EP1042335A1 - Derives de vitamine d avec des atomes de phosphore dans les chaines laterales - Google Patents

Derives de vitamine d avec des atomes de phosphore dans les chaines laterales

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Publication number
EP1042335A1
EP1042335A1 EP98966616A EP98966616A EP1042335A1 EP 1042335 A1 EP1042335 A1 EP 1042335A1 EP 98966616 A EP98966616 A EP 98966616A EP 98966616 A EP98966616 A EP 98966616A EP 1042335 A1 EP1042335 A1 EP 1042335A1
Authority
EP
European Patent Office
Prior art keywords
tetraen
secochola
dihydroxy
phosphonic acid
homo
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Withdrawn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
EP98966616A
Other languages
German (de)
English (en)
Inventor
Andreas Steinmeyer
Günter Neef
Gerald Kirsch
Katica Schwarz
Herbert Wiesinger
Martin Haberey
Marianne Fähnrich
Gernot Langer
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Priority claimed from EP97250374A external-priority patent/EP0927721A1/fr
Priority claimed from DE1997158119 external-priority patent/DE19758119C1/de
Application filed by Schering AG filed Critical Schering AG
Priority to EP98966616A priority Critical patent/EP1042335A1/fr
Publication of EP1042335A1 publication Critical patent/EP1042335A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/383—Cycloaliphatic acids
    • 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)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • 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
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4018—Esters of cycloaliphatic acids
    • 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
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/404—Esters of poly(thio)phosphonic acids containing hydroxy substituents in the hydrocarbon radicals
    • 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
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • 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
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/532—Cycloaliphatic phosphine oxides or thioxides

Definitions

  • the invention relates to new vitamin D derivatives of the general formula I.
  • the natural vitamins D 2 and D 3 are inherently biologically inactive and only become biologically active metabolites [l ⁇ , 25-dihydroxyvitamin D 3 (calcitriol) after hydroxylation on the C atom 25 in the liver and on the C atom 1 in the kidney. or -D 2 ] l - converted.
  • the effect of the active metabolites is the regulation of the calcium and phosphate concentration in the serum; they counteract a decrease in the calcium concentration in the serum by increasing the calcium absorption in the intestine and, under certain circumstances, promoting calcium mobilization from the bone.
  • Figure 1 shows the structure of some known vitamin D derivatives.
  • the active metabolites of vitamin D 2 and D 3 and its synthetic derivatives have a proliferation-inhibiting and differentiation-stimulating effect on tumor cells and normal cells, such as skin cells. Furthermore, a pronounced effect on cells of the immune system (inhibition of proliferation and interleukin 2 synthesis of lymphocytes, increase in cytotoxicity and phagocytosis in vitro of monocytes) was found, which manifests itself in an immunomodulatory effect, finally due to a promoting effect on bone-forming cells increased bone formation was found in normal and osteoporotic rats [R. Bouillon et al. "Short term course of 1.25- (OH) 2 D 3 stimulates osteoblasts but not osteoclasts". Calc. Tissue int. 49, 168 (1991)]
  • Structural manipulations of the side chain can be used to separate therapeutically effective qualities from the undesirable hypercalcemic activity.
  • a suitable structural variant is the introduction of a 24-hydroxy group.
  • WO 94/07853 describes 25-carboxylic acid derivatives of calcitriol hydroxylated on C-24, which have a more favorable spectrum of action than calcitriol.
  • new vitamin D derivatives with other substituents .an C-25 WO 97/00242.
  • the ability to trigger a Hypercalcaemia is significantly weakened, the proliferation-inhibiting and differentiation-stimulating effects are retained.
  • the introduction of the 24-hydroxyl group leads to the metabolic destabilization of the derivatives, especially if there is a cyclopropyl ring in the neighboring position. For this reason, these connections are only conditionally suitable for systemic application.
  • the present invention therefore relates to vitamin D derivatives of the general formula I
  • R 5 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • R is a hydrogen atom or a group - (CO) R 6 , wherein R is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • R and R 2 each represent a hydrogen atom or together an exocyclic methylene group
  • R 3 and R independently of one another a hydrogen atom, a chlorine or
  • Fluorine atom an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with the quaternary carbon atom 20 a 3-7-membered, saturated or unsaturated carbocyclic ring,
  • V and W together are an E double bond or V is a hydroxyl group and W is a hydrogen atom or V and W are each hydrogen atoms,
  • X, and X 2 independently of one another are a hydrogen atom, a hydroxyl group, a group -OR 7 or 0 (CO) R 7 , in which
  • R 7 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • R 8 is independently a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • X ⁇ and X 2 together represent a carbonyl group
  • p is the number 1 or 0, E t a group PO OR ⁇ , a group PO (N (R 9 ) 2 ) 2 , a group
  • Rg is independently a hydrogen atom or an aliphatic or aromatic radical having 1 to 12 carbon atoms
  • Q is a hydrogen atom, an aliphatic or aromatic radical with 1 to
  • R 10 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • Z is an aliphatic or aromatic radical with 1 to 12 C atoms, an aliphatic or aromatic acyl group with 1 to 12 C atoms or a group E 2 ,
  • the invention further relates to processes for the preparation of the compounds according to the invention, intermediates of the production process and the use of the compounds according to the invention for the production of medicaments.
