextrose broth. Colony Morphology
  • Substrate mycelium is light orange yellow (70.1 OY) and colonies are opaque, raised, lobate and rubbery. The colony surface is rough. Aerial mycelia appear after 5 days incubation and are white (263 White) Spore mass, when present, is white to pale yellow (263 White - 89 p.Y).
  • Micromorphology Aerial mycelium (0.76 ⁇ m dia) radiate from the substrate mycelium and is straight and highly branched. In mature cultures, aerial mycelia terminate in chains of spores that are borne in tightly coiled spirals. Sclerotia are observed on other media especially Sigma water agar.
  • Carbon source utilization pattern is as follows: good utilization of ⁇ -D-lactose, ⁇ -D-lactose; moderate utilization of L-arabinose, cellobiose, D-fructose, inositol, D-maltose, D-mannitol, D-mannose, D-raffinose, D-xylose; no utilization of D-arabinose, L-rhamnose, sucrose, L-xylose.
  • this culture exhibits some similarity with strains currently identified as Streptomyces rimosus. Carbohydrate utilization patterns are quite similar with the type strain. MA6817 does, however, exhibit morphological characteristics (production of sclerotia and nest-like structures) that are not reported for strains currently clustered within this group. Placement within this species is tentative.
  • Compound I is produced during the aerobic fermentation of a suitable aqueous nutrient media in the presence of Compound III under conditions described hereinafter, with a producing strain of the Streptomyces sp.
  • Such nutrient media contain sources of carbon and nitrogen assimilable by the microorganism and generally low levels of inorganic salts.
  • the fermentation media may contain traces of metals necessary for the growth of the microorganisms. These are usually present in sufficient concentration in the complex sources of carbon and nitrogen which may be used as nutrient sources, but can, of course, be added separately to the medium if desired.
  • carbohydrates such as sugars, for example dextrose, maltose, lactose, dextran, cerelose and the like, and starches are suitable sources of assimilable carbon in the nutrient media.
  • the exact quantity of the carbon source which is utilized in the medium will depend, in part, upon the other ingredients in the medium but it is usually found that an amount of carbohydrate between about 0.5 and 5% by weight of the medium is satisfactory.
  • These carbon sources can be used individually or several such carbon sources may be combined in the same medium.
  • Various nitrogen sources such as yeast hydrolys tes, yeast autoysate, soybean meal, casein hydrolysates, yeast extracts, corn steep liquors, distillers solubles, cottonseed meal, meat extract and the like, are readily assimilable by Streptomyces sp. in the production of Compound I.
  • the various sources of nitrogen can be used alone or in combination in amounts ranging from about 0.2 to 6% by weight of the medium.
  • nutrient inorganic salts which can be incorporated in the culture media are the customary salts capable of yielding sodium potassium, magnesium, ammonium, calicum, phosphate, sulfate, chloride, carbonate and like ions. Also included are trace metals such as cobalt, manganese, iron and the like.
  • Step A Preparation of (1S,3S,4S,5R,6R,7R)-1-[(4S)- acetoxy-3-methylene-5-methyl-6-phenyl]- hexyl-4,6,7-trihydroxy-6-0-(4,6-dimethyl-2- octenoyl)-2,8-dioxabicyclo[3.2.1]octane-3,4, 5-tricarboxylic acid (II)
  • Culture MF5453 (ATCC 20986) was inoculated into KF seed medium using one glass scoop of the original soil tube. The KF seed flask was incubated for 73 hours at 25 ⁇ C, 220 rpm, 85% humidity. At the end of this incubation, 2.0 mis aliquots were aseptically transferred to each of 75 MBM production medium flasks. These production flasks were then incubated at 25 C C, 220 rpm, 85% humidity, with a fermentation cycle of 14 days. Flasks were harvested as follows: mycelial growth was homogenized for 20 seconds at high speed using Biohomogenizer/ mixer (Biospec Products Inc.
  • Compound II is dissolved in DMSO (2.5 mg/ml) and the solution allowed to stand at room temperature for a period of 4 to 12 months. In a slow process (e.g., 15% conversion in eleven months), Compound III is formed from Compound II.
  • Compound III is isolated by means of a preparative HPLC on a Beckman Ultrasphere Octyl column (10 x 250 mm) with gradient elution.
  • the gradient program is 30% B/70% A for 0-3 minutes, linear gradient to reach 80% B/20% A from 3-33 minutes, then 100% B from 33-35 minutes and remains there for the final 10 minutes.
  • the flow rate is constant at 3.00 ml/minute.
  • Solvent A was 0.1% HCOOH in water and B was 0.1% HCOOH in acetonitrile-water (17:3).
  • Fermentation Production flasks (medium #2, 50 ml in 250 ml baffled flasks) were inoculated with 2 ml of the seed medium and shaken at 27 ⁇ C and 220 rpm on a rotary shaker. After 24 hours, a substrate containing the crude mixture of Compounds II and III, prepared above (Step Bl), was added to each flask. Thus, a DMSO solution of the substrate containing Compound II (1.217 mg, 76.1%) and Compound III (0.382 mg, 23.9%) was used for each of two shakeflasks. Incubation continued for 72 hours.
  • the first separation was accomplished on a Beckman Ultrasphere Cyano column (10x250mm) in a gradient from 20% solvent B/80% solvent A to 65% solvent B/35% solvent A in 35 minutes at a flow rate of 3.00 ml/min. Fractions were collected every 3 minutes or according to peaks detected at 213 nm, as appropriate. The selected fractions (22.5-24.0 min) were evaporated to dryness and chromatographed again on a Beckman Ultrasphere Octyl column (10x250mm) in a gradient from 30% B/70% A to 80% B/20% A in 35 minutes then at 100% solvent B for an additional 10 minutes. The remaining conditions were the same as in the first separation.
  • Solvent A was 20 mM HCOOH and B was acetonitrile-water (17:3 v/v) containing the same amount of HCOOH as solvent A. Evaporation of the selected fractions (retention time 33.6 min.) provided the product, Compound I, with the following physical characteristics:
  • Solvent A 10 mM H 3 P0 4 in water
  • Solvent B Acetonitrile-water (85:15 v/v)
  • an oral composition of a compound of this invention 20 mg of Compound I from Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
