| Microbiological process for the production of 7-substitued 11-hydroxy steroids, 7,17-substituted 11-halogen steroids, and uses thereof -> Monitor Keywords |
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  Microbiological process for the production of 7-substitued 11-hydroxy steroids, 7,17-substituted 11-halogen steroids, and uses thereofUSPTO Application #: 20070298456Title: Microbiological process for the production of 7-substitued 11-hydroxy steroids, 7,17-substituted 11-halogen steroids, and uses thereof Abstract: A novel method of synthesis for the manufacture of upstream products for the production of compounds with general formulas 8, 10, and 12 is described. In this synthesis, compounds with general formula 4,B are produced in a microbiological reaction. The meanings of R7, R10, R11, R13, R17 and R17′ as well as of the grouping U—V—W—X—Y-Z are indicated in the claims. (end of abstract) Agent: Millen, White, Zelano & Branigan, P.C. - Arlington, VA, US Inventors: Lud-wig Zorn, Rolf Bohlmann, Norbert Gallus, Hermann Kuenzer, Hans-Peter Muhn, Reinhard Nubbemeyer USPTO Applicaton #: 20070298456 - Class: 435052000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Preparing Compound Containing A Cyclopentanohydrophenanthrene Nucleus; Nor-, Homo-, Or D-ring Lactone Derivatives Thereof The Patent Description & Claims data below is from USPTO Patent Application 20070298456. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a divisional application of U.S. application Ser. No. 10/625,559, filed on Jul. 24, 2003; this application and Ser. No. 10/625,559 claim the benefit of the filing date of U.S. Provisional Application Ser. No. 60/402,953 filed Aug. 14, 2002. DESCRIPTION [0002] The invention relates to microbiological processes for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids, 7.alpha.,17.alpha.-substituted 11.beta.-halogen steroids that can be produced therefrom, production processes for the latter compounds as well as their use and pharmaceutical preparations that contain these compounds. In addition, the invention relates to other 7.alpha.-substituted 11.beta.-halogen steroids, namely 7.alpha.-substituted estra-1,3,5(10)-trienes that can be obtained from the 7.alpha.-substituted 11.alpha.-hydroxy steroids. [0003] For treatment of male menopause and for development of male sexual organs as well as for male birth control, androgens, especially testosterone, are used. In addition, these hormones also have partial anabolic active components, which promote, i.a., muscle growth. [0004] Male menopause is characterized by an age-related reduction in the endogenous androgen production, such that hormone replacement is carried out for treatment thereof (HRT: hormone replacement therapy). [0005] In addition to a reduction in spermatogenesis, the LH-RH administration for male birth control also results in the release of LH and in the dropping of testosterone levels and libido, which are compensated for by administering testosterone pharmaceutical agents (D. E. Cummings et al., "Prostate-Sparing Effects of the Potent Androgen 7.alpha.-Methyl-19-Nortestosterone: A Potential Alternative to Testosterone for Androgen Replacement and Male Contraception," Journal of Clinical Endocrinology and Metabolism, Vol. 83, No. 12, pages 4212-4219 (1998)). [0006] A combination therapy with the administration of androgens and a gestagenically active component can be used for control of male fertility (see, for example, WO 01/60376 A as well as the documents cited therein). [0007] In the case of a treatment with testosterone, it has been shown that side effects develop, especially an enlargement of the prostate owing to an increase in the number of cells and glands of the stroma (BPH: benign prostate hyperplasia). In the metabolism of testosterone that is mediated by 5.alpha.-reductase, dihydrotestosterone (DHT) that can result, i.a., in the occurrence of BPH is produced (Cummings et al., ibid.; WO 99/13883 A1). The inhibition of the 5.alpha.-reductase is therefore used for treating BPH in clinical practice (finasterides). [0008] The quick metabolism of the androgenic steroid testosterone in the human body further results not only in the formation of undesirable DHT, but also in that an oral administration of higher doses is necessary to reach the desired effect level of testosterone. Alternative forms for dispensing, such as i.m.