  • the groups E [and E 2 stand inter alia for phosphonic acid or carboxylic acid derivatives or for phosphine oxide derivatives.
  • phosphonic acid or carboxylic acid derivatives includes the free phosphonic or carboxylic acids (-P0 3 H 2 , -C0 2 H), phosphonic or carboxylic acid esters (-P0 3 (R 9 ) 2 , -C0 2 R 9 ), phosphonic or Carboxamides (e.g.
  • the groups Xj and X 2 represent, inter alia, hydrogen atoms, hydroxyl groups, etherified or esterified hydroxyl groups. But you can also for the already defined above (Ej and E 2 ) under phosphonic acid derivatives (-P0 3 H 2 , -P0 3 (R 8 ), -PO (N (R 8 ) 2 ) 2 , -PO (NHR 8 ) 2 , but also phosphonic acid monoesters or amides). This constellation and its synthesis is described for example in Example 29.
  • the groups X j and X 2 can also together represent a carbonyl group (see, for example, Example 10).
  • the index p stands for the numbers 1 or 0. If p stands for 0, this means that the C atom 25 does not exist and the group El is linked directly to C-24. This constellation and its synthesis is described by way of example in Examples 29 and 30.
  • the groups R 3 and R 4 can independently of one another be a hydrogen atom, a chlorine or fluorine atom, an alkyl group having 1 to 4 carbon atoms (methyl, ethyl, - n-propyl, i-propyl, n-butyl, i-butyl -, t-Butyl-), together represent a methylene group or together with the quaternary carbon atom 20 represent a 3-7-membered, saturated or unsaturated carbocyclic ring.
  • R 3 and R 4 together form a methylene group or together with the quaternary carbon atom 20 a cyclopropyl ring.
  • the optional radicals R 5 , R 6 , R 7 , R 8 , Rg and R 10 are organic groups with 1 to 12 carbon atoms. These radicals can be saturated or unsaturated, branched or unbranched, acyclic, carbocyclic or heterocyclic. Examples of the radicals R 5 , R 6 , R 7 , R 8 , R 9 and R i o are methyl, ethyl, propyl, i-propyl, butyl or phenyl groups.
  • residues of naturally occurring amino acids are also possible, such as - CH 2 -CH (CH 3 ) 2 , -CH Ph, -CH 2 OH, -CH (OH) -CH 3 , -CH 2 SH, -CH 2 - SCH 3 , -CH 2 C0 2 H, -CH 2 CH 2 -C0 2 H, - (CH 2 ) 4 -NH 2 , - (CH 2 ) 3 -C (NH) NH 2 , but also the residues of the amino acids Tryptophan, tyrosine or histamine.
  • R 5 , Rg, R 7 , R 8 , R 9 and R 10 are derived from C r to C 9 , in particular C 2 to C 5 alkane carboxylic acids such as, for example, acetic acid, propionic acid, butyric acid or pivaloyl acid.
  • C 2 to C 5 alkane carboxylic acids such as, for example, acetic acid, propionic acid, butyric acid or pivaloyl acid.
  • the aromatic groups the phenyl group and substituted phenyl groups are preferred.
  • V and W are each hydrogen atoms or either together form an E double bond or V is a hydroxyl group and W is a hydrogen atom.
  • the options for the relevant structural element are shown below:
  • V and W and X x and E 2 each represent an E double bond, while X 2 and Q are hydrogen atoms.
  • This constellation and its synthesis is described for example in Example 27.
  • LXVI. (5Z, 7E, 22E) - (IS, 3R) - (1,3-dihydroxy-24-nor-9,10-secocholesta-5,7,10 (19), 22-tetraen-26,27-diyl) bis [phosphonic acid diethyl ester] LXVII.
  • LXXIV. (5Z, 7E, 22E, 24E) - (IS, 3R) - (1,3-Dihydroxy-24a-homo-9,10-secochola-5,7,10 (19), 22,24-pentaen-24a, 24a-diyl) bis [phosphonic acid dipropyl ester]
  • LXXVI. (5Z, 7E, 22E, 24E) - (1 S, 3R) - (1, 3-Dihydroxy-24a-homo-9, 10-secochola- 5 J, 10 (19), 22,24-pentaen-24a, 24a-diyl) bis [phosphonic acid] LXXVII.
  • LXXXIII (5ZJE, 22E) - (1 S, 3R) - (1, 3-Dihydroxy-24a-homo-9, 10-secochola-5,7,10 (19), 22-tetraen-24-in-24a-yl ) dimethyl phosphonic ester LXXXIV. (5Z, 7E, 22E) - (IS, 3R) - (1,3-Dihydroxy-24a-homo-9,10-secochola-5,1, 10 (19), 22-tetraen-24-in-24a- yl) diethyl phosphonic acid
  • CLXIV. (5ZJE, 22E) - (IS, 3R, 24R) - (l, 3,24-trihydroxy-9,10-secochola-5J, 10 (19), 22-tetraen-24-yl) dimethyl phosphonic acid CLXV.
