- FED BATCH SOLID STATE FERMENTATION FOR THE PRODUCTION OF HMG-COA REDUCTASE INHIBITORS
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The present invention provides a novel method for producing compound of formula (I), its acid form or any salt form, where R1 is H or CH3, by solid state fermentation using fed-batch technique by culturing microorganisms capable of producing the compound of formula (I).
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Page 12 - 13
(2008/06/13)
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- Treatment of type 1 diabetes with PDE5 inhibitors
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The use of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Type 1 Diabetes. A method of treating Type 1 Diabetes in an individual suffering from Type 1 Diabetes, which method comprises administering to said individual an effective amount of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof.
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- Method for producing pharmaceutical dosage forms
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The invention relates to a method for producing a granulate while using spray-dried D-mannitol and to the production of pharmaceutical dosage forms comprised of granulates of this type. The invention additionally relates to granulates obtained by using this method and to pharmaceutical dosage forms, which contain statins, especially cerivastatin, and which can be produced from said granulates.
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- Total synthesis of (+)-compactin by a double Michael protocol
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The total synthesis of (+)-compactin 1 has been achieved by employing a double Michael reaction of (R)-1-acetyl-3-(tert-butyldimethylsiloxy)cyclohexene 16 with methyl crotonate as the key reaction.
- Hagiwara, Hisahiro,Nakano, Takashi,Kon-no, Masakazu,Uda, Hisashi
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p. 777 - 784
(2007/10/02)
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- Antihypercholesterolemic compounds and synthesis thereof
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A method of preparing compactin and mevinolin, ketoacid, enone, and glutarate analogs thereof, and related compounds. The compounds are prepared in substantially enantiomerically pure form using a structurally convergent synthesis. Total syntheses of (+)-compactin, (+)-mevinolin and related compounds are provided. Novel compounds are identified, several of which show significant anti-hypercholesterolemic activity.
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- Total synthesis of both (+)-compactin and (+)-mevinolin. A general strategy based on the use of a special titanium reagent for dicarbonyl coupling
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A strategy is described for stereocontrolled synthesis of hypocholesterolemic compounds, (+)-compactin and (+)-mevinolin, by an approach (Scheme II) based on 6, 7, 4-pentenal (9a), and (R)-3-methyl-4-pentenal (9b). The Evans asymmetric Diels-Alder technique was used (Scheme III) to prepare 13, which was converted into the cis ester 17. Chain extension, iodolactonization, and elimination of HI then gave optically pure 6. The homochiral epoxide 24, made (Scheme IV) from (S)-malic acid, was converted into 25 and then, by iodocarbonation, hydrolysis, and ketalization, into the iodo ketal 7. Evans asymmetric alkylation was used (Scheme V) to prepare 9b. Ozonolysis, ketalization, and reduction (LiAlH4) of 28 gave 31, which was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into 9b. An optically pure intermediate (8), common to both syntheses, was assembled (Scheme VI) by alkylation of 6 with 7, reduction to a mixture of lactols, allylic oxidation, and decarbonylation. Aldol condensation (Scheme VII) of 8 with 4-pentenal, triethylsilylation, and ozonolysis gave the enone aldehydes 39, epimeric at C-1. A modified McMurry reaction requiring an excess of a reagent prepared from C8K and TiCl3 (2:1 molar ratio) in DME, produced the ethers 40, which were converted into (+)-compactin by appropriate modification of the oxygen functionality. The strategy is general and was applied with minor modifications (Scheme VIII) to the synthesis of (+)-mevinolin.
- Clive,Murthy,Wee,Prasad,Da Silva,Majewski,Anderson,Evans,Haugen,Heerze,Barrie
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p. 3018 - 3028
(2007/10/02)
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- Total Synthesis and Biological Evaluation of Structural Analogues of Compactin and Dihydromevinolin
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The full experimetal details for the total synthesis of (+)-compactin and 19 structural analogues are reported.We have evaluated three classes of analogues as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase: (1) functional and stereoisomeric analogues that posses the full carbon skeleton of compactin or dihydromevinolin, (2) functional analogues in which one carbon of the skeleton has been replaced by oxygen, and (3) analogues in which all of the 3,5-dihydroxyvaleric acid moiety has been omitted.Our most potent inhibitors belong to the first class of analogues.Compounds 42 (5-ketocompactin) and 69 (5-ketodihydromevinolin) are as active as the natural products compactin and dihydromevinolin, respectively (I50 = 1-20 nM).The corresponding enones 37 and 68 are less active, having I50 values 20-30 times larger.Inverting the stereochemistry at C-3 or C-5 or about the hexahydronaphthalene ring of compactin results in the elevation of the I50 to values in the micromolar range, comparable to the KM of the natural substrate 3-hydroxy-3-methylglutaryl coenzyme A.Class 2 analogues are active in this concentration range also.The synthetic sequence developed for compactin and its analogues includes a new method that permits the selective preparation of either the R or the S epimer at C-3 of the 3,5-dihydroxyvaleric acid moiety.This entails the reaction of anhydride 9 with either (R)- or (S)-1-phenylethanol in the presence of 4-(N,N-dimethylamino)pyridine and triethylamine.The prochiral recognition is surprisingly high; under optimum conditions, the reaction of 9 with (R)-1-phenylethanol leads to a 15:1 ratio of diesters 17 and 18.