  • the present invention is also concerned with a process for making Compound I by incubation of a Streptomyces sp. f in a nutrient medium in the presence of a Compound III.
  • Compound III can be produced by allowing the compound of structural formula II:
  • Compound II to stand in a suitable polar organic solvent such as DMSO or acetonitrile.
  • a suitable polar organic solvent such as DMSO or acetonitrile.
  • Compound II which has been previously left standing in DMSO for a minimum of four months such that a detectable amount of Compound III is produced, is incubated with Streptomyces sp. in a nutrient medium to form Compound I.
  • the present invention is also concerned with a method of treating hypercholesterolemia which comprises the administration to a subject in need of such treatment of a nontoxic therapeutically effective amount of a Compound I or a Compound III or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention are useful as antihypercholesterolemic agents for the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia and the like diseases in humans. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route.
  • Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but a daily dosage for adults is within a range of from about 20 mg to 2000 mg (preferably 20 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required.
  • the present invention is also concerned with a method of inhibiting squalene synthetase which comprises the administration to a subject in need of such treatment of a nontoxic therapeutically effective amount of a Compound I or a Compound III or a pharmaceutically acceptable salt thereof.
  • the compounds of this invention are useful in treating disease conditions such as, but not limited to, hypercholesterolemia conditions which require the action of the enzyme squalene synthetase. They may be administered by the same routes in the same dosages as described for the method of treating hypercholesterolemia.
  • the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetra ethyl- ammonium hydroxide.
  • the salts included herein encompass those wherein one, or two of the carboxyl groups are in the salt form.
  • the compounds of this invention may also be administered in combination with other cholesterol lowering agents such as those which inhibit an enzymatic pathway in the biosynthesis of cholesterol.
  • cholesterol lowering agents such as those which inhibit an enzymatic pathway in the biosynthesis of cholesterol.
  • examples of such agents would include but are not limited to HMG-CoA reductase inhibitors, HMG-COA synthase inhibitors, and squalene epoxidase inhibitors.
  • Illustrative of such inhibitors are lovastatin, simvastatin, pravastatin and fluvastatin.
  • Other cholesterol lowering agents that may be administered include niacin, probucol, and the fibric acids, clofibrate and gemfibrozil. Appropriate daily dosages for adults are niacin (2-8 gm), probucol (up to 1000 mg), clofibrate (up to 2 gm) and gemfibrozil (800-1500 mg).
  • the compounds of this invention may also be coadministered with pharmaceutically acceptable nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastro ⁇ intestinal tract.
  • pharmaceutically acceptable nontoxic cationic polymers capable of binding bile acids in a non-reabsorbable form in the gastro ⁇ intestinal tract.
  • examples of such polymers include cholestyramine, colestipol and poly[methyl-(3-tri- methylaminopropyl)imino-trimethylene dihalide] .
  • the relative amounts of the compounds of this invention and these polymers is between 1:100 and 1:15,000.
  • the intrinsic squalene synthetase inhibitory activity of the compounds of this invention was measured by the standard in vitro protocol described below:
  • Culture Medium Minimum essential medium (MEM) with non-essential amino acids, sodium pyruvate, and 10% fetal bovine serum. The medium was changed twice weekly. A confluent monolayer was achieved in 1 week. The growth medium is prepared as listed below.
  • Hyclone fetal bovine serum defined, Hyclone #A-111-L 100
  • Subculture Procedure Remove medium, wash with PBS, add fresh trypsin (0.25%)-EDTA (0.02%) with Hank's Balanced Salt solution and let flask stand for a minute and remove the trypsin solution . Incubate flask at 37 ⁇ C until cells detached. Add fresh medium, disperse and dispense cells into new flasks. Subcultivation ratio: 1:6.
  • Cell extracts Sonicate (probe sonicator setting #60, pulse) the cell suspension on ice for 2 min. After a 1 min. cooling on ice, the sonication is repeated until greater than 90% of the cells are broken as observed microscopically. Centrifuge cell suspension for 10 mins. at 10,000 rpm. Transfer supernatant to clean tube and centrifuge at 20,000 rpm for 20 mins. The HepG2 enzyme preparation was centrifuged at 34,000 rpm to separate the cytosol and icrosomal enzymes. The resulting pellet from the 34,000 rpm centrifugation, containing the squalene synthetase, was resuspended in 5 ml of enzyme suspension buffer. The enzyme suspension was diluted 1 to 1,536 and used to perform the squalene synthetase assay using 3 ⁇ M - -farnesyl pyrophosphate as the substrate. Squalene Synthetase Assay
  • Buffer mixture and subtrate mixture for the assay were prepared from the following solution:
  • Buffer mixture contains 270 mM HEPES, pH 7.5, 20 mM Potassium fluoride and 5.4 mM Dithiothreitol(DTT). 55 ⁇ l of this mixture was used per assay. The final concentrations of HEPES, KF and DTT in the assay are 150 mM, 11 mM and 3 mM respectively.
  • IC50 values were determined by plotting the log of the concentration of the test compound versus the percentage inhibition.
  • the IC50 is the concentration of inhibitor that give 50% inhibition as determined from these plots.
  • the IC5 Q of the compound of this invention (i.e., Compound I) against squalene synthetase is estimated to be 0.67 nM.
  • the heptane extractable products of the enzyme control and the enzyme reaction in the presence of 30 nM of the compound of invention were spiked with 5 ⁇ l of 0.5% squalene and then were analyzed by reverse phase high performance liquid chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Biochemistry (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