  • CLXIX (5Z, 7E, 22E) - (1 S, 3R, 24S) - (1, 3, 24-trihydroxy-9, 10-secochola-5, 7,10 (19), 22-tetraen-24-yl) phosphonic acid dipropylester
  • CLXX (5Z, 7E, 22E) - (1 S, 3R, 24R) - (1, 3, 24-trihydroxy-9, 10-secochola-5, 7,10 (19), 22-tetraen-24-yl) phosphonic acid dipropylester
  • CLXXIV. (5ZJE, 22E) - (IS, 3R, 24R) - (l, 3,24-trihydroxy-9,10-secochola-5J, 10 (19), 22-tetraen-24-yl) phosphonic acid CLXXV.
  • CLXXV. (5Z, 7E, 22E) - (IS, 3R) - (1,3-Dihydroxy-24-oxo-9,10-secochola-5J, 10 (19), 22-tetraen-24-yl) dimethyl phosphonic ester
  • CLXXX. (5Z, 7E, 22E) - (IS, 3R) - (1,3-Dihydroxy-24-oxo-9,10-secochola-5J, 10 (19), 22-tetraen-24-yl) phosphonic acid
  • CLXXXI. (5Z, 7E, 22E) - (1 p.3 S) - (l, 3-Dihydroxy-24-oxo-24a-homo-9.10-secochola- 5,7,10 (19), 22-tetraen-24a- yl) dimethyl phosphonic acid
  • CLXXXV CLXXXV.
  • 5ZJE, 22E - (lS, 3S) - (l, 3-Dihydroxy-24-oxo-24a-homo-9,10-secochola- 5, 1, 10 (19), 22-tetraen-24a-yl) phosphonic dibuty ester CLXXXVI.
  • 5ZJE, 22E - (IS, 3S) - (1,3-Dihydroxy-24-oxo-24a-homo-9,10-secochola-5J, 10 (19), 22-tetraen-24a-yl) phosphonic acid
  • Y * i is a hydrogen atom, a hydroxyl group, a fluorine, chlorine or
  • R * 5 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • Y * 2 is a hydrogen atom or a group - (CO) R ' 6 , wherein R ' 6 is an aliphatic or aromatic radical having 1 to 12 carbon atoms
  • R * and R * 2 each represent a hydrogen atom or together an exocyclic methylene group
  • R * 3 and R * 4 independently of one another a hydrogen atom, a chlorine or
  • Fluorine atom an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with the quaternary carbon atom 20 a 3-7-membered, saturated or unsaturated carbocyclic ring,
  • V * and W * together represent an E double bond or V * a hydroxyl group
  • W ' is a hydrogen atom or V * and W * are each hydrogen atoms
  • X '. and X * 2 together represent a carbonyl group or a hydrogen atom or X * 2 represent a hydrogen atom and X ' [ a hydroxyl group or a group -
  • R * 7 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • X ' is a hydrogen atom and X * 2 is a hydroxyl group or a group -0 (CO) R ' 8 , wherein
  • R * 8 is an aliphatic or aromatic radical with 1 to 12 carbon atoms
  • Z ' is an aliphatic or aromatic radical having 1 to 12 C atoms, an aliphatic or aromatic acyl group having 1 to 12 C atoms or a group E * 2 , E * ⁇ a group PO (OR * 9 ) 2 , a group PO (N (R * 9 ) 2 ) 2 , a group
  • R * 9 is a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms
  • E * 2 a group PO (OR * 9 ), a group PO (N (R ' 9 ) 2 ) 2 , a group
  • Q ' is a hydrogen atom, an aliphatic or aromatic radical with 1 to
  • R * 10 is an aliphatic or aromatic radical with 1 to 12
  • the substances according to the invention have a significantly higher metabolic stability than the structurally used compounds of the prior art and are therefore particularly suitable for systemic applications.
  • some of the substances according to the invention are furthermore distinguished by the fact that they have a strong action on cell differentiation, the action on the calcium balance not increasing.
  • the vitamin D activity of the substances according to the invention is determined by means of the calcitriol receptor test. It is made using a protein extract from the Gut carried out by young pigs. Receptor-containing protein extract is incubated with 3 H-calcitriol (5 x 10 " 10 mol / 1) in a reaction volume of 0.27 ml in the absence and in the presence of the test substances for two hours at 4 ° C. in a test tube. To separate free and Charcoal dextran absorption is carried out by receptor-bound calcitriol by adding 250 ⁇ l of a Charcoal dextran suspension to each test tube and incubating at 4 ° C. for 20 minutes, after which the samples are centrifuged at 10,000 g for 5 minutes at 4 ° C. The supernatant is decanted and measured in a ⁇ -counter after equilibration in Picofluor 15 TM for one hour.
  • the competition curves obtained with different concentrations of the test substance and the reference substance (unlabelled calcitriol) at constant concentration of the reference substance ( 3 H-calcitriol) are correlated and a competition factor (KF) is determined.
  • HL 60 cells are cultivated in tissue culture medium (RPMI 10% fetal calf serum) at 37 ° C. in an atmosphere of 5% CO 2 in air.
  • tissue culture medium RPMI 10% fetal calf serum
  • the cells are centrifuged off and 2.0 ⁇ 10 5 cells / ml are taken up in tissue culture medium free of phenol red.
  • the test substances are dissolved in ethanol and diluted to the desired concentration with tissue culture medium without phenol red.