-injections or large patches, are therefore necessary. [0009] To replace testosterone in the above-mentioned indication areas, 7.alpha.-methyl-19-nortestosterone (MeNT) was proposed which has, on the one hand, a higher biological effectiveness as testosterone, since it has a higher binding affinity to the androgen receptors. On the other hand, because of a steric inhibition by the 7.alpha.-methyl group, it presumably resists metabolization by 5.alpha.-reductase (Cummings et al., ibid., WO 99/13883 A1, WO 99/13812 A1, U.S. Pat. No. 5,342,834). [0010] During metabolism of testosterone, a smaller portion of this compound is also reacted by aromatization of ring A of the steroid system to form estradiol, especially in the brain, in the liver and in the fatty tissue. With respect to the total action of the testosterone and its metabolites, estradiol is substantially responsible for sex-specific behavior and gonadotrophin regulation. Therefore, its action just like that of testosterone for the adult male is regarded as advantageous (Cummings et al., ibid.). [0011] It has been shown, however, that the pharmacokinetics of testosterone is not satisfactory. In particular in the case of oral dispensing, testosterone is quickly excreted again, so that the effectiveness and the duration of action of the thus produced pharmaceutical agents is unsatisfactory. Other testosterone derivatives were therefore also synthesized. Such derivatives are described in, i.a., U.S. Pat. No. 5,952,319, in particular 7.alpha.-,11.beta.-dimethyl derivatives of 19-nortestosterone, namely 7.alpha.,11.beta.-dimethyl-17.beta.-hydroxyestr-4-en-3-one, 7.alpha.,11.beta.-dimethyl-17.beta.-heptanoyloxyestr-4-en-3-one, 7.alpha.,11.beta.-dimethyl-17.beta.-[[(2-cyclopentylethyl)-carbonyl]-oxy]- -estr-4-en-3-one, 7.alpha.,11.beta.-dimethyl-17.beta.-(phenylacetyloxy]-estr-4-en-3-one, and 7.alpha.,11.beta.-dimethyl-17.beta.-[[(trans-4-[n-butyl]cyclohexyl)-c- arbonyl]-oxy]-estr-4-en-3-one. [0012] The above-mentioned 7.alpha.,11.beta.-dimethyl derivatives have the above-mentioned advantages, like MeNT, including an improved pharmacokinetics, i.e., their effectiveness and duration of action are improved relative to testosterone. These derivatives, however, can be produced only via an expensive synthesis method. [0013] A synthesis of steroids in the microbiological method is described in EP 0 900 283 B 1. It is indicated there that estr-4-ene-3,17-dione and canrenone can be transformed with use of a microorganism that is selected from the group that comprises Apergillus nigricans, Rhizopus arrhizus and strains of Pestelotia into the corresponding 11.alpha.-hydroxy analog. In the introduction of the description, however, reference is also made to Shibahara et al., Biochim. Biophys. Acta, 202 (1970), 172-179, who reported that the microbiological 11.alpha.-hydroxylation reaction in steroids can be unpredictable. [0014] The problem on which this invention is based is solved by [0015] microbiological processes for the production of 7.alpha.-substituted steroids as follows: [0016] microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B: in which [0017] R.sup.7 is the grouping P-Q, whereby [0018] P represents a C.sub.1- to C.sub.4-alkylene, and Q represents a C.sub.1- to C.sub.4-alkyl- or C.sub.1- to C.sub.4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, [0019] R.sup.10 can be in .alpha.- or .beta.-position and stands for H, CH.sub.3 or CF.sub.3, and [0020] R.sup.13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A: in which R.sup.7, R.sup.10 and R.sup.13 have the same meanings as indicated above, [0021] is hydroxylated and oxidized with use of a microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Glomerella sp., Gnomonia sp., Haplosporella sp. and Rhizopus sp; [0022] microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B: in which [0023] R.sup.7 is the grouping P-Q, whereby [0024] P represents a C.sub.1- to C.sub.4-alkylene and Q represents a C.sub.1- to C.sub.4-alkyl- or C.sub.1- to C.sub.4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, [0025] R.sup.10 can be in .alpha.