On produit un composé (I) pouvant être utilisé comme hypocholestérolémiant en cultivant un Streptomyces sp. dans un milieu nourricier en présence d'un substrat composé d'une solution préalablement préparée d'un composé de la formule développée (II) dans du dyméthylsulfoxyde (DMSO).
EP19920914946 1991-06-14 1992-06-12 Nouveau compose hypocholesterolemiant. Withdrawn EP0590083A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US71551891A 1991-06-14 1991-06-14
US715518 1991-06-14
PCT/US1992/005108 WO1992022660A1 (fr) 1991-06-14 1992-06-12 Nouveau compose hypocholesterolemiant

Publications (2)

Publication Number Publication Date
EP0590083A1 true EP0590083A1 (fr) 1994-04-06
EP0590083A4 EP0590083A4 (fr) 1994-10-12

Family

ID=24874359

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19920914946 Withdrawn EP0590083A4 (fr) 1991-06-14 1992-06-12 Nouveau compose hypocholesterolemiant.

Country Status (3)

Country Link
EP (1) EP0590083A4 (fr)
CA (1) CA2103164A1 (fr)
WO (1) WO1992022660A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5359096A (en) * 1991-06-14 1994-10-25 Merck & Co., Inc. Cholesterol lowering compounds
US5264593A (en) * 1993-01-15 1993-11-23 Merck & Co., Inc. Cholesterol lowering compounds
US5430055A (en) * 1994-04-08 1995-07-04 Pfizer Inc. Inhibitor of squalene synthase

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5053425A (en) * 1990-03-21 1991-10-01 Merck & Co., Inc. Novel anti-fungal compounds
US5026554A (en) * 1990-09-13 1991-06-25 Merck & Co., Inc. Method of inhibiting fungal growth using squalene synthetase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9222660A1 *

Also Published As

Publication number Publication date
CA2103164A1 (fr) 1992-12-15
EP0590083A4 (fr) 1994-10-12
WO1992022660A1 (fr) 1992-12-23

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