  • the dilution stages are mixed with the cell suspension in a ratio of 1:10 and 100 ⁇ l of this cell suspension with substance added are pipetted into a well of a 96-well plate.
  • a cell suspension is mixed analogously with the solvent.
  • NBT nitrogen bisulfide
  • TPA Tetradecanoylphorbolmyristat-13-acetate
  • NBT is reduced to insoluble formazan in the cells differentiated to macrophages as a result of the intracellular release of oxygen radicals, stimulated by TPA.
  • the wells of the 96-well plate are suctioned off and the cells are fixed to the plate bottom by adding methanol and dried after fixation.
  • the concentration of formazan formed is a measure of the induction of differentiation of the HL 60 cells into macrophages.
  • the result is as Dosisrelat i on - indicated (DR factor test substance dose / reference substance dose for comparable anywaymax i paint effects).
  • test substances (5ZJE, 22E) - (1 S, 3R) - (1, 3 -Dihydroxy-24-oxo-24a-homo-9, 10-secochola-5 J, 10 (19), 22-tetraen- 24a-yl) dimethyl phosphonate 5
  • hypercalcaemia is only induced at much higher doses than calcitriol.
  • the build-up of new bone material is induced in a non-hypercalcaemic dose.
  • the substances according to the invention are particularly suitable for the production of medicaments for the treatment of diseases which are characterized by hyperproliferation and a lack of cell differentiation.
  • diseases which are characterized by hyperproliferation and a lack of cell differentiation.
  • diseases which are characterized by hyperproliferation and a lack of cell differentiation.
  • diseases include, for example, hyperproliferative diseases of the skin (psoriasis, pituriasis subia pilasis, acne, ichthyosis) and pruritus as well as tumor diseases and precancerous diseases (e.g. intestinal tumors, breast cancer, lung tumors, prostate cancer, leukemia, T-cell lymphomas, melanoma, batazell Carcinoma, actinic keratoses, cervical dysplasia, metastatic tumors of any kind).
  • the substances according to the invention are also suitable for the treatment and prophylaxis of diseases which are characterized by a disturbance in the balance of the immune system.
  • diseases which are characterized by a disturbance in the balance of the immune system.
  • diseases include eczema and diseases of the atopic form and inflammatory diseases (rheumatoid arthritis, respiratory diseases e.g. asthma) as well as autoimmune diseases such as multiple sclerosis, type I diabetes mellitus, myasthenia gravis, lupus erythematosus, scleroderma, bullous skin diseases (pemphigus, pemphigoid reaction) for autologous, allogeneic or xenogeneic grafts as well as AIDS.
  • the new compound of general formula I can advantageously be combined with other immunosuppressive substances such as cyclosporin A, FK 506, rapamycin and anti-CD 4 antibodies.
  • the substances are also suitable for the therapy of secondary hyperparathyroidism and renal osteodystrophy due to the property of calcitriols to reduce parathyroid synthesis.
  • the substances Due to the presence of the vitamin D receptor in the insulin-producing cells of the pancreas, the substances are suitable for treating type II diabetes by increasing insulin secretion.
  • topical application of the compounds according to the invention to the skin of mice, rats and guinea pigs can induce increased reddening of the skin and an increase in the thickness of the epidermis.
  • the increase in reddening of the skin is determined on the basis of the increase in the red value of the skin surface that can be quantified with a color measuring device. The red value is typically increased by 1.5 times after three substance applications (dose 0.003%) every 24 hours.
  • the increase in epidermal thickness is quantified in the histological specimen. It is typically increased 2.5 times.
  • the number of proliferating epidermal cells is determined by flow cytometry and is typically increased by a factor of 6.
  • Vitamin D 3 receptor proteins have been detected in cell populations of the hair follicle that make a decisive contribution to hair growth or hair cycle regulation [Stumpf, WE et al., Cell Tissue Res. 238, 489 (1984); Milde, P. et al., J. Invest. Dermatol. 97: 230 (1991)].
  • in vitro findings on isolated hair follicle keratinocytes show a proliferation-inhibiting and differentiation-stimulating influence of 1,25- (OH) 2 D 3 .
  • analogues are therefore particularly suitable for the production of medicaments for the treatment of diseases which are associated with impaired hair growth (androgenetic alopecia, alopezia areata totalis, chemotherapy-induced alopecia), or for supporting physiological hair growth without the side effects of calcitriol (in particular Hypercalcaemia).
  • Senile and postmenopausal osteoporosis is characterized by increased bone turnover with an overall negative balance. Due to the bone loss, especially of trabecular bone, bone fractures occur to an increased extent. Due to the beneficial effects of calcitriol on both the number and the synthetic performance of new bone-forming cells (osteoblasts), the substances according to the invention are suitable for the therapy and prophylaxis of senile and postmenopausal osteoporosis (EP 0 634 173 AI), steroid-induced osteoporosis and for accelerated healing of joint plasties without causing the side effects of calcitriol (especially hypercalcaemia). For the therapy of various forms of osteoporosis, they can advantageously be combined with estradiol or other derivatives of estrogen.
  • calcitriol increases the synthesis of a growth substance for nerve cells (nerve growth factor) [MS Saporito et al. Brain Res. 633, 189 (1994)].