- or .beta.-position and stands for H, CH.sub.3 or CF.sub.3, and [0026] R.sup.13 is methyl or ethyl, in which a 7.alpha.-substituted steroid with general formula 3,A: in which R.sup.7, R.sup.10 and R.sup.13 have the same meanings as previously indicated, [0027] is hydroxylated in 11.alpha.-position in a first microbiological process step with use of a first microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Gibberella sp., Glomerella sp., Gnomonia sp., Metarrhizium sp., Nigrospora sp., Rhizopus sp. and Verticillium sp., with the formation of a 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C: in which R.sup.7, R.sup.10 and R.sup.13 have the same meanings as indicated above, and [0028] the 7.alpha.-substituted 11.alpha.-hydroxy steroid with general formula C that is produced is then oxidized in a second microbiological process step with use of a second microorganism that is selected from the group that comprises Bacillus sp., Mycobacterium sp., Nocardia sp. and Pseudomonas sp., with the formation of the 7.alpha.-substituted steroid with general formula 4,B; [0029] microbiological process for the production of 7.alpha.-substituted 11.alpha.-hydroxy steroids with general formula 4,B: in which [0030] R.sup.7 is the grouping P-Q, whereby [0031] P represents a C.sub.1- to C.sub.4-alkylene and Q represents a C.sub.1- to C.sub.4-alkyl- or C.sub.1- to C.sub.4-fluoroalkyl, and the grouping P-Q is bonded via P to the steroid skeleton, [0032] R.sup.10 stands for H, CH.sub.3 or CF.sub.3, and [0033] R.sup.13 is methyl or ethyl, in which 7.alpha.-substituted steroids with general formula D: in which R.sup.7, R.sup.10 and R.sup.13 have the same meanings as indicated above, [0034] are hydroxylated with use of a microorganism that is selected from the group that comprises Aspergillus sp., Beauveria sp., Curvularia sp., Gibberella sp., Glomerella sp., Gnomonia sp., Haplosporella sp., Helicostylum sp., Nigrospora sp., Rhizopus sp. and Syncephalastrum sp; [0035] 7.alpha.,17.alpha.-Substituted 11.beta.-halogen steroids with general formulas 8, 10, and 12: in which [0036] U--V--W--X--Y-Z stands for one of ring structures C.sup.1--C.sup.2--C.sup.3--C.sup.4.dbd.C.sup.5--C.sup.10, C.sup.1--C.sup.2--C.sup.3--C.sup.4--C.sup.5.dbd.C.sup.10 or C.sup.1--C.sup.2--C.sup.3--C.sup.4--C.sup.5--C.sup.10, whereby in this case, an oxo group (.dbd.O) is bonded to W (.dbd.C.sup.3), or for ring structure C.sup.1.dbd.C.sup.2--C.sup.3.dbd.C.sup.4--C.sup.5.dbd.C.sup.6, whereby in this case radical OR.sup.3 is bonded to W (.dbd.C.sup.3), [0037] R.sup.3 stands for H, C.sub.1- to C.sub.4-alkyl, C.sub.1- to C.sub.4-alkanoyl or a cyclic C.sub.3- to C.sub.7-ether with the O-atom of the OR.sup.3-radical, [0038] R.sup.7 is the grouping P-Q, whereby [0039] P represents a C.sub.1- to C.sub.4-alkylene and Q represents a C.sub.1- to C.sub.4-alkyl- or C.sub.1- to C.sub.4-fluoroalkyl, and grouping P-Q is bonded via P to the steroid skeleton, [0040] R.sup.10 can be in .alpha.- or .beta.-position and stands for H, CH.sub.3 or CF.sub.3, and is present only if X--Y-Z is not C.sup.4--C.sup.5.dbd.C.sup.10, [0041] R.sup.11 is a halogen, [0042] R.sup.13 is methyl or ethyl, [0043] R.sup.17 stands for H, C.sub.1- to C.sub.18-alkyl, alicyclic C.sub.1- to C.sub.18-alkyl, C.sub.1- to C.sub.18-alkenyl, alicyclic C.sub.1- to C.sub.18-alkenyl, C.sub.1- to C.sub.18-alkinyl, C.sub.1- to C.sub.18-alkylaryl, C.sub.1- to C.sub.8-alkylenenitrile or for the grouping P-Q, whereby the grouping P-Q has the above-mentioned meaning, [0044] R.sup.17' stands for H, C.sub.1- to C.sub.18-alkyl, alicyclic C.sub.1- to C.sub.18-alkyl, C.sub.1- to C.sub.18-alkenyl, alicyclic C.sub.1- to C.sub.18-alkenyl, C.sub.1- to C.sub.18-alkinyl or C.sub.1- to C.sub.18-alkylaryl, whereby R.sup.17' also can be bonded via a keto group to the 17.beta.-oxy group, and whereby R.sup.17' also in addition can be substituted with one or more groups NR.sup.18R.sup.19 or one or more groups SO.sub.xR.sup.20, whereby x=0, 1 or 2 and R.sup.18, R.sup.19 and R.sup.20 in each case independently of one another can have the same meaning as R.sup.17, Continue reading... 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