- Heathcock, Clayton H.,Hadley, Cheri R.,Rosen, Terry,Theisen, Peter D.,Hecker, Scott J.
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p. 1858 - 1873
(2007/10/02)
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- The Isoxazoline Route to the Hypocholesterolemic Agent Compactin: Use of the Isoxazoline as a 1,3-Diene Equivalent
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A total synthesis of the hypocholesterolemic agent compactin is described in which the hexahydronaphthalene portion of this molecule is constructed by an intramolecular nitrile oxide cycloaddition reaction.In the context of this synthesis, the isoxazoline ring system was found to serve as a useful 1,3-diene equivalent.The protocol developed for this conversion involves transformation of the isoxazoline to an allylic alcohol followed by regioselective dehydration using aluminum oxide.Molecular mechanics calculations on compactin-related octahydronaphthisoxazoles are also presented.
- Kozikowski, Alan P.,Li, Chun-Sing
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p. 3541 - 3552
(2007/10/02)
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- A Highly Convergent Total Synthesis of (+)-Compactin
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An intramolecular Diels-Alder approach to the construction of (+)-compactin is described.Alkylation of the lithium enolate of (acetylmethylene)triphenylphosphorane with the tosylate of allenic alcohol 15 affords phosphorane 16, which condenses with aldehyde 6 (prepared from tri-O-acetyl-D-glucal) to afford enone 3.Intramolecular Diels-Alder reaction, reduction with lithium tri-sec-butylborohydride, and acylation with (S)-(+)-2-methylbutyric anhydride yields a chromatographically separable mixture of diastereomers; conversion to compactin was accomplished by acid hydrolysis followed by oxidation.
- Keck, Gary E.,Kachensky, David F.
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p. 2487 - 2493
(2007/10/02)
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- Convergent, Enantiospecific Total Synthesis of the Hypocholesterolemic Agent (+)-Compactin
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A convergent, enantiospecific total synthesis of (+)-compactin (1) is described.The strategy for the construction of the (+)-1 centers around a Diels-Alder reaction between chiral dienophile 23 and chiral diene 62 which provides in a single operation access to allylic sulfide 85 possessing the desired configuration at C(8'), C(8a'), and C(1').Dienophile 23 is made readily available by resolution of the known racemic β-nitro acid 66.The synthesis of diene 62 commences with the known epoxide 7 derived from tri-O-acetyl-D-glucal.Diels-Alder adduct 85 is transformed into allylic alcohol 87 which sets the stage for incorporation of the C(2') methyl group.Elaboration of the hexalol portion of compactin with liberation of the C(8') hydroxyl group is achieved via a Grob-like fragmentation on alcohol 95.Acylation 94, subsequent adjustment of the oxidation state at C(1), and demethylation give way to (+)-compactin.
- Grieco, Paul A.,Lis, Randall,Zelle, Robert E.,Finn, John
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p. 5908 - 5919
(2007/10/02)
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- A new route in the sequential total synthesis of compactin
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The synthesis and regioselective hydrogenation of 1,2,6,7,8,8aβ-hexahydro-8α-hydroxy-2-methylene-1β-naphthaleneacetic acid methyl ester 4a, has provided a novel synthetic pathway to the hypocholesterolemic agent, compactin 9.
- Girotra,Wendler
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p. 3687 - 3688
(2007/10/02)
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- Total synthesis of the hypocholesterolemic agent compactin
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A total synthesis of ( plus )-compactin (ML-236B), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is presented. The key chiral hexahydronaphthalene intermediate was efficiently synthesized in 70% overall yield from the optically active diol. In turn, the diol was obtained via microbiological reduction of the racemic dione. ( plus )-Compactin was prepared in 14 steps from the chiral hexahydronaphthalene intermediate in 0. 8% yield. Refs.
- Hsu,Wang,Latimer,Sih
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p. 593 - 601
(2007/10/02)
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