  • the compounds according to the invention are therefore also suitable for the treatment of degenerative diseases of the peripheral and central nervous system, such as Alzheimer's disease and amyotrophic lateral sclerosis.
  • Such compounds can be used in the therapy of hypercalcaemia, such as in hypervitaminosis D or intoxication with calcitriol and calcitriol-like substances, or in the case of increased extrarenal calcitriol synthesis in granulomatous diseases (sarcoidosis, tuberculosis). Also paraneoplastic hypercalcemia (for example in osteolytic metastases and tumors with increased synthesis of parathormone-related peptides) and in hypercalcemia in hyperparathyroidism.
  • Calcitriol antagonists should also be used for fertility control.
  • the vitamin D receptor is expressed in the reproductive tract of female and male animals. It is known that the female and male fertility of vitamin D deficient animals is reduced. Reproductive performance can be increased by short-term substitution of calcitriol. Therefore calcitriol antagonists are able to influence female and male fertility. .
  • calcitriol receptor antagonists are also used as immunostimulants, e.g. B. with infection control weakness to use AIDS.
  • Calcitriol is known to modulate hair growth. Calcitriol antagonists can therefore with unwanted hair growth, e.g. B. in hirsutism, find therapeutic use.
  • a beneficial role of vitamin D in the formation of arteriosclerotic plaques has long been known.
  • a calcitriol-regulated protein, the osteopontin is increasingly found in such vascular lesions and is believed to play a role in vascular calcification [R. Eisenstein et al. Arch. Path. 77, 27 (1964), L.A. Fitzpatrick et al. J. Clin. Invest. 94, 1597 (1994)].
  • Calcitriol antagonists are therefore suitable for the therapy and prophylaxis of all forms of arteriosclerosis.
  • calcitriol antagonists are suitable for the therapy of due to the property of calcitriol to increase nonspecific immune reactions of monocytic cells inflammatory diseases especially chronic, such as rheumatoid arthritis, Crohn's disease, Colins ulcerosa. and granulomatous diseases such as sarcoidosis and other foreign body reactions.
  • the compounds according to the invention are able to achieve a therapeutic effect in the PC diseases mentioned, without causing the side effects of calcitriol (in particular hypercalcaemia).
  • the present invention thus relates to pharmaceutical preparations which contain at least one compound of the general formula I together with a pharmaceutically acceptable carrier.
  • the compounds can be formulated as solutions in pharmaceutically acceptable solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers or as pills, tablets or capsules which contain solid carriers in a manner known per se.
  • the compounds are advantageously formulated as creams or ointments or in a similar pharmaceutical form suitable for topical use.
  • Each such formulation may also contain other pharmaceutically acceptable and non-toxic excipients, such as e.g. Stabilizers, antioxidants, binders, dyes, emulsifiers or taste correctors.
  • the compounds are advantageously applied by injection, intravenous infusion in suitable sterile solutions, as an aerosol via the bronchi and lungs or as an oral dosage via the nutritional tract or topically in the form of creams, ointments, lotions or suitable transdermal patches, as in EP-A 0 387 077.
  • the daily dose is 0.1 ⁇ g / patient / day - 1000 ⁇ g / patient / day,
  • the vitamin D derivatives of the general formula I are prepared from a compound of the general formula II,
  • Y '. is a hydrogen atom, a halogen atom or a protected hydroxyl group and Y ' 2 is a hydroxy protecting group.
  • X'i, X ' 2 and Q' differ from X., X 2 and Q in that hydroxyl, amino or keto groups which may be present can be present in protected form.
  • the protective groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, for example the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or Triisopropylsilyl groups (TIPS) or another common hydroxy protecting group (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl tetrahydropyranyl groups) for the keto groups are preferably ketals (1,3-dioxolanes, 1,3-dioxanes, dialkoxy ketals) ( see TW Greene, PGM Wuts "Protective Groups in Organic Synthesis", 2 nd edition, John Wiley & Sons, 1991).
  • silyl protective groups or the trimethylsilylethoxymethyl group tetrabutylammonium fluoride, hydrofluoric acid or hydrofluoric acid / pyridine or acidic ion exchangers are used to split them off; in the case of ether groups (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl ether) and ketals, these are catalyzed by acid, for example split off p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, hydrochloric acid, phosphoric acid or an acidic ion exchanger.
  • ether groups methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl ether
  • ketals these are catalyzed by acid, for example split off p-toluenesulfonic acid, pyr
  • the phosphonic acid esters can be cleaved by the usual methods by the action of acidic reagents (e.g. hydrochloric acid, acidic ion exchangers, trialkylsilyl halides).
  • acidic reagents e.g. hydrochloric acid, acidic ion exchangers, trialkylsilyl halides.
  • the free hydroxyl groups can be esterified by customary processes with the corresponding carboxylic acid chlorides, bromides or anhydrides.
  • the preparation of the starting compounds for the general formula II is based on different starting compounds, depending on the ultimately desired substitution pattern in the 3-, 10- and 20-position.
  • Protecting groups for Y ' ] and Y' 2 other than those mentioned in the literature references can be obtained by an analogous procedure using appropriately modified silyl chlorides (for example tert-butyldiphenylsilyl chloride instead of tert-butyldimethylsilyl chloride).
  • silyl chlorides for example tert-butyldiphenylsilyl chloride instead of tert-butyldimethylsilyl chloride.
  • R ⁇ and R are aliphatic or aromatic radicals having 1 to 12 carbon atoms, esters of the general formula IX or amides of the general formula X are produced.
  • the compounds of the general formula IX and X can now be mixed with a base such as, for example, “butyl lithium, t-butyl lithium, lithium diisopropylamide,
  • the latter compounds of the general formula II can also be reacted by reacting the phosphorus compound of the general formula XI with an aldehyde of the general formula XIII, which by reducing the ester of the general formula IX or the amide of the general formula X with a reducing agent such as e.g. Diisobutyl aluminum hydride, lithium aluminum hydride, etc. can be obtained.
  • a reducing agent such as e.g. Diisobutyl aluminum hydride, lithium aluminum hydride, etc.
  • the alcohol of general formula XIV can be obtained from the aldehyde of general formula XIII, the ester of general formula IX or amide of general formula X with a reducing agent such as diisobutyl aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, etc.
  • a reducing agent such as diisobutyl aluminum hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, etc.
  • the hydroxyl group must then be converted under the usual conditions into a leaving group such as a methanesulfonic acid ester, p-toluenesulfonic acid ester or a halogen atom (fluorine, chlorine, bromine). Isolation of this connection is not absolutely necessary.
  • the reaction can now be carried out with a phosphorus compound of the general formula XVI deprotonated by a B.ase such as, for example, n-butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates etc.
  • a B.ase such as, for example, n-butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates etc.
  • the compound of general formula XVI can also under palladium catalysis with compounds of general formula XIV or general formula XV for the applies that L means acetate, carbonate or similar groups [see DE Bergbreiter et al. J. Chem. Soc, Chem. Comm. 883-884 (1989), J. Tsuji "Organic Synthesis with Palladium Compounds", Springer Verlag, Berlin, 1980], compounds of the general formula II of the above meaning being formed and, as described, can be converted into compounds of the general formula I.
  • T represents a halide, a cyanide group or another activating group (e.g. anhydride).
  • the compound of the general formula XVII can be prepared after hydrolysis of the ester group of the general formula IX and functionalization under the usual conditions.
  • reaction can now be carried out using a phosphorus compound of the general formula XVI deprotonated by a base such as, for example, “butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates, etc., to give compounds of the general formula II, which are converted into compounds of the general formula I as described.
  • a base such as, for example, “butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates, etc.
  • a special case is the reaction of the aldehyde of the general formula XIII with a compound of the general formula XVI, for which it applies that Ej and E 2 are the same are.
  • a compound of the general formula XVIII is generated with the elimination of a phosphorus-containing group
  • the compound of the general formula XVIII can also be reacted with nucleophilic reagents in Michael additions, which gives rise to compounds of the general formula II which, as described, are converted into compounds of the general formula I with corresponding meanings for Xi and X.
  • E i has the definition described and E 2 represents a hydrogen atom, deprotonated with a base such as, for example, “-butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates and then reacted with a compound of the general formula XIX.
  • a base such as, for example, “-butyllithium, t-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium alcoholates, potassium alcoholates and then reacted with a compound of the general formula XIX.
  • L must be a hydroxy group, an acetate, carbonate or a comparable group [see D.E. Bergbreiter et al. J. Chem. Soc., Chem. Comm. 883-884 (1989), J. Tsuji "Orga ic Synthesis with Palladium Compounds", Springer Verlag, Berlin, 1980].
  • Y ' 3 is an acyl, alkyl or aryl substituted silyl or a tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxyethyl, an acyl group (e.g. acetyl, benzoyl group) or another hydroxy protecting group (see TW Greene, PGM Wuts Protective Groups in Organic Synthesis, 2 nd Edition, John Wiley and Sons, Inc. 1991).
  • Y ' 3 triethylsilyl
  • Y' 3 is selectively cleaved (for example with tetrabutylammonium fluoride), the compound of the general formula XXVI being obtained.
  • Oxidation by a known method eg pyridinium chlorochromate, pyridinium dichromate, Swem conditions, etc.
  • a base eg lithium diisopropylamide, «-butyllithium
  • Y ' 2 has the meaning already described
  • Y' ⁇ OY' 2 is converted.
  • the further conversion into the compound of general formula I takes place as already described.
  • the protecting group strategy shown above is only one example of the generation of the 3-epi derivative. In principle, various other strategies are possible. Acetylation of the free hydroxyl group and cleavage of the silyne unit leads to alcohol XXXI, which can now be inverted using known methods (tosylation or mesylation and nucleophilic substitution; Mitsonobu inversion, etc.). Change of the protective groups leads back to the sequence known from the literature [M. Calverley Tetrahedron 43, 4909 (1987)].
  • the connection XXXIV can be treated exactly like the corresponding connection of the normal series and can supply all products described for this - in the 3-epi series.
  • shark means chlorine or bromine.
  • a lithium alkyl compound eg n-butyllithium, t-butyllithium, methyl lithium
  • an acetylide anion is obtained as an intermediate, which is reacted with electrophiles [eg Cl-PO (OR 9 ) 2 ] to give compounds of the general formula II can be, which, as described, can be converted into compounds of general formula I for which X ,, X 2 , E ⁇ , E 2 and Q have corresponding meanings.
  • the hydroxyl group in the side chain can also be oxidized to the carbonyl group, for which purpose an oxidizing agent (for example manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, oxalyl chloride / dimethyl sulfoxide, Dess-Martin reagent) is used and the conversion into compounds of the general formula I is then carried out.
  • an oxidizing agent for example manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, oxalyl chloride / dimethyl sulfoxide, Dess-Martin reagent
  • M.an treats 300 mg of the phosphonic ester 8 analogously to 2a) and receives 190 mg (5Z, 7E, 22E) - (1S, 3R) - [1, 3-bis [[dimethyl (1, 1-dimethylethyl) silyl] oxy] -24-hydroxy-24a-homo-9, 10-secochola-5J, 10 (19), 22-tetraen-24a-yl] phosphonic acid diethyl ester 10 as a colorless foam (1: 1 mixture of the diastereomers with respect to C-24 ).
  • 250 mg of the phosphonic acid ester 12 are treated analogously to 2a) and 178 mg (5ZJE, 22E) - (lS, 3i?) - [l, 3-bis [[dimethyl (l, l-dimethylethyl) silyl] oxy] -24- hydroxy-24a-homo-9, 10-secochola-5J, 10 (19), 22-tetraen-24a-yl] phosphonic acid bis (1 - methylethyl) ester 14 as a colorless foam (1: 1 mixture of the diastereomers with respect to C- 24).
  • Lithium diisopropylamide is prepared from 0.16 ml of diisopropylamine and 0.48 ml of n-butyllithium solution (1.6 M in hexane) in 20 ml of THF at -78 ° C. under nitrogen and 650 mg of ketone 8 are added dropwise. The mixture is stirred at this temperature for 30 min and then 414 mg of diethy ichlorophosphate are added. The mixture is warmed to 0 ° C. and stirred for 1 h. Then quenched with sodium chloride solution, extracted with ethyl acetate, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and concentrated.
  • LDA Lithium diisopropylamide
  • the in situ generated tosylate is added dropwise to this solution and the mixture is stirred for 1 h at room temperature.
  • the reaction mixture is concentrated and the residue is dissolved in 3 ml of chloroform.
  • 0.5 ml of hydrogen peroxide solution (5% in water) are now added and the mixture is stirred at room temperature for 2 h.
  • the phases are separated, the organic phase is washed with sodium thiosulfate solution, dried over sodium sulfate and concentrated.
  • ketophosphonate 9 40 mg are placed in 9 ml of dichloromethane and 0.1 ml of collidine and 0.06 ml of trimethylsilyl bromide are added. The mixture is stirred at room temperature for 4 h and then quenched with water. After extraction of the water phase with ethyl acetate, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and the solvent is removed. The residue is purified by chromatography on silica gel with ethyl acetate / hexane, 12 mg of the title compound 24 and 14 mg of the title compound 25 being obtained successively as colorless foams.
  • Example 17 (5ZJE, 22E) - (IS, 3R) - (1,3-dihydroxy-24a-homo-9,10-secochola-5J, 10 (19), 22-tetraen-24-in-24a-yl) phosphonic acid - monoethyl esters 39 and (5Z, 7E, 22E) - (1S, 3R) - (1,3-dihydroxy-24a-homo-9, 10-secochola-5J, 10 (19), 22-tetraen-24-in-24a -yl) phosphonic acid 40
  • ⁇ 0.05 ppm (s, 12 H); 0.54 (s, 3H); 0.86 (s, 18H); 1.09 (d. 3H); 1.28 (t, 6H); 3.37 (m, IH); 4.06 (q, 4H); 4.18 (m, IH); 4.37 (m, IH); 4.83 (s, IH); 4.96 (d, IH); 5.01 (d, IH); 5.16 (s, IH); 5.68 (m, IH); 6.00 (d, IH); 6.18 (d, IH); 6.22 (d, IH); 6J2 (dd, IH)
  • ⁇ 0.05 ppm (s, 12 H); 0.54 (s, 3H); 0.86 (s, 18H); 0.87 (t, 3H); 1.07 (d. 3H); 1.27 (t, 6H); 3.16 (m, IH); 4.05 (q, 4H); 4.17 (m, IH); 4.37 (m, IH); 4.83 (s, IH); 5.17 (s, IH); 6.00 (d, IH); 6.22 (d, IH); 6.23 (d, IH); 6J3 (dddd, IH)
  • a) 0.1 ml of diethyl phosphite is placed in 3 ml of THF and the mixture is cooled to -78 ° C. At this temperature, 0.3 ml of n-butyllithium solution (1.6 M in hexane) is added dropwise and stirring is continued for 15 minutes. Then 300 mg of the aldehyde 18 in 2 ml of THF are added and the mixture is stirred at 0 ° C. for 1.5 h. Then quenched with sodium chloride solution, extracted with ethyl acetate, dried over sodium sulfate and the solvent removed.
  • n-butyllithium solution 1.6 M in hexane
  • M.an dissolves 1.22 g of acetate 70 in 35 ml of THF and adds 1.41 g of triphenylphoshin and 939 mg of diethyl azodicarboxylic acid and 324 mg of acetic acid at room temperature. After 12 h at room temperature, the mixture is diluted with sodium chloride solution, extracted with ethyl acetate, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and the solvent is removed.
  • M.an dissolves 1.36 g of diol 72 in 30 ml of dimethylformamide (DMF) and adds 1J9 g of imidazole and 44 ml of tert-butyldimethylsilyl chloride.
  • the crude product (5.1 g) is dissolved in 100 ml of ethanol, 6J g of sodium hydrogen carbonate are added and the mixture is heated to boiling for 1 h.
  • the reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is removed.
  • the residue is chromatographed on silica gel with ethyl acetate / hexane and 3.1 g (5E, 7E) - (1 S, 3 S) - 1, 3-bis [[dimethyl (1, 1-dimethylethyl) silyl] oxy] - are obtained. 9, 10-secopregna-5J, 10 (19) -triene-20-carbaldehyde 74 as a colorless foam.

Abstract

L'invention concerne de nouveaux dérivés de vitamine D de la formule générale (I), un procédé permettant de les préparer, des produits intermédiaires du procédé et leur utilisation pour préparer des médicaments.
EP98966616A 1997-12-17 1998-12-16 Derives de vitamine d avec des atomes de phosphore dans les chaines laterales Withdrawn EP1042335A1 (fr)

Priority Applications (1)

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EP98966616A EP1042335A1 (fr) 1997-12-17 1998-12-16 Derives de vitamine d avec des atomes de phosphore dans les chaines laterales

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP97250374 1997-12-17
EP97250374A EP0927721A1 (fr) 1997-12-17 1997-12-17 Nouveaux dérivés de la vitamine D ayant des atomes de phosphore sur les chaines latérales, intermédiaires pour leur préparation et leur utilisation pour la préparation de médicaments
DE19758119 1997-12-17
DE1997158119 DE19758119C1 (de) 1997-12-17 1997-12-17 Neue Vitamin D-Derivate mit Phosphoratomen in den Seitenketten, Zwischenprodukte bei ihrer Herstellung und die Verwendung zur Herstellung von Arzneimitteln
EP98966616A EP1042335A1 (fr) 1997-12-17 1998-12-16 Derives de vitamine d avec des atomes de phosphore dans les chaines laterales
PCT/EP1998/008137 WO1999031112A1 (fr) 1997-12-17 1998-12-16 Derives de vitamine d avec des atomes de phosphore dans les chaines laterales

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DE19935771A1 (de) * 1999-07-23 2001-02-01 Schering Ag Neue Vitamin D-Derivate mit cyclischen Substrukturen in den Seitenketten, Verfahren und Zwischenprodukte zu ihrer Herstellung und die Verwendung zur Herstellung von Arzneimitteln
EP1470220B1 (fr) * 2002-01-10 2011-10-05 Teva Pharmaceutical Industries, Ltd. Esterification et solvolyse enzymatiques selectives d'un analogue epimerique de la vitamine d et separation des epimeres
CA2489593C (fr) * 2002-06-13 2009-09-29 Teva Pharmaceutical Industries Ltd Epimerisation d'analogues de la vitamine d
CA2544522A1 (fr) * 2003-11-20 2005-06-09 Eli Lilly And Company Modulateurs du recepteur de la vitamine d
US7253293B2 (en) * 2004-01-06 2007-08-07 Andrzej Slominski Enzymatic method to produce 7-dehydropregnenolone, vitamin D3-like compounds and derivatives thereof
KR20110113664A (ko) * 2006-08-29 2011-10-17 테바 파마슈티컬 인더스트리즈 리미티드 비타민 ｄ 및 코르티코스테로이드를 포함하는 약학 조성물
US9544911B2 (en) * 2007-08-10 2017-01-10 Futurewei Technologies, Inc. System and method for assigning communications resources in a wireless communications system
MX366076B (es) * 2009-08-14 2019-06-27 Berg Llc Vitamina d3 y analogos de la misma para tratar alopecia.
CN107722054A (zh) * 2017-10-25 2018-02-23 无锡福祈制药有限公司 一种维生素d3磷酰胺及其制备方法

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US4230700A (en) * 1977-12-07 1980-10-28 The Procter & Gamble Company Methods for inhibiting mobilization of calcium phosphate in animal tissue
GB8904153D0 (en) * 1989-02-23 1989-04-05 Leo Pharm Prod Ltd Chemical compounds
IL107185A (en) * 1992-10-06 1998-02-22 Schering Ag History of 52-carboxylic acid, processes for their preparation and pharmaceutical preparations containing them
US5449668A (en) 1993-06-04 1995-09-12 Duphar International Research B.V. Vitamin D compounds and method of preparing these compounds
JPH11507649A (ja) * 1995-06-14 1999-07-06 シエーリング アクチエンゲゼルシヤフト ２５位の炭素に置換基を有する新規なビタミンｄ誘導体、その製造方法、中間生成物及び薬剤の製造のためのその使用
PL336231A1 (en) 1997-02-13 2000-06-19 Bone Care International System for aimed therapeutic delivery of vitamin d compounds
JP2002505668A (ja) * 1997-05-16 2002-02-19 ウィメン アンド インファンツ ホスピタル 環状エーテルビタミンＤ３化合物、１α（ＯＨ）３−エピ−ビタミンＤ３化合物及びそれらの